https://www.wikidoc.org/api.php?action=feedcontributions&feedformat=atom&user=Abdurahman+Khalilwikidoc - User contributions [en]2026-04-06T03:46:15ZUser contributionsMediaWiki 1.45.1https://www.wikidoc.org/index.php?title=Carvedilol&diff=962340Carvedilol2014-04-03T21:26:32Z<p>Abdurahman Khalil: Undo revision 962338 by Abdurahman Khalil (talk)</p>
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<div>{{DrugProjectFormSinglePage<br />
|authorTag={{AK}}<br />
|genericName=Carvedilol<br />
|aOrAn=an<br />
|drugClass=Alpha-adrenergic blocker, Beta-adrenergic blocker<br />
|indication=Heart failure of ischemic or cardiomyopathic origin, hypertension<br />
|adverseReactions=Fatigue, hypotension, dizziness, hyperglycemia<br />
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)<br />
|fdaLIADAdult=&lt;h4&gt;Condition 1&lt;/h5&gt;<br />
<br />
* Dosing Information<br />
<br />
:: (Dosage)<br />
|contraindications=Carvedilol is '''contraindicated''' in the following conditions:<br />
<br />
:*[[Bronchial asthma]] or related bronchospastic conditions. Deaths from [[status asthmaticus]] have been reported following single doses of COREG.<br />
:*[[AV block]] (Second- or third-degree) <br />
:*[[Sick sinus syndrome]]<br />
:*Severe [[bradycardia]] (unless a permanent pacemaker is in place).<br />
:*[[Cardiogenic shock]] or who have decompensated [[heart failure]] requiring the use of intravenous [[inotropic]] therapy. Such patients should first be weaned from intravenous therapy before initiating COREG<br />
:*Severe hepatic impairment<br />
:*Serious [[hypersensitivity]] reaction (e.g., [[Stevens-Johnson syndrome]], [[anaphylactic reaction]], [[angioedema]]) to any component of this medication or other medications containing carvedilol.<br />
|warnings=*Acute exacerbation of coronary artery disease upon cessation of therapy: Do not abruptly discontinue. <br />
*Bradycardia, hypotension, fluid retention may occur. Reduce the dose as needed. <br />
<br />
*Non-allergic bronchospasm (e.g., chronic bronchitis and emphysema): Avoid β-blockers. <br />
<br />
*However, if deemed necessary, use with caution and at lowest effective dose.<br />
Diabetes: Monitor glucose as β-blockers may mask symptoms of hypoglycemia or worsen hyperglycemia. <br />
<br />
=====Cessation of Therapy=====<br />
<br />
'''Patients with [[coronary artery disease]], who are being treated with carvedilol, should be advised against abrupt discontinuation of therapy. Severe exacerbation of [[angina]] and the occurrence of [[myocardial infarction]] and [[ventricular arrhythmias]] have been reported in angina patients following the abrupt discontinuation of therapy with β-blockers. The last 2 complications may occur with or without preceding exacerbation of the angina pectoris. As with other β-blockers, when discontinuation of carvedilol is planned, the patients should be carefully observed and advised to limit physical activity to a minimum. carvedilol should be discontinued over 1 to 2 weeks whenever possible. If the angina worsens or acute coronary insufficiency develops, it is recommended that carvedilol be promptly reinstituted, at least temporarily. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue therapy with carvedilol abruptly even in patients treated only for hypertension or heart failure.'''<br />
<br />
===Bradycardia===<br />
<br />
In clinical trials, carvedilol caused[[ bradycardia]] in about 2% of hypertensive subjects, 9% of heart failure subjects, and 6.5% of myocardial infarction subjects with left ventricular dysfunction. If pulse rate drops below 55 beats/minute, the dosage should be reduced.<br />
<br />
=====Hypotension=====<br />
In clinical trials of primarily mild‑to‑moderate [[heart failure]], [[hypotension]] and [[postural hypotension]] occurred in 9.7% and syncope in 3.4% of subjects receiving carvedilol compared with 3.6% and 2.5% of placebo subjects, respectively. The risk for these events was highest during the first 30 days of dosing, corresponding to the up‑titration period and was a cause for discontinuation of therapy in 0.7% of subjects receiving carvedilol, compared with 0.4% of placebo subjects. In a long‑term, placebo‑controlled trial in severe heart failure (COPERNICUS), hypotension and postural hypotension occurred in 15.1% and syncope in 2.9% of heart failure subjects receiving carvedilol compared with 8.7% and 2.3% of placebo subjects, respectively. These events were a cause for discontinuation of therapy in 1.1% of subjects receiving carvedilol, compared with 0.8% of placebo subjects.<br />
<br />
Postural hypotension occurred in 1.8% and syncope in 0.1% of hypertensive subjects, primarily following the initial dose or at the time of dose increase and was a cause for discontinuation of therapy in 1% of subjects.<br />
<br />
In the CAPRICORN trial of survivors of an acute[[ myocardial infarction]], hypotension or postural hypotension occurred in 20.2% of subjects receiving carvedilol compared with 12.6% of placebo subjects. Syncope was reported in 3.9% and 1.9% of subjects, respectively. These events were a cause for discontinuation of therapy in 2.5% of subjects receiving carvedilol, compared with 0.2% of placebo subjects.<br />
<br />
Starting with a low dose, administration with food, and gradual up-titration should decrease the likelihood of syncope or excessive hypotension [see [[Carvedilol dosage and administration|Dosage and Administration]] ]. During initiation of therapy, the patient should be cautioned to avoid situations such as driving or hazardous tasks, where injury could result should syncope occur.<br />
<br />
=====Heart Failure/Fluid Retention=====<br />
Worsening heart failure or fluid retention may occur during up-titration of carvedilol. If such symptoms occur, diuretics should be increased and the carvedilol dose should not be advanced until clinical stability resumes [see Dosage and Administration (2)]. Occasionally it is necessary to lower the carvedilol dose or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of, or a favorable response to, carvedilol. In a placebo-controlled trial of subjects with severe heart failure, worsening heart failure during the first 3 months was reported to a similar degree with carvedilol and with placebo. When treatment was maintained beyond 3 months, worsening heart failure was reported less frequently in subjects treated with carvedilol than with placebo. Worsening heart failure observed during long-term therapy is more likely to be related to the patients’ underlying disease than to treatment with carvedilol.<br />
<br />
=====Non-allergic Bronchospasm=====<br />
Patients with bronchospastic disease (e.g., [[chronic bronchitis]] and [[emphysema]]) should, in general, not receive β-blockers. carvedilol may be used with caution, however, in patients who do not respond to, or cannot tolerate, other antihypertensive agents. It is prudent, if carvedilol is used, to use the smallest effective dose, so that inhibition of endogenous or exogenous β-agonists is minimized.<br />
<br />
In clinical trials of subjects with heart failure, subjects with bronchospastic disease were enrolled if they did not require oral or inhaled medication to treat their bronchospastic disease. In such patients, it is recommended that carvedilol be used with caution. The dosing recommendations should be followed closely and the dose should be lowered if any evidence of bronchospasm is observed during up-titration.<br />
<br />
=====Glycemic Control in Type 2 Diabetes=====<br />
In general, β-blockers may mask some of the manifestations of hypoglycemia, particularly [[tachycardia]]. Nonselective β-blockers may potentiate insulin-induced [[hypoglycemia]] and delay recovery of serum glucose levels. Patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be cautioned about these possibilities.<br />
<br />
In heart failure patients with diabetes, carvedilol therapy may lead to worsening [[hyperglycemia]], which responds to intensification of hypoglycemic therapy. It is recommended that blood glucose be monitored when carvedilol dosing is initiated, adjusted, or discontinued. Trials designed to examine the effects of carvedilol on glycemic control in patients with diabetes and heart failure have not been conducted.<br />
<br />
In a trial designed to examine the effects of carvedilol on glycemic control in a population with mild-to-moderate hypertension and well-controlled type 2[[ diabetes mellitus]], carvedilol had no adverse effect on glycemic control, based on [[HbA1c]] measurements [see Carvidilol clinical studies|Clinical Studies]]].<br />
<br />
=====Peripheral Vascular Disease=====<br />
β-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Caution should be exercised in such individuals.<br />
<br />
=====Deterioration of Renal Function=====<br />
Rarely, use of carvedilol in patients with heart failure has resulted in deterioration of renal function. Patients at risk appear to be those with low blood pressure (systolic blood pressure <100 mm Hg), [[ischemic heart disease]] and diffuse vascular disease, and/or underlying renal insufficiency. Renal function has returned to baseline when carvedilol was stopped. In patients with these risk factors it is recommended that renal function be monitored during up-titration of carvedilol and the drug discontinued or dosage reduced if worsening of renal function occurs.<br />
<br />
===Major Surgery===<br />
Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.<br />
<br />
=====Thyrotoxicosis=====<br />
β-adrenergic blockade may mask clinical signs of [[hyperthyroidism]], such as [[tachycardia]]. Abrupt withdrawal of β-blockade may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate [[thyroid storm]].<br />
<br />
=====Pheochromocytoma=====<br />
In patients with [[pheochromocytoma]], an α-blocking agent should be initiated prior to the use of any β-blocking agent. Although carvedilol has both α- and β-blocking pharmacologic activities, there has been no experience with its use in this condition. Therefore, caution should be taken in the administration of carvedilol to patients suspected of having [[pheochromocytoma]].<br />
<br />
=====Prinzmetal’s Variant Angina=====<br />
Agents with non-selective β-blocking activity may provoke chest pain in patients with [[Prinzmetal’s]] variant angina. There has been no clinical experience with carvedilol in these patients although the α-blocking activity may prevent such symptoms. However, caution should be taken in the administration of carvedilol to patients suspected of having Prinzmetal’s variant angina.<br />
<br />
===Risk of Anaphylactic Reaction===<br />
While taking β-blockers, patients with a history of severe [[anaphylactic reaction]] to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.<br />
<br />
===Intraoperative Floppy Iris Syndrome===<br />
Intraoperative Floppy Iris Syndrome (IFIS) has been observed during [[cataract]] surgery in some patients treated with [[alpha-1 blockers]] (carvedilol is an alpha/beta blocker). This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative [[miosis]] despite preoperative dilation with standard [[mydriatic]] drugs, and potential prolapse of the iris toward the phacoemulsification incisions. The patient’s ophthalmologist should be prepared for possible modifications to the surgical technique, such as utilization of iris hooks, iris dilator rings, or viscoelastic substances. There does not appear to be a benefit of stopping alpha-1 blocker therapy prior to cataract surgery.<br />
<br />
|FDAPregCat=C<br />
|useInPregnancyFDA=Studies performed in pregnant rats and rabbits given carvedilol revealed increased post-implantation loss in rats at doses of 300 mg/kg/day (50 times the maximum recommended human dose [MRHD] as mg/m2) and in rabbits at doses of 75 mg/kg/day (25 times the MRHD as mg/m2). In the rats, there was also a decrease in fetal body weight at the maternally toxic dose of 300 mg/kg/day (50 times the MRHD as mg/m2), which was accompanied by an elevation in the frequency of fetuses with delayed skeletal development (missing or stunted 13th rib). In rats the no-observed-effect level for developmental toxicity was 60 mg/kg/day (10 times the MRHD as mg/m2); in rabbits it was 15 mg/kg/day (5 times the MRHD as mg/m2). There are no adequate and well-controlled studies in pregnant women. COREG should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br />
|useInNursing=It is not known whether this drug is excreted in human milk. Studies in rats have shown that carvedilol and/or its metabolites (as well as other β-blockers) cross the placental barrier and are excreted in breast milk. There was increased mortality at one week post-partum in neonates from rats treated with 60 mg/kg/day (10 times the MRHD as mg/m2) and above during the last trimester through day 22 of lactation. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from β-blockers, especially [[bradycardia]], a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. The effects of other α- and β-blocking agents have included perinatal and neonatal distress.<br />
|useInPed=Effectiveness of carvedilol in patients younger than 18 years has not been established.<br />
<br />
In a double-blind trial, 161 children (mean age: 6 years, range: 2 months to 17 years; 45% younger than 2 years) with chronic[[ heart failure]] [NYHA class II-IV, left ventricular [[ejection fraction]] <40% for children with a systemic left ventricle (LV), and moderate-severe ventricular dysfunction qualitatively by echo for those with a systemic ventricle that was not an LV] who were receiving standard background treatment were randomized to placebo or to 2 dose levels of carvedilol. These dose levels produced placebo-corrected heart rate reduction of 4 to 6 heart beats per minute, indicative of β -blockade activity. Exposure appeared to be lower in pediatric subjects than adults. After 8 months of follow-up, there was no significant effect of treatment on clinical outcomes. Adverse reactions in this trial that occurred in greater than 10% of subjects treated with carvedilol and at twice the rate of placebo-treated subjects included chest pain (17% versus 6%), dizziness (13% versus 2%), and dyspnea (11% versus 0%).<br />
|useInGeri=Plasma levels of carvedilol average about 50% higher in the elderly compared with young subjects.<br />
<br />
Of the 765 subjects with heart failure randomized to carvedilol in US clinical trials, 31% (235) were 65 years of age or older, and 7.3% (56) were 75 years of age or older. Of the 1,156 subjects randomized to carvedilol in a long‑term, placebo‑controlled trial in severe heart failure, 47% (547) were 65 years of age or older, and 15% (174) were 75 years of age or older. Of 3,025 subjects receiving carvedilol in heart failure trials worldwide, 42% were 65 years of age or older.<br />
<br />
Of the 975 [[myocardial infarction]] subjects randomized to carvedilol in the CAPRICORN trial, 48% (468) were 65 years of age or older, and 11% (111) were 75 years of age or older.<br />
<br />
Of the 2,065 hypertensive subjects in US clinical trials of efficacy or safety who were treated with carvedilol, 21% (436) were 65 years of age or older. Of 3,722 subjects receiving carvedilol in hypertension clinical trials conducted worldwide, 24% were 65 years of age or older.<br />
<br />
With the exception of [[dizziness ]]in hypertensive subjects (incidence 8.8% in the elderly versus 6% in younger subjects), no overall differences in the safety or effectiveness (see Figures 2 and 4) were observed between the older subjects and younger subjects in each of these populations. Similarly, other reported clinical experience has not identified differences in responses between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.<br />
|useInRenalImpair=Although carvedilol is metabolized primarily by the liver, plasma concentrations of carvedilol have been reported to be increased in patients with renal impairment. Based on mean AUC data, approximately 40% to 50% higher plasma concentrations of carvedilol were observed in hypertensive subjects with moderate to severe renal impairment compared to a control group of hypertensive subjects with normal renal function. However, the ranges of AUC values were similar for both groups. Changes in mean peak plasma levels were less pronounced, approximately 12% to 26% higher in subjects with impaired renal function.<br />
<br />
Consistent with its high degree of plasma protein‑binding, carvedilol does not appear to be cleared significantly by [[hemodialysis]].<br />
|useInHepaticImpair=Compared with healthy subjects, patients with severe liver impairment ([[cirrhosis]]) exhibit a 4- to 7-fold increase in carvedilol levels. <br />
Carvedilol is contraindicated in patients with severe liver impairment.<br />
|othersTitle=Heart Failure<br />
|useInOthers=[[Steady‑state ]]plasma concentrations of carvedilol and its enantiomers increased proportionally over the 6.25 to 50 mg dose range in subjects with heart failure. Compared with healthy subjects, heart failure subjects had increased mean AUC and Cmax values for carvedilol and its enantiomers, with up to 50% to 100% higher values observed in 6 subjects with NYHA class IV heart failure. The mean apparent terminal elimination half‑life for carvedilol was similar to that observed in healthy subjects.<br />
|overdose====Acute Overdose===<br />
=====Signs and Symptoms=====<br />
Overdosage may cause severe [[hypotension]], [[bradycardia]], [[cardiac insufficiency]], [[cardiogenic shock]], and [[cardiac arrest]]. Respiratory problems, bronchospasms, vomiting, lapses of consciousness, and generalized [[seizures]] may also occur.<br />
=====Management=====<br />
:*The patient should be placed in a '''[[supine]] position''' and, where necessary and '''kept under observation'''<br />
<br />
:*The patient should be treated under intensive-care conditions. <br />
:*'''Gastric lavage''' or pharmacologically induced [[emesis]] may be used shortly after ingestion. <br />
The following agents may be '''administered for excessive [[bradycardia]]''':<br />
:* [[Atropine]], 2 mg IV.<br />
'''To support cardiovascular function:''' <br />
<br />
:*Glucagon, 5 to 10 mg IV rapidly over 30 seconds, followed by a continuous infusion of 5 mg/hour<br><br />
:*Sympathomimetics ([[dobutamine]], [[isoprenaline]], adrenaline) at doses according to body weight and effect.<br />
'''If peripheral vasodilation dominates:''' <br />
:*Administer [[adrenaline]] or[[ noradrenaline]] with continuous monitoring of circulatory conditions.<br />
'''For therapy-resistant [[bradycardia]]'''<br />
:*pacemaker therapy should be performed.<br />
'''For bronchospasm'''<br />
:*β-sympathomimetics (as aerosol or IV) or [[Aminophylline]] IV should be given. <br />
'''In the event of [[seizures]]'''<br />
:*Administer slow IV injection of [[diazepam]] or [[clonazepam]] is recommended.<br />
<br />
'''NOTE:''' In the event of severe intoxication where there are symptoms of shock, treatment with antidotes must be continued for a sufficiently '''long period of time consistent with the 7-10 hour half-life of carvedilol'''.<br />
<br />
Cases of overdosage with COREG alone or in combination with other drugs have been reported. Quantities ingested in some cases exceeded 1,000 milligrams. Symptoms experienced included low blood pressure and heart rate. '''Standard supportive treatment''' was provided and individuals recovered.<br />
|mechAction=Carvedilol is a racemic mixture in which nonselective β-adrenoreceptor blocking activity is present in the S(-) enantiomer and α1-adrenergic blocking activity is present in both R(+) and S(-) enantiomers at equal potency. Carvedilol has no intrinsic sympathomimetic activity.<br />
|PD=====Heart Failure====<br />
<br />
:*The basis for the '''beneficial effects''' of carvedilol in heart failure is '''not established.'''<br />
<br />
:*Two placebo‑controlled trials compared the acute hemodynamic effects of carvedilol with baseline measurements in 59 and 49 subjects with NYHA class II‑IV heart failure receiving [[diuretics]], [[ACE inhibitors]], and [[digitalis]]. There were significant reductions in systemic blood pressure, pulmonary artery pressure, pulmonary capillary wedge pressure, and heart rate. Initial effects on cardiac output, stroke volume index, and systemic vascular resistance were small and variable.<br />
<br />
:*These trials measured hemodynamic effects again at 12 to 14 weeks. carvedilol significantly '''reduced systemic blood pressure, pulmonary artery pressure, right atrial pressure, systemic vascular resistance, and heart rate''', while stroke volume index was increased.<br />
<br />
:*Among 839 subjects with NYHA class II‑III heart failure treated for 26 to 52 weeks in 4 US placebo‑controlled trials, average left ventricular ejection fraction (EF) measured by radionuclide ventriculography increased by 9 EF units (%) in subjects receiving carvedilol and by 2 EF units in placebo subjects at a target dose of 25 to 50 mg twice daily. <br />
<br />
:*'''The effects of carvedilol on ejection fraction were related to dose'''. <u>Doses of 6.25 mg twice daily, 12.5 mg twice daily, and 25 mg twice daily</u> were associated with placebo‑corrected increases in EF of 5 EF units, 6 EF units, and 8 EF units, respectively; each of these effects were nominally statistically significant.<br />
<br />
====Left Ventricular Dysfunction Following Myocardial Infarction====<br />
<br />
The basis for the beneficial effects of carvedilol in patients with left ventricular dysfunction following an [[acute myocardial infarction]] is not established.<br />
<br />
====Hypertension====<br />
<br />
The mechanism by which β-blockade produces an antihypertensive effect has not been established.<br />
<br />
:*β-adrenoreceptor blocking activity has been demonstrated in animal and human studies showing that carvedilol (1) reduces cardiac output in normal subjects; (2) reduces exercise- and/or [[isoproterenol]]-induced tachycardia; and (3) reduces reflex orthostatic [[tachycardia]]. Significant β-adrenoreceptor blocking effect is usually seen within 1 hour of drug administration.<br />
<br />
:*α1-adrenoreceptor blocking activity has been demonstrated in human and animal studies, showing that carvedilol (1) attenuates the pressor effects of [[phenylephrine]]; (2) causes vasodilation; and (3) reduces peripheral vascular resistance. These effects contribute to the reduction of blood pressure and usually are seen within 30 minutes of drug administration.<br />
<br />
:*Due to the α1-receptor blocking activity of carvedilol, blood pressure is lowered more in the standing than in the supine position, and symptoms of postural hypotension (1.8%), including rare instances of syncope, can occur. Following oral administration, when [[postural hypotension]] has occurred, it has been transient and is uncommon when carvedilol is administered with food at the recommended starting dose and titration increments are closely followed [see Dosage and Administration (2)].<br />
<br />
:*In hypertensive patients with normal renal function, therapeutic doses of carvedilol decreased renal vascular resistance with no change in glomerular filtration rate or renal plasma flow. Changes in excretion of sodium, potassium, uric acid, and phosphorus in hypertensive patients with normal renal function were similar after carvedilol and placebo.<br />
<br />
:*carvedilol has little effect on plasma [[catecholamines]], plasma [[aldosterone]], or electrolyte levels, but it does significantly reduce plasma renin activity when given for at least 4 weeks. It also increases levels of [[atrial natriuretic peptide]].<br />
|PK=:*carvedilol is rapidly and extensively absorbed following oral administration, with absolute bioavailability of approximately 25% to 35% due to a significant degree of first-pass metabolism. Following oral administration, the apparent mean terminal elimination half-life of carvedilol generally ranges from 7 to 10 hours. Plasma concentrations achieved are proportional to the oral dose administered. When administered with food, the rate of absorption is slowed, as evidenced by a delay in the time to reach peak plasma levels, with no significant difference in extent of bioavailability. Taking carvedilol with food should minimize the risk of[[ orthostatic hypotension]].<br />
<br />
:*'''Carvedilol is extensively metabolized'''. Following oral administration of radiolabelled carvedilol to healthy volunteers, carvedilol accounted for only about 7% of the total radioactivity in plasma as measured by area under the curve (AUC). Less than 2% of the dose was excreted unchanged in the urine. Carvedilol is metabolized primarily by aromatic ring oxidation and glucuronidation. The oxidative metabolites are further metabolized by conjugation via glucuronidation and sulfation. The metabolites of carvedilol are excreted primarily via the bile into the feces. Demethylation and hydroxylation at the phenol ring produce 3 active metabolites with β-receptor blocking activity. Based on preclinical studies, the 4'-hydroxyphenyl metabolite is approximately 13 times more potent than carvedilol for β-blockade.<br />
<br />
:*Compared with carvedilol, the 3 active metabolites exhibit weak vasodilating activity. Plasma concentrations of the active metabolites are about one-tenth of those observed for carvedilol and have pharmacokinetics similar to the parent.<br />
<br />
:*Carvedilol undergoes stereoselective first-pass metabolism with plasma levels of R(+)-carvedilol approximately 2 to 3 times higher than S(-)-carvedilol following oral administration in healthy subjects. The mean apparent terminal elimination half-lives for R(+)-carvedilol range from 5 to 9 hours compared with 7 to 11 hours for the S(-)-enantiomer.<br />
<br />
:*The primary P450 enzymes responsible for the metabolism of both R(+) and S(-)-carvedilol in human liver microsomes were CYP2D6 and CYP2C9 and to a lesser extent CYP3A4, 2C19, 1A2, and 2E1. CYP2D6 is thought to be the major enzyme in the 4’- and 5’-hydroxylation of carvedilol, with a potential contribution from 3A4. CYP2C9 is thought to be of primary importance in the O-methylation pathway of S(-)-carvedilol.<br />
<br />
:*Carvedilol is subject to the effects of genetic[[ polymorphism]] with poor metabolizers of debrisoquin (a marker for cytochrome P450 2D6) exhibiting 2- to 3-fold higher plasma concentrations of R(+)-carvedilol compared with extensive metabolizers. In contrast, plasma levels of S(-)-carvedilol are increased only about 20% to 25% in poor metabolizers, indicating this enantiomer is metabolized to a lesser extent by cytochrome P450 2D6 than R(+)-carvedilol. The pharmacokinetics of carvedilol do not appear to be different in poor metabolizers of S-mephenytoin (patients deficient in cytochrome P450 2C19).<br />
<br />
:*Carvedilol is more than 98% bound to plasma proteins, primarily with [[albumin]]. The plasma-protein binding is independent of concentration over the therapeutic range. Carvedilol is a basic, lipophilic compound with a steady-state volume of distribution of approximately 115 L, indicating substantial distribution into extravascular tissues. Plasma clearance ranges from 500 to 700 mL/min.<br />
|nonClinToxic======Carcinogenesis, Mutagenesis, Impairment of Fertility=====<br />
In 2-year studies conducted in rats given carvedilol at doses up to 75 mg/kg/day (12 times the MRHD when compared on a mg/m2 basis) or in mice given up to 200 mg/kg/day (16 times the MRHD on a mg/m2 basis), carvedilol had '''no carcinogenic effect.'''<br />
<br />
Carvedilol was negative when tested in a battery of [[genotoxicity]] assays, including the Ames and the CHO/HGPRT assays for mutagenicity and the in vitro hamster micronucleus and in vivo human lymphocyte cell tests for clastogenicity.<br />
<br />
At doses ≥200 mg/kg/day ( ≥ 32 times the MRHD as mg/m2) carvedilol was toxic to adult rats (sedation, reduced weight gain) and was associated with a reduced number of successful matings, prolonged mating time, significantly fewer corpora lutea and implants per dam, and complete resorption of 18% of the litters. <br />
The '''no-observed-effect dose''' level for overt toxicity and impairment of fertility was 60 mg/kg/day (10 times the MRHD as mg/m2).<br />
|clinicalStudies======Heart Failure====<br />
A total of 6,975 subjects with mild to severe heart failure were evaluated in placebo-controlled trials of carvedilol.<br />
<br />
=====Mild-to-Moderate Heart Failure=====<br />
Carvedilol was studied in 5 multicenter, placebo‑controlled trials, and in 1 active-controlled trial (COMET trial) involving subjects with mild-to-moderate heart failure.<br />
<br />
Four US multicenter, double‑blind, placebo‑controlled trials enrolled 1,094 subjects (696 randomized to carvedilol) with NYHA class II‑III heart failure and ejection fraction ≤0.35. The vast majority were on [[digitalis]], [[diuretics]], and an [[ACE inhibitor]] at trial entry. Patients were assigned to the trials based upon exercise ability. An Australia‑New Zealand double‑blind, placebo‑controlled trial enrolled 415 subjects (half randomized to carvedilol) with less severe heart failure. All protocols excluded subjects expected to undergo cardiac transplantation during the 7.5 to 15 months of double‑blind follow‑up. All randomized subjects had tolerated a 2‑week course on carvedilol 6.25 mg twice daily.<br />
<br />
In each trial, there was a primary end point, either progression of heart failure (1 US trial) or exercise tolerance (2 US trials meeting enrollment goals and the Australia‑New Zealand trial). There were many secondary end points specified in these trials, including NYHA classification, patient and physician global assessments, and cardiovascular hospitalization. Other analyses not prospectively planned included the sum of deaths and total cardiovascular hospitalizations. In situations where the primary end points of a trial do not show a significant benefit of treatment, assignment of significance values to the other results is complex, and such values need to be interpreted cautiously.<br />
<br />
'''The results of the US and Australia‑New Zealand trials were as follows''':<br />
<br />
:Slowing Progression of Heart Failure: One US multicenter trial (366 subjects) had as its primary end point the sum of cardiovascular mortality, cardiovascular hospitalization, and sustained increase in heart failure medications. Heart failure progression was reduced, during an average follow‑up of 7 months, by 48% (P = 0.008).<br />
<br />
:In the Australia‑New Zealand trial, death and total hospitalizations were reduced by about 25% over 18 to 24 months. In the 3 largest US trials, death and total hospitalizations were reduced by 19%, 39%, and 49%, nominally statistically significant in the last 2 trials. The Australia‑New Zealand results were statistically borderline.<br />
<br />
:Functional Measures: None of the multicenter trials had NYHA classification as a primary end point, but all such trials had it as a secondary end point. There was at least a trend toward improvement in NYHA class in all trials. Exercise tolerance was the primary end point in 3 trials; in none was a statistically significant effect found.<br />
<br />
:Subjective Measures: Health-related quality of life, as measured with a standard questionnaire (a primary end point in 1 trials), was unaffected by carvedilol. However, patients’ and investigators’ global assessments showed significant improvement in most trials.<br />
<br />
:Mortality: Death was not a pre-specified end point in any trial, but was analyzed in all trials. Overall, in these 4 US trials, mortality was reduced, nominally significantly so in 2 trials.<br />
<br />
======COMET Trial======<br />
In this double-blind trial, 3,029 subjects with NYHA class II-IV heart failure (left ventricular ejection fraction ≤35%) were randomized to receive either carvedilol (target dose: 25 mg twice daily) or immediate-release [[metoprolol]] tartrate (target dose: 50 mg twice daily). The mean age of the subjects was approximately 62 years, 80% were males, and the mean left ventricular [[ejection fraction]] at baseline was 26%. Approximately 96% of the subjects had NYHA class II or III heart failure. Concomitant treatment included diuretics (99%), ACE inhibitors (91%), digitalis (59%), [[aldosterone]]antagonists (11%), and “[[statin]]” lipid-lowering agents (21%). The mean duration of follow-up was 4.8 years. The mean dose of carvedilol was 42 mg per day.<br />
<br />
The trial had 2 primary end points: all-cause mortality and the composite of death plus hospitalization for any reason. The results of COMET are presented in Table 3 below. All-cause mortality carried most of the statistical weight and was the primary determinant of the trial size. All-cause mortality was 34% in the subjects treated with carvedilol and was 40% in the immediate-release metoprolol group (P = 0.0017; hazard ratio = 0.83, 95%CI: 0.74 to 0.93). The effect on mortality was primarily due to a reduction in cardiovascular death. The difference between the 2 groups with respect to the composite end point was not significant (P = 0.122). The estimated mean survival was 8.0 years with carvedilol and 6.6 years with immediate-release metoprolol.<br />
{|<br />
|[[File:Carvidelolt3.JPG|600px|thumb]]<br />
|}<br />
<br />
It is not known whether this formulation of metoprolol at any dose or this low dose of [[metoprolol]] in any formulation has any effect on survival or hospitalization in patients with heart failure. Thus, this trial extends the time over which carvedilol manifests benefits on survival in heart failure, but it is not evidence that carvedilol improves outcome over the formulation of metoprolol (TOPROL-XL®) with benefits in[[ heart failure]].<br />
<br />
=====Severe Heart Failure(COPERNICUS)=====<br />
<br />
In a double-blind trial (COPERNICUS), 2,289 subjects with heart failure at rest or with minimal exertion and left ventricular [[ejection fraction]] <25% (mean 20%), despite digitalis (66%), diuretics (99%), and ACE inhibitors (89%) were randomized to placebo or carvedilol. Carvedilol was titrated from a starting dose of 3.125 mg twice daily to the maximum tolerated dose or up to 25 mg twice daily over a minimum of 6 weeks. Most subjects achieved the target dose of 25 mg. The trial was conducted in Eastern and Western Europe, the United States, Israel, and Canada. Similar numbers of subjects per group (about 100) withdrew during the titration period.<br />
<br />
The primary end point of the trial was all‑cause mortality, but cause‑specific mortality and the risk of death or hospitalization (total, cardiovascular [CV], or heart failure [HF]) were also examined. The developing trial data were followed by a data monitoring committee, and mortality analyses were adjusted for these multiple looks. The trial was stopped after a median follow‑up of 10 months because of an observed 35% reduction in mortality (from 19.7% per patient-year on placebo to 12.8% on carvedilol, hazard ratio 0.65, 95% CI: 0.52 to 0.81, P = 0.0014, adjusted) (see Figure 1). The results of COPERNICUS are shown in Table 4.<br />
<br />
{|<br />
|[[File:Carvidelolt4.JPG|600px|thumb]]<br />
|}<br />
<br />
The effect on mortality was principally the result of a reduction in the rate of sudden death among subjects without worsening heart failure.<br />
<br />
Patients' global assessments, in which carvedilol‑treated subjects were compared with placebo, were based on pre-specified, periodic patient self-assessments regarding whether clinical status post-treatment showed improvement, worsening or no change compared with baseline. Subjects treated with carvedilol showed significant improvements in global assessments compared with those treated with placebo in COPERNICUS.<br />
<br />
The protocol also specified that hospitalizations would be assessed. Fewer subjects on COREG than on placebo were hospitalized for any reason (372 versus 432, P = 0.0029), for cardiovascular reasons (246 versus 314, P = 0.0003), or for worsening heart failure (198 versus 268, P = 0.0001).<br />
<br />
COREG had a consistent and beneficial effect on all‑cause mortality as well as the combined end points of all‑cause mortality plus hospitalization (total, CV, or for heart failure) in the overall trial population and in all subgroups examined, including men and women, elderly and non‑elderly, blacks and non‑blacks, and diabetics and non-diabetics (see Figure 2).<br />
<br />
{|<br />
|[[File:Carvidelolfig2.JPG|600px|thumb]]<br />
|}<br />
<br />
=====Left Ventricular Dysfunction Following Myocardial Infarction=====<br />
====CAPRICORN Trial====<br />
<br />
CAPRICORN was a double‑blind trial comparing carvedilol and placebo in 1,959 subjects with a recent myocardial infarction (within 21 days) and left ventricular ejection fraction of ≤40%, with (47%) or without symptoms of heart failure. Subjects given carvedilol received 6.25 mg twice daily, titrated as tolerated to 25 mg twice daily. Subjects had to have a systolic blood pressure >90 mm Hg, a sitting heart rate >60 beats/minute, and no contraindication to β‑blocker use. Treatment of the index infarction included aspirin (85%), IV or oral β‑blockers (37%), nitrates (73%), heparin (64%), thrombolytics (40%), and acute angioplasty (12%). Background treatment included ACE inhibitors or angiotensin receptor blockers (97%), anticoagulants (20%), lipid‑lowering agents (23%), and diuretics (34%). Baseline population characteristics included an average age of 63 years, 74% male, 95% Caucasian, mean blood pressure 121/74 mm Hg, 22% with diabetes, and 54% with a history of hypertension. Mean dosage achieved of carvedilol was 20 mg twice daily; mean duration of follow‑up was 15 months.<br />
<br />
All‑cause mortality was 15% in the placebo group and 12% in the carvedilol group, indicating a 23% risk reduction in subjects treated with carvedilol (95% CI: 2% to 40%, P = 0.03), as shown in Figure 3. The effects on mortality in various subgroups are shown in Figure 4. Nearly all deaths were cardiovascular (which were reduced by 25% by carvedilol), and most of these deaths were sudden or related to pump failure (both types of death were reduced by carvedilol).Another trial end point, total mortality and all-cause hospitalization, did not show a significant improvement.<br />
<br />
There was also a significant 40% reduction in fatal or non-fatal myocardial infarction observed in the group treated with carvedilol (95% CI: 11% to 60%, P = 0.01). A similar reduction in the risk of myocardial infarction was also observed in a meta-analysis of placebo-controlled trials of carvedilol in heart failure.<br />
<br />
{|<br />
|[[File:Carvidelolfig4.JPG|400px|thumb]]<br />
|}<br />
<br />
=====Hypertension=====<br />
COREG was studied in 2 placebo‑controlled trials that utilized twice‑daily dosing, at total daily doses of 12.5 to 50 mg. In these and other trials, the starting dose did not exceed 12.5 mg. At 50 mg/day, COREG reduced sitting trough (12‑hour) blood pressure by about 9/5.5 mm Hg; at 25 mg/day the effect was about 7.5/3.5 mm Hg. Comparisons of trough to peak blood pressure showed a trough to peak ratio for blood pressure response of about 65%. Heart rate fell by about 7.5 beats/minute at 50 mg/day. In general, as is true for other β‑blockers, responses were smaller in black than non‑black subjects. There were no age‑ or gender‑related differences in response.<br />
<br />
The peak antihypertensive effect occurred 1 to 2 hours after a dose. The dose‑related blood pressure response was accompanied by a dose‑related increase in adverse effects.<br />
<br />
===Hypertension With Type 2 Diabetes Mellitus===<br />
In a double-blind trial (GEMINI), COREG, added to an ACE inhibitor or [[angiotensin receptor blocker]], was evaluated in a population with mild‑to‑moderate hypertension and well-controlled type 2 diabetes mellitus. The mean HbA1c at baseline was 7.2%. COREG was titrated to a mean dose of 17.5 mg twice daily and maintained for 5 months. COREG had no adverse effect on glycemic control, based on HbA1c measurements (mean change from baseline of 0.02%, 95% CI: ‑0.06 to 0.10, P = NS) .<br />
}}</div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=Carvedilol&diff=962338Carvedilol2014-04-03T21:25:05Z<p>Abdurahman Khalil: </p>
<hr />
<div>{{DrugProjectFormSinglePage<br />
|authorTag={{AK}}<br />
|genericName=Carvedilol<br />
|aOrAn=an<br />
|drugClass=Alpha-adrenergic blocker, Beta-adrenergic blocker<br />
|indication=Heart failure of ischemic or cardiomyopathic origin, hypertension<br />
|adverseReactions=Fatigue, hypotension, dizziness, hyperglycemia<br />
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)<br />
|fdaLIADAdult=&lt;h4&gt;Condition 1&lt;/h5&gt;<br />
<br />
* Dosing Information<br />
<br />
:: (Dosage)<br />
|contraindications=Carvedilol is '''contraindicated''' in the following conditions:<br />
<br />
:*[[Bronchial asthma]] or related bronchospastic conditions. Deaths from [[status asthmaticus]] have been reported following single doses of COREG.<br />
:*[[AV block]] (Second- or third-degree) <br />
:*[[Sick sinus syndrome]]<br />
:*Severe [[bradycardia]] (unless a permanent pacemaker is in place).<br />
:*[[Cardiogenic shock]] or who have decompensated [[heart failure]] requiring the use of intravenous [[inotropic]] therapy. Such patients should first be weaned from intravenous therapy before initiating COREG<br />
:*Severe hepatic impairment<br />
:*Serious [[hypersensitivity]] reaction (e.g., [[Stevens-Johnson syndrome]], [[anaphylactic reaction]], [[angioedema]]) to any component of this medication or other medications containing carvedilol.<br />
|warnings=*Acute exacerbation of coronary artery disease upon cessation of therapy: Do not abruptly discontinue. <br />
*Bradycardia, hypotension, fluid retention may occur. Reduce the dose as needed. <br />
<br />
*Non-allergic bronchospasm (e.g., chronic bronchitis and emphysema): Avoid β-blockers. <br />
<br />
*However, if deemed necessary, use with caution and at lowest effective dose.<br />
Diabetes: Monitor glucose as β-blockers may mask symptoms of hypoglycemia or worsen hyperglycemia. <br />
<br />
=====Cessation of Therapy=====<br />
<br />
'''Patients with [[coronary artery disease]], who are being treated with carvedilol, should be advised against abrupt discontinuation of therapy. Severe exacerbation of [[angina]] and the occurrence of [[myocardial infarction]] and [[ventricular arrhythmias]] have been reported in angina patients following the abrupt discontinuation of therapy with β-blockers. The last 2 complications may occur with or without preceding exacerbation of the angina pectoris. As with other β-blockers, when discontinuation of carvedilol is planned, the patients should be carefully observed and advised to limit physical activity to a minimum. carvedilol should be discontinued over 1 to 2 weeks whenever possible. If the angina worsens or acute coronary insufficiency develops, it is recommended that carvedilol be promptly reinstituted, at least temporarily. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue therapy with carvedilol abruptly even in patients treated only for hypertension or heart failure.'''<br />
<br />
===Bradycardia===<br />
<br />
In clinical trials, carvedilol caused[[ bradycardia]] in about 2% of hypertensive subjects, 9% of heart failure subjects, and 6.5% of myocardial infarction subjects with left ventricular dysfunction. If pulse rate drops below 55 beats/minute, the dosage should be reduced.<br />
<br />
=====Hypotension=====<br />
In clinical trials of primarily mild‑to‑moderate [[heart failure]], [[hypotension]] and [[postural hypotension]] occurred in 9.7% and syncope in 3.4% of subjects receiving carvedilol compared with 3.6% and 2.5% of placebo subjects, respectively. The risk for these events was highest during the first 30 days of dosing, corresponding to the up‑titration period and was a cause for discontinuation of therapy in 0.7% of subjects receiving carvedilol, compared with 0.4% of placebo subjects. In a long‑term, placebo‑controlled trial in severe heart failure (COPERNICUS), hypotension and postural hypotension occurred in 15.1% and syncope in 2.9% of heart failure subjects receiving carvedilol compared with 8.7% and 2.3% of placebo subjects, respectively. These events were a cause for discontinuation of therapy in 1.1% of subjects receiving carvedilol, compared with 0.8% of placebo subjects.<br />
<br />
Postural hypotension occurred in 1.8% and syncope in 0.1% of hypertensive subjects, primarily following the initial dose or at the time of dose increase and was a cause for discontinuation of therapy in 1% of subjects.<br />
<br />
In the CAPRICORN trial of survivors of an acute[[ myocardial infarction]], hypotension or postural hypotension occurred in 20.2% of subjects receiving carvedilol compared with 12.6% of placebo subjects. Syncope was reported in 3.9% and 1.9% of subjects, respectively. These events were a cause for discontinuation of therapy in 2.5% of subjects receiving carvedilol, compared with 0.2% of placebo subjects.<br />
<br />
Starting with a low dose, administration with food, and gradual up-titration should decrease the likelihood of syncope or excessive hypotension [see [[Carvedilol dosage and administration|Dosage and Administration]] ]. During initiation of therapy, the patient should be cautioned to avoid situations such as driving or hazardous tasks, where injury could result should syncope occur.<br />
<br />
=====Heart Failure/Fluid Retention=====<br />
Worsening heart failure or fluid retention may occur during up-titration of carvedilol. If such symptoms occur, diuretics should be increased and the carvedilol dose should not be advanced until clinical stability resumes [see Dosage and Administration (2)]. Occasionally it is necessary to lower the carvedilol dose or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of, or a favorable response to, carvedilol. In a placebo-controlled trial of subjects with severe heart failure, worsening heart failure during the first 3 months was reported to a similar degree with carvedilol and with placebo. When treatment was maintained beyond 3 months, worsening heart failure was reported less frequently in subjects treated with carvedilol than with placebo. Worsening heart failure observed during long-term therapy is more likely to be related to the patients’ underlying disease than to treatment with carvedilol.<br />
<br />
=====Non-allergic Bronchospasm=====<br />
Patients with bronchospastic disease (e.g., [[chronic bronchitis]] and [[emphysema]]) should, in general, not receive β-blockers. carvedilol may be used with caution, however, in patients who do not respond to, or cannot tolerate, other antihypertensive agents. It is prudent, if carvedilol is used, to use the smallest effective dose, so that inhibition of endogenous or exogenous β-agonists is minimized.<br />
<br />
In clinical trials of subjects with heart failure, subjects with bronchospastic disease were enrolled if they did not require oral or inhaled medication to treat their bronchospastic disease. In such patients, it is recommended that carvedilol be used with caution. The dosing recommendations should be followed closely and the dose should be lowered if any evidence of bronchospasm is observed during up-titration.<br />
<br />
=====Glycemic Control in Type 2 Diabetes=====<br />
In general, β-blockers may mask some of the manifestations of hypoglycemia, particularly [[tachycardia]]. Nonselective β-blockers may potentiate insulin-induced [[hypoglycemia]] and delay recovery of serum glucose levels. Patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be cautioned about these possibilities.<br />
<br />
In heart failure patients with diabetes, carvedilol therapy may lead to worsening [[hyperglycemia]], which responds to intensification of hypoglycemic therapy. It is recommended that blood glucose be monitored when carvedilol dosing is initiated, adjusted, or discontinued. Trials designed to examine the effects of carvedilol on glycemic control in patients with diabetes and heart failure have not been conducted.<br />
<br />
In a trial designed to examine the effects of carvedilol on glycemic control in a population with mild-to-moderate hypertension and well-controlled type 2[[ diabetes mellitus]], carvedilol had no adverse effect on glycemic control, based on [[HbA1c]] measurements [see Carvidilol clinical studies|Clinical Studies]]].<br />
<br />
=====Peripheral Vascular Disease=====<br />
β-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Caution should be exercised in such individuals.<br />
<br />
=====Deterioration of Renal Function=====<br />
Rarely, use of carvedilol in patients with heart failure has resulted in deterioration of renal function. Patients at risk appear to be those with low blood pressure (systolic blood pressure <100 mm Hg), [[ischemic heart disease]] and diffuse vascular disease, and/or underlying renal insufficiency. Renal function has returned to baseline when carvedilol was stopped. In patients with these risk factors it is recommended that renal function be monitored during up-titration of carvedilol and the drug discontinued or dosage reduced if worsening of renal function occurs.<br />
<br />
===Major Surgery===<br />
Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.<br />
<br />
=====Thyrotoxicosis=====<br />
β-adrenergic blockade may mask clinical signs of [[hyperthyroidism]], such as [[tachycardia]]. Abrupt withdrawal of β-blockade may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate [[thyroid storm]].<br />
<br />
=====Pheochromocytoma=====<br />
In patients with [[pheochromocytoma]], an α-blocking agent should be initiated prior to the use of any β-blocking agent. Although carvedilol has both α- and β-blocking pharmacologic activities, there has been no experience with its use in this condition. Therefore, caution should be taken in the administration of carvedilol to patients suspected of having [[pheochromocytoma]].<br />
<br />
=====Prinzmetal’s Variant Angina=====<br />
Agents with non-selective β-blocking activity may provoke chest pain in patients with [[Prinzmetal’s]] variant angina. There has been no clinical experience with carvedilol in these patients although the α-blocking activity may prevent such symptoms. However, caution should be taken in the administration of carvedilol to patients suspected of having Prinzmetal’s variant angina.<br />
<br />
===Risk of Anaphylactic Reaction===<br />
While taking β-blockers, patients with a history of severe [[anaphylactic reaction]] to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.<br />
<br />
===Intraoperative Floppy Iris Syndrome===<br />
Intraoperative Floppy Iris Syndrome (IFIS) has been observed during [[cataract]] surgery in some patients treated with [[alpha-1 blockers]] (carvedilol is an alpha/beta blocker). This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative [[miosis]] despite preoperative dilation with standard [[mydriatic]] drugs, and potential prolapse of the iris toward the phacoemulsification incisions. The patient’s ophthalmologist should be prepared for possible modifications to the surgical technique, such as utilization of iris hooks, iris dilator rings, or viscoelastic substances. There does not appear to be a benefit of stopping alpha-1 blocker therapy prior to cataract surgery.<br />
|FDAPregCat=C<br />
|useInPregnancyFDA=Studies performed in pregnant rats and rabbits given carvedilol revealed increased post-implantation loss in rats at doses of 300 mg/kg/day (50 times the maximum recommended human dose [MRHD] as mg/m2) and in rabbits at doses of 75 mg/kg/day (25 times the MRHD as mg/m2). In the rats, there was also a decrease in fetal body weight at the maternally toxic dose of 300 mg/kg/day (50 times the MRHD as mg/m2), which was accompanied by an elevation in the frequency of fetuses with delayed skeletal development (missing or stunted 13th rib). In rats the no-observed-effect level for developmental toxicity was 60 mg/kg/day (10 times the MRHD as mg/m2); in rabbits it was 15 mg/kg/day (5 times the MRHD as mg/m2). There are no adequate and well-controlled studies in pregnant women. COREG should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br />
|useInNursing=It is not known whether this drug is excreted in human milk. Studies in rats have shown that carvedilol and/or its metabolites (as well as other β-blockers) cross the placental barrier and are excreted in breast milk. There was increased mortality at one week post-partum in neonates from rats treated with 60 mg/kg/day (10 times the MRHD as mg/m2) and above during the last trimester through day 22 of lactation. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from β-blockers, especially [[bradycardia]], a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. The effects of other α- and β-blocking agents have included perinatal and neonatal distress.<br />
|useInPed=Effectiveness of carvedilol in patients younger than 18 years has not been established.<br />
<br />
In a double-blind trial, 161 children (mean age: 6 years, range: 2 months to 17 years; 45% younger than 2 years) with chronic[[ heart failure]] [NYHA class II-IV, left ventricular [[ejection fraction]] <40% for children with a systemic left ventricle (LV), and moderate-severe ventricular dysfunction qualitatively by echo for those with a systemic ventricle that was not an LV] who were receiving standard background treatment were randomized to placebo or to 2 dose levels of carvedilol. These dose levels produced placebo-corrected heart rate reduction of 4 to 6 heart beats per minute, indicative of β -blockade activity. Exposure appeared to be lower in pediatric subjects than adults. After 8 months of follow-up, there was no significant effect of treatment on clinical outcomes. Adverse reactions in this trial that occurred in greater than 10% of subjects treated with carvedilol and at twice the rate of placebo-treated subjects included chest pain (17% versus 6%), dizziness (13% versus 2%), and dyspnea (11% versus 0%).<br />
|useInGeri=Plasma levels of carvedilol average about 50% higher in the elderly compared with young subjects.<br />
<br />
Of the 765 subjects with heart failure randomized to carvedilol in US clinical trials, 31% (235) were 65 years of age or older, and 7.3% (56) were 75 years of age or older. Of the 1,156 subjects randomized to carvedilol in a long‑term, placebo‑controlled trial in severe heart failure, 47% (547) were 65 years of age or older, and 15% (174) were 75 years of age or older. Of 3,025 subjects receiving carvedilol in heart failure trials worldwide, 42% were 65 years of age or older.<br />
<br />
Of the 975 [[myocardial infarction]] subjects randomized to carvedilol in the CAPRICORN trial, 48% (468) were 65 years of age or older, and 11% (111) were 75 years of age or older.<br />
<br />
Of the 2,065 hypertensive subjects in US clinical trials of efficacy or safety who were treated with carvedilol, 21% (436) were 65 years of age or older. Of 3,722 subjects receiving carvedilol in hypertension clinical trials conducted worldwide, 24% were 65 years of age or older.<br />
<br />
With the exception of [[dizziness ]]in hypertensive subjects (incidence 8.8% in the elderly versus 6% in younger subjects), no overall differences in the safety or effectiveness (see Figures 2 and 4) were observed between the older subjects and younger subjects in each of these populations. Similarly, other reported clinical experience has not identified differences in responses between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.<br />
|useInRenalImpair=Although carvedilol is metabolized primarily by the liver, plasma concentrations of carvedilol have been reported to be increased in patients with renal impairment. Based on mean AUC data, approximately 40% to 50% higher plasma concentrations of carvedilol were observed in hypertensive subjects with moderate to severe renal impairment compared to a control group of hypertensive subjects with normal renal function. However, the ranges of AUC values were similar for both groups. Changes in mean peak plasma levels were less pronounced, approximately 12% to 26% higher in subjects with impaired renal function.<br />
<br />
Consistent with its high degree of plasma protein‑binding, carvedilol does not appear to be cleared significantly by [[hemodialysis]].<br />
|useInHepaticImpair=Compared with healthy subjects, patients with severe liver impairment ([[cirrhosis]]) exhibit a 4- to 7-fold increase in carvedilol levels. <br />
Carvedilol is contraindicated in patients with severe liver impairment.<br />
|othersTitle=Heart Failure<br />
|useInOthers=[[Steady‑state ]]plasma concentrations of carvedilol and its enantiomers increased proportionally over the 6.25 to 50 mg dose range in subjects with heart failure. Compared with healthy subjects, heart failure subjects had increased mean AUC and Cmax values for carvedilol and its enantiomers, with up to 50% to 100% higher values observed in 6 subjects with NYHA class IV heart failure. The mean apparent terminal elimination half‑life for carvedilol was similar to that observed in healthy subjects.<br />
|administration='''DOSAGE MUST BE INDIVIDUALIZED AND MONITORED DURING UP-TITRATION'''. Treatment with carvedilol tablets may be started as an inpatient or outpatient and should be started after the patient is hemodynamically stable and fluid retention has been minimized. It is recommended that carvedilol tablets be started at 6.25 mg twice daily and increased after 3 to 10 days, based on tolerability, to 12.5 mg twice daily, then again to the target dose of 25 mg twice daily. A lower starting dose may be used (3.125 mg twice daily) and/or the rate of up-titration may be slowed if clinically indicated (e.g., due to low blood pressure or heart rate, or fluid retention). Patients should be maintained on lower doses if higher doses are not tolerated. The recommended dosing regimen need not be altered in patients who received treatment with an IV or oral β-blocker during the acute phase of the myocardial infarction.<br />
<br />
'''DOSAGE MUST BE INDIVIDUALIZED'''. The recommended starting dose of carvedilol tablets is 6.25 mg twice daily. If this dose is tolerated, using standing systolic pressure measured about 1 hour after dosing as a guide, the dose should be maintained for 7 to 14 days, and then increased to 12.5 mg twice daily if needed, based on trough blood pressure, again using standing systolic pressure one hour after dosing as a guide for tolerance. This dose should also be maintained for 7 to 14 days and can then be adjusted upward to 25 mg twice daily if tolerated and needed. The full antihypertensive effect of carvedilol tablets is seen within 7 to 14 days. Total daily dose should not exceed 50 mg.<br />
Concomitant administration with a diuretic can be expected to produce additive effects and exaggerate the orthostatic component of carvedilol action.<br />
<br />
Carvedilol tablets should not be given to patients with severe hepatic impairment<br />
|monitoring=* Monitor glucose as β-blockers may mask symptoms of hypoglycemia or worsen hyperglycemia<br />
*Rarely, use of carvedilol in patients with heart failure has resulted in deterioration of renal function. Patients at risk appear to be those with low blood pressure (systolic blood pressure <100 mm Hg), ischemic heart disease and diffuse vascular disease, and/or underlying renal insufficiency. Renal function has returned to baseline when carvedilol was stopped. In patients with these risk factors it is recommended that renal function be monitored during up-titration of carvedilol and the drug discontinued or dosage reduced if worsening of renal function occurs.<br />
<br />
*Modest increases in mean trough cyclosporine concentrations were observed following initiation of carvedilol treatment in 21 renal transplant patients suffering from chronic vascular rejection. In about 30% of patients, the dose of cyclosporine had to be reduced in order to maintain cyclosporine concentrations within the therapeutic range, while in the remainder no adjustment was needed. On the average for the group, the dose of cyclosporine was reduced about 20% in these patients. Due to wide interindividual variability in the dose adjustment required, it is recommended that cyclosporine concentrations be monitored closely after initiation of carvedilol therapy and that the dose of cyclosporine be adjusted as appropriate.<br />
<br />
*Both digitalis glycosides and β-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. Digoxin concentrations are increased by about 15% when digoxin and carvedilol are administered concomitantly. Therefore, increased monitoring of digoxin is recommended when initiating, adjusting, or discontinuing carvedilol tablets<br />
<br />
*Conduction disturbance (rarely with hemodynamic compromise) has been observed when carvedilol tablets are co-administered with diltiazem. As with other agents with β-blocking properties, if carvedilol is to be administered with calcium channel blockers of the verapamil or diltiazem type, it is recommended that ECG and blood pressure be monitored.<br />
<br />
*Agents with β-blocking properties may enhance the blood-sugar-reducing effect of insulin and oral hypoglycemics. Therefore, in patients taking insulin or oral hypoglycemics, regular monitoring of blood glucose is recommended<br />
|overdose====Acute Overdose===<br />
=====Signs and Symptoms=====<br />
Overdosage may cause severe [[hypotension]], [[bradycardia]], [[cardiac insufficiency]], [[cardiogenic shock]], and [[cardiac arrest]]. Respiratory problems, bronchospasms, vomiting, lapses of consciousness, and generalized [[seizures]] may also occur.<br />
=====Management=====<br />
:*The patient should be placed in a '''[[supine]] position''' and, where necessary and '''kept under observation'''<br />
<br />
:*The patient should be treated under intensive-care conditions. <br />
:*'''Gastric lavage''' or pharmacologically induced [[emesis]] may be used shortly after ingestion. <br />
The following agents may be '''administered for excessive [[bradycardia]]''':<br />
:* [[Atropine]], 2 mg IV.<br />
'''To support cardiovascular function:''' <br />
<br />
:*Glucagon, 5 to 10 mg IV rapidly over 30 seconds, followed by a continuous infusion of 5 mg/hour<br><br />
:*Sympathomimetics ([[dobutamine]], [[isoprenaline]], adrenaline) at doses according to body weight and effect.<br />
'''If peripheral vasodilation dominates:''' <br />
:*Administer [[adrenaline]] or[[ noradrenaline]] with continuous monitoring of circulatory conditions.<br />
'''For therapy-resistant [[bradycardia]]'''<br />
:*pacemaker therapy should be performed.<br />
'''For bronchospasm'''<br />
:*β-sympathomimetics (as aerosol or IV) or [[Aminophylline]] IV should be given. <br />
'''In the event of [[seizures]]'''<br />
:*Administer slow IV injection of [[diazepam]] or [[clonazepam]] is recommended.<br />
<br />
'''NOTE:''' In the event of severe intoxication where there are symptoms of shock, treatment with antidotes must be continued for a sufficiently '''long period of time consistent with the 7-10 hour half-life of carvedilol'''.<br />
<br />
Cases of overdosage with COREG alone or in combination with other drugs have been reported. Quantities ingested in some cases exceeded 1,000 milligrams. Symptoms experienced included low blood pressure and heart rate. '''Standard supportive treatment''' was provided and individuals recovered.<br />
|drugBox={{Drugbox2<br />
| verifiedrevid = 457636154<br />
| IUPAC_name = (±)-[3-(9''H''-carbazol-4-yloxy)-2-hydroxypropyl][2-(2-methoxyphenoxy)ethyl]amine<br />
| image = Carvedilol.svg<br />
| image2 = Carvedilol-I-3D-balls.png<br />
| imagename = 1 : 1 mixture (racemate)<br />
| drug_name = Carvedilol<br />
<br />
<!--Clinical data--><br />
| tradename = Coreg<br />
| Drugs.com = {{drugs.com|monograph|carvedilol}}<br />
| MedlinePlus = a697042<br />
| pregnancy_category = C<br />
| legal_status = Rx-only<br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = 25–35%<br />
| protein_bound = 98%<br />
| metabolism = [[Liver]] ([[CYP2D6]], [[CYP2C9]])<br />
| elimination_half-life = 7–10 hours<br />
| excretion = [[Urine]] (16%), [[Feces]] (60%)<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 72956-09-3<br />
| ATC_prefix = C07<br />
| ATC_suffix = AG02<br />
| PubChem = 2585<br />
| IUPHAR_ligand = 551<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01136<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2487<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = 0K47UL67F2<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D00255<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 3441<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 723<br />
<br />
<!--Chemical data--><br />
| C=24 | H=26 | N=2 | O=4 <br />
| molecular_weight = 406.474<br />
| smiles = O(c4ccccc4OCCNCC(O)COc3cccc2c3c1c(cccc1)n2)C<br />
| InChI = 1/C24H26N2O4/c1-28-21-10-4-5-11-22(21)29-14-13-25-15-17(27)16-30-23-12-6-9-20-24(23)18-7-2-3-8-19(18)26-20/h2-12,17,25-27H,13-16H2,1H3<br />
| InChIKey = OGHNVEJMJSYVRP-UHFFFAOYAP<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C24H26N2O4/c1-28-21-10-4-5-11-22(21)29-14-13-25-15-17(27)16-30-23-12-6-9-20-24(23)18-7-2-3-8-19(18)26-20/h2-12,17,25-27H,13-16H2,1H3<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = OGHNVEJMJSYVRP-UHFFFAOYSA-N<br />
}}<br />
|mechAction=Carvedilol is a racemic mixture in which nonselective β-adrenoreceptor blocking activity is present in the S(-) enantiomer and α1-adrenergic blocking activity is present in both R(+) and S(-) enantiomers at equal potency. Carvedilol has no intrinsic sympathomimetic activity.<br />
|structure=Carvedilol is a nonselective β-adrenergic blocking agent with α1-blocking activity. It is (±)-1-(Carbazol-4-yloxy)-3-[[2-(o-methoxyphenoxy)ethyl]amino]-2-propanol.<br />
<br />
Carvedilol is a white, oval, film-coated tablet containing 3.125 mg, 6.25 mg, 12.5 mg, or 25 mg of carvedilol. The 6.25-mg, 12.5-mg, and 25-mg tablets are TILTAB® tablets. Inactive ingredients consist of colloidal silicon dioxide, crospovidone, hypromellose, lactose, magnesium stearate, polyethylene glycol, polysorbate 80, povidone, sucrose, and titanium dioxide.<br />
<br />
Carvedilol is a white to off-white powder with a molecular weight of 406.5 and a molecular formula of C24H26N2O4. It is freely soluble in dimethylsulfoxide; soluble in methylene chloride and methanol; sparingly soluble in 95% ethanol and isopropanol; slightly soluble in ethyl ether; and practically insoluble in water, gastric fluid (simulated, TS, pH 1.1), and intestinal fluid (simulated, TS without pancreatin, pH 7.5).<br />
|PD=====Heart Failure====<br />
<br />
:*The basis for the '''beneficial effects''' of carvedilol in heart failure is '''not established.'''<br />
<br />
:*Two placebo‑controlled trials compared the acute hemodynamic effects of carvedilol with baseline measurements in 59 and 49 subjects with NYHA class II‑IV heart failure receiving [[diuretics]], [[ACE inhibitors]], and [[digitalis]]. There were significant reductions in systemic blood pressure, pulmonary artery pressure, pulmonary capillary wedge pressure, and heart rate. Initial effects on cardiac output, stroke volume index, and systemic vascular resistance were small and variable.<br />
<br />
:*These trials measured hemodynamic effects again at 12 to 14 weeks. carvedilol significantly '''reduced systemic blood pressure, pulmonary artery pressure, right atrial pressure, systemic vascular resistance, and heart rate''', while stroke volume index was increased.<br />
<br />
:*Among 839 subjects with NYHA class II‑III heart failure treated for 26 to 52 weeks in 4 US placebo‑controlled trials, average left ventricular ejection fraction (EF) measured by radionuclide ventriculography increased by 9 EF units (%) in subjects receiving carvedilol and by 2 EF units in placebo subjects at a target dose of 25 to 50 mg twice daily. <br />
<br />
:*'''The effects of carvedilol on ejection fraction were related to dose'''. <u>Doses of 6.25 mg twice daily, 12.5 mg twice daily, and 25 mg twice daily</u> were associated with placebo‑corrected increases in EF of 5 EF units, 6 EF units, and 8 EF units, respectively; each of these effects were nominally statistically significant.<br />
<br />
====Left Ventricular Dysfunction Following Myocardial Infarction====<br />
<br />
The basis for the beneficial effects of carvedilol in patients with left ventricular dysfunction following an [[acute myocardial infarction]] is not established.<br />
<br />
====Hypertension====<br />
<br />
The mechanism by which β-blockade produces an antihypertensive effect has not been established.<br />
<br />
:*β-adrenoreceptor blocking activity has been demonstrated in animal and human studies showing that carvedilol (1) reduces cardiac output in normal subjects; (2) reduces exercise- and/or [[isoproterenol]]-induced tachycardia; and (3) reduces reflex orthostatic [[tachycardia]]. Significant β-adrenoreceptor blocking effect is usually seen within 1 hour of drug administration.<br />
<br />
:*α1-adrenoreceptor blocking activity has been demonstrated in human and animal studies, showing that carvedilol (1) attenuates the pressor effects of [[phenylephrine]]; (2) causes vasodilation; and (3) reduces peripheral vascular resistance. These effects contribute to the reduction of blood pressure and usually are seen within 30 minutes of drug administration.<br />
<br />
:*Due to the α1-receptor blocking activity of carvedilol, blood pressure is lowered more in the standing than in the supine position, and symptoms of postural hypotension (1.8%), including rare instances of syncope, can occur. Following oral administration, when [[postural hypotension]] has occurred, it has been transient and is uncommon when carvedilol is administered with food at the recommended starting dose and titration increments are closely followed [see Dosage and Administration (2)].<br />
<br />
:*In hypertensive patients with normal renal function, therapeutic doses of carvedilol decreased renal vascular resistance with no change in glomerular filtration rate or renal plasma flow. Changes in excretion of sodium, potassium, uric acid, and phosphorus in hypertensive patients with normal renal function were similar after carvedilol and placebo.<br />
<br />
:*carvedilol has little effect on plasma [[catecholamines]], plasma [[aldosterone]], or electrolyte levels, but it does significantly reduce plasma renin activity when given for at least 4 weeks. It also increases levels of [[atrial natriuretic peptide]].<br />
|PK=:*carvedilol is rapidly and extensively absorbed following oral administration, with absolute bioavailability of approximately 25% to 35% due to a significant degree of first-pass metabolism. Following oral administration, the apparent mean terminal elimination half-life of carvedilol generally ranges from 7 to 10 hours. Plasma concentrations achieved are proportional to the oral dose administered. When administered with food, the rate of absorption is slowed, as evidenced by a delay in the time to reach peak plasma levels, with no significant difference in extent of bioavailability. Taking carvedilol with food should minimize the risk of[[ orthostatic hypotension]].<br />
<br />
:*'''Carvedilol is extensively metabolized'''. Following oral administration of radiolabelled carvedilol to healthy volunteers, carvedilol accounted for only about 7% of the total radioactivity in plasma as measured by area under the curve (AUC). Less than 2% of the dose was excreted unchanged in the urine. Carvedilol is metabolized primarily by aromatic ring oxidation and glucuronidation. The oxidative metabolites are further metabolized by conjugation via glucuronidation and sulfation. The metabolites of carvedilol are excreted primarily via the bile into the feces. Demethylation and hydroxylation at the phenol ring produce 3 active metabolites with β-receptor blocking activity. Based on preclinical studies, the 4'-hydroxyphenyl metabolite is approximately 13 times more potent than carvedilol for β-blockade.<br />
<br />
:*Compared with carvedilol, the 3 active metabolites exhibit weak vasodilating activity. Plasma concentrations of the active metabolites are about one-tenth of those observed for carvedilol and have pharmacokinetics similar to the parent.<br />
<br />
:*Carvedilol undergoes stereoselective first-pass metabolism with plasma levels of R(+)-carvedilol approximately 2 to 3 times higher than S(-)-carvedilol following oral administration in healthy subjects. The mean apparent terminal elimination half-lives for R(+)-carvedilol range from 5 to 9 hours compared with 7 to 11 hours for the S(-)-enantiomer.<br />
<br />
:*The primary P450 enzymes responsible for the metabolism of both R(+) and S(-)-carvedilol in human liver microsomes were CYP2D6 and CYP2C9 and to a lesser extent CYP3A4, 2C19, 1A2, and 2E1. CYP2D6 is thought to be the major enzyme in the 4’- and 5’-hydroxylation of carvedilol, with a potential contribution from 3A4. CYP2C9 is thought to be of primary importance in the O-methylation pathway of S(-)-carvedilol.<br />
<br />
:*Carvedilol is subject to the effects of genetic[[ polymorphism]] with poor metabolizers of debrisoquin (a marker for cytochrome P450 2D6) exhibiting 2- to 3-fold higher plasma concentrations of R(+)-carvedilol compared with extensive metabolizers. In contrast, plasma levels of S(-)-carvedilol are increased only about 20% to 25% in poor metabolizers, indicating this enantiomer is metabolized to a lesser extent by cytochrome P450 2D6 than R(+)-carvedilol. The pharmacokinetics of carvedilol do not appear to be different in poor metabolizers of S-mephenytoin (patients deficient in cytochrome P450 2C19).<br />
<br />
:*Carvedilol is more than 98% bound to plasma proteins, primarily with [[albumin]]. The plasma-protein binding is independent of concentration over the therapeutic range. Carvedilol is a basic, lipophilic compound with a steady-state volume of distribution of approximately 115 L, indicating substantial distribution into extravascular tissues. Plasma clearance ranges from 500 to 700 mL/min.<br />
|nonClinToxic======Carcinogenesis, Mutagenesis, Impairment of Fertility=====<br />
In 2-year studies conducted in rats given carvedilol at doses up to 75 mg/kg/day (12 times the MRHD when compared on a mg/m2 basis) or in mice given up to 200 mg/kg/day (16 times the MRHD on a mg/m2 basis), carvedilol had '''no carcinogenic effect.'''<br />
<br />
Carvedilol was negative when tested in a battery of [[genotoxicity]] assays, including the Ames and the CHO/HGPRT assays for mutagenicity and the in vitro hamster micronucleus and in vivo human lymphocyte cell tests for clastogenicity.<br />
<br />
At doses ≥200 mg/kg/day ( ≥ 32 times the MRHD as mg/m2) carvedilol was toxic to adult rats (sedation, reduced weight gain) and was associated with a reduced number of successful matings, prolonged mating time, significantly fewer corpora lutea and implants per dam, and complete resorption of 18% of the litters. <br />
The '''no-observed-effect dose''' level for overt toxicity and impairment of fertility was 60 mg/kg/day (10 times the MRHD as mg/m2).<br />
|clinicalStudies=====Heart Failure====<br />
A total of 6,975 subjects with mild to severe heart failure were evaluated in placebo-controlled trials of carvedilol.<br />
<br />
=====Mild-to-Moderate Heart Failure=====<br />
Carvedilol was studied in 5 multicenter, placebo‑controlled trials, and in 1 active-controlled trial (COMET trial) involving subjects with mild-to-moderate heart failure.<br />
<br />
Four US multicenter, double‑blind, placebo‑controlled trials enrolled 1,094 subjects (696 randomized to carvedilol) with NYHA class II‑III heart failure and ejection fraction ≤0.35. The vast majority were on [[digitalis]], [[diuretics]], and an [[ACE inhibitor]] at trial entry. Patients were assigned to the trials based upon exercise ability. An Australia‑New Zealand double‑blind, placebo‑controlled trial enrolled 415 subjects (half randomized to carvedilol) with less severe heart failure. All protocols excluded subjects expected to undergo cardiac transplantation during the 7.5 to 15 months of double‑blind follow‑up. All randomized subjects had tolerated a 2‑week course on carvedilol 6.25 mg twice daily.<br />
<br />
In each trial, there was a primary end point, either progression of heart failure (1 US trial) or exercise tolerance (2 US trials meeting enrollment goals and the Australia‑New Zealand trial). There were many secondary end points specified in these trials, including NYHA classification, patient and physician global assessments, and cardiovascular hospitalization. Other analyses not prospectively planned included the sum of deaths and total cardiovascular hospitalizations. In situations where the primary end points of a trial do not show a significant benefit of treatment, assignment of significance values to the other results is complex, and such values need to be interpreted cautiously.<br />
<br />
'''The results of the US and Australia‑New Zealand trials were as follows''':<br />
<br />
:Slowing Progression of Heart Failure: One US multicenter trial (366 subjects) had as its primary end point the sum of cardiovascular mortality, cardiovascular hospitalization, and sustained increase in heart failure medications. Heart failure progression was reduced, during an average follow‑up of 7 months, by 48% (P = 0.008).<br />
<br />
:In the Australia‑New Zealand trial, death and total hospitalizations were reduced by about 25% over 18 to 24 months. In the 3 largest US trials, death and total hospitalizations were reduced by 19%, 39%, and 49%, nominally statistically significant in the last 2 trials. The Australia‑New Zealand results were statistically borderline.<br />
<br />
:Functional Measures: None of the multicenter trials had NYHA classification as a primary end point, but all such trials had it as a secondary end point. There was at least a trend toward improvement in NYHA class in all trials. Exercise tolerance was the primary end point in 3 trials; in none was a statistically significant effect found.<br />
<br />
:Subjective Measures: Health-related quality of life, as measured with a standard questionnaire (a primary end point in 1 trials), was unaffected by carvedilol. However, patients’ and investigators’ global assessments showed significant improvement in most trials.<br />
<br />
:Mortality: Death was not a pre-specified end point in any trial, but was analyzed in all trials. Overall, in these 4 US trials, mortality was reduced, nominally significantly so in 2 trials.<br />
<br />
======COMET Trial======<br />
In this double-blind trial, 3,029 subjects with NYHA class II-IV heart failure (left ventricular ejection fraction ≤35%) were randomized to receive either carvedilol (target dose: 25 mg twice daily) or immediate-release [[metoprolol]] tartrate (target dose: 50 mg twice daily). The mean age of the subjects was approximately 62 years, 80% were males, and the mean left ventricular [[ejection fraction]] at baseline was 26%. Approximately 96% of the subjects had NYHA class II or III heart failure. Concomitant treatment included diuretics (99%), ACE inhibitors (91%), digitalis (59%), [[aldosterone]]antagonists (11%), and “[[statin]]” lipid-lowering agents (21%). The mean duration of follow-up was 4.8 years. The mean dose of carvedilol was 42 mg per day.<br />
<br />
The trial had 2 primary end points: all-cause mortality and the composite of death plus hospitalization for any reason. The results of COMET are presented in Table 3 below. All-cause mortality carried most of the statistical weight and was the primary determinant of the trial size. All-cause mortality was 34% in the subjects treated with carvedilol and was 40% in the immediate-release metoprolol group (P = 0.0017; hazard ratio = 0.83, 95%CI: 0.74 to 0.93). The effect on mortality was primarily due to a reduction in cardiovascular death. The difference between the 2 groups with respect to the composite end point was not significant (P = 0.122). The estimated mean survival was 8.0 years with carvedilol and 6.6 years with immediate-release metoprolol.<br />
{|<br />
|[[File:Carvidelolt3.JPG|600px|thumb]]<br />
|}<br />
<br />
It is not known whether this formulation of metoprolol at any dose or this low dose of [[metoprolol]] in any formulation has any effect on survival or hospitalization in patients with heart failure. Thus, this trial extends the time over which carvedilol manifests benefits on survival in heart failure, but it is not evidence that carvedilol improves outcome over the formulation of metoprolol (TOPROL-XL®) with benefits in[[ heart failure]].<br />
<br />
=====Severe Heart Failure(COPERNICUS)=====<br />
<br />
In a double-blind trial (COPERNICUS), 2,289 subjects with heart failure at rest or with minimal exertion and left ventricular [[ejection fraction]] <25% (mean 20%), despite digitalis (66%), diuretics (99%), and ACE inhibitors (89%) were randomized to placebo or carvedilol. Carvedilol was titrated from a starting dose of 3.125 mg twice daily to the maximum tolerated dose or up to 25 mg twice daily over a minimum of 6 weeks. Most subjects achieved the target dose of 25 mg. The trial was conducted in Eastern and Western Europe, the United States, Israel, and Canada. Similar numbers of subjects per group (about 100) withdrew during the titration period.<br />
<br />
The primary end point of the trial was all‑cause mortality, but cause‑specific mortality and the risk of death or hospitalization (total, cardiovascular [CV], or heart failure [HF]) were also examined. The developing trial data were followed by a data monitoring committee, and mortality analyses were adjusted for these multiple looks. The trial was stopped after a median follow‑up of 10 months because of an observed 35% reduction in mortality (from 19.7% per patient-year on placebo to 12.8% on carvedilol, hazard ratio 0.65, 95% CI: 0.52 to 0.81, P = 0.0014, adjusted) (see Figure 1). The results of COPERNICUS are shown in Table 4.<br />
<br />
{|<br />
|[[File:Carvidelolt4.JPG|600px|thumb]]<br />
|}<br />
<br />
The effect on mortality was principally the result of a reduction in the rate of sudden death among subjects without worsening heart failure.<br />
<br />
Patients' global assessments, in which carvedilol‑treated subjects were compared with placebo, were based on pre-specified, periodic patient self-assessments regarding whether clinical status post-treatment showed improvement, worsening or no change compared with baseline. Subjects treated with carvedilol showed significant improvements in global assessments compared with those treated with placebo in COPERNICUS.<br />
<br />
The protocol also specified that hospitalizations would be assessed. Fewer subjects on COREG than on placebo were hospitalized for any reason (372 versus 432, P = 0.0029), for cardiovascular reasons (246 versus 314, P = 0.0003), or for worsening heart failure (198 versus 268, P = 0.0001).<br />
<br />
COREG had a consistent and beneficial effect on all‑cause mortality as well as the combined end points of all‑cause mortality plus hospitalization (total, CV, or for heart failure) in the overall trial population and in all subgroups examined, including men and women, elderly and non‑elderly, blacks and non‑blacks, and diabetics and non-diabetics (see Figure 2).<br />
<br />
{|<br />
|[[File:Carvidelolfig2.JPG|600px|thumb]]<br />
|}<br />
<br />
=====Left Ventricular Dysfunction Following Myocardial Infarction=====<br />
====CAPRICORN Trial====<br />
<br />
CAPRICORN was a double‑blind trial comparing carvedilol and placebo in 1,959 subjects with a recent myocardial infarction (within 21 days) and left ventricular ejection fraction of ≤40%, with (47%) or without symptoms of heart failure. Subjects given carvedilol received 6.25 mg twice daily, titrated as tolerated to 25 mg twice daily. Subjects had to have a systolic blood pressure >90 mm Hg, a sitting heart rate >60 beats/minute, and no contraindication to β‑blocker use. Treatment of the index infarction included aspirin (85%), IV or oral β‑blockers (37%), nitrates (73%), heparin (64%), thrombolytics (40%), and acute angioplasty (12%). Background treatment included ACE inhibitors or angiotensin receptor blockers (97%), anticoagulants (20%), lipid‑lowering agents (23%), and diuretics (34%). Baseline population characteristics included an average age of 63 years, 74% male, 95% Caucasian, mean blood pressure 121/74 mm Hg, 22% with diabetes, and 54% with a history of hypertension. Mean dosage achieved of carvedilol was 20 mg twice daily; mean duration of follow‑up was 15 months.<br />
<br />
All‑cause mortality was 15% in the placebo group and 12% in the carvedilol group, indicating a 23% risk reduction in subjects treated with carvedilol (95% CI: 2% to 40%, P = 0.03), as shown in Figure 3. The effects on mortality in various subgroups are shown in Figure 4. Nearly all deaths were cardiovascular (which were reduced by 25% by carvedilol), and most of these deaths were sudden or related to pump failure (both types of death were reduced by carvedilol).Another trial end point, total mortality and all-cause hospitalization, did not show a significant improvement.<br />
<br />
There was also a significant 40% reduction in fatal or non-fatal myocardial infarction observed in the group treated with carvedilol (95% CI: 11% to 60%, P = 0.01). A similar reduction in the risk of myocardial infarction was also observed in a meta-analysis of placebo-controlled trials of carvedilol in heart failure.<br />
<br />
{|<br />
|[[File:Carvidelolfig4.JPG|400px|thumb]]<br />
|}<br />
<br />
=====Hypertension=====<br />
COREG was studied in 2 placebo‑controlled trials that utilized twice‑daily dosing, at total daily doses of 12.5 to 50 mg. In these and other trials, the starting dose did not exceed 12.5 mg. At 50 mg/day, COREG reduced sitting trough (12‑hour) blood pressure by about 9/5.5 mm Hg; at 25 mg/day the effect was about 7.5/3.5 mm Hg. Comparisons of trough to peak blood pressure showed a trough to peak ratio for blood pressure response of about 65%. Heart rate fell by about 7.5 beats/minute at 50 mg/day. In general, as is true for other β‑blockers, responses were smaller in black than non‑black subjects. There were no age‑ or gender‑related differences in response.<br />
<br />
The peak antihypertensive effect occurred 1 to 2 hours after a dose. The dose‑related blood pressure response was accompanied by a dose‑related increase in adverse effects.<br />
<br />
===Hypertension With Type 2 Diabetes Mellitus===<br />
In a double-blind trial (GEMINI), COREG, added to an ACE inhibitor or [[angiotensin receptor blocker]], was evaluated in a population with mild‑to‑moderate hypertension and well-controlled type 2 diabetes mellitus. The mean HbA1c at baseline was 7.2%. COREG was titrated to a mean dose of 17.5 mg twice daily and maintained for 5 months. COREG had no adverse effect on glycemic control, based on HbA1c measurements (mean change from baseline of 0.02%, 95% CI: ‑0.06 to 0.10, P = NS) .<br />
}}</div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=Carvedilol&diff=962280Carvedilol2014-04-03T19:11:55Z<p>Abdurahman Khalil: </p>
<hr />
<div>{{DrugProjectFormSinglePage<br />
|authorTag={{AK}}<br />
|genericName=Carvedilol<br />
|aOrAn=an<br />
|drugClass=Alpha-adrenergic blocker, Beta-adrenergic blocker<br />
|indication=Heart failure of ischemic or cardiomyopathic origin, hypertension<br />
|adverseReactions=Fatigue, hypotension, dizziness, hyperglycemia<br />
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)<br />
|fdaLIADAdult=&lt;h4&gt;Condition 1&lt;/h5&gt;<br />
<br />
* Dosing Information<br />
<br />
:: (Dosage)<br />
|contraindications=Carvedilol is '''contraindicated''' in the following conditions:<br />
<br />
:*[[Bronchial asthma]] or related bronchospastic conditions. Deaths from [[status asthmaticus]] have been reported following single doses of COREG.<br />
:*[[AV block]] (Second- or third-degree) <br />
:*[[Sick sinus syndrome]]<br />
:*Severe [[bradycardia]] (unless a permanent pacemaker is in place).<br />
:*[[Cardiogenic shock]] or who have decompensated [[heart failure]] requiring the use of intravenous [[inotropic]] therapy. Such patients should first be weaned from intravenous therapy before initiating COREG<br />
:*Severe hepatic impairment<br />
:*Serious [[hypersensitivity]] reaction (e.g., [[Stevens-Johnson syndrome]], [[anaphylactic reaction]], [[angioedema]]) to any component of this medication or other medications containing carvedilol.<br />
|warnings=*Acute exacerbation of coronary artery disease upon cessation of therapy: Do not abruptly discontinue. <br />
*Bradycardia, hypotension, fluid retention may occur. Reduce the dose as needed. <br />
<br />
*Non-allergic bronchospasm (e.g., chronic bronchitis and emphysema): Avoid β-blockers. <br />
<br />
*However, if deemed necessary, use with caution and at lowest effective dose.<br />
Diabetes: Monitor glucose as β-blockers may mask symptoms of hypoglycemia or worsen hyperglycemia. <br />
<br />
=====Cessation of Therapy=====<br />
<br />
'''Patients with [[coronary artery disease]], who are being treated with carvedilol, should be advised against abrupt discontinuation of therapy. Severe exacerbation of [[angina]] and the occurrence of [[myocardial infarction]] and [[ventricular arrhythmias]] have been reported in angina patients following the abrupt discontinuation of therapy with β-blockers. The last 2 complications may occur with or without preceding exacerbation of the angina pectoris. As with other β-blockers, when discontinuation of carvedilol is planned, the patients should be carefully observed and advised to limit physical activity to a minimum. carvedilol should be discontinued over 1 to 2 weeks whenever possible. If the angina worsens or acute coronary insufficiency develops, it is recommended that carvedilol be promptly reinstituted, at least temporarily. Because coronary artery disease is common and may be unrecognized, it may be prudent not to discontinue therapy with carvedilol abruptly even in patients treated only for hypertension or heart failure.'''<br />
<br />
===Bradycardia===<br />
<br />
In clinical trials, carvedilol caused[[ bradycardia]] in about 2% of hypertensive subjects, 9% of heart failure subjects, and 6.5% of myocardial infarction subjects with left ventricular dysfunction. If pulse rate drops below 55 beats/minute, the dosage should be reduced.<br />
<br />
=====Hypotension=====<br />
In clinical trials of primarily mild‑to‑moderate [[heart failure]], [[hypotension]] and [[postural hypotension]] occurred in 9.7% and syncope in 3.4% of subjects receiving carvedilol compared with 3.6% and 2.5% of placebo subjects, respectively. The risk for these events was highest during the first 30 days of dosing, corresponding to the up‑titration period and was a cause for discontinuation of therapy in 0.7% of subjects receiving carvedilol, compared with 0.4% of placebo subjects. In a long‑term, placebo‑controlled trial in severe heart failure (COPERNICUS), hypotension and postural hypotension occurred in 15.1% and syncope in 2.9% of heart failure subjects receiving carvedilol compared with 8.7% and 2.3% of placebo subjects, respectively. These events were a cause for discontinuation of therapy in 1.1% of subjects receiving carvedilol, compared with 0.8% of placebo subjects.<br />
<br />
Postural hypotension occurred in 1.8% and syncope in 0.1% of hypertensive subjects, primarily following the initial dose or at the time of dose increase and was a cause for discontinuation of therapy in 1% of subjects.<br />
<br />
In the CAPRICORN trial of survivors of an acute[[ myocardial infarction]], hypotension or postural hypotension occurred in 20.2% of subjects receiving carvedilol compared with 12.6% of placebo subjects. Syncope was reported in 3.9% and 1.9% of subjects, respectively. These events were a cause for discontinuation of therapy in 2.5% of subjects receiving carvedilol, compared with 0.2% of placebo subjects.<br />
<br />
Starting with a low dose, administration with food, and gradual up-titration should decrease the likelihood of syncope or excessive hypotension [see [[Carvedilol dosage and administration|Dosage and Administration]] ]. During initiation of therapy, the patient should be cautioned to avoid situations such as driving or hazardous tasks, where injury could result should syncope occur.<br />
<br />
=====Heart Failure/Fluid Retention=====<br />
Worsening heart failure or fluid retention may occur during up-titration of carvedilol. If such symptoms occur, diuretics should be increased and the carvedilol dose should not be advanced until clinical stability resumes [see Dosage and Administration (2)]. Occasionally it is necessary to lower the carvedilol dose or temporarily discontinue it. Such episodes do not preclude subsequent successful titration of, or a favorable response to, carvedilol. In a placebo-controlled trial of subjects with severe heart failure, worsening heart failure during the first 3 months was reported to a similar degree with carvedilol and with placebo. When treatment was maintained beyond 3 months, worsening heart failure was reported less frequently in subjects treated with carvedilol than with placebo. Worsening heart failure observed during long-term therapy is more likely to be related to the patients’ underlying disease than to treatment with carvedilol.<br />
<br />
=====Non-allergic Bronchospasm=====<br />
Patients with bronchospastic disease (e.g., [[chronic bronchitis]] and [[emphysema]]) should, in general, not receive β-blockers. carvedilol may be used with caution, however, in patients who do not respond to, or cannot tolerate, other antihypertensive agents. It is prudent, if carvedilol is used, to use the smallest effective dose, so that inhibition of endogenous or exogenous β-agonists is minimized.<br />
<br />
In clinical trials of subjects with heart failure, subjects with bronchospastic disease were enrolled if they did not require oral or inhaled medication to treat their bronchospastic disease. In such patients, it is recommended that carvedilol be used with caution. The dosing recommendations should be followed closely and the dose should be lowered if any evidence of bronchospasm is observed during up-titration.<br />
<br />
=====Glycemic Control in Type 2 Diabetes=====<br />
In general, β-blockers may mask some of the manifestations of hypoglycemia, particularly [[tachycardia]]. Nonselective β-blockers may potentiate insulin-induced [[hypoglycemia]] and delay recovery of serum glucose levels. Patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be cautioned about these possibilities.<br />
<br />
In heart failure patients with diabetes, carvedilol therapy may lead to worsening [[hyperglycemia]], which responds to intensification of hypoglycemic therapy. It is recommended that blood glucose be monitored when carvedilol dosing is initiated, adjusted, or discontinued. Trials designed to examine the effects of carvedilol on glycemic control in patients with diabetes and heart failure have not been conducted.<br />
<br />
In a trial designed to examine the effects of carvedilol on glycemic control in a population with mild-to-moderate hypertension and well-controlled type 2[[ diabetes mellitus]], carvedilol had no adverse effect on glycemic control, based on [[HbA1c]] measurements [see Carvidilol clinical studies|Clinical Studies]]].<br />
<br />
=====Peripheral Vascular Disease=====<br />
β-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Caution should be exercised in such individuals.<br />
<br />
=====Deterioration of Renal Function=====<br />
Rarely, use of carvedilol in patients with heart failure has resulted in deterioration of renal function. Patients at risk appear to be those with low blood pressure (systolic blood pressure <100 mm Hg), [[ischemic heart disease]] and diffuse vascular disease, and/or underlying renal insufficiency. Renal function has returned to baseline when carvedilol was stopped. In patients with these risk factors it is recommended that renal function be monitored during up-titration of carvedilol and the drug discontinued or dosage reduced if worsening of renal function occurs.<br />
<br />
===Major Surgery===<br />
Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.<br />
<br />
=====Thyrotoxicosis=====<br />
β-adrenergic blockade may mask clinical signs of [[hyperthyroidism]], such as [[tachycardia]]. Abrupt withdrawal of β-blockade may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate [[thyroid storm]].<br />
<br />
=====Pheochromocytoma=====<br />
In patients with [[pheochromocytoma]], an α-blocking agent should be initiated prior to the use of any β-blocking agent. Although carvedilol has both α- and β-blocking pharmacologic activities, there has been no experience with its use in this condition. Therefore, caution should be taken in the administration of carvedilol to patients suspected of having [[pheochromocytoma]].<br />
<br />
=====Prinzmetal’s Variant Angina=====<br />
Agents with non-selective β-blocking activity may provoke chest pain in patients with [[Prinzmetal’s]] variant angina. There has been no clinical experience with carvedilol in these patients although the α-blocking activity may prevent such symptoms. However, caution should be taken in the administration of carvedilol to patients suspected of having Prinzmetal’s variant angina.<br />
<br />
===Risk of Anaphylactic Reaction===<br />
While taking β-blockers, patients with a history of severe [[anaphylactic reaction]] to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reaction.<br />
<br />
===Intraoperative Floppy Iris Syndrome===<br />
Intraoperative Floppy Iris Syndrome (IFIS) has been observed during [[cataract]] surgery in some patients treated with [[alpha-1 blockers]] (carvedilol is an alpha/beta blocker). This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative [[miosis]] despite preoperative dilation with standard [[mydriatic]] drugs, and potential prolapse of the iris toward the phacoemulsification incisions. The patient’s ophthalmologist should be prepared for possible modifications to the surgical technique, such as utilization of iris hooks, iris dilator rings, or viscoelastic substances. There does not appear to be a benefit of stopping alpha-1 blocker therapy prior to cataract surgery.<br />
<br />
|FDAPregCat=C<br />
|useInPregnancyFDA=Studies performed in pregnant rats and rabbits given carvedilol revealed increased post-implantation loss in rats at doses of 300 mg/kg/day (50 times the maximum recommended human dose [MRHD] as mg/m2) and in rabbits at doses of 75 mg/kg/day (25 times the MRHD as mg/m2). In the rats, there was also a decrease in fetal body weight at the maternally toxic dose of 300 mg/kg/day (50 times the MRHD as mg/m2), which was accompanied by an elevation in the frequency of fetuses with delayed skeletal development (missing or stunted 13th rib). In rats the no-observed-effect level for developmental toxicity was 60 mg/kg/day (10 times the MRHD as mg/m2); in rabbits it was 15 mg/kg/day (5 times the MRHD as mg/m2). There are no adequate and well-controlled studies in pregnant women. COREG should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br />
|useInNursing=It is not known whether this drug is excreted in human milk. Studies in rats have shown that carvedilol and/or its metabolites (as well as other β-blockers) cross the placental barrier and are excreted in breast milk. There was increased mortality at one week post-partum in neonates from rats treated with 60 mg/kg/day (10 times the MRHD as mg/m2) and above during the last trimester through day 22 of lactation. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from β-blockers, especially [[bradycardia]], a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. The effects of other α- and β-blocking agents have included perinatal and neonatal distress.<br />
|useInPed=Effectiveness of carvedilol in patients younger than 18 years has not been established.<br />
<br />
In a double-blind trial, 161 children (mean age: 6 years, range: 2 months to 17 years; 45% younger than 2 years) with chronic[[ heart failure]] [NYHA class II-IV, left ventricular [[ejection fraction]] <40% for children with a systemic left ventricle (LV), and moderate-severe ventricular dysfunction qualitatively by echo for those with a systemic ventricle that was not an LV] who were receiving standard background treatment were randomized to placebo or to 2 dose levels of carvedilol. These dose levels produced placebo-corrected heart rate reduction of 4 to 6 heart beats per minute, indicative of β -blockade activity. Exposure appeared to be lower in pediatric subjects than adults. After 8 months of follow-up, there was no significant effect of treatment on clinical outcomes. Adverse reactions in this trial that occurred in greater than 10% of subjects treated with carvedilol and at twice the rate of placebo-treated subjects included chest pain (17% versus 6%), dizziness (13% versus 2%), and dyspnea (11% versus 0%).<br />
|useInGeri=Plasma levels of carvedilol average about 50% higher in the elderly compared with young subjects.<br />
<br />
Of the 765 subjects with heart failure randomized to carvedilol in US clinical trials, 31% (235) were 65 years of age or older, and 7.3% (56) were 75 years of age or older. Of the 1,156 subjects randomized to carvedilol in a long‑term, placebo‑controlled trial in severe heart failure, 47% (547) were 65 years of age or older, and 15% (174) were 75 years of age or older. Of 3,025 subjects receiving carvedilol in heart failure trials worldwide, 42% were 65 years of age or older.<br />
<br />
Of the 975 [[myocardial infarction]] subjects randomized to carvedilol in the CAPRICORN trial, 48% (468) were 65 years of age or older, and 11% (111) were 75 years of age or older.<br />
<br />
Of the 2,065 hypertensive subjects in US clinical trials of efficacy or safety who were treated with carvedilol, 21% (436) were 65 years of age or older. Of 3,722 subjects receiving carvedilol in hypertension clinical trials conducted worldwide, 24% were 65 years of age or older.<br />
<br />
With the exception of [[dizziness ]]in hypertensive subjects (incidence 8.8% in the elderly versus 6% in younger subjects), no overall differences in the safety or effectiveness (see Figures 2 and 4) were observed between the older subjects and younger subjects in each of these populations. Similarly, other reported clinical experience has not identified differences in responses between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.<br />
|useInRenalImpair=Although carvedilol is metabolized primarily by the liver, plasma concentrations of carvedilol have been reported to be increased in patients with renal impairment. Based on mean AUC data, approximately 40% to 50% higher plasma concentrations of carvedilol were observed in hypertensive subjects with moderate to severe renal impairment compared to a control group of hypertensive subjects with normal renal function. However, the ranges of AUC values were similar for both groups. Changes in mean peak plasma levels were less pronounced, approximately 12% to 26% higher in subjects with impaired renal function.<br />
<br />
Consistent with its high degree of plasma protein‑binding, carvedilol does not appear to be cleared significantly by [[hemodialysis]].<br />
|useInHepaticImpair=Compared with healthy subjects, patients with severe liver impairment ([[cirrhosis]]) exhibit a 4- to 7-fold increase in carvedilol levels. <br />
Carvedilol is contraindicated in patients with severe liver impairment.<br />
|othersTitle=Heart Failure<br />
|useInOthers=[[Steady‑state ]]plasma concentrations of carvedilol and its enantiomers increased proportionally over the 6.25 to 50 mg dose range in subjects with heart failure. Compared with healthy subjects, heart failure subjects had increased mean AUC and Cmax values for carvedilol and its enantiomers, with up to 50% to 100% higher values observed in 6 subjects with NYHA class IV heart failure. The mean apparent terminal elimination half‑life for carvedilol was similar to that observed in healthy subjects.<br />
|overdose====Acute Overdose===<br />
=====Signs and Symptoms=====<br />
Overdosage may cause severe [[hypotension]], [[bradycardia]], [[cardiac insufficiency]], [[cardiogenic shock]], and [[cardiac arrest]]. Respiratory problems, bronchospasms, vomiting, lapses of consciousness, and generalized [[seizures]] may also occur.<br />
=====Management=====<br />
:*The patient should be placed in a '''[[supine]] position''' and, where necessary and '''kept under observation'''<br />
<br />
:*The patient should be treated under intensive-care conditions. <br />
:*'''Gastric lavage''' or pharmacologically induced [[emesis]] may be used shortly after ingestion. <br />
The following agents may be '''administered for excessive [[bradycardia]]''':<br />
:* [[Atropine]], 2 mg IV.<br />
'''To support cardiovascular function:''' <br />
<br />
:*Glucagon, 5 to 10 mg IV rapidly over 30 seconds, followed by a continuous infusion of 5 mg/hour<br><br />
:*Sympathomimetics ([[dobutamine]], [[isoprenaline]], adrenaline) at doses according to body weight and effect.<br />
'''If peripheral vasodilation dominates:''' <br />
:*Administer [[adrenaline]] or[[ noradrenaline]] with continuous monitoring of circulatory conditions.<br />
'''For therapy-resistant [[bradycardia]]'''<br />
:*pacemaker therapy should be performed.<br />
'''For bronchospasm'''<br />
:*β-sympathomimetics (as aerosol or IV) or [[Aminophylline]] IV should be given. <br />
'''In the event of [[seizures]]'''<br />
:*Administer slow IV injection of [[diazepam]] or [[clonazepam]] is recommended.<br />
<br />
'''NOTE:''' In the event of severe intoxication where there are symptoms of shock, treatment with antidotes must be continued for a sufficiently '''long period of time consistent with the 7-10 hour half-life of carvedilol'''.<br />
<br />
Cases of overdosage with COREG alone or in combination with other drugs have been reported. Quantities ingested in some cases exceeded 1,000 milligrams. Symptoms experienced included low blood pressure and heart rate. '''Standard supportive treatment''' was provided and individuals recovered.<br />
|mechAction=Carvedilol is a racemic mixture in which nonselective β-adrenoreceptor blocking activity is present in the S(-) enantiomer and α1-adrenergic blocking activity is present in both R(+) and S(-) enantiomers at equal potency. Carvedilol has no intrinsic sympathomimetic activity.<br />
|PD=====Heart Failure====<br />
<br />
:*The basis for the '''beneficial effects''' of carvedilol in heart failure is '''not established.'''<br />
<br />
:*Two placebo‑controlled trials compared the acute hemodynamic effects of carvedilol with baseline measurements in 59 and 49 subjects with NYHA class II‑IV heart failure receiving [[diuretics]], [[ACE inhibitors]], and [[digitalis]]. There were significant reductions in systemic blood pressure, pulmonary artery pressure, pulmonary capillary wedge pressure, and heart rate. Initial effects on cardiac output, stroke volume index, and systemic vascular resistance were small and variable.<br />
<br />
:*These trials measured hemodynamic effects again at 12 to 14 weeks. carvedilol significantly '''reduced systemic blood pressure, pulmonary artery pressure, right atrial pressure, systemic vascular resistance, and heart rate''', while stroke volume index was increased.<br />
<br />
:*Among 839 subjects with NYHA class II‑III heart failure treated for 26 to 52 weeks in 4 US placebo‑controlled trials, average left ventricular ejection fraction (EF) measured by radionuclide ventriculography increased by 9 EF units (%) in subjects receiving carvedilol and by 2 EF units in placebo subjects at a target dose of 25 to 50 mg twice daily. <br />
<br />
:*'''The effects of carvedilol on ejection fraction were related to dose'''. <u>Doses of 6.25 mg twice daily, 12.5 mg twice daily, and 25 mg twice daily</u> were associated with placebo‑corrected increases in EF of 5 EF units, 6 EF units, and 8 EF units, respectively; each of these effects were nominally statistically significant.<br />
<br />
====Left Ventricular Dysfunction Following Myocardial Infarction====<br />
<br />
The basis for the beneficial effects of carvedilol in patients with left ventricular dysfunction following an [[acute myocardial infarction]] is not established.<br />
<br />
====Hypertension====<br />
<br />
The mechanism by which β-blockade produces an antihypertensive effect has not been established.<br />
<br />
:*β-adrenoreceptor blocking activity has been demonstrated in animal and human studies showing that carvedilol (1) reduces cardiac output in normal subjects; (2) reduces exercise- and/or [[isoproterenol]]-induced tachycardia; and (3) reduces reflex orthostatic [[tachycardia]]. Significant β-adrenoreceptor blocking effect is usually seen within 1 hour of drug administration.<br />
<br />
:*α1-adrenoreceptor blocking activity has been demonstrated in human and animal studies, showing that carvedilol (1) attenuates the pressor effects of [[phenylephrine]]; (2) causes vasodilation; and (3) reduces peripheral vascular resistance. These effects contribute to the reduction of blood pressure and usually are seen within 30 minutes of drug administration.<br />
<br />
:*Due to the α1-receptor blocking activity of carvedilol, blood pressure is lowered more in the standing than in the supine position, and symptoms of postural hypotension (1.8%), including rare instances of syncope, can occur. Following oral administration, when [[postural hypotension]] has occurred, it has been transient and is uncommon when carvedilol is administered with food at the recommended starting dose and titration increments are closely followed [see Dosage and Administration (2)].<br />
<br />
:*In hypertensive patients with normal renal function, therapeutic doses of carvedilol decreased renal vascular resistance with no change in glomerular filtration rate or renal plasma flow. Changes in excretion of sodium, potassium, uric acid, and phosphorus in hypertensive patients with normal renal function were similar after carvedilol and placebo.<br />
<br />
:*carvedilol has little effect on plasma [[catecholamines]], plasma [[aldosterone]], or electrolyte levels, but it does significantly reduce plasma renin activity when given for at least 4 weeks. It also increases levels of [[atrial natriuretic peptide]].<br />
|PK=:*carvedilol is rapidly and extensively absorbed following oral administration, with absolute bioavailability of approximately 25% to 35% due to a significant degree of first-pass metabolism. Following oral administration, the apparent mean terminal elimination half-life of carvedilol generally ranges from 7 to 10 hours. Plasma concentrations achieved are proportional to the oral dose administered. When administered with food, the rate of absorption is slowed, as evidenced by a delay in the time to reach peak plasma levels, with no significant difference in extent of bioavailability. Taking carvedilol with food should minimize the risk of[[ orthostatic hypotension]].<br />
<br />
:*'''Carvedilol is extensively metabolized'''. Following oral administration of radiolabelled carvedilol to healthy volunteers, carvedilol accounted for only about 7% of the total radioactivity in plasma as measured by area under the curve (AUC). Less than 2% of the dose was excreted unchanged in the urine. Carvedilol is metabolized primarily by aromatic ring oxidation and glucuronidation. The oxidative metabolites are further metabolized by conjugation via glucuronidation and sulfation. The metabolites of carvedilol are excreted primarily via the bile into the feces. Demethylation and hydroxylation at the phenol ring produce 3 active metabolites with β-receptor blocking activity. Based on preclinical studies, the 4'-hydroxyphenyl metabolite is approximately 13 times more potent than carvedilol for β-blockade.<br />
<br />
:*Compared with carvedilol, the 3 active metabolites exhibit weak vasodilating activity. Plasma concentrations of the active metabolites are about one-tenth of those observed for carvedilol and have pharmacokinetics similar to the parent.<br />
<br />
:*Carvedilol undergoes stereoselective first-pass metabolism with plasma levels of R(+)-carvedilol approximately 2 to 3 times higher than S(-)-carvedilol following oral administration in healthy subjects. The mean apparent terminal elimination half-lives for R(+)-carvedilol range from 5 to 9 hours compared with 7 to 11 hours for the S(-)-enantiomer.<br />
<br />
:*The primary P450 enzymes responsible for the metabolism of both R(+) and S(-)-carvedilol in human liver microsomes were CYP2D6 and CYP2C9 and to a lesser extent CYP3A4, 2C19, 1A2, and 2E1. CYP2D6 is thought to be the major enzyme in the 4’- and 5’-hydroxylation of carvedilol, with a potential contribution from 3A4. CYP2C9 is thought to be of primary importance in the O-methylation pathway of S(-)-carvedilol.<br />
<br />
:*Carvedilol is subject to the effects of genetic[[ polymorphism]] with poor metabolizers of debrisoquin (a marker for cytochrome P450 2D6) exhibiting 2- to 3-fold higher plasma concentrations of R(+)-carvedilol compared with extensive metabolizers. In contrast, plasma levels of S(-)-carvedilol are increased only about 20% to 25% in poor metabolizers, indicating this enantiomer is metabolized to a lesser extent by cytochrome P450 2D6 than R(+)-carvedilol. The pharmacokinetics of carvedilol do not appear to be different in poor metabolizers of S-mephenytoin (patients deficient in cytochrome P450 2C19).<br />
<br />
:*Carvedilol is more than 98% bound to plasma proteins, primarily with [[albumin]]. The plasma-protein binding is independent of concentration over the therapeutic range. Carvedilol is a basic, lipophilic compound with a steady-state volume of distribution of approximately 115 L, indicating substantial distribution into extravascular tissues. Plasma clearance ranges from 500 to 700 mL/min.<br />
|nonClinToxic======Carcinogenesis, Mutagenesis, Impairment of Fertility=====<br />
In 2-year studies conducted in rats given carvedilol at doses up to 75 mg/kg/day (12 times the MRHD when compared on a mg/m2 basis) or in mice given up to 200 mg/kg/day (16 times the MRHD on a mg/m2 basis), carvedilol had '''no carcinogenic effect.'''<br />
<br />
Carvedilol was negative when tested in a battery of [[genotoxicity]] assays, including the Ames and the CHO/HGPRT assays for mutagenicity and the in vitro hamster micronucleus and in vivo human lymphocyte cell tests for clastogenicity.<br />
<br />
At doses ≥200 mg/kg/day ( ≥ 32 times the MRHD as mg/m2) carvedilol was toxic to adult rats (sedation, reduced weight gain) and was associated with a reduced number of successful matings, prolonged mating time, significantly fewer corpora lutea and implants per dam, and complete resorption of 18% of the litters. <br />
The '''no-observed-effect dose''' level for overt toxicity and impairment of fertility was 60 mg/kg/day (10 times the MRHD as mg/m2).<br />
|clinicalStudies======Heart Failure====<br />
A total of 6,975 subjects with mild to severe heart failure were evaluated in placebo-controlled trials of carvedilol.<br />
<br />
=====Mild-to-Moderate Heart Failure=====<br />
Carvedilol was studied in 5 multicenter, placebo‑controlled trials, and in 1 active-controlled trial (COMET trial) involving subjects with mild-to-moderate heart failure.<br />
<br />
Four US multicenter, double‑blind, placebo‑controlled trials enrolled 1,094 subjects (696 randomized to carvedilol) with NYHA class II‑III heart failure and ejection fraction ≤0.35. The vast majority were on [[digitalis]], [[diuretics]], and an [[ACE inhibitor]] at trial entry. Patients were assigned to the trials based upon exercise ability. An Australia‑New Zealand double‑blind, placebo‑controlled trial enrolled 415 subjects (half randomized to carvedilol) with less severe heart failure. All protocols excluded subjects expected to undergo cardiac transplantation during the 7.5 to 15 months of double‑blind follow‑up. All randomized subjects had tolerated a 2‑week course on carvedilol 6.25 mg twice daily.<br />
<br />
In each trial, there was a primary end point, either progression of heart failure (1 US trial) or exercise tolerance (2 US trials meeting enrollment goals and the Australia‑New Zealand trial). There were many secondary end points specified in these trials, including NYHA classification, patient and physician global assessments, and cardiovascular hospitalization. Other analyses not prospectively planned included the sum of deaths and total cardiovascular hospitalizations. In situations where the primary end points of a trial do not show a significant benefit of treatment, assignment of significance values to the other results is complex, and such values need to be interpreted cautiously.<br />
<br />
'''The results of the US and Australia‑New Zealand trials were as follows''':<br />
<br />
:Slowing Progression of Heart Failure: One US multicenter trial (366 subjects) had as its primary end point the sum of cardiovascular mortality, cardiovascular hospitalization, and sustained increase in heart failure medications. Heart failure progression was reduced, during an average follow‑up of 7 months, by 48% (P = 0.008).<br />
<br />
:In the Australia‑New Zealand trial, death and total hospitalizations were reduced by about 25% over 18 to 24 months. In the 3 largest US trials, death and total hospitalizations were reduced by 19%, 39%, and 49%, nominally statistically significant in the last 2 trials. The Australia‑New Zealand results were statistically borderline.<br />
<br />
:Functional Measures: None of the multicenter trials had NYHA classification as a primary end point, but all such trials had it as a secondary end point. There was at least a trend toward improvement in NYHA class in all trials. Exercise tolerance was the primary end point in 3 trials; in none was a statistically significant effect found.<br />
<br />
:Subjective Measures: Health-related quality of life, as measured with a standard questionnaire (a primary end point in 1 trials), was unaffected by carvedilol. However, patients’ and investigators’ global assessments showed significant improvement in most trials.<br />
<br />
:Mortality: Death was not a pre-specified end point in any trial, but was analyzed in all trials. Overall, in these 4 US trials, mortality was reduced, nominally significantly so in 2 trials.<br />
<br />
======COMET Trial======<br />
In this double-blind trial, 3,029 subjects with NYHA class II-IV heart failure (left ventricular ejection fraction ≤35%) were randomized to receive either carvedilol (target dose: 25 mg twice daily) or immediate-release [[metoprolol]] tartrate (target dose: 50 mg twice daily). The mean age of the subjects was approximately 62 years, 80% were males, and the mean left ventricular [[ejection fraction]] at baseline was 26%. Approximately 96% of the subjects had NYHA class II or III heart failure. Concomitant treatment included diuretics (99%), ACE inhibitors (91%), digitalis (59%), [[aldosterone]]antagonists (11%), and “[[statin]]” lipid-lowering agents (21%). The mean duration of follow-up was 4.8 years. The mean dose of carvedilol was 42 mg per day.<br />
<br />
The trial had 2 primary end points: all-cause mortality and the composite of death plus hospitalization for any reason. The results of COMET are presented in Table 3 below. All-cause mortality carried most of the statistical weight and was the primary determinant of the trial size. All-cause mortality was 34% in the subjects treated with carvedilol and was 40% in the immediate-release metoprolol group (P = 0.0017; hazard ratio = 0.83, 95%CI: 0.74 to 0.93). The effect on mortality was primarily due to a reduction in cardiovascular death. The difference between the 2 groups with respect to the composite end point was not significant (P = 0.122). The estimated mean survival was 8.0 years with carvedilol and 6.6 years with immediate-release metoprolol.<br />
{|<br />
|[[File:Carvidelolt3.JPG|600px|thumb]]<br />
|}<br />
<br />
It is not known whether this formulation of metoprolol at any dose or this low dose of [[metoprolol]] in any formulation has any effect on survival or hospitalization in patients with heart failure. Thus, this trial extends the time over which carvedilol manifests benefits on survival in heart failure, but it is not evidence that carvedilol improves outcome over the formulation of metoprolol (TOPROL-XL®) with benefits in[[ heart failure]].<br />
<br />
=====Severe Heart Failure(COPERNICUS)=====<br />
<br />
In a double-blind trial (COPERNICUS), 2,289 subjects with heart failure at rest or with minimal exertion and left ventricular [[ejection fraction]] <25% (mean 20%), despite digitalis (66%), diuretics (99%), and ACE inhibitors (89%) were randomized to placebo or carvedilol. Carvedilol was titrated from a starting dose of 3.125 mg twice daily to the maximum tolerated dose or up to 25 mg twice daily over a minimum of 6 weeks. Most subjects achieved the target dose of 25 mg. The trial was conducted in Eastern and Western Europe, the United States, Israel, and Canada. Similar numbers of subjects per group (about 100) withdrew during the titration period.<br />
<br />
The primary end point of the trial was all‑cause mortality, but cause‑specific mortality and the risk of death or hospitalization (total, cardiovascular [CV], or heart failure [HF]) were also examined. The developing trial data were followed by a data monitoring committee, and mortality analyses were adjusted for these multiple looks. The trial was stopped after a median follow‑up of 10 months because of an observed 35% reduction in mortality (from 19.7% per patient-year on placebo to 12.8% on carvedilol, hazard ratio 0.65, 95% CI: 0.52 to 0.81, P = 0.0014, adjusted) (see Figure 1). The results of COPERNICUS are shown in Table 4.<br />
<br />
{|<br />
|[[File:Carvidelolt4.JPG|600px|thumb]]<br />
|}<br />
<br />
The effect on mortality was principally the result of a reduction in the rate of sudden death among subjects without worsening heart failure.<br />
<br />
Patients' global assessments, in which carvedilol‑treated subjects were compared with placebo, were based on pre-specified, periodic patient self-assessments regarding whether clinical status post-treatment showed improvement, worsening or no change compared with baseline. Subjects treated with carvedilol showed significant improvements in global assessments compared with those treated with placebo in COPERNICUS.<br />
<br />
The protocol also specified that hospitalizations would be assessed. Fewer subjects on COREG than on placebo were hospitalized for any reason (372 versus 432, P = 0.0029), for cardiovascular reasons (246 versus 314, P = 0.0003), or for worsening heart failure (198 versus 268, P = 0.0001).<br />
<br />
COREG had a consistent and beneficial effect on all‑cause mortality as well as the combined end points of all‑cause mortality plus hospitalization (total, CV, or for heart failure) in the overall trial population and in all subgroups examined, including men and women, elderly and non‑elderly, blacks and non‑blacks, and diabetics and non-diabetics (see Figure 2).<br />
<br />
{|<br />
|[[File:Carvidelolfig2.JPG|600px|thumb]]<br />
|}<br />
<br />
=====Left Ventricular Dysfunction Following Myocardial Infarction=====<br />
====CAPRICORN Trial====<br />
<br />
CAPRICORN was a double‑blind trial comparing carvedilol and placebo in 1,959 subjects with a recent myocardial infarction (within 21 days) and left ventricular ejection fraction of ≤40%, with (47%) or without symptoms of heart failure. Subjects given carvedilol received 6.25 mg twice daily, titrated as tolerated to 25 mg twice daily. Subjects had to have a systolic blood pressure >90 mm Hg, a sitting heart rate >60 beats/minute, and no contraindication to β‑blocker use. Treatment of the index infarction included aspirin (85%), IV or oral β‑blockers (37%), nitrates (73%), heparin (64%), thrombolytics (40%), and acute angioplasty (12%). Background treatment included ACE inhibitors or angiotensin receptor blockers (97%), anticoagulants (20%), lipid‑lowering agents (23%), and diuretics (34%). Baseline population characteristics included an average age of 63 years, 74% male, 95% Caucasian, mean blood pressure 121/74 mm Hg, 22% with diabetes, and 54% with a history of hypertension. Mean dosage achieved of carvedilol was 20 mg twice daily; mean duration of follow‑up was 15 months.<br />
<br />
All‑cause mortality was 15% in the placebo group and 12% in the carvedilol group, indicating a 23% risk reduction in subjects treated with carvedilol (95% CI: 2% to 40%, P = 0.03), as shown in Figure 3. The effects on mortality in various subgroups are shown in Figure 4. Nearly all deaths were cardiovascular (which were reduced by 25% by carvedilol), and most of these deaths were sudden or related to pump failure (both types of death were reduced by carvedilol).Another trial end point, total mortality and all-cause hospitalization, did not show a significant improvement.<br />
<br />
There was also a significant 40% reduction in fatal or non-fatal myocardial infarction observed in the group treated with carvedilol (95% CI: 11% to 60%, P = 0.01). A similar reduction in the risk of myocardial infarction was also observed in a meta-analysis of placebo-controlled trials of carvedilol in heart failure.<br />
<br />
{|<br />
|[[File:Carvidelolfig4.JPG|400px|thumb]]<br />
|}<br />
<br />
=====Hypertension=====<br />
COREG was studied in 2 placebo‑controlled trials that utilized twice‑daily dosing, at total daily doses of 12.5 to 50 mg. In these and other trials, the starting dose did not exceed 12.5 mg. At 50 mg/day, COREG reduced sitting trough (12‑hour) blood pressure by about 9/5.5 mm Hg; at 25 mg/day the effect was about 7.5/3.5 mm Hg. Comparisons of trough to peak blood pressure showed a trough to peak ratio for blood pressure response of about 65%. Heart rate fell by about 7.5 beats/minute at 50 mg/day. In general, as is true for other β‑blockers, responses were smaller in black than non‑black subjects. There were no age‑ or gender‑related differences in response.<br />
<br />
The peak antihypertensive effect occurred 1 to 2 hours after a dose. The dose‑related blood pressure response was accompanied by a dose‑related increase in adverse effects.<br />
<br />
===Hypertension With Type 2 Diabetes Mellitus===<br />
In a double-blind trial (GEMINI), COREG, added to an ACE inhibitor or [[angiotensin receptor blocker]], was evaluated in a population with mild‑to‑moderate hypertension and well-controlled type 2 diabetes mellitus. The mean HbA1c at baseline was 7.2%. COREG was titrated to a mean dose of 17.5 mg twice daily and maintained for 5 months. COREG had no adverse effect on glycemic control, based on HbA1c measurements (mean change from baseline of 0.02%, 95% CI: ‑0.06 to 0.10, P = NS) .<br />
}}</div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=Carvedilol&diff=962274Carvedilol2014-04-03T18:51:34Z<p>Abdurahman Khalil: </p>
<hr />
<div>{{DrugProjectFormSinglePage<br />
|authorTag={{AK}}<br />
|genericName=Carvedilol<br />
|aOrAn=an<br />
|drugClass=Alpha-adrenergic blocker, Beta-adrenergic blocker<br />
|indication=Heart failure of ischemic or cardiomyopathic origin, hypertension<br />
|adverseReactions=Fatigue, hypotension, dizziness, hyperglycemia<br />
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)<br />
|fdaLIADAdult=&lt;h4&gt;Condition 1&lt;/h5&gt;<br />
<br />
* Dosing Information<br />
<br />
:: (Dosage)<br />
|FDAPregCat=C<br />
|useInPregnancyFDA=Studies performed in pregnant rats and rabbits given carvedilol revealed increased post-implantation loss in rats at doses of 300 mg/kg/day (50 times the maximum recommended human dose [MRHD] as mg/m2) and in rabbits at doses of 75 mg/kg/day (25 times the MRHD as mg/m2). In the rats, there was also a decrease in fetal body weight at the maternally toxic dose of 300 mg/kg/day (50 times the MRHD as mg/m2), which was accompanied by an elevation in the frequency of fetuses with delayed skeletal development (missing or stunted 13th rib). In rats the no-observed-effect level for developmental toxicity was 60 mg/kg/day (10 times the MRHD as mg/m2); in rabbits it was 15 mg/kg/day (5 times the MRHD as mg/m2). There are no adequate and well-controlled studies in pregnant women. COREG should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br />
|useInNursing=It is not known whether this drug is excreted in human milk. Studies in rats have shown that carvedilol and/or its metabolites (as well as other β-blockers) cross the placental barrier and are excreted in breast milk. There was increased mortality at one week post-partum in neonates from rats treated with 60 mg/kg/day (10 times the MRHD as mg/m2) and above during the last trimester through day 22 of lactation. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from β-blockers, especially [[bradycardia]], a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. The effects of other α- and β-blocking agents have included perinatal and neonatal distress.<br />
|useInPed=Effectiveness of carvedilol in patients younger than 18 years has not been established.<br />
<br />
In a double-blind trial, 161 children (mean age: 6 years, range: 2 months to 17 years; 45% younger than 2 years) with chronic[[ heart failure]] [NYHA class II-IV, left ventricular [[ejection fraction]] <40% for children with a systemic left ventricle (LV), and moderate-severe ventricular dysfunction qualitatively by echo for those with a systemic ventricle that was not an LV] who were receiving standard background treatment were randomized to placebo or to 2 dose levels of carvedilol. These dose levels produced placebo-corrected heart rate reduction of 4 to 6 heart beats per minute, indicative of β -blockade activity. Exposure appeared to be lower in pediatric subjects than adults. After 8 months of follow-up, there was no significant effect of treatment on clinical outcomes. Adverse reactions in this trial that occurred in greater than 10% of subjects treated with carvedilol and at twice the rate of placebo-treated subjects included chest pain (17% versus 6%), dizziness (13% versus 2%), and dyspnea (11% versus 0%).<br />
|useInGeri=Plasma levels of carvedilol average about 50% higher in the elderly compared with young subjects.<br />
<br />
Of the 765 subjects with heart failure randomized to carvedilol in US clinical trials, 31% (235) were 65 years of age or older, and 7.3% (56) were 75 years of age or older. Of the 1,156 subjects randomized to carvedilol in a long‑term, placebo‑controlled trial in severe heart failure, 47% (547) were 65 years of age or older, and 15% (174) were 75 years of age or older. Of 3,025 subjects receiving carvedilol in heart failure trials worldwide, 42% were 65 years of age or older.<br />
<br />
Of the 975 [[myocardial infarction]] subjects randomized to carvedilol in the CAPRICORN trial, 48% (468) were 65 years of age or older, and 11% (111) were 75 years of age or older.<br />
<br />
Of the 2,065 hypertensive subjects in US clinical trials of efficacy or safety who were treated with carvedilol, 21% (436) were 65 years of age or older. Of 3,722 subjects receiving carvedilol in hypertension clinical trials conducted worldwide, 24% were 65 years of age or older.<br />
<br />
With the exception of [[dizziness ]]in hypertensive subjects (incidence 8.8% in the elderly versus 6% in younger subjects), no overall differences in the safety or effectiveness (see Figures 2 and 4) were observed between the older subjects and younger subjects in each of these populations. Similarly, other reported clinical experience has not identified differences in responses between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.<br />
|useInRenalImpair=Although carvedilol is metabolized primarily by the liver, plasma concentrations of carvedilol have been reported to be increased in patients with renal impairment. Based on mean AUC data, approximately 40% to 50% higher plasma concentrations of carvedilol were observed in hypertensive subjects with moderate to severe renal impairment compared to a control group of hypertensive subjects with normal renal function. However, the ranges of AUC values were similar for both groups. Changes in mean peak plasma levels were less pronounced, approximately 12% to 26% higher in subjects with impaired renal function.<br />
<br />
Consistent with its high degree of plasma protein‑binding, carvedilol does not appear to be cleared significantly by [[hemodialysis]].<br />
|useInHepaticImpair=Compared with healthy subjects, patients with severe liver impairment ([[cirrhosis]]) exhibit a 4- to 7-fold increase in carvedilol levels. <br />
Carvedilol is contraindicated in patients with severe liver impairment.<br />
|othersTitle=Heart Failure<br />
|useInOthers=[[Steady‑state ]]plasma concentrations of carvedilol and its enantiomers increased proportionally over the 6.25 to 50 mg dose range in subjects with heart failure. Compared with healthy subjects, heart failure subjects had increased mean AUC and Cmax values for carvedilol and its enantiomers, with up to 50% to 100% higher values observed in 6 subjects with NYHA class IV heart failure. The mean apparent terminal elimination half‑life for carvedilol was similar to that observed in healthy subjects.<br />
|overdose====Acute Overdose===<br />
=====Signs and Symptoms=====<br />
Overdosage may cause severe [[hypotension]], [[bradycardia]], [[cardiac insufficiency]], [[cardiogenic shock]], and [[cardiac arrest]]. Respiratory problems, bronchospasms, vomiting, lapses of consciousness, and generalized [[seizures]] may also occur.<br />
=====Management=====<br />
:*The patient should be placed in a '''[[supine]] position''' and, where necessary and '''kept under observation'''<br />
<br />
:*The patient should be treated under intensive-care conditions. <br />
:*'''Gastric lavage''' or pharmacologically induced [[emesis]] may be used shortly after ingestion. <br />
The following agents may be '''administered for excessive [[bradycardia]]''':<br />
:* [[Atropine]], 2 mg IV.<br />
'''To support cardiovascular function:''' <br />
<br />
:*Glucagon, 5 to 10 mg IV rapidly over 30 seconds, followed by a continuous infusion of 5 mg/hour<br><br />
:*Sympathomimetics ([[dobutamine]], [[isoprenaline]], adrenaline) at doses according to body weight and effect.<br />
'''If peripheral vasodilation dominates:''' <br />
:*Administer [[adrenaline]] or[[ noradrenaline]] with continuous monitoring of circulatory conditions.<br />
'''For therapy-resistant [[bradycardia]]'''<br />
:*pacemaker therapy should be performed.<br />
'''For bronchospasm'''<br />
:*β-sympathomimetics (as aerosol or IV) or [[Aminophylline]] IV should be given. <br />
'''In the event of [[seizures]]'''<br />
:*Administer slow IV injection of [[diazepam]] or [[clonazepam]] is recommended.<br />
<br />
'''NOTE:''' In the event of severe intoxication where there are symptoms of shock, treatment with antidotes must be continued for a sufficiently '''long period of time consistent with the 7-10 hour half-life of carvedilol'''.<br />
<br />
Cases of overdosage with COREG alone or in combination with other drugs have been reported. Quantities ingested in some cases exceeded 1,000 milligrams. Symptoms experienced included low blood pressure and heart rate. '''Standard supportive treatment''' was provided and individuals recovered.<br />
|mechAction=Carvedilol is a racemic mixture in which nonselective β-adrenoreceptor blocking activity is present in the S(-) enantiomer and α1-adrenergic blocking activity is present in both R(+) and S(-) enantiomers at equal potency. Carvedilol has no intrinsic sympathomimetic activity.<br />
|PD=====Heart Failure====<br />
<br />
:*The basis for the '''beneficial effects''' of carvedilol in heart failure is '''not established.'''<br />
<br />
:*Two placebo‑controlled trials compared the acute hemodynamic effects of carvedilol with baseline measurements in 59 and 49 subjects with NYHA class II‑IV heart failure receiving [[diuretics]], [[ACE inhibitors]], and [[digitalis]]. There were significant reductions in systemic blood pressure, pulmonary artery pressure, pulmonary capillary wedge pressure, and heart rate. Initial effects on cardiac output, stroke volume index, and systemic vascular resistance were small and variable.<br />
<br />
:*These trials measured hemodynamic effects again at 12 to 14 weeks. carvedilol significantly '''reduced systemic blood pressure, pulmonary artery pressure, right atrial pressure, systemic vascular resistance, and heart rate''', while stroke volume index was increased.<br />
<br />
:*Among 839 subjects with NYHA class II‑III heart failure treated for 26 to 52 weeks in 4 US placebo‑controlled trials, average left ventricular ejection fraction (EF) measured by radionuclide ventriculography increased by 9 EF units (%) in subjects receiving carvedilol and by 2 EF units in placebo subjects at a target dose of 25 to 50 mg twice daily. <br />
<br />
:*'''The effects of carvedilol on ejection fraction were related to dose'''. <u>Doses of 6.25 mg twice daily, 12.5 mg twice daily, and 25 mg twice daily</u> were associated with placebo‑corrected increases in EF of 5 EF units, 6 EF units, and 8 EF units, respectively; each of these effects were nominally statistically significant.<br />
<br />
====Left Ventricular Dysfunction Following Myocardial Infarction====<br />
<br />
The basis for the beneficial effects of carvedilol in patients with left ventricular dysfunction following an [[acute myocardial infarction]] is not established.<br />
<br />
====Hypertension====<br />
<br />
The mechanism by which β-blockade produces an antihypertensive effect has not been established.<br />
<br />
:*β-adrenoreceptor blocking activity has been demonstrated in animal and human studies showing that carvedilol (1) reduces cardiac output in normal subjects; (2) reduces exercise- and/or [[isoproterenol]]-induced tachycardia; and (3) reduces reflex orthostatic [[tachycardia]]. Significant β-adrenoreceptor blocking effect is usually seen within 1 hour of drug administration.<br />
<br />
:*α1-adrenoreceptor blocking activity has been demonstrated in human and animal studies, showing that carvedilol (1) attenuates the pressor effects of [[phenylephrine]]; (2) causes vasodilation; and (3) reduces peripheral vascular resistance. These effects contribute to the reduction of blood pressure and usually are seen within 30 minutes of drug administration.<br />
<br />
:*Due to the α1-receptor blocking activity of carvedilol, blood pressure is lowered more in the standing than in the supine position, and symptoms of postural hypotension (1.8%), including rare instances of syncope, can occur. Following oral administration, when [[postural hypotension]] has occurred, it has been transient and is uncommon when carvedilol is administered with food at the recommended starting dose and titration increments are closely followed [see Dosage and Administration (2)].<br />
<br />
:*In hypertensive patients with normal renal function, therapeutic doses of carvedilol decreased renal vascular resistance with no change in glomerular filtration rate or renal plasma flow. Changes in excretion of sodium, potassium, uric acid, and phosphorus in hypertensive patients with normal renal function were similar after carvedilol and placebo.<br />
<br />
:*carvedilol has little effect on plasma [[catecholamines]], plasma [[aldosterone]], or electrolyte levels, but it does significantly reduce plasma renin activity when given for at least 4 weeks. It also increases levels of [[atrial natriuretic peptide]].<br />
|PK=:*carvedilol is rapidly and extensively absorbed following oral administration, with absolute bioavailability of approximately 25% to 35% due to a significant degree of first-pass metabolism. Following oral administration, the apparent mean terminal elimination half-life of carvedilol generally ranges from 7 to 10 hours. Plasma concentrations achieved are proportional to the oral dose administered. When administered with food, the rate of absorption is slowed, as evidenced by a delay in the time to reach peak plasma levels, with no significant difference in extent of bioavailability. Taking carvedilol with food should minimize the risk of[[ orthostatic hypotension]].<br />
<br />
:*'''Carvedilol is extensively metabolized'''. Following oral administration of radiolabelled carvedilol to healthy volunteers, carvedilol accounted for only about 7% of the total radioactivity in plasma as measured by area under the curve (AUC). Less than 2% of the dose was excreted unchanged in the urine. Carvedilol is metabolized primarily by aromatic ring oxidation and glucuronidation. The oxidative metabolites are further metabolized by conjugation via glucuronidation and sulfation. The metabolites of carvedilol are excreted primarily via the bile into the feces. Demethylation and hydroxylation at the phenol ring produce 3 active metabolites with β-receptor blocking activity. Based on preclinical studies, the 4'-hydroxyphenyl metabolite is approximately 13 times more potent than carvedilol for β-blockade.<br />
<br />
:*Compared with carvedilol, the 3 active metabolites exhibit weak vasodilating activity. Plasma concentrations of the active metabolites are about one-tenth of those observed for carvedilol and have pharmacokinetics similar to the parent.<br />
<br />
:*Carvedilol undergoes stereoselective first-pass metabolism with plasma levels of R(+)-carvedilol approximately 2 to 3 times higher than S(-)-carvedilol following oral administration in healthy subjects. The mean apparent terminal elimination half-lives for R(+)-carvedilol range from 5 to 9 hours compared with 7 to 11 hours for the S(-)-enantiomer.<br />
<br />
:*The primary P450 enzymes responsible for the metabolism of both R(+) and S(-)-carvedilol in human liver microsomes were CYP2D6 and CYP2C9 and to a lesser extent CYP3A4, 2C19, 1A2, and 2E1. CYP2D6 is thought to be the major enzyme in the 4’- and 5’-hydroxylation of carvedilol, with a potential contribution from 3A4. CYP2C9 is thought to be of primary importance in the O-methylation pathway of S(-)-carvedilol.<br />
<br />
:*Carvedilol is subject to the effects of genetic[[ polymorphism]] with poor metabolizers of debrisoquin (a marker for cytochrome P450 2D6) exhibiting 2- to 3-fold higher plasma concentrations of R(+)-carvedilol compared with extensive metabolizers. In contrast, plasma levels of S(-)-carvedilol are increased only about 20% to 25% in poor metabolizers, indicating this enantiomer is metabolized to a lesser extent by cytochrome P450 2D6 than R(+)-carvedilol. The pharmacokinetics of carvedilol do not appear to be different in poor metabolizers of S-mephenytoin (patients deficient in cytochrome P450 2C19).<br />
<br />
:*Carvedilol is more than 98% bound to plasma proteins, primarily with [[albumin]]. The plasma-protein binding is independent of concentration over the therapeutic range. Carvedilol is a basic, lipophilic compound with a steady-state volume of distribution of approximately 115 L, indicating substantial distribution into extravascular tissues. Plasma clearance ranges from 500 to 700 mL/min.<br />
|nonClinToxic======Carcinogenesis, Mutagenesis, Impairment of Fertility=====<br />
In 2-year studies conducted in rats given carvedilol at doses up to 75 mg/kg/day (12 times the MRHD when compared on a mg/m2 basis) or in mice given up to 200 mg/kg/day (16 times the MRHD on a mg/m2 basis), carvedilol had '''no carcinogenic effect.'''<br />
<br />
Carvedilol was negative when tested in a battery of [[genotoxicity]] assays, including the Ames and the CHO/HGPRT assays for mutagenicity and the in vitro hamster micronucleus and in vivo human lymphocyte cell tests for clastogenicity.<br />
<br />
At doses ≥200 mg/kg/day ( ≥ 32 times the MRHD as mg/m2) carvedilol was toxic to adult rats (sedation, reduced weight gain) and was associated with a reduced number of successful matings, prolonged mating time, significantly fewer corpora lutea and implants per dam, and complete resorption of 18% of the litters. <br />
The '''no-observed-effect dose''' level for overt toxicity and impairment of fertility was 60 mg/kg/day (10 times the MRHD as mg/m2).<br />
|clinicalStudies======Heart Failure====<br />
A total of 6,975 subjects with mild to severe heart failure were evaluated in placebo-controlled trials of carvedilol.<br />
<br />
=====Mild-to-Moderate Heart Failure=====<br />
Carvedilol was studied in 5 multicenter, placebo‑controlled trials, and in 1 active-controlled trial (COMET trial) involving subjects with mild-to-moderate heart failure.<br />
<br />
Four US multicenter, double‑blind, placebo‑controlled trials enrolled 1,094 subjects (696 randomized to carvedilol) with NYHA class II‑III heart failure and ejection fraction ≤0.35. The vast majority were on [[digitalis]], [[diuretics]], and an [[ACE inhibitor]] at trial entry. Patients were assigned to the trials based upon exercise ability. An Australia‑New Zealand double‑blind, placebo‑controlled trial enrolled 415 subjects (half randomized to carvedilol) with less severe heart failure. All protocols excluded subjects expected to undergo cardiac transplantation during the 7.5 to 15 months of double‑blind follow‑up. All randomized subjects had tolerated a 2‑week course on carvedilol 6.25 mg twice daily.<br />
<br />
In each trial, there was a primary end point, either progression of heart failure (1 US trial) or exercise tolerance (2 US trials meeting enrollment goals and the Australia‑New Zealand trial). There were many secondary end points specified in these trials, including NYHA classification, patient and physician global assessments, and cardiovascular hospitalization. Other analyses not prospectively planned included the sum of deaths and total cardiovascular hospitalizations. In situations where the primary end points of a trial do not show a significant benefit of treatment, assignment of significance values to the other results is complex, and such values need to be interpreted cautiously.<br />
<br />
'''The results of the US and Australia‑New Zealand trials were as follows''':<br />
<br />
:Slowing Progression of Heart Failure: One US multicenter trial (366 subjects) had as its primary end point the sum of cardiovascular mortality, cardiovascular hospitalization, and sustained increase in heart failure medications. Heart failure progression was reduced, during an average follow‑up of 7 months, by 48% (P = 0.008).<br />
<br />
:In the Australia‑New Zealand trial, death and total hospitalizations were reduced by about 25% over 18 to 24 months. In the 3 largest US trials, death and total hospitalizations were reduced by 19%, 39%, and 49%, nominally statistically significant in the last 2 trials. The Australia‑New Zealand results were statistically borderline.<br />
<br />
:Functional Measures: None of the multicenter trials had NYHA classification as a primary end point, but all such trials had it as a secondary end point. There was at least a trend toward improvement in NYHA class in all trials. Exercise tolerance was the primary end point in 3 trials; in none was a statistically significant effect found.<br />
<br />
:Subjective Measures: Health-related quality of life, as measured with a standard questionnaire (a primary end point in 1 trials), was unaffected by carvedilol. However, patients’ and investigators’ global assessments showed significant improvement in most trials.<br />
<br />
:Mortality: Death was not a pre-specified end point in any trial, but was analyzed in all trials. Overall, in these 4 US trials, mortality was reduced, nominally significantly so in 2 trials.<br />
<br />
======COMET Trial======<br />
In this double-blind trial, 3,029 subjects with NYHA class II-IV heart failure (left ventricular ejection fraction ≤35%) were randomized to receive either carvedilol (target dose: 25 mg twice daily) or immediate-release [[metoprolol]] tartrate (target dose: 50 mg twice daily). The mean age of the subjects was approximately 62 years, 80% were males, and the mean left ventricular [[ejection fraction]] at baseline was 26%. Approximately 96% of the subjects had NYHA class II or III heart failure. Concomitant treatment included diuretics (99%), ACE inhibitors (91%), digitalis (59%), [[aldosterone]]antagonists (11%), and “[[statin]]” lipid-lowering agents (21%). The mean duration of follow-up was 4.8 years. The mean dose of carvedilol was 42 mg per day.<br />
<br />
The trial had 2 primary end points: all-cause mortality and the composite of death plus hospitalization for any reason. The results of COMET are presented in Table 3 below. All-cause mortality carried most of the statistical weight and was the primary determinant of the trial size. All-cause mortality was 34% in the subjects treated with carvedilol and was 40% in the immediate-release metoprolol group (P = 0.0017; hazard ratio = 0.83, 95%CI: 0.74 to 0.93). The effect on mortality was primarily due to a reduction in cardiovascular death. The difference between the 2 groups with respect to the composite end point was not significant (P = 0.122). The estimated mean survival was 8.0 years with carvedilol and 6.6 years with immediate-release metoprolol.<br />
{|<br />
|[[File:Carvidelolt3.JPG|600px|thumb]]<br />
|}<br />
<br />
It is not known whether this formulation of metoprolol at any dose or this low dose of [[metoprolol]] in any formulation has any effect on survival or hospitalization in patients with heart failure. Thus, this trial extends the time over which carvedilol manifests benefits on survival in heart failure, but it is not evidence that carvedilol improves outcome over the formulation of metoprolol (TOPROL-XL®) with benefits in[[ heart failure]].<br />
<br />
=====Severe Heart Failure(COPERNICUS)=====<br />
<br />
In a double-blind trial (COPERNICUS), 2,289 subjects with heart failure at rest or with minimal exertion and left ventricular [[ejection fraction]] <25% (mean 20%), despite digitalis (66%), diuretics (99%), and ACE inhibitors (89%) were randomized to placebo or carvedilol. Carvedilol was titrated from a starting dose of 3.125 mg twice daily to the maximum tolerated dose or up to 25 mg twice daily over a minimum of 6 weeks. Most subjects achieved the target dose of 25 mg. The trial was conducted in Eastern and Western Europe, the United States, Israel, and Canada. Similar numbers of subjects per group (about 100) withdrew during the titration period.<br />
<br />
The primary end point of the trial was all‑cause mortality, but cause‑specific mortality and the risk of death or hospitalization (total, cardiovascular [CV], or heart failure [HF]) were also examined. The developing trial data were followed by a data monitoring committee, and mortality analyses were adjusted for these multiple looks. The trial was stopped after a median follow‑up of 10 months because of an observed 35% reduction in mortality (from 19.7% per patient-year on placebo to 12.8% on carvedilol, hazard ratio 0.65, 95% CI: 0.52 to 0.81, P = 0.0014, adjusted) (see Figure 1). The results of COPERNICUS are shown in Table 4.<br />
<br />
{|<br />
|[[File:Carvidelolt4.JPG|600px|thumb]]<br />
|}<br />
<br />
The effect on mortality was principally the result of a reduction in the rate of sudden death among subjects without worsening heart failure.<br />
<br />
Patients' global assessments, in which carvedilol‑treated subjects were compared with placebo, were based on pre-specified, periodic patient self-assessments regarding whether clinical status post-treatment showed improvement, worsening or no change compared with baseline. Subjects treated with carvedilol showed significant improvements in global assessments compared with those treated with placebo in COPERNICUS.<br />
<br />
The protocol also specified that hospitalizations would be assessed. Fewer subjects on COREG than on placebo were hospitalized for any reason (372 versus 432, P = 0.0029), for cardiovascular reasons (246 versus 314, P = 0.0003), or for worsening heart failure (198 versus 268, P = 0.0001).<br />
<br />
COREG had a consistent and beneficial effect on all‑cause mortality as well as the combined end points of all‑cause mortality plus hospitalization (total, CV, or for heart failure) in the overall trial population and in all subgroups examined, including men and women, elderly and non‑elderly, blacks and non‑blacks, and diabetics and non-diabetics (see Figure 2).<br />
<br />
{|<br />
|[[File:Carvidelolfig2.JPG|600px|thumb]]<br />
|}<br />
<br />
=====Left Ventricular Dysfunction Following Myocardial Infarction=====<br />
====CAPRICORN Trial====<br />
<br />
CAPRICORN was a double‑blind trial comparing carvedilol and placebo in 1,959 subjects with a recent myocardial infarction (within 21 days) and left ventricular ejection fraction of ≤40%, with (47%) or without symptoms of heart failure. Subjects given carvedilol received 6.25 mg twice daily, titrated as tolerated to 25 mg twice daily. Subjects had to have a systolic blood pressure >90 mm Hg, a sitting heart rate >60 beats/minute, and no contraindication to β‑blocker use. Treatment of the index infarction included aspirin (85%), IV or oral β‑blockers (37%), nitrates (73%), heparin (64%), thrombolytics (40%), and acute angioplasty (12%). Background treatment included ACE inhibitors or angiotensin receptor blockers (97%), anticoagulants (20%), lipid‑lowering agents (23%), and diuretics (34%). Baseline population characteristics included an average age of 63 years, 74% male, 95% Caucasian, mean blood pressure 121/74 mm Hg, 22% with diabetes, and 54% with a history of hypertension. Mean dosage achieved of carvedilol was 20 mg twice daily; mean duration of follow‑up was 15 months.<br />
<br />
All‑cause mortality was 15% in the placebo group and 12% in the carvedilol group, indicating a 23% risk reduction in subjects treated with carvedilol (95% CI: 2% to 40%, P = 0.03), as shown in Figure 3. The effects on mortality in various subgroups are shown in Figure 4. Nearly all deaths were cardiovascular (which were reduced by 25% by carvedilol), and most of these deaths were sudden or related to pump failure (both types of death were reduced by carvedilol).Another trial end point, total mortality and all-cause hospitalization, did not show a significant improvement.<br />
<br />
There was also a significant 40% reduction in fatal or non-fatal myocardial infarction observed in the group treated with carvedilol (95% CI: 11% to 60%, P = 0.01). A similar reduction in the risk of myocardial infarction was also observed in a meta-analysis of placebo-controlled trials of carvedilol in heart failure.<br />
<br />
{|<br />
|[[File:Carvidelolfig4.JPG|400px|thumb]]<br />
|}<br />
<br />
=====Hypertension=====<br />
COREG was studied in 2 placebo‑controlled trials that utilized twice‑daily dosing, at total daily doses of 12.5 to 50 mg. In these and other trials, the starting dose did not exceed 12.5 mg. At 50 mg/day, COREG reduced sitting trough (12‑hour) blood pressure by about 9/5.5 mm Hg; at 25 mg/day the effect was about 7.5/3.5 mm Hg. Comparisons of trough to peak blood pressure showed a trough to peak ratio for blood pressure response of about 65%. Heart rate fell by about 7.5 beats/minute at 50 mg/day. In general, as is true for other β‑blockers, responses were smaller in black than non‑black subjects. There were no age‑ or gender‑related differences in response.<br />
<br />
The peak antihypertensive effect occurred 1 to 2 hours after a dose. The dose‑related blood pressure response was accompanied by a dose‑related increase in adverse effects.<br />
<br />
===Hypertension With Type 2 Diabetes Mellitus===<br />
In a double-blind trial (GEMINI), COREG, added to an ACE inhibitor or [[angiotensin receptor blocker]], was evaluated in a population with mild‑to‑moderate hypertension and well-controlled type 2 diabetes mellitus. The mean HbA1c at baseline was 7.2%. COREG was titrated to a mean dose of 17.5 mg twice daily and maintained for 5 months. COREG had no adverse effect on glycemic control, based on HbA1c measurements (mean change from baseline of 0.02%, 95% CI: ‑0.06 to 0.10, P = NS) .<br />
}}</div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=Carvedilol&diff=962273Carvedilol2014-04-03T18:40:07Z<p>Abdurahman Khalil: </p>
<hr />
<div>{{DrugProjectFormSinglePage<br />
|authorTag={{AK}}<br />
|genericName=Carvedilol<br />
|aOrAn=an<br />
|drugClass=Alpha-adrenergic blocker, Beta-adrenergic blocker<br />
|indication=Heart failure of ischemic or cardiomyopathic origin, hypertension<br />
|adverseReactions=Fatigue, hypotension, dizziness, hyperglycemia<br />
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)<br />
|fdaLIADAdult=&lt;h4&gt;Condition 1&lt;/h5&gt;<br />
<br />
* Dosing Information<br />
<br />
:: (Dosage)<br />
|FDAPregCat=C<br />
|useInPregnancyFDA=Studies performed in pregnant rats and rabbits given carvedilol revealed increased post-implantation loss in rats at doses of 300 mg/kg/day (50 times the maximum recommended human dose [MRHD] as mg/m2) and in rabbits at doses of 75 mg/kg/day (25 times the MRHD as mg/m2). In the rats, there was also a decrease in fetal body weight at the maternally toxic dose of 300 mg/kg/day (50 times the MRHD as mg/m2), which was accompanied by an elevation in the frequency of fetuses with delayed skeletal development (missing or stunted 13th rib). In rats the no-observed-effect level for developmental toxicity was 60 mg/kg/day (10 times the MRHD as mg/m2); in rabbits it was 15 mg/kg/day (5 times the MRHD as mg/m2). There are no adequate and well-controlled studies in pregnant women. COREG should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.<br />
|useInNursing=It is not known whether this drug is excreted in human milk. Studies in rats have shown that carvedilol and/or its metabolites (as well as other β-blockers) cross the placental barrier and are excreted in breast milk. There was increased mortality at one week post-partum in neonates from rats treated with 60 mg/kg/day (10 times the MRHD as mg/m2) and above during the last trimester through day 22 of lactation. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from β-blockers, especially [[bradycardia]], a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. The effects of other α- and β-blocking agents have included perinatal and neonatal distress.<br />
|useInPed=Effectiveness of carvedilol in patients younger than 18 years has not been established.<br />
<br />
In a double-blind trial, 161 children (mean age: 6 years, range: 2 months to 17 years; 45% younger than 2 years) with chronic[[ heart failure]] [NYHA class II-IV, left ventricular [[ejection fraction]] <40% for children with a systemic left ventricle (LV), and moderate-severe ventricular dysfunction qualitatively by echo for those with a systemic ventricle that was not an LV] who were receiving standard background treatment were randomized to placebo or to 2 dose levels of carvedilol. These dose levels produced placebo-corrected heart rate reduction of 4 to 6 heart beats per minute, indicative of β -blockade activity. Exposure appeared to be lower in pediatric subjects than adults. After 8 months of follow-up, there was no significant effect of treatment on clinical outcomes. Adverse reactions in this trial that occurred in greater than 10% of subjects treated with carvedilol and at twice the rate of placebo-treated subjects included chest pain (17% versus 6%), dizziness (13% versus 2%), and dyspnea (11% versus 0%).<br />
|useInGeri=Plasma levels of carvedilol average about 50% higher in the elderly compared with young subjects.<br />
<br />
|useInRenalImpair=Although carvedilol is metabolized primarily by the liver, plasma concentrations of carvedilol have been reported to be increased in patients with renal impairment. Based on mean AUC data, approximately 40% to 50% higher plasma concentrations of carvedilol were observed in hypertensive subjects with moderate to severe renal impairment compared to a control group of hypertensive subjects with normal renal function. However, the ranges of AUC values were similar for both groups. Changes in mean peak plasma levels were less pronounced, approximately 12% to 26% higher in subjects with impaired renal function.<br />
<br />
Consistent with its high degree of plasma protein‑binding, carvedilol does not appear to be cleared significantly by [[hemodialysis]].<br />
|useInHepaticImpair=Compared with healthy subjects, patients with severe liver impairment ([[cirrhosis]]) exhibit a 4- to 7-fold increase in carvedilol levels. <br />
Carvedilol is contraindicated in patients with severe liver impairment.<br />
|othersTitle=Heart Failure<br />
|useInOthers=[[Steady‑state ]]plasma concentrations of carvedilol and its enantiomers increased proportionally over the 6.25 to 50 mg dose range in subjects with heart failure. Compared with healthy subjects, heart failure subjects had increased mean AUC and Cmax values for carvedilol and its enantiomers, with up to 50% to 100% higher values observed in 6 subjects with NYHA class IV heart failure. The mean apparent terminal elimination half‑life for carvedilol was similar to that observed in healthy subjects.<br />
|overdose====Acute Overdose===<br />
=====Signs and Symptoms=====<br />
Overdosage may cause severe [[hypotension]], [[bradycardia]], [[cardiac insufficiency]], [[cardiogenic shock]], and [[cardiac arrest]]. Respiratory problems, bronchospasms, vomiting, lapses of consciousness, and generalized [[seizures]] may also occur.<br />
=====Management=====<br />
:*The patient should be placed in a '''[[supine]] position''' and, where necessary and '''kept under observation'''<br />
<br />
:*The patient should be treated under intensive-care conditions. <br />
:*'''Gastric lavage''' or pharmacologically induced [[emesis]] may be used shortly after ingestion. <br />
The following agents may be '''administered for excessive [[bradycardia]]''':<br />
:* [[Atropine]], 2 mg IV.<br />
'''To support cardiovascular function:''' <br />
<br />
:*Glucagon, 5 to 10 mg IV rapidly over 30 seconds, followed by a continuous infusion of 5 mg/hour<br><br />
:*Sympathomimetics ([[dobutamine]], [[isoprenaline]], adrenaline) at doses according to body weight and effect.<br />
'''If peripheral vasodilation dominates:''' <br />
:*Administer [[adrenaline]] or[[ noradrenaline]] with continuous monitoring of circulatory conditions.<br />
'''For therapy-resistant [[bradycardia]]'''<br />
:*pacemaker therapy should be performed.<br />
'''For bronchospasm'''<br />
:*β-sympathomimetics (as aerosol or IV) or [[Aminophylline]] IV should be given. <br />
'''In the event of [[seizures]]'''<br />
:*Administer slow IV injection of [[diazepam]] or [[clonazepam]] is recommended.<br />
<br />
'''NOTE:''' In the event of severe intoxication where there are symptoms of shock, treatment with antidotes must be continued for a sufficiently '''long period of time consistent with the 7-10 hour half-life of carvedilol'''.<br />
<br />
Cases of overdosage with COREG alone or in combination with other drugs have been reported. Quantities ingested in some cases exceeded 1,000 milligrams. Symptoms experienced included low blood pressure and heart rate. '''Standard supportive treatment''' was provided and individuals recovered.<br />
|mechAction=Carvedilol is a racemic mixture in which nonselective β-adrenoreceptor blocking activity is present in the S(-) enantiomer and α1-adrenergic blocking activity is present in both R(+) and S(-) enantiomers at equal potency. Carvedilol has no intrinsic sympathomimetic activity.<br />
|PD=====Heart Failure====<br />
<br />
:*The basis for the '''beneficial effects''' of carvedilol in heart failure is '''not established.'''<br />
<br />
:*Two placebo‑controlled trials compared the acute hemodynamic effects of carvedilol with baseline measurements in 59 and 49 subjects with NYHA class II‑IV heart failure receiving [[diuretics]], [[ACE inhibitors]], and [[digitalis]]. There were significant reductions in systemic blood pressure, pulmonary artery pressure, pulmonary capillary wedge pressure, and heart rate. Initial effects on cardiac output, stroke volume index, and systemic vascular resistance were small and variable.<br />
<br />
:*These trials measured hemodynamic effects again at 12 to 14 weeks. carvedilol significantly '''reduced systemic blood pressure, pulmonary artery pressure, right atrial pressure, systemic vascular resistance, and heart rate''', while stroke volume index was increased.<br />
<br />
:*Among 839 subjects with NYHA class II‑III heart failure treated for 26 to 52 weeks in 4 US placebo‑controlled trials, average left ventricular ejection fraction (EF) measured by radionuclide ventriculography increased by 9 EF units (%) in subjects receiving carvedilol and by 2 EF units in placebo subjects at a target dose of 25 to 50 mg twice daily. <br />
<br />
:*'''The effects of carvedilol on ejection fraction were related to dose'''. <u>Doses of 6.25 mg twice daily, 12.5 mg twice daily, and 25 mg twice daily</u> were associated with placebo‑corrected increases in EF of 5 EF units, 6 EF units, and 8 EF units, respectively; each of these effects were nominally statistically significant.<br />
<br />
====Left Ventricular Dysfunction Following Myocardial Infarction====<br />
<br />
The basis for the beneficial effects of carvedilol in patients with left ventricular dysfunction following an [[acute myocardial infarction]] is not established.<br />
<br />
====Hypertension====<br />
<br />
The mechanism by which β-blockade produces an antihypertensive effect has not been established.<br />
<br />
:*β-adrenoreceptor blocking activity has been demonstrated in animal and human studies showing that carvedilol (1) reduces cardiac output in normal subjects; (2) reduces exercise- and/or [[isoproterenol]]-induced tachycardia; and (3) reduces reflex orthostatic [[tachycardia]]. Significant β-adrenoreceptor blocking effect is usually seen within 1 hour of drug administration.<br />
<br />
:*α1-adrenoreceptor blocking activity has been demonstrated in human and animal studies, showing that carvedilol (1) attenuates the pressor effects of [[phenylephrine]]; (2) causes vasodilation; and (3) reduces peripheral vascular resistance. These effects contribute to the reduction of blood pressure and usually are seen within 30 minutes of drug administration.<br />
<br />
:*Due to the α1-receptor blocking activity of carvedilol, blood pressure is lowered more in the standing than in the supine position, and symptoms of postural hypotension (1.8%), including rare instances of syncope, can occur. Following oral administration, when [[postural hypotension]] has occurred, it has been transient and is uncommon when carvedilol is administered with food at the recommended starting dose and titration increments are closely followed [see Dosage and Administration (2)].<br />
<br />
:*In hypertensive patients with normal renal function, therapeutic doses of carvedilol decreased renal vascular resistance with no change in glomerular filtration rate or renal plasma flow. Changes in excretion of sodium, potassium, uric acid, and phosphorus in hypertensive patients with normal renal function were similar after carvedilol and placebo.<br />
<br />
:*carvedilol has little effect on plasma [[catecholamines]], plasma [[aldosterone]], or electrolyte levels, but it does significantly reduce plasma renin activity when given for at least 4 weeks. It also increases levels of [[atrial natriuretic peptide]].<br />
|PK=:*carvedilol is rapidly and extensively absorbed following oral administration, with absolute bioavailability of approximately 25% to 35% due to a significant degree of first-pass metabolism. Following oral administration, the apparent mean terminal elimination half-life of carvedilol generally ranges from 7 to 10 hours. Plasma concentrations achieved are proportional to the oral dose administered. When administered with food, the rate of absorption is slowed, as evidenced by a delay in the time to reach peak plasma levels, with no significant difference in extent of bioavailability. Taking carvedilol with food should minimize the risk of[[ orthostatic hypotension]].<br />
<br />
:*'''Carvedilol is extensively metabolized'''. Following oral administration of radiolabelled carvedilol to healthy volunteers, carvedilol accounted for only about 7% of the total radioactivity in plasma as measured by area under the curve (AUC). Less than 2% of the dose was excreted unchanged in the urine. Carvedilol is metabolized primarily by aromatic ring oxidation and glucuronidation. The oxidative metabolites are further metabolized by conjugation via glucuronidation and sulfation. The metabolites of carvedilol are excreted primarily via the bile into the feces. Demethylation and hydroxylation at the phenol ring produce 3 active metabolites with β-receptor blocking activity. Based on preclinical studies, the 4'-hydroxyphenyl metabolite is approximately 13 times more potent than carvedilol for β-blockade.<br />
<br />
:*Compared with carvedilol, the 3 active metabolites exhibit weak vasodilating activity. Plasma concentrations of the active metabolites are about one-tenth of those observed for carvedilol and have pharmacokinetics similar to the parent.<br />
<br />
:*Carvedilol undergoes stereoselective first-pass metabolism with plasma levels of R(+)-carvedilol approximately 2 to 3 times higher than S(-)-carvedilol following oral administration in healthy subjects. The mean apparent terminal elimination half-lives for R(+)-carvedilol range from 5 to 9 hours compared with 7 to 11 hours for the S(-)-enantiomer.<br />
<br />
:*The primary P450 enzymes responsible for the metabolism of both R(+) and S(-)-carvedilol in human liver microsomes were CYP2D6 and CYP2C9 and to a lesser extent CYP3A4, 2C19, 1A2, and 2E1. CYP2D6 is thought to be the major enzyme in the 4’- and 5’-hydroxylation of carvedilol, with a potential contribution from 3A4. CYP2C9 is thought to be of primary importance in the O-methylation pathway of S(-)-carvedilol.<br />
<br />
:*Carvedilol is subject to the effects of genetic[[ polymorphism]] with poor metabolizers of debrisoquin (a marker for cytochrome P450 2D6) exhibiting 2- to 3-fold higher plasma concentrations of R(+)-carvedilol compared with extensive metabolizers. In contrast, plasma levels of S(-)-carvedilol are increased only about 20% to 25% in poor metabolizers, indicating this enantiomer is metabolized to a lesser extent by cytochrome P450 2D6 than R(+)-carvedilol. The pharmacokinetics of carvedilol do not appear to be different in poor metabolizers of S-mephenytoin (patients deficient in cytochrome P450 2C19).<br />
<br />
:*Carvedilol is more than 98% bound to plasma proteins, primarily with [[albumin]]. The plasma-protein binding is independent of concentration over the therapeutic range. Carvedilol is a basic, lipophilic compound with a steady-state volume of distribution of approximately 115 L, indicating substantial distribution into extravascular tissues. Plasma clearance ranges from 500 to 700 mL/min.<br />
}}</div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=Carvedilol&diff=962167Carvedilol2014-04-03T14:04:38Z<p>Abdurahman Khalil: </p>
<hr />
<div>{{DrugProjectFormSinglePage<br />
|authorTag={{AK}}<br />
|genericName=Carvedilol<br />
|aOrAn=an<br />
|drugClass=Alpha-adrenergic blocker, Beta-adrenergic blocker<br />
|indication=Heart failure of ischemic or cardiomyopathic origin, hypertension<br />
|adverseReactions=Fatigue, hypotension, dizziness, hyperglycemia<br />
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)<br />
|fdaLIADAdult=&lt;h4&gt;Condition 1&lt;/h5&gt;<br />
<br />
* Dosing Information<br />
<br />
:: (Dosage)<br />
|overdose====Acute Overdose===<br />
=====Signs and Symptoms=====<br />
Overdosage may cause severe [[hypotension]], [[bradycardia]], [[cardiac insufficiency]], [[cardiogenic shock]], and [[cardiac arrest]]. Respiratory problems, bronchospasms, vomiting, lapses of consciousness, and generalized [[seizures]] may also occur.<br />
=====Management=====<br />
:*The patient should be placed in a '''[[supine]] position''' and, where necessary and '''kept under observation'''<br />
<br />
:*The patient should be treated under intensive-care conditions. <br />
:*'''Gastric lavage''' or pharmacologically induced [[emesis]] may be used shortly after ingestion. <br />
The following agents may be '''administered for excessive [[bradycardia]]''':<br />
:* [[Atropine]], 2 mg IV.<br />
'''To support cardiovascular function:''' <br />
<br />
:*Glucagon, 5 to 10 mg IV rapidly over 30 seconds, followed by a continuous infusion of 5 mg/hour<br><br />
:*Sympathomimetics ([[dobutamine]], [[isoprenaline]], adrenaline) at doses according to body weight and effect.<br />
'''If peripheral vasodilation dominates:''' <br />
:*Administer [[adrenaline]] or[[ noradrenaline]] with continuous monitoring of circulatory conditions.<br />
'''For therapy-resistant [[bradycardia]]'''<br />
:*pacemaker therapy should be performed.<br />
'''For bronchospasm'''<br />
:*β-sympathomimetics (as aerosol or IV) or [[Aminophylline]] IV should be given. <br />
'''In the event of [[seizures]]'''<br />
:*Administer slow IV injection of [[diazepam]] or [[clonazepam]] is recommended.<br />
<br />
'''NOTE:''' In the event of severe intoxication where there are symptoms of shock, treatment with antidotes must be continued for a sufficiently '''long period of time consistent with the 7-10 hour half-life of carvedilol'''.<br />
<br />
Cases of overdosage with COREG alone or in combination with other drugs have been reported. Quantities ingested in some cases exceeded 1,000 milligrams. Symptoms experienced included low blood pressure and heart rate. '''Standard supportive treatment''' was provided and individuals recovered.<br />
}}</div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=Carvedilol&diff=962145Carvedilol2014-04-03T11:21:07Z<p>Abdurahman Khalil: </p>
<hr />
<div>{{DrugProjectFormSinglePage<br />
|authorTag={{AK}}<br />
|genericName=Carvedilol<br />
|aOrAn=an<br />
|drugClass=Alpha-adrenergic blocker, Beta-adrenergic blocker<br />
|indication=Heart failure of ischemic or cardiomyopathic origin, hypertension<br />
|adverseReactions=Fatigue, hypotension, dizziness, hyperglycemia<br />
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)<br />
|fdaLIADAdult=&lt;h4&gt;Condition 1&lt;/h5&gt;<br />
<br />
* Dosing Information<br />
<br />
:: (Dosage)<br />
}}</div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=Carvedilol&diff=962144Carvedilol2014-04-03T11:17:49Z<p>Abdurahman Khalil: Undo revision 962143 by Abdurahman Khalil (talk)</p>
<hr />
<div>{{DrugProjectFormSinglePage<br />
|authorTag={{AK}}<br />
|genericName=Carvedilol<br />
|drugClass=Alpha-adrenergic blocker, Beta-adrenergic blocker<br />
|indication=Heart failure of ischemic or cardiomyopathic origin, hypertension<br />
|adverseReactions=Fatigue, hypotension, dizziness, hyperglycemia<br />
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)<br />
|fdaLIADAdult=&lt;h4&gt;Condition 1&lt;/h5&gt;<br />
<br />
* Dosing Information<br />
<br />
:: (Dosage)<br />
}}</div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=Carvedilol&diff=962143Carvedilol2014-04-03T11:17:16Z<p>Abdurahman Khalil: </p>
<hr />
<div>{{DrugProjectFormSinglePage<br />
|authorTag={{AK}}<br />
|genericName=Carvedilol<br />
|drugClass=Alpha-adrenergic blocker, Beta-adrenergic blocker<br />
|indication=Heart failure of ischemic or cardiomyopathic origin, hypertension<br />
|adverseReactions=Fatigue, hypotension, dizziness, hyperglycemia<br />
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)<br />
|fdaLIADAdult=&lt;h4&gt;Condition 1&lt;/h5&gt;</div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=Carvedilol&diff=962141Carvedilol2014-04-03T11:12:53Z<p>Abdurahman Khalil: </p>
<hr />
<div>{{DrugProjectFormSinglePage<br />
|authorTag={{AK}}<br />
|genericName=Carvedilol<br />
|drugClass=Alpha-adrenergic blocker, Beta-adrenergic blocker<br />
|indication=Heart failure of ischemic or cardiomyopathic origin, hypertension<br />
|adverseReactions=Fatigue, hypotension, dizziness, hyperglycemia<br />
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)<br />
|fdaLIADAdult=&lt;h4&gt;Condition 1&lt;/h5&gt;<br />
<br />
* Dosing Information<br />
<br />
:: (Dosage)<br />
}}<br />
__NOTOC__<br />
{{Carvedilol}}<br />
{{CMG}}; {{AE}} {{AZ}}<br />
<br />
'''''For patient information, click <u>[[Carvedilol (patient information)|here]]'''''</u>.<br />
<br />
{{SB}} COREG®, COREG CR®<br />
<br />
==Overview==<br />
<br />
==Category==<br />
<br />
==FDA Package Insert==<br />
<br />
'''| [[Carvedilol indications and usage|Indications and Usage]]'''<br />
'''| [[Carvedilol dosage and administration|Dosage and Administration]]'''<br />
'''| [[Carvedilol dosage forms and strengths|Dosage Forms and Strengths]]'''<br />
'''| [[Carvedilol contraindications|Contraindications]]'''<br />
'''| [[Carvedilol warnings|Warnings and Precautions]]'''<br />
'''| [[Carvedilol adverse reactions|Adverse Reactions]]'''<br />
'''| [[Carvedilol drug interactions|Drug Interactions]]'''<br />
'''| [[Carvedilol use in specific populations|Use in Specific Populations]]'''<br />
'''| [[Carvedilol overdosage|Overdosage]]'''<br />
'''| [[Carvedilol description|Description]]'''<br />
'''| [[Carvedilol clinical pharmacology|Clinical Pharmacology]]'''<br />
'''| [[Carvedilol nonclinical toxicology|Nonclinical Toxicology]]'''<br />
'''| [[Carvedilol clinical studies|Clinical Studies]]'''<br />
'''| [[Carvedilol how supplied storage and handling|How Supplied/Storage and Handling]]'''<br />
'''| [[Carvedilol patient counseling information|Patient Counseling Information]]'''<br />
'''| [[Carvedilol labels and packages|Labels and Packages]]'''<br />
<br />
==Mechanism of Action==<br />
<br />
==References==<br />
<br />
{{Reflist|2}}<br />
<br />
[[Category:Drugs]]</div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=Cilostazol&diff=962135Cilostazol2014-04-03T10:58:58Z<p>Abdurahman Khalil: </p>
<hr />
<div>{{DrugProjectFormSinglePage<br />
|authorTag={{AK}}<br />
|genericName=Cilostazol<br />
|aOrAn=a<br />
|drugClass=Phosphodiesterase 3 inhibitor<br />
|indication=Intermittent claudication<br />
|hasBlackBoxWarning=Yes<br />
|adverseReactions=headache, dizziness, palpitation, diarrhea, rhinitis and pharyngitis.<br />
|blackBoxWarningTitle=Contraindication<br />
|blackBoxWarningBody=<i><span style="color:#FF0000;">Heart failure</span></i> '' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
|fdaLIADAdult=&lt;h4&gt;Intermittent claudication 1&lt;/h5&gt;<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
|offLabelAdultGuideSupport======Secondary prevention of stroke and TIA=====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid'''<ref name="Lansberg-2012">{{Cite journal | last1 = Lansberg | first1 = MG. | last2 = O'Donnell | first2 = MJ. | last3 = Khatri | first3 = P. | last4 = Lang | first4 = ES. | last5 = Nguyen-Huynh | first5 = MN. | last6 = Schwartz | first6 = NE. | last7 = Sonnenberg | first7 = FA. | last8 = Schulman | first8 = S. | last9 = Vandvik | first9 = PO. | title = Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e601S-36S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2302 | PMID = 22315273 }}</ref><br />
<br />
=====Thrombosis prophylaxis in percutaneous coronary intervention =====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid'''<ref name="Vandvik-2012">{{Cite journal | last1 = Vandvik | first1 = PO. | last2 = Lincoff | first2 = AM. | last3 = Gore | first3 = JM. | last4 = Gutterman | first4 = DD. | last5 = Sonnenberg | first5 = FA. | last6 = Alonso-Coello | first6 = P. | last7 = Akl | first7 = EA. | last8 = Lansberg | first8 = MG. | last9 = Guyatt | first9 = GH. | title = Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e637S-68S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2306 | PMID = 22315274 }}</ref><br />
|offLabelAdultNoGuideSupport======Secondary prevention of femoral artery occlusion after peripheral intervention=====<br />
<ref name="Iida-2013">{{Cite journal | last1 = Iida | first1 = O. | last2 = Yokoi | first2 = H. | last3 = Soga | first3 = Y. | last4 = Inoue | first4 = N. | last5 = Suzuki | first5 = K. | last6 = Yokoi | first6 = Y. | last7 = Kawasaki | first7 = D. | last8 = Zen | first8 = K. | last9 = Urasawa | first9 = K. | title = Cilostazol reduces angiographic restenosis after endovascular therapy for femoropopliteal lesions in the Sufficient Treatment of Peripheral Intervention by Cilostazol study. | journal = Circulation | volume = 127 | issue = 23 | pages = 2307-15 | month = Jun | year = 2013 | doi = 10.1161/CIRCULATIONAHA.112.000711 | PMID = 23652861 }}</ref><br />
|contraindications=* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
|warnings======Hematologic Adverse Reactions=====<br />
Rare cases have been reported of [[thrombocytopenia ]]or [[leukopenia ]]progressing to [[agranulocytosis ]]when cilostazol was not immediately discontinued. The agranulocytosis, however, was reversible on discontinuation of cilostazol.<br />
<br />
=====Use with Clopidogrel=====<br />
There is limited information with respect to the efficacy or safety of the concurrent use of cilostazol and [[clopidogrel]], a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Although it cannot be determined whether there was an additive effect on bleeding times during concomitant administration with cilostazol and [[clopidogrel]], caution is advised for checking bleeding times during co-administration.<br />
|clinicalTrials=Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol and 134 days for patients on placebo.<br />
<br />
The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with PLETAL 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included [[palpitation ]]and [[diarrhea]], both 1.1% for cilostazol (all doses) versus 0.1% for placebo.<br />
<br />
======Body as a Whole======<br />
*Common:<br />
:*Abdominal pain<br />
:*Back pain<br />
:*Headache <br />
:*Infection<br />
<br />
*Less common:<br />
[[Chills]], face [[edema]], [[fever]], [[generalized edema]], [[malaise]], [[neck rigidity]], [[pelvic pain]], [[retroperitoneal haemorrhage]].<br />
<br />
======Central Nervous System======<br />
<br />
*Common:<br />
:*Dizziness<br />
:*Vertigo<br />
<br />
*Less common:<br />
[[Anxiety]], [[insomnia]], [[neuralgia]].<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
*Common:<br />
:*Abnormal stool<br />
:*Diarrhea<br />
:*Dyspepsia<br />
:*Flatulence<br />
:*Nausea<br />
<br />
*Less common:<br />
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Metabolic & Nutritional======<br />
*Common:<br />
:*Peripheral edema<br />
<br />
*Less common:<br />
Increased [[creatinine]], [[gout]], [[hyperlipemia]], [[hyperuricemia]].<br />
<br />
======Musculoskeletal======<br />
<br />
*Common:<br />
:*Myalgia<br />
<br />
*Less common:<br />
[[Arthralgia]], bone pain, [[bursitis]].<br />
<br />
======Miscellaneous======<br />
Less common adverse reactions:<br />
<br />
*'''Endocrine:''' [[Diabetes mellitus]].<br />
<br />
*'''Hemic and Lymphatic:''' [[Anemia]], [[ecchymosis]],[[ iron deficiency anemia]], [[polycythemia]], [[purpura]].<br />
<br />
*'''Skin and Appendages:''' Dry skin, [[furunculosis]], skin hypertrophy, [[urticaria]].<br />
<br />
*'''Special Senses:''' [[Amblyopia]], [[blindness]], [[conjunctivitis]], [[diplopia]], ear pain, eye haemorrhage, [[retinal haemorrhage]], [[tinnitus]].<br />
<br />
*'''Urogenital:''' [[Albuminuria]], [[cystitis]], [[urinary frequency]], vaginal haemorrhage, vaginitis.<br />
|postmarketing=The following events have been reported spontaneously from worldwide post-marketing experience since the launch of PLETAL in the US.<br />
<br />
======Blood and lymphatic system disorders:======<br />
[[Agranulocytosis]],[[ aplastic anemia]], [[granulocytopenia]], [[pancytopenia]], [[thrombocytopenia]], [[leukopenia]], <br />
[[bleeding tendency]]<br />
<br />
======Cardiac disorders:======<br />
<br />
[[Torsades de pointes]], [[QT prolongation|QTc prolongation]] (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. [[complete atrioventricular block]], c[[ardiac failure ]]and [[bradyarrythmia]], when treated with cilostazol. Cilostazol was used "off label" due to its positive [[chronotropic]] action)<br />
<br />
======Gastrointestinal disorders:======<br />
<br />
*Gastrointestinal haemorrhage<br />
<br />
======General disorders and administration site conditions:======<br />
<br />
*Pain<br />
*[[chest pain]] <br />
*[[hot flushes]]<br />
<br />
======Hepatobiliary disorders:======<br />
<br />
*Hepatic dysfunction/abnormal liver function tests <br />
*[[jaundice]]<br />
<br />
======Injury, poisoning and procedural complications:======<br />
<br />
*Extradural [[haematoma ]] <br />
*Subdural haematoma<br />
<br />
=====Investigations:=====<br />
<br />
*[[Blood glucose]] increased, blood [[uric acid]] increased, [[platelet count]] decreased, [[white blood cell count]] decreased, increase in [[BUN]] (blood urea increased), blood pressure increase<br />
<br />
======Nervous system disorders:======<br />
<br />
*[[Intracranial haemorrhage]] <br />
*[[cerebral haemorrhage]] <br />
*[[cerebrovascular accident]]<br />
<br />
======Respiratory, thoracic and mediastinal disorders:======<br />
<br />
*Pulmonary haemorrhage<br />
*[[ interstitial pneumonia]]<br />
<br />
'''Skin and subcutaneous tissue disorders:'''<br />
<br />
*Haemorrhage subcutaneous, [[pruritus]], skin eruptions including [[Stevens-Johnson syndrome]], skin drug eruption ([[dermatitis medicamentosa]])<br />
<br />
======Vascular disorders:======<br />
<br />
*Subacute [[thrombosis ]](these cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting)<br />
|drugInteractions======Aspirin=====<br />
<br />
*Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of ADP-induced ex vivo platelet aggregation by 22% to 37% when compared to either aspirin or cilostazol alone. Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to cilostazol alone and by 48% compared to aspirin alone. However, short-term co-administration of aspirin with cilostazol had no clinically significant impact on PT, aPTT or bleeding time compared to aspirin alone. <br />
<br />
*Effects of long-term co-administration in the general population are unknown. In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was co-administered with cilostazol to 201 patients. The most frequent doses and mean durations of aspirin therapy were 75 mg to 81 mg daily for 137 days (107 patients) and 325 mg daily for 54 days (85 patients). There was no apparent increase in incidence of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.<br />
<br />
=====Warfarin=====<br />
<br />
The cytochrome P-450 isoenzymes involved in the metabolism of R-warfarin are CYP3A4, CYP1A2 and CYP2C19 and in the metabolism of S-warfarin, CYP2C9. Cilostazol did not inhibit either the metabolism or the pharmacologic effects (PT, aPTT, bleeding time or platelet aggregation) of R- and S-warfarin after a single 25-mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and cilostazol on the pharmacokinetics and pharmacodynamics of both drugs is unknown.<br />
<br />
=====Clopidogrel=====<br />
<br />
Multiple doses of clopidogrel do not significantly increase steady state plasma concentrations of cilostazol.<br />
<br />
=====Inhibitors of CYP3A4=====<br />
<br />
======Strong Inhibitors of CYP3A4======<br />
<br />
A priming dose of [[ketoconazole ]]400 mg (a strong inhibitor of CYP3A4), was given one day prior to co-administration of single doses of [[ketoconazole ]]400 mg and cilostazol 100 mg. This regimen increased cilostazol Cmax by 94% and AUC by 117%. Other strong inhibitors of CYP3A4, such as [[itraconazole]], [[fluconazole]], [[miconazole]], [[fluvoxamine]], [[fluoxetine]], [[nefazodone ]]and [[sertraline]], would be expected to have a similar effect <br />
<br />
======Moderate Inhibitors of CYP3A4======<br />
<br />
*[[Erythromycin ]]and Other [[Macrolide ]]Antibiotics: [[Erythromycin ]]is a moderately strong inhibitor of CYP3A4. Co-administration of erythromycin 500 mg q 8h with a single dose of cilostazol 100 mg increased cilostazol Cmax by 47% and AUC by 73%. Inhibition of cilostazol metabolism by erythromycin increased the AUC of 4´-trans-hydroxy-cilostazol by 141%. Other macrolide antibiotics (e.g., [[clarithromycin]]), but not all (e.g., [[azithromycin]]), would be expected to have a similar effect.<br />
<br />
*Diltiazem: [[Diltiazem]] 180 mg decreased the clearance of cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC increased ~40%.<br />
<br />
*Grapefruit Juice: [[Grapefruit juice]] increased the Cmax of cilostazol by ~50% , but had no effect on AUC.<br />
=====Inhibitors of CYP2C19=====<br />
<br />
[[Omeprazole]]: Co-administration of omeprazole did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%, probably the result of omeprazole’s potent inhibition of CYP2C19 <br />
<br />
=====Quinidine =====<br />
<br />
Concomitant administration of [[quinidine ]]with a single dose of cilostazol 100 mg did not alter cilostazol pharmacokinetics.<br />
<br />
=====Lovastatin=====<br />
<br />
The concomitant administration of [[lovastatin ]]with cilostazol decreases cilostazol Css, max and AUCT by 15%. There is also a decrease, although nonsignificant, in cilostazol metabolite concentrations. Co-administration of cilostazol with lovastatin increases lovastatin and β–hydroxy lovastatin AUC approximately 70%. This is most likely clinically insignificant.<br />
|FDAPregCat=<br />
|useInPregnancyFDA=In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
|AUSPregCat=<br />
|useInNursing=Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
|useInPed=The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
|useInGeri=Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
|useInGender=The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range.<br />
|useInRenalImpair=Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
|useInHepaticImpair=Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
|othersTitle=Smokers<br />
|useInOthers=Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
|administration=Oral<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability)<br />
|overdose=Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
|drugBox={{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
|mechAction=The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
|structure=*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
|PK=Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
<br />
====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4 dehydro cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4 dehydro cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
|nonClinToxic=====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the<br />
|clinicalStudies=*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
<br />
{|<br />
| [[image:Cilo2.png|400px|thumb]]<br />
|}<br />
<br />
<br />
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
|howSupplied='''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other.<br />
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other.<br />
|NDC=0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
|storage=Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
|manBy=Sandoz Inc.Princeton, NJ 08540<br />
|distBy=Bryant Ranch Prepack<br />
|packLabel={|<br />
| [[image:Cilostazollabel.jpg|400px|thumb]]<br />
|}<br />
<br />
{|<br />
| [[image:Cilostazollabel1.png|400px|thumb]]<br />
|}<br />
<br />
|isPill=Yes<br />
|dosageValue=50<br />
|dosageUnit=mg<br />
|pillImprint=E 123<br />
|pillSize=9<br />
|pillShape=Round<br />
|pillColor=White<br />
|pillScoring=1<br />
|pillImage=Cilostazol50mg.jpg<br />
|fdaPatientInfo=(sil-OS-tah-zol)<br />
<br />
Please read this leaflet before you start taking cilostazol tablets and each time you renew it in case anything has changed. This leaflet does not replace careful discussions with your doctor. You and your doctor should discuss cilostazol when you start taking it and at regular check-ups. You should follow your doctor’s advice about when to have check-ups.<br />
'''What is cilostazol for?'''<br />
Cilostazol may improve the symptoms of patients with a medical condition called intermittent claudication.<br />
What is intermittent claudication?<br />
Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. It occurs because narrowing or blockage of the arteries decreases blood flow to the legs. The decreased blood flow does not supply enough oxygen to the leg muscles during walking, resulting in these painful leg cramps.<br />
<br />
'''What treatments are available for intermittent claudication?'''<br />
<br />
The three main treatments available for intermittent claudication are:<br />
*Exercise. Your doctor may advise an exercise program.<br />
*Medication. Your doctor may prescribe a medication such as cilostazol. (See Who should not take cilostazol tablets?)<br />
*Surgery. Your doctor may recommend a surgical procedure to bypass the blocked segment of the artery. Another procedure is called a percutaneous transluminal angioplasty. In this procedure, a catheter (a flexible tube) is inserted into the artery to reduce the blockage and improve blood flow.<br />
<br />
'''How does cilostazol work?'''<br />
<br />
*The exact way that many drugs work is not well understood. Although how cilostazol works is not completely clear, its main effects are to dilate (widen) the arteries supplying blood to the legs and to decrease the ability of platelets in the blood to stick together. Platelets are particles that circulate in the blood and play a role in clotting.<br />
*Cilostazol may reduce the leg pain that patients with intermittent claudication experience, allowing them to walk farther before their leg pain occurs.<br />
*Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks. If you have not noticed any benefit from cilostazol tablets after 12 weeks you and your doctor may wish to discuss other forms of treatment.<br />
*Sometimes blood vessel disease of the legs causes pain at rest or breakdown of skin in the leg. Cilostazol has not been shown to work in patients with these problems.<br />
<br />
'''Who should not take cilostazol tablets?'''<br />
<br />
*Patients who have congestive heart failure (CHF) must not take cilostazol tablets. The most common symptoms of CHF are shortness of breath and swelling of the legs. However, other conditions may also cause these symptoms. It is important that you discuss with your doctor whether you have CHF.<br />
*Over 1,300 patients took cilostazol in studies that lasted for 3 to 6 months. The mortality rate in these patients was similar to placebo (less than 1%). These studies were too small to be sure there is not some increased risk of dying with longer use or in patients sicker than those in the studies.<br />
<br />
'''How should cilostazol tablets be taken?'''<br />
<br />
*Follow your doctor’s advice about how to take cilostazol tablets.<br />
*You should take cilostazol tablets twice a day, at least one half-hour before or two hours after breakfast and dinner. Take cilostazol tablets at about the same times each day.<br />
*Do not share cilostazol tablets with anyone else. It was prescribed only for you.<br />
*Keep cilostazol tablets and all drugs out of the reach of children.<br />
<br />
'''Can cilostazol tablets be taken with other drugs?'''<br />
<br />
Certain drugs and foods can increase the amount of cilostazol in the blood. Because of this, your doctor may adjust your dose of cilostazol or even stop it if you are taking or are going to take one of the following medications.<br />
Drugs Interacting with Cilostazol<br />
Generic Name (Brand Names)Type of Drug<br />
[[erythromycin]] (such as E.E.S.®, Erythrocin®) Antibiotic<br />
[[ketoconazole]] (Nizoral®), [[itraconazole]] (Sporanox®) Antifungal<br />
[[diltiazem]] (Cardizem®) Antihypertensive<br />
[[omeprazole]] (Prilosec®) Gastric acid reducer<br />
This list does not include every drug that may interact with cilostazol tablets. Therefore, you should tell your doctor about all medications that you are taking, including vitamins, herbal supplements and over-the-counter drugs you can buy without a prescription. You should also check with your doctor before taking a new medication after you have begun cilostazol tablets.<br />
<br />
'''What are the possible side effects of cilostazol tablets?'''<br />
<br />
Cilostazol tablets may cause side effects including headache, diarrhea, abnormal stools, increased heart rate and palpitations.<br />
You should discuss possible side effects with your doctor before taking cilostazol tablets and any time you think you are having a side effect.<br />
This provides only a summary of information about cilostazol tablets. If you have any questions about cilostazol tablets, talk to your doctor.<br />
'''Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.'''<br />
<br />
|nlmPatientInfo=For patient information about Cilostazol from NLM, click [[Cilostazol (patient information)|here]].<br />
<br />
|price=[http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price Price]<br />
<br />
|drugShortage=[http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm Drug Shortage Status]<br />
}}<br />
{|class="infobox" style="position: fixed; top: 180px; right: 20px; margin: 0 0 0 0; border: 0; float: right; width: 15%; background: #104E8B; border-radius: 10px 10px 10px 10px;" cellpadding="0" cellspacing="0";<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #104E8B;" | [[{{PAGENAME}}|{{fontcolor|#F8F8FF|{{PAGENAME}}®}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #000000; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|Black Box Warning}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adult Indications and Dosage|{{fontcolor|#F8F8FF|Adult Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pediatric Indications and Dosage|{{fontcolor|#F8F8FF|Pediatric Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Contraindications|{{fontcolor|#F8F8FF|Contraindications}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Warnings|{{fontcolor|#F8F8FF|Warnings}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adverse Reactions|{{fontcolor|#F8F8FF|Adverse Reactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Drug Interactions|{{fontcolor|#F8F8FF|Drug Interactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Use in Specific Populations|{{fontcolor|#F8F8FF|Use in Specific Populations}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Administration and Monitoring|{{fontcolor|#F8F8FF|Administration and Monitoring}}]]<br />
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pharmacology|{{fontcolor|#F8F8FF|Pharmacology}}]]<br />
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Clinical Studies|{{fontcolor|#F8F8FF|Clinical Studies}}]]<br />
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#How Supplied|{{fontcolor|#F8F8FF|How Supplied}}]]<br />
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Precautions with Alcohol|{{fontcolor|#F8F8FF|Precautions with Alcohol}}]]<br />
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|-<br />
|}<br />
<div style="width: 80%"><br />
__NOTOC__<br />
{{CMG}}<br />
<br />
{{SB}} Cilostazol®, Pletal®<br />
<br />
==Disclaimer==<br />
<br />
'''''WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature. The information provided is not a medical advice or treatment. WikiDoc does not promote any medication or off-label use of drugs. Please read our full disclaimer [[wikidoc:General_disclaimer|{{fontcolor|#FF0000|here}}]].'''''<br />
<br />
==<span style="color:#FF0000; background:#000000;">Black Box Warning</span>==<br />
<br />
FDA Package Insert for {{PAGENAME}} contains no information regarding ''Black Box Warning''.<br />
<br />
{| style="border: 3px solid #696969;"<br />
| style="background: #000000; border: 0px; padding: 20px 20px; width: 800px;" |<br />
<center><br />
<font color="#F8F8FF" style="font-weight: bold;">CONTRAINDICATION</font><br />
</center><br />
<br />
<center><br />
<font color="#F8F8FF" size="1" style="font-style: italic;">See full prescribing information for complete boxed warning.</font><br />
</center><br />
<br />
<font color="#F8F8FF" style="font-weight: bold;"><br />
''{{fontcolor|#FF0000|Condition Name:}}'' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
</font><br />
|}<br />
<br />
==Overview==<br />
<br />
{{PAGENAME}} is a_Phosphodiesterase 3 Inhibitor drug that is FDA approved for the treatment of intermittent claudication. There is a Black Box Warning for this drug as shown <span style="background:#000000;">'''[[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|here}}]]'''</span>. Common adverse reactions include headache, dizziness, palpitation, diarrhea, rhinitis and pharyngitis.<br />
<br />
==Adult Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Adult)===<br />
<br />
=====Intermittent claudication=====<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
<br />
===Off-Label Use and Dosage (Adult)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Secondary prevention of stroke and TIA=====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid'''<ref name="Lansberg-2012">{{Cite journal | last1 = Lansberg | first1 = MG. | last2 = O'Donnell | first2 = MJ. | last3 = Khatri | first3 = P. | last4 = Lang | first4 = ES. | last5 = Nguyen-Huynh | first5 = MN. | last6 = Schwartz | first6 = NE. | last7 = Sonnenberg | first7 = FA. | last8 = Schulman | first8 = S. | last9 = Vandvik | first9 = PO. | title = Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e601S-36S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2302 | PMID = 22315273 }}</ref><br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid''<ref name="Vandvik-2012">{{Cite journal | last1 = Vandvik | first1 = PO. | last2 = Lincoff | first2 = AM. | last3 = Gore | first3 = JM. | last4 = Gutterman | first4 = DD. | last5 = Sonnenberg | first5 = FA. | last6 = Alonso-Coello | first6 = P. | last7 = Akl | first7 = EA. | last8 = Lansberg | first8 = MG. | last9 = Guyatt | first9 = GH. | title = Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e637S-68S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2306 | PMID = 22315274 }}</ref><br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* There is limited information about ''Off-Label Non–Guideline-Supported Use'' of {{PAGENAME}} in adult patients.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Pediatric Indications and Dosage==<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
==Contraindications==<br />
* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
<br />
==Warnings==<br />
<br />
=====Hematologic Adverse Reactions=====<br />
Rare cases have been reported of [[thrombocytopenia ]]or [[leukopenia ]]progressing to [[agranulocytosis ]]when cilostazol was not immediately discontinued. The agranulocytosis, however, was reversible on discontinuation of cilostazol.<br />
<br />
=====Use with Clopidogrel=====<br />
There is limited information with respect to the efficacy or safety of the concurrent use of cilostazol and [[clopidogrel]], a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Although it cannot be determined whether there was an additive effect on bleeding times during concomitant administration with cilostazol and [[clopidogrel]], caution is advised for checking bleeding times during co-administration.<br />
<br />
==Adverse Reactions==<br />
<br />
===Clinical Trials Experience===<br />
Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol and 134 days for patients on placebo.<br />
<br />
The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with PLETAL 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included [[palpitation ]]and [[diarrhea]], both 1.1% for cilostazol (all doses) versus 0.1% for placebo.<br />
<br />
======Body as a Whole======<br />
*Common:<br />
:*Abdominal pain<br />
:*Back pain<br />
:*Headache <br />
:*Infection<br />
<br />
*Less common:<br />
[[Chills]], face [[edema]], [[fever]], [[generalized edema]], [[malaise]], [[neck rigidity]], [[pelvic pain]], [[retroperitoneal haemorrhage]].<br />
<br />
======Central Nervous System======<br />
<br />
*Common:<br />
:*Dizziness<br />
:*Vertigo<br />
<br />
*Less common:<br />
[[Anxiety]], [[insomnia]], [[neuralgia]].<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
*Common:<br />
:*Abnormal stool<br />
:*Diarrhea<br />
:*Dyspepsia<br />
:*Flatulence<br />
:*Nausea<br />
<br />
*Less common:<br />
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Metabolic & Nutritional======<br />
*Common:<br />
:*Peripheral edema<br />
<br />
*Less common:<br />
Increased [[creatinine]], [[gout]], [[hyperlipemia]], [[hyperuricemia]].<br />
<br />
======Musculoskeletal======<br />
<br />
*Common:<br />
:*Myalgia<br />
<br />
*Less common:<br />
[[Arthralgia]], bone pain, [[bursitis]].<br />
<br />
======Miscellaneous======<br />
Less common adverse reactions:<br />
<br />
*'''Endocrine:''' [[Diabetes mellitus]].<br />
<br />
*'''Hemic and Lymphatic:''' [[Anemia]], [[ecchymosis]],[[ iron deficiency anemia]], [[polycythemia]], [[purpura]].<br />
<br />
*'''Skin and Appendages:''' Dry skin, [[furunculosis]], skin hypertrophy, [[urticaria]].<br />
<br />
*'''Special Senses:''' [[Amblyopia]], [[blindness]], [[conjunctivitis]], [[diplopia]], ear pain, eye haemorrhage, [[retinal haemorrhage]], [[tinnitus]].<br />
<br />
*'''Urogenital:''' [[Albuminuria]], [[cystitis]], [[urinary frequency]], vaginal haemorrhage, vaginitis.<br />
<br />
===Postmarketing Experience===<br />
<br />
The following events have been reported spontaneously from worldwide post-marketing experience since the launch of PLETAL in the US.<br />
<br />
======Blood and lymphatic system disorders:======<br />
[[Agranulocytosis]],[[ aplastic anemia]], [[granulocytopenia]], [[pancytopenia]], [[thrombocytopenia]], [[leukopenia]], <br />
[[bleeding tendency]]<br />
<br />
======Cardiac disorders:======<br />
<br />
[[Torsades de pointes]], [[QT prolongation|QTc prolongation]] (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. [[complete atrioventricular block]], c[[ardiac failure ]]and [[bradyarrythmia]], when treated with cilostazol. Cilostazol was used "off label" due to its positive [[chronotropic]] action)<br />
<br />
======Gastrointestinal disorders:======<br />
<br />
*Gastrointestinal haemorrhage<br />
<br />
======General disorders and administration site conditions:======<br />
<br />
*Pain<br />
*[[chest pain]] <br />
*[[hot flushes]]<br />
<br />
======Hepatobiliary disorders:======<br />
<br />
*Hepatic dysfunction/abnormal liver function tests <br />
*[[jaundice]]<br />
<br />
======Injury, poisoning and procedural complications:======<br />
<br />
*Extradural [[haematoma ]] <br />
*Subdural haematoma<br />
<br />
=====Investigations:=====<br />
<br />
*[[Blood glucose]] increased, blood [[uric acid]] increased, [[platelet count]] decreased, [[white blood cell count]] decreased, increase in [[BUN]] (blood urea increased), blood pressure increase<br />
<br />
======Nervous system disorders:======<br />
<br />
*[[Intracranial haemorrhage]] <br />
*[[cerebral haemorrhage]] <br />
*[[cerebrovascular accident]]<br />
<br />
======Respiratory, thoracic and mediastinal disorders:======<br />
<br />
*Pulmonary haemorrhage<br />
*[[ interstitial pneumonia]]<br />
<br />
'''Skin and subcutaneous tissue disorders:'''<br />
<br />
*Haemorrhage subcutaneous, [[pruritus]], skin eruptions including [[Stevens-Johnson syndrome]], skin drug eruption ([[dermatitis medicamentosa]])<br />
<br />
======Vascular disorders:======<br />
<br />
*Subacute [[thrombosis ]](these cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting)<br />
<br />
==Drug Interactions==<br />
<br />
=====Aspirin=====<br />
<br />
*Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of ADP-induced ex vivo platelet aggregation by 22% to 37% when compared to either aspirin or cilostazol alone. Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to cilostazol alone and by 48% compared to aspirin alone. However, short-term co-administration of aspirin with cilostazol had no clinically significant impact on PT, aPTT or bleeding time compared to aspirin alone. <br />
<br />
*Effects of long-term co-administration in the general population are unknown. In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was co-administered with cilostazol to 201 patients. The most frequent doses and mean durations of aspirin therapy were 75 mg to 81 mg daily for 137 days (107 patients) and 325 mg daily for 54 days (85 patients). There was no apparent increase in incidence of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.<br />
<br />
=====Warfarin=====<br />
<br />
The cytochrome P-450 isoenzymes involved in the metabolism of R-warfarin are CYP3A4, CYP1A2 and CYP2C19 and in the metabolism of S-warfarin, CYP2C9. Cilostazol did not inhibit either the metabolism or the pharmacologic effects (PT, aPTT, bleeding time or platelet aggregation) of R- and S-warfarin after a single 25-mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and cilostazol on the pharmacokinetics and pharmacodynamics of both drugs is unknown.<br />
<br />
=====Clopidogrel=====<br />
<br />
Multiple doses of clopidogrel do not significantly increase steady state plasma concentrations of cilostazol.<br />
<br />
=====Inhibitors of CYP3A4=====<br />
<br />
======Strong Inhibitors of CYP3A4======<br />
<br />
A priming dose of [[ketoconazole ]]400 mg (a strong inhibitor of CYP3A4), was given one day prior to co-administration of single doses of [[ketoconazole ]]400 mg and cilostazol 100 mg. This regimen increased cilostazol Cmax by 94% and AUC by 117%. Other strong inhibitors of CYP3A4, such as [[itraconazole]], [[fluconazole]], [[miconazole]], [[fluvoxamine]], [[fluoxetine]], [[nefazodone ]]and [[sertraline]], would be expected to have a similar effect <br />
<br />
======Moderate Inhibitors of CYP3A4======<br />
<br />
*[[Erythromycin ]]and Other [[Macrolide ]]Antibiotics: [[Erythromycin ]]is a moderately strong inhibitor of CYP3A4. Co-administration of erythromycin 500 mg q 8h with a single dose of cilostazol 100 mg increased cilostazol Cmax by 47% and AUC by 73%. Inhibition of cilostazol metabolism by erythromycin increased the AUC of 4´-trans-hydroxy-cilostazol by 141%. Other macrolide antibiotics (e.g., [[clarithromycin]]), but not all (e.g., [[azithromycin]]), would be expected to have a similar effect.<br />
<br />
*Diltiazem: [[Diltiazem]] 180 mg decreased the clearance of cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC increased ~40%.<br />
<br />
*Grapefruit Juice: [[Grapefruit juice]] increased the Cmax of cilostazol by ~50% , but had no effect on AUC.<br />
=====Inhibitors of CYP2C19=====<br />
<br />
[[Omeprazole]]: Co-administration of omeprazole did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%, probably the result of omeprazole’s potent inhibition of CYP2C19 <br />
<br />
=====Quinidine =====<br />
<br />
Concomitant administration of [[quinidine ]]with a single dose of cilostazol 100 mg did not alter cilostazol pharmacokinetics.<br />
<br />
=====Lovastatin=====<br />
<br />
The concomitant administration of [[lovastatin ]]with cilostazol decreases cilostazol Css, max and AUCT by 15%. There is also a decrease, although nonsignificant, in cilostazol metabolite concentrations. Co-administration of cilostazol with lovastatin increases lovastatin and β–hydroxy lovastatin AUC approximately 70%. This is most likely clinically insignificant.<br />
<br />
==Use in Specific Populations==<br />
<br />
====Pregnancy====<br />
<br />
* '''[[Pregnancy category#United States|Pregnancy Category (FDA)]]: C'''<br />
<br />
* '''[[Pregnancy category#Australia|Pregnancy Category (AUS)]]: {{PAGENAME}} is not included in Australian Drug Evaluation Committee (ADEC) Pregnancy Categories.'''<br />
<br />
In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
<br />
====Labor and Delivery====<br />
<br />
FDA package insert doesn't contain any information regarding "'''Labor and Delivery'''"<br />
<br />
====Nursing Mothers====<br />
<br />
Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
<br />
====Pediatric Use====<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
====Geriatric Use====<br />
Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
====Gender====<br />
<br />
The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range<br />
<br />
====Race====<br />
<br />
(Description)<br />
<br />
====Renal Impairment====<br />
<br />
Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
<br />
====Hepatic Impairment====<br />
<br />
Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
<br />
====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the exposure in humans at the MRHD.<br />
<br />
====Immunocompromised Patients====<br />
<br />
(Description)<br />
<br />
====Miscellaneous====<br />
<br />
=====Smokers=====<br />
Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
<br />
==Administration and Monitoring==<br />
<br />
====Administration====<br />
<br />
Oral<br />
<br />
====Monitoring====<br />
FDA package insert does't contain any information regarding "'''Monitoring'''"<br />
<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability).<br />
<br />
==IV Compatibility==<br />
<br />
FDA package insert doesn't contain any information regarding '''IV Compatibility'''<br />
<br />
==Overdosage==<br />
<br />
===Acute Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
<br />
====Management====<br />
<br />
FDA package insert doesn't contain any information regarding "'''Management '''"<br />
<br />
==Pharmacology==<br />
<br />
{{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
<br />
===Mechanism of Action===<br />
<br />
The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
<br />
===Structure===<br />
<br />
*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
<br />
<br />
===Pharmacodynamics===<br />
<br />
(Description)<br />
<br />
===Pharmacokinetics===<br />
<br />
Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
<br />
====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4‑dehydro‑cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4‑dehydro‑cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
<br />
===Nonclinical Toxicology===<br />
<br />
==Clinical Studies==<br />
<br />
*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
<br />
{|<br />
| [[image:Cilo2.png|400px|thumb]]<br />
|}<br />
<br />
<br />
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
<br />
==How Supplied==<br />
<br />
'''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
<br />
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0223-60 bottles of 60 and 0185-0223-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
==Images==<br />
<br />
===Drug Images===<br />
<br />
{|<br />
| [[File:Cilostazol50mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 50 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;123 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
{|<br />
| [[File:Cilostazol100mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 100 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;223 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
===Package and Label Display Panel===<br />
<br />
Sandoz Inc.<br />
Princeton, NJ 08540<br />
OS8128<br />
Rev. 02/13<br />
MF0223REV02/13<br />
Cilostazol 100mg Tablet<br />
<br />
{|<br />
| [[image:Cilostazollabel.jpg|400px|thumb]]<br />
|}<br />
<br />
{|<br />
| [[image:Cilostazollabel1.png|400px|thumb]]<br />
|}<br />
<br />
==Patient Information==<br />
<br />
===Patient Information from FDA===<br />
(sil-OS-tah-zol)<br />
<br />
Please read this leaflet before you start taking cilostazol tablets and each time you renew it in case anything has changed. This leaflet does not replace careful discussions with your doctor. You and your doctor should discuss cilostazol when you start taking it and at regular check-ups. You should follow your doctor’s advice about when to have check-ups.<br />
What is cilostazol for?<br />
Cilostazol may improve the symptoms of patients with a medical condition called intermittent claudication.<br />
What is intermittent claudication?<br />
Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. It occurs because narrowing or blockage of the arteries decreases blood flow to the legs. The decreased blood flow does not supply enough oxygen to the leg muscles during walking, resulting in these painful leg cramps.<br />
<br />
'''What treatments are available for intermittent claudication?'''<br />
<br />
The three main treatments available for intermittent claudication are:<br />
*Exercise. Your doctor may advise an exercise program.<br />
*Medication. Your doctor may prescribe a medication such as cilostazol. (See Who should not take cilostazol tablets?)<br />
*Surgery. Your doctor may recommend a surgical procedure to bypass the blocked segment of the artery. Another procedure is called a percutaneous transluminal angioplasty. In this procedure, a catheter (a flexible tube) is inserted into the artery to reduce the blockage and improve blood flow.<br />
<br />
'''How does cilostazol work?'''<br />
<br />
*The exact way that many drugs work is not well understood. Although how cilostazol works is not completely clear, its main effects are to dilate (widen) the arteries supplying blood to the legs and to decrease the ability of platelets in the blood to stick together. Platelets are particles that circulate in the blood and play a role in clotting.<br />
*Cilostazol may reduce the leg pain that patients with intermittent claudication experience, allowing them to walk farther before their leg pain occurs.<br />
*Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks. If you have not noticed any benefit from cilostazol tablets after 12 weeks you and your doctor may wish to discuss other forms of treatment.<br />
*Sometimes blood vessel disease of the legs causes pain at rest or breakdown of skin in the leg. Cilostazol has not been shown to work in patients with these problems.<br />
<br />
'''Who should not take cilostazol tablets?'''<br />
<br />
*Patients who have congestive heart failure (CHF) must not take cilostazol tablets. The most common symptoms of CHF are shortness of breath and swelling of the legs. However, other conditions may also cause these symptoms. It is important that you discuss with your doctor whether you have CHF.<br />
*Over 1,300 patients took cilostazol in studies that lasted for 3 to 6 months. The mortality rate in these patients was similar to placebo (less than 1%). These studies were too small to be sure there is not some increased risk of dying with longer use or in patients sicker than those in the studies.<br />
<br />
'''How should cilostazol tablets be taken?'''<br />
<br />
*Follow your doctor’s advice about how to take cilostazol tablets.<br />
*You should take cilostazol tablets twice a day, at least one half-hour before or two hours after breakfast and dinner. Take cilostazol tablets at about the same times each day.<br />
*Do not share cilostazol tablets with anyone else. It was prescribed only for you.<br />
*Keep cilostazol tablets and all drugs out of the reach of children.<br />
<br />
'''Can cilostazol tablets be taken with other drugs?'''<br />
<br />
Certain drugs and foods can increase the amount of cilostazol in the blood. Because of this, your doctor may adjust your dose of cilostazol or even stop it if you are taking or are going to take one of the following medications.<br />
Drugs Interacting with Cilostazol<br />
Generic Name (Brand Names)Type of Drug<br />
[[erythromycin]] (such as E.E.S.®, Erythrocin®) Antibiotic<br />
[[ketoconazole]] (Nizoral®), [[itraconazole]] (Sporanox®) Antifungal<br />
[[diltiazem]] (Cardizem®) Antihypertensive<br />
[[omeprazole]] (Prilosec®) Gastric acid reducer<br />
This list does not include every drug that may interact with cilostazol tablets. Therefore, you should tell your doctor about all medications that you are taking, including vitamins, herbal supplements and over-the-counter drugs you can buy without a prescription. You should also check with your doctor before taking a new medication after you have begun cilostazol tablets.<br />
<br />
'''What are the possible side effects of cilostazol tablets?'''<br />
<br />
Cilostazol tablets may cause side effects including headache, diarrhea, abnormal stools, increased heart rate and palpitations.<br />
You should discuss possible side effects with your doctor before taking cilostazol tablets and any time you think you are having a side effect.<br />
This provides only a summary of information about cilostazol tablets. If you have any questions about cilostazol tablets, talk to your doctor.<br />
'''Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.'''<br />
<br />
===Patient Information from NLM===<br />
<br />
For patient information about Cilostazol from NLM, click [[Cilostazol (patient information)|here]].<br />
<br />
==Precautions with Alcohol==<br />
<br />
Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
<br />
==Brand Names==<br />
<br />
Cilostazol®, Platel®.<br />
<br />
==Look-Alike Drug Names==<br />
<br />
* (Paired Confused Name 1a) — (Paired Confused Name 1b)<br />
* (Paired Confused Name 2a) — (Paired Confused Name 2b)<br />
* (Paired Confused Name 3a) — (Paired Confused Name 3b)<br />
<br />
==[http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm Drug Shortage Status]==<br />
<br />
==[http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price Price]==<br />
<br />
==References==<br />
<br />
{{reflist}}<br />
<br />
</div></div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=Cilostazol&diff=962132Cilostazol2014-04-03T10:51:01Z<p>Abdurahman Khalil: </p>
<hr />
<div>{{DrugProjectFormSinglePage<br />
|authorTag={{AK}}<br />
|genericName=Cilostazol<br />
|aOrAn=a<br />
|drugClass=Phosphodiesterase 3 inhibitor<br />
|indication=Intermittent claudication<br />
|hasBlackBoxWarning=Yes<br />
|adverseReactions=headache, dizziness, palpitation, diarrhea, rhinitis and pharyngitis.<br />
|blackBoxWarningTitle=Contraindication<br />
|blackBoxWarningBody=<i><span style="color:#FF0000;">Heart failure</span></i> '' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
|fdaLIADAdult=&lt;h4&gt;Intermittent claudication 1&lt;/h5&gt;<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
|offLabelAdultGuideSupport======Secondary prevention of stroke and TIA=====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid'''<ref name="Lansberg-2012">{{Cite journal | last1 = Lansberg | first1 = MG. | last2 = O'Donnell | first2 = MJ. | last3 = Khatri | first3 = P. | last4 = Lang | first4 = ES. | last5 = Nguyen-Huynh | first5 = MN. | last6 = Schwartz | first6 = NE. | last7 = Sonnenberg | first7 = FA. | last8 = Schulman | first8 = S. | last9 = Vandvik | first9 = PO. | title = Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e601S-36S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2302 | PMID = 22315273 }}</ref><br />
<br />
=====Thrombosis prophylaxis in percutaneous coronary intervention =====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid'''<ref name="Vandvik-2012">{{Cite journal | last1 = Vandvik | first1 = PO. | last2 = Lincoff | first2 = AM. | last3 = Gore | first3 = JM. | last4 = Gutterman | first4 = DD. | last5 = Sonnenberg | first5 = FA. | last6 = Alonso-Coello | first6 = P. | last7 = Akl | first7 = EA. | last8 = Lansberg | first8 = MG. | last9 = Guyatt | first9 = GH. | title = Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e637S-68S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2306 | PMID = 22315274 }}</ref><br />
|offLabelAdultNoGuideSupport======Secondary prevention of femoral artery occlusion after peripheral intervention=====<br />
<ref name="Iida-2013">{{Cite journal | last1 = Iida | first1 = O. | last2 = Yokoi | first2 = H. | last3 = Soga | first3 = Y. | last4 = Inoue | first4 = N. | last5 = Suzuki | first5 = K. | last6 = Yokoi | first6 = Y. | last7 = Kawasaki | first7 = D. | last8 = Zen | first8 = K. | last9 = Urasawa | first9 = K. | title = Cilostazol reduces angiographic restenosis after endovascular therapy for femoropopliteal lesions in the Sufficient Treatment of Peripheral Intervention by Cilostazol study. | journal = Circulation | volume = 127 | issue = 23 | pages = 2307-15 | month = Jun | year = 2013 | doi = 10.1161/CIRCULATIONAHA.112.000711 | PMID = 23652861 }}</ref><br />
<br />
|contraindications=* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
|warnings======Hematologic Adverse Reactions=====<br />
Rare cases have been reported of [[thrombocytopenia ]]or [[leukopenia ]]progressing to [[agranulocytosis ]]when cilostazol was not immediately discontinued. The agranulocytosis, however, was reversible on discontinuation of cilostazol.<br />
<br />
=====Use with Clopidogrel=====<br />
There is limited information with respect to the efficacy or safety of the concurrent use of cilostazol and [[clopidogrel]], a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Although it cannot be determined whether there was an additive effect on bleeding times during concomitant administration with cilostazol and [[clopidogrel]], caution is advised for checking bleeding times during co-administration.<br />
|clinicalTrials=Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol and 134 days for patients on placebo.<br />
<br />
The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with PLETAL 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included [[palpitation ]]and [[diarrhea]], both 1.1% for cilostazol (all doses) versus 0.1% for placebo.<br />
<br />
======Body as a Whole======<br />
*Common:<br />
:*Abdominal pain<br />
:*Back pain<br />
:*Headache <br />
:*Infection<br />
<br />
*Less common:<br />
[[Chills]], face [[edema]], [[fever]], [[generalized edema]], [[malaise]], [[neck rigidity]], [[pelvic pain]], [[retroperitoneal haemorrhage]].<br />
<br />
======Central Nervous System======<br />
<br />
*Common:<br />
:*Dizziness<br />
:*Vertigo<br />
<br />
*Less common:<br />
[[Anxiety]], [[insomnia]], [[neuralgia]].<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
*Common:<br />
:*Abnormal stool<br />
:*Diarrhea<br />
:*Dyspepsia<br />
:*Flatulence<br />
:*Nausea<br />
<br />
*Less common:<br />
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Metabolic & Nutritional======<br />
*Common:<br />
:*Peripheral edema<br />
<br />
*Less common:<br />
Increased [[creatinine]], [[gout]], [[hyperlipemia]], [[hyperuricemia]].<br />
<br />
======Musculoskeletal======<br />
<br />
*Common:<br />
:*Myalgia<br />
<br />
*Less common:<br />
[[Arthralgia]], bone pain, [[bursitis]].<br />
<br />
======Miscellaneous======<br />
Less common adverse reactions:<br />
<br />
*'''Endocrine:''' [[Diabetes mellitus]].<br />
<br />
*'''Hemic and Lymphatic:''' [[Anemia]], [[ecchymosis]],[[ iron deficiency anemia]], [[polycythemia]], [[purpura]].<br />
<br />
*'''Skin and Appendages:''' Dry skin, [[furunculosis]], skin hypertrophy, [[urticaria]].<br />
<br />
*'''Special Senses:''' [[Amblyopia]], [[blindness]], [[conjunctivitis]], [[diplopia]], ear pain, eye haemorrhage, [[retinal haemorrhage]], [[tinnitus]].<br />
<br />
*'''Urogenital:''' [[Albuminuria]], [[cystitis]], [[urinary frequency]], vaginal haemorrhage, vaginitis.<br />
|postmarketing=The following events have been reported spontaneously from worldwide post-marketing experience since the launch of PLETAL in the US.<br />
<br />
======Blood and lymphatic system disorders:======<br />
[[Agranulocytosis]],[[ aplastic anemia]], [[granulocytopenia]], [[pancytopenia]], [[thrombocytopenia]], [[leukopenia]], <br />
[[bleeding tendency]]<br />
<br />
======Cardiac disorders:======<br />
<br />
[[Torsades de pointes]], [[QT prolongation|QTc prolongation]] (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. [[complete atrioventricular block]], c[[ardiac failure ]]and [[bradyarrythmia]], when treated with cilostazol. Cilostazol was used "off label" due to its positive [[chronotropic]] action)<br />
<br />
======Gastrointestinal disorders:======<br />
<br />
*Gastrointestinal haemorrhage<br />
<br />
======General disorders and administration site conditions:======<br />
<br />
*Pain<br />
*[[chest pain]] <br />
*[[hot flushes]]<br />
<br />
======Hepatobiliary disorders:======<br />
<br />
*Hepatic dysfunction/abnormal liver function tests <br />
*[[jaundice]]<br />
<br />
======Injury, poisoning and procedural complications:======<br />
<br />
*Extradural [[haematoma ]] <br />
*Subdural haematoma<br />
<br />
=====Investigations:=====<br />
<br />
*[[Blood glucose]] increased, blood [[uric acid]] increased, [[platelet count]] decreased, [[white blood cell count]] decreased, increase in [[BUN]] (blood urea increased), blood pressure increase<br />
<br />
======Nervous system disorders:======<br />
<br />
*[[Intracranial haemorrhage]] <br />
*[[cerebral haemorrhage]] <br />
*[[cerebrovascular accident]]<br />
<br />
======Respiratory, thoracic and mediastinal disorders:======<br />
<br />
*Pulmonary haemorrhage<br />
*[[ interstitial pneumonia]]<br />
<br />
'''Skin and subcutaneous tissue disorders:'''<br />
<br />
*Haemorrhage subcutaneous, [[pruritus]], skin eruptions including [[Stevens-Johnson syndrome]], skin drug eruption ([[dermatitis medicamentosa]])<br />
<br />
======Vascular disorders:======<br />
<br />
*Subacute [[thrombosis ]](these cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting)<br />
|drugInteractions======Aspirin=====<br />
<br />
*Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of ADP-induced ex vivo platelet aggregation by 22% to 37% when compared to either aspirin or cilostazol alone. Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to cilostazol alone and by 48% compared to aspirin alone. However, short-term co-administration of aspirin with cilostazol had no clinically significant impact on PT, aPTT or bleeding time compared to aspirin alone. <br />
<br />
*Effects of long-term co-administration in the general population are unknown. In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was co-administered with cilostazol to 201 patients. The most frequent doses and mean durations of aspirin therapy were 75 mg to 81 mg daily for 137 days (107 patients) and 325 mg daily for 54 days (85 patients). There was no apparent increase in incidence of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.<br />
<br />
=====Warfarin=====<br />
<br />
The cytochrome P-450 isoenzymes involved in the metabolism of R-warfarin are CYP3A4, CYP1A2 and CYP2C19 and in the metabolism of S-warfarin, CYP2C9. Cilostazol did not inhibit either the metabolism or the pharmacologic effects (PT, aPTT, bleeding time or platelet aggregation) of R- and S-warfarin after a single 25-mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and cilostazol on the pharmacokinetics and pharmacodynamics of both drugs is unknown.<br />
<br />
=====Clopidogrel=====<br />
<br />
Multiple doses of clopidogrel do not significantly increase steady state plasma concentrations of cilostazol.<br />
<br />
=====Inhibitors of CYP3A4=====<br />
<br />
======Strong Inhibitors of CYP3A4======<br />
<br />
A priming dose of [[ketoconazole ]]400 mg (a strong inhibitor of CYP3A4), was given one day prior to co-administration of single doses of [[ketoconazole ]]400 mg and cilostazol 100 mg. This regimen increased cilostazol Cmax by 94% and AUC by 117%. Other strong inhibitors of CYP3A4, such as [[itraconazole]], [[fluconazole]], [[miconazole]], [[fluvoxamine]], [[fluoxetine]], [[nefazodone ]]and [[sertraline]], would be expected to have a similar effect <br />
<br />
======Moderate Inhibitors of CYP3A4======<br />
<br />
*[[Erythromycin ]]and Other [[Macrolide ]]Antibiotics: [[Erythromycin ]]is a moderately strong inhibitor of CYP3A4. Co-administration of erythromycin 500 mg q 8h with a single dose of cilostazol 100 mg increased cilostazol Cmax by 47% and AUC by 73%. Inhibition of cilostazol metabolism by erythromycin increased the AUC of 4´-trans-hydroxy-cilostazol by 141%. Other macrolide antibiotics (e.g., [[clarithromycin]]), but not all (e.g., [[azithromycin]]), would be expected to have a similar effect.<br />
<br />
*Diltiazem: [[Diltiazem]] 180 mg decreased the clearance of cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC increased ~40%.<br />
<br />
*Grapefruit Juice: [[Grapefruit juice]] increased the Cmax of cilostazol by ~50% , but had no effect on AUC.<br />
=====Inhibitors of CYP2C19=====<br />
<br />
[[Omeprazole]]: Co-administration of omeprazole did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%, probably the result of omeprazole’s potent inhibition of CYP2C19 <br />
<br />
=====Quinidine =====<br />
<br />
Concomitant administration of [[quinidine ]]with a single dose of cilostazol 100 mg did not alter cilostazol pharmacokinetics.<br />
<br />
=====Lovastatin=====<br />
<br />
The concomitant administration of [[lovastatin ]]with cilostazol decreases cilostazol Css, max and AUCT by 15%. There is also a decrease, although nonsignificant, in cilostazol metabolite concentrations. Co-administration of cilostazol with lovastatin increases lovastatin and β–hydroxy lovastatin AUC approximately 70%. This is most likely clinically insignificant.<br />
|useInPregnancyFDA=In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
|useInNursing=Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
|useInPed=The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
|useInGeri=Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
|useInGender=The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range.<br />
|useInRenalImpair=Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
|useInHepaticImpair=Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
|othersTitle=Smokers<br />
|useInOthers=Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
|administration=Oral<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability)<br />
|overdose=Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
|drugBox={{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
|mechAction=The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
|structure=*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
|PK=Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
<br />
====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4 dehydro cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4 dehydro cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
|nonClinToxic=====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the<br />
|clinicalStudies=*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
<br />
{|<br />
| [[image:Cilo2.png|400px|thumb]]<br />
|}<br />
<br />
<br />
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
|howSupplied='''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other.<br />
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other.<br />
|NDC=0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
|storage=Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
|manBy=Sandoz Inc.Princeton, NJ 08540<br />
|distBy=Bryant Ranch Prepack<br />
|isPill=Yes<br />
|dosageValue=50<br />
|dosageUnit=mg<br />
|pillImprint=E 123<br />
|pillSize=9<br />
|pillShape=Round<br />
|pillColor=White<br />
|pillScoring=1<br />
|pillImage=Cilostazol50mg.jpg<br />
}}<br />
{|class="infobox" style="position: fixed; top: 180px; right: 20px; margin: 0 0 0 0; border: 0; float: right; width: 15%; background: #104E8B; border-radius: 10px 10px 10px 10px;" cellpadding="0" cellspacing="0";<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #104E8B;" | [[{{PAGENAME}}|{{fontcolor|#F8F8FF|{{PAGENAME}}®}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #000000; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|Black Box Warning}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adult Indications and Dosage|{{fontcolor|#F8F8FF|Adult Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pediatric Indications and Dosage|{{fontcolor|#F8F8FF|Pediatric Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Contraindications|{{fontcolor|#F8F8FF|Contraindications}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Warnings|{{fontcolor|#F8F8FF|Warnings}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adverse Reactions|{{fontcolor|#F8F8FF|Adverse Reactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Drug Interactions|{{fontcolor|#F8F8FF|Drug Interactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Use in Specific Populations|{{fontcolor|#F8F8FF|Use in Specific Populations}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Administration and Monitoring|{{fontcolor|#F8F8FF|Administration and Monitoring}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#IV Compatibility|{{fontcolor|#F8F8FF|IV Compatibility}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Overdosage|{{fontcolor|#F8F8FF|Overdosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pharmacology|{{fontcolor|#F8F8FF|Pharmacology}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Clinical Studies|{{fontcolor|#F8F8FF|Clinical Studies}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#How Supplied|{{fontcolor|#F8F8FF|How Supplied}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Images|{{fontcolor|#F8F8FF|Images}}]]<br />
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm {{fontcolor|#F8F8FF|Drug Shortage Status}}]<br />
|-<br />
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|-<br />
|}<br />
<div style="width: 80%"><br />
__NOTOC__<br />
{{CMG}}<br />
<br />
{{SB}} Cilostazol®, Pletal®<br />
<br />
==Disclaimer==<br />
<br />
'''''WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature. The information provided is not a medical advice or treatment. WikiDoc does not promote any medication or off-label use of drugs. Please read our full disclaimer [[wikidoc:General_disclaimer|{{fontcolor|#FF0000|here}}]].'''''<br />
<br />
==<span style="color:#FF0000; background:#000000;">Black Box Warning</span>==<br />
<br />
FDA Package Insert for {{PAGENAME}} contains no information regarding ''Black Box Warning''.<br />
<br />
{| style="border: 3px solid #696969;"<br />
| style="background: #000000; border: 0px; padding: 20px 20px; width: 800px;" |<br />
<center><br />
<font color="#F8F8FF" style="font-weight: bold;">CONTRAINDICATION</font><br />
</center><br />
<br />
<center><br />
<font color="#F8F8FF" size="1" style="font-style: italic;">See full prescribing information for complete boxed warning.</font><br />
</center><br />
<br />
<font color="#F8F8FF" style="font-weight: bold;"><br />
''{{fontcolor|#FF0000|Condition Name:}}'' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
</font><br />
|}<br />
<br />
==Overview==<br />
<br />
{{PAGENAME}} is a_Phosphodiesterase 3 Inhibitor drug that is FDA approved for the treatment of intermittent claudication. There is a Black Box Warning for this drug as shown <span style="background:#000000;">'''[[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|here}}]]'''</span>. Common adverse reactions include headache, dizziness, palpitation, diarrhea, rhinitis and pharyngitis.<br />
<br />
==Adult Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Adult)===<br />
<br />
=====Intermittent claudication=====<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
<br />
===Off-Label Use and Dosage (Adult)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Secondary prevention of stroke and TIA=====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid'''<ref name="Lansberg-2012">{{Cite journal | last1 = Lansberg | first1 = MG. | last2 = O'Donnell | first2 = MJ. | last3 = Khatri | first3 = P. | last4 = Lang | first4 = ES. | last5 = Nguyen-Huynh | first5 = MN. | last6 = Schwartz | first6 = NE. | last7 = Sonnenberg | first7 = FA. | last8 = Schulman | first8 = S. | last9 = Vandvik | first9 = PO. | title = Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e601S-36S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2302 | PMID = 22315273 }}</ref><br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid''<ref name="Vandvik-2012">{{Cite journal | last1 = Vandvik | first1 = PO. | last2 = Lincoff | first2 = AM. | last3 = Gore | first3 = JM. | last4 = Gutterman | first4 = DD. | last5 = Sonnenberg | first5 = FA. | last6 = Alonso-Coello | first6 = P. | last7 = Akl | first7 = EA. | last8 = Lansberg | first8 = MG. | last9 = Guyatt | first9 = GH. | title = Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e637S-68S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2306 | PMID = 22315274 }}</ref><br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* There is limited information about ''Off-Label Non–Guideline-Supported Use'' of {{PAGENAME}} in adult patients.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Pediatric Indications and Dosage==<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
==Contraindications==<br />
* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
<br />
==Warnings==<br />
<br />
=====Hematologic Adverse Reactions=====<br />
Rare cases have been reported of [[thrombocytopenia ]]or [[leukopenia ]]progressing to [[agranulocytosis ]]when cilostazol was not immediately discontinued. The agranulocytosis, however, was reversible on discontinuation of cilostazol.<br />
<br />
=====Use with Clopidogrel=====<br />
There is limited information with respect to the efficacy or safety of the concurrent use of cilostazol and [[clopidogrel]], a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Although it cannot be determined whether there was an additive effect on bleeding times during concomitant administration with cilostazol and [[clopidogrel]], caution is advised for checking bleeding times during co-administration.<br />
<br />
==Adverse Reactions==<br />
<br />
===Clinical Trials Experience===<br />
Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol and 134 days for patients on placebo.<br />
<br />
The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with PLETAL 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included [[palpitation ]]and [[diarrhea]], both 1.1% for cilostazol (all doses) versus 0.1% for placebo.<br />
<br />
======Body as a Whole======<br />
*Common:<br />
:*Abdominal pain<br />
:*Back pain<br />
:*Headache <br />
:*Infection<br />
<br />
*Less common:<br />
[[Chills]], face [[edema]], [[fever]], [[generalized edema]], [[malaise]], [[neck rigidity]], [[pelvic pain]], [[retroperitoneal haemorrhage]].<br />
<br />
======Central Nervous System======<br />
<br />
*Common:<br />
:*Dizziness<br />
:*Vertigo<br />
<br />
*Less common:<br />
[[Anxiety]], [[insomnia]], [[neuralgia]].<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
*Common:<br />
:*Abnormal stool<br />
:*Diarrhea<br />
:*Dyspepsia<br />
:*Flatulence<br />
:*Nausea<br />
<br />
*Less common:<br />
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Metabolic & Nutritional======<br />
*Common:<br />
:*Peripheral edema<br />
<br />
*Less common:<br />
Increased [[creatinine]], [[gout]], [[hyperlipemia]], [[hyperuricemia]].<br />
<br />
======Musculoskeletal======<br />
<br />
*Common:<br />
:*Myalgia<br />
<br />
*Less common:<br />
[[Arthralgia]], bone pain, [[bursitis]].<br />
<br />
======Miscellaneous======<br />
Less common adverse reactions:<br />
<br />
*'''Endocrine:''' [[Diabetes mellitus]].<br />
<br />
*'''Hemic and Lymphatic:''' [[Anemia]], [[ecchymosis]],[[ iron deficiency anemia]], [[polycythemia]], [[purpura]].<br />
<br />
*'''Skin and Appendages:''' Dry skin, [[furunculosis]], skin hypertrophy, [[urticaria]].<br />
<br />
*'''Special Senses:''' [[Amblyopia]], [[blindness]], [[conjunctivitis]], [[diplopia]], ear pain, eye haemorrhage, [[retinal haemorrhage]], [[tinnitus]].<br />
<br />
*'''Urogenital:''' [[Albuminuria]], [[cystitis]], [[urinary frequency]], vaginal haemorrhage, vaginitis.<br />
<br />
===Postmarketing Experience===<br />
<br />
The following events have been reported spontaneously from worldwide post-marketing experience since the launch of PLETAL in the US.<br />
<br />
======Blood and lymphatic system disorders:======<br />
[[Agranulocytosis]],[[ aplastic anemia]], [[granulocytopenia]], [[pancytopenia]], [[thrombocytopenia]], [[leukopenia]], <br />
[[bleeding tendency]]<br />
<br />
======Cardiac disorders:======<br />
<br />
[[Torsades de pointes]], [[QT prolongation|QTc prolongation]] (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. [[complete atrioventricular block]], c[[ardiac failure ]]and [[bradyarrythmia]], when treated with cilostazol. Cilostazol was used "off label" due to its positive [[chronotropic]] action)<br />
<br />
======Gastrointestinal disorders:======<br />
<br />
*Gastrointestinal haemorrhage<br />
<br />
======General disorders and administration site conditions:======<br />
<br />
*Pain<br />
*[[chest pain]] <br />
*[[hot flushes]]<br />
<br />
======Hepatobiliary disorders:======<br />
<br />
*Hepatic dysfunction/abnormal liver function tests <br />
*[[jaundice]]<br />
<br />
======Injury, poisoning and procedural complications:======<br />
<br />
*Extradural [[haematoma ]] <br />
*Subdural haematoma<br />
<br />
=====Investigations:=====<br />
<br />
*[[Blood glucose]] increased, blood [[uric acid]] increased, [[platelet count]] decreased, [[white blood cell count]] decreased, increase in [[BUN]] (blood urea increased), blood pressure increase<br />
<br />
======Nervous system disorders:======<br />
<br />
*[[Intracranial haemorrhage]] <br />
*[[cerebral haemorrhage]] <br />
*[[cerebrovascular accident]]<br />
<br />
======Respiratory, thoracic and mediastinal disorders:======<br />
<br />
*Pulmonary haemorrhage<br />
*[[ interstitial pneumonia]]<br />
<br />
'''Skin and subcutaneous tissue disorders:'''<br />
<br />
*Haemorrhage subcutaneous, [[pruritus]], skin eruptions including [[Stevens-Johnson syndrome]], skin drug eruption ([[dermatitis medicamentosa]])<br />
<br />
======Vascular disorders:======<br />
<br />
*Subacute [[thrombosis ]](these cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting)<br />
<br />
==Drug Interactions==<br />
<br />
=====Aspirin=====<br />
<br />
*Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of ADP-induced ex vivo platelet aggregation by 22% to 37% when compared to either aspirin or cilostazol alone. Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to cilostazol alone and by 48% compared to aspirin alone. However, short-term co-administration of aspirin with cilostazol had no clinically significant impact on PT, aPTT or bleeding time compared to aspirin alone. <br />
<br />
*Effects of long-term co-administration in the general population are unknown. In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was co-administered with cilostazol to 201 patients. The most frequent doses and mean durations of aspirin therapy were 75 mg to 81 mg daily for 137 days (107 patients) and 325 mg daily for 54 days (85 patients). There was no apparent increase in incidence of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.<br />
<br />
=====Warfarin=====<br />
<br />
The cytochrome P-450 isoenzymes involved in the metabolism of R-warfarin are CYP3A4, CYP1A2 and CYP2C19 and in the metabolism of S-warfarin, CYP2C9. Cilostazol did not inhibit either the metabolism or the pharmacologic effects (PT, aPTT, bleeding time or platelet aggregation) of R- and S-warfarin after a single 25-mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and cilostazol on the pharmacokinetics and pharmacodynamics of both drugs is unknown.<br />
<br />
=====Clopidogrel=====<br />
<br />
Multiple doses of clopidogrel do not significantly increase steady state plasma concentrations of cilostazol.<br />
<br />
=====Inhibitors of CYP3A4=====<br />
<br />
======Strong Inhibitors of CYP3A4======<br />
<br />
A priming dose of [[ketoconazole ]]400 mg (a strong inhibitor of CYP3A4), was given one day prior to co-administration of single doses of [[ketoconazole ]]400 mg and cilostazol 100 mg. This regimen increased cilostazol Cmax by 94% and AUC by 117%. Other strong inhibitors of CYP3A4, such as [[itraconazole]], [[fluconazole]], [[miconazole]], [[fluvoxamine]], [[fluoxetine]], [[nefazodone ]]and [[sertraline]], would be expected to have a similar effect <br />
<br />
======Moderate Inhibitors of CYP3A4======<br />
<br />
*[[Erythromycin ]]and Other [[Macrolide ]]Antibiotics: [[Erythromycin ]]is a moderately strong inhibitor of CYP3A4. Co-administration of erythromycin 500 mg q 8h with a single dose of cilostazol 100 mg increased cilostazol Cmax by 47% and AUC by 73%. Inhibition of cilostazol metabolism by erythromycin increased the AUC of 4´-trans-hydroxy-cilostazol by 141%. Other macrolide antibiotics (e.g., [[clarithromycin]]), but not all (e.g., [[azithromycin]]), would be expected to have a similar effect.<br />
<br />
*Diltiazem: [[Diltiazem]] 180 mg decreased the clearance of cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC increased ~40%.<br />
<br />
*Grapefruit Juice: [[Grapefruit juice]] increased the Cmax of cilostazol by ~50% , but had no effect on AUC.<br />
=====Inhibitors of CYP2C19=====<br />
<br />
[[Omeprazole]]: Co-administration of omeprazole did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%, probably the result of omeprazole’s potent inhibition of CYP2C19 <br />
<br />
=====Quinidine =====<br />
<br />
Concomitant administration of [[quinidine ]]with a single dose of cilostazol 100 mg did not alter cilostazol pharmacokinetics.<br />
<br />
=====Lovastatin=====<br />
<br />
The concomitant administration of [[lovastatin ]]with cilostazol decreases cilostazol Css, max and AUCT by 15%. There is also a decrease, although nonsignificant, in cilostazol metabolite concentrations. Co-administration of cilostazol with lovastatin increases lovastatin and β–hydroxy lovastatin AUC approximately 70%. This is most likely clinically insignificant.<br />
<br />
==Use in Specific Populations==<br />
<br />
====Pregnancy====<br />
<br />
* '''[[Pregnancy category#United States|Pregnancy Category (FDA)]]: C'''<br />
<br />
* '''[[Pregnancy category#Australia|Pregnancy Category (AUS)]]: {{PAGENAME}} is not included in Australian Drug Evaluation Committee (ADEC) Pregnancy Categories.'''<br />
<br />
In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
<br />
====Labor and Delivery====<br />
<br />
FDA package insert doesn't contain any information regarding "'''Labor and Delivery'''"<br />
<br />
====Nursing Mothers====<br />
<br />
Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
<br />
====Pediatric Use====<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
====Geriatric Use====<br />
Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
====Gender====<br />
<br />
The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range<br />
<br />
====Race====<br />
<br />
(Description)<br />
<br />
====Renal Impairment====<br />
<br />
Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
<br />
====Hepatic Impairment====<br />
<br />
Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
<br />
====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the exposure in humans at the MRHD.<br />
<br />
====Immunocompromised Patients====<br />
<br />
(Description)<br />
<br />
====Miscellaneous====<br />
<br />
=====Smokers=====<br />
Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
<br />
==Administration and Monitoring==<br />
<br />
====Administration====<br />
<br />
Oral<br />
<br />
====Monitoring====<br />
FDA package insert does't contain any information regarding "'''Monitoring'''"<br />
<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability).<br />
<br />
==IV Compatibility==<br />
<br />
FDA package insert doesn't contain any information regarding '''IV Compatibility'''<br />
<br />
==Overdosage==<br />
<br />
===Acute Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
<br />
====Management====<br />
<br />
FDA package insert doesn't contain any information regarding "'''Management '''"<br />
<br />
==Pharmacology==<br />
<br />
{{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
<br />
===Mechanism of Action===<br />
<br />
The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
<br />
===Structure===<br />
<br />
*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
<br />
<br />
===Pharmacodynamics===<br />
<br />
(Description)<br />
<br />
===Pharmacokinetics===<br />
<br />
Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
<br />
====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4‑dehydro‑cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4‑dehydro‑cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
<br />
===Nonclinical Toxicology===<br />
<br />
==Clinical Studies==<br />
<br />
*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
<br />
{|<br />
| [[image:Cilo2.png|400px|thumb]]<br />
|}<br />
<br />
<br />
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
<br />
==How Supplied==<br />
<br />
'''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
<br />
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0223-60 bottles of 60 and 0185-0223-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
==Images==<br />
<br />
===Drug Images===<br />
<br />
{|<br />
| [[File:Cilostazol50mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 50 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;123 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
{|<br />
| [[File:Cilostazol100mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 100 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;223 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
===Package and Label Display Panel===<br />
<br />
Sandoz Inc.<br />
Princeton, NJ 08540<br />
OS8128<br />
Rev. 02/13<br />
MF0223REV02/13<br />
Cilostazol 100mg Tablet<br />
<br />
{|<br />
| [[image:Cilostazollabel.jpg|400px|thumb]]<br />
|}<br />
<br />
{|<br />
| [[image:Cilostazollabel1.png|400px|thumb]]<br />
|}<br />
<br />
==Patient Information==<br />
<br />
===Patient Information from FDA===<br />
(sil-OS-tah-zol)<br />
<br />
Please read this leaflet before you start taking cilostazol tablets and each time you renew it in case anything has changed. This leaflet does not replace careful discussions with your doctor. You and your doctor should discuss cilostazol when you start taking it and at regular check-ups. You should follow your doctor’s advice about when to have check-ups.<br />
What is cilostazol for?<br />
Cilostazol may improve the symptoms of patients with a medical condition called intermittent claudication.<br />
What is intermittent claudication?<br />
Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. It occurs because narrowing or blockage of the arteries decreases blood flow to the legs. The decreased blood flow does not supply enough oxygen to the leg muscles during walking, resulting in these painful leg cramps.<br />
<br />
'''What treatments are available for intermittent claudication?'''<br />
<br />
The three main treatments available for intermittent claudication are:<br />
*Exercise. Your doctor may advise an exercise program.<br />
*Medication. Your doctor may prescribe a medication such as cilostazol. (See Who should not take cilostazol tablets?)<br />
*Surgery. Your doctor may recommend a surgical procedure to bypass the blocked segment of the artery. Another procedure is called a percutaneous transluminal angioplasty. In this procedure, a catheter (a flexible tube) is inserted into the artery to reduce the blockage and improve blood flow.<br />
<br />
'''How does cilostazol work?'''<br />
<br />
*The exact way that many drugs work is not well understood. Although how cilostazol works is not completely clear, its main effects are to dilate (widen) the arteries supplying blood to the legs and to decrease the ability of platelets in the blood to stick together. Platelets are particles that circulate in the blood and play a role in clotting.<br />
*Cilostazol may reduce the leg pain that patients with intermittent claudication experience, allowing them to walk farther before their leg pain occurs.<br />
*Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks. If you have not noticed any benefit from cilostazol tablets after 12 weeks you and your doctor may wish to discuss other forms of treatment.<br />
*Sometimes blood vessel disease of the legs causes pain at rest or breakdown of skin in the leg. Cilostazol has not been shown to work in patients with these problems.<br />
<br />
'''Who should not take cilostazol tablets?'''<br />
<br />
*Patients who have congestive heart failure (CHF) must not take cilostazol tablets. The most common symptoms of CHF are shortness of breath and swelling of the legs. However, other conditions may also cause these symptoms. It is important that you discuss with your doctor whether you have CHF.<br />
*Over 1,300 patients took cilostazol in studies that lasted for 3 to 6 months. The mortality rate in these patients was similar to placebo (less than 1%). These studies were too small to be sure there is not some increased risk of dying with longer use or in patients sicker than those in the studies.<br />
<br />
'''How should cilostazol tablets be taken?'''<br />
<br />
*Follow your doctor’s advice about how to take cilostazol tablets.<br />
*You should take cilostazol tablets twice a day, at least one half-hour before or two hours after breakfast and dinner. Take cilostazol tablets at about the same times each day.<br />
*Do not share cilostazol tablets with anyone else. It was prescribed only for you.<br />
*Keep cilostazol tablets and all drugs out of the reach of children.<br />
<br />
'''Can cilostazol tablets be taken with other drugs?'''<br />
<br />
Certain drugs and foods can increase the amount of cilostazol in the blood. Because of this, your doctor may adjust your dose of cilostazol or even stop it if you are taking or are going to take one of the following medications.<br />
Drugs Interacting with Cilostazol<br />
Generic Name (Brand Names)Type of Drug<br />
[[erythromycin]] (such as E.E.S.®, Erythrocin®) Antibiotic<br />
[[ketoconazole]] (Nizoral®), [[itraconazole]] (Sporanox®) Antifungal<br />
[[diltiazem]] (Cardizem®) Antihypertensive<br />
[[omeprazole]] (Prilosec®) Gastric acid reducer<br />
This list does not include every drug that may interact with cilostazol tablets. Therefore, you should tell your doctor about all medications that you are taking, including vitamins, herbal supplements and over-the-counter drugs you can buy without a prescription. You should also check with your doctor before taking a new medication after you have begun cilostazol tablets.<br />
<br />
'''What are the possible side effects of cilostazol tablets?'''<br />
<br />
Cilostazol tablets may cause side effects including headache, diarrhea, abnormal stools, increased heart rate and palpitations.<br />
You should discuss possible side effects with your doctor before taking cilostazol tablets and any time you think you are having a side effect.<br />
This provides only a summary of information about cilostazol tablets. If you have any questions about cilostazol tablets, talk to your doctor.<br />
'''Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.'''<br />
<br />
===Patient Information from NLM===<br />
<br />
For patient information about Cilostazol from NLM, click [[Cilostazol (patient information)|here]].<br />
<br />
==Precautions with Alcohol==<br />
<br />
Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
<br />
==Brand Names==<br />
<br />
Cilostazol®, Platel®.<br />
<br />
==Look-Alike Drug Names==<br />
<br />
* (Paired Confused Name 1a) — (Paired Confused Name 1b)<br />
* (Paired Confused Name 2a) — (Paired Confused Name 2b)<br />
* (Paired Confused Name 3a) — (Paired Confused Name 3b)<br />
<br />
==[http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm Drug Shortage Status]==<br />
<br />
==[http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price Price]==<br />
<br />
==References==<br />
<br />
{{reflist}}<br />
<br />
</div></div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=Cilostazol&diff=962131Cilostazol2014-04-03T10:41:43Z<p>Abdurahman Khalil: </p>
<hr />
<div>{{DrugProjectFormSinglePage<br />
|authorTag={{AK}}<br />
|genericName=Cilostazol<br />
|aOrAn=a<br />
|drugClass=Phosphodiesterase 3 inhibitor<br />
|indication=Intermittent claudication<br />
|hasBlackBoxWarning=Yes<br />
|adverseReactions=headache, dizziness, palpitation, diarrhea, rhinitis and pharyngitis.<br />
|blackBoxWarningTitle=Contraindication<br />
|blackBoxWarningBody=<i><span style="color:#FF0000;">Heart failure</span></i> '' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
|fdaLIADAdult=&lt;h4&gt;Intermittent claudication 1&lt;/h5&gt;<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
|offLabelAdultGuideSupport======Secondary prevention of stroke and TIA=====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid'''<ref name="Lansberg-2012">{{Cite journal | last1 = Lansberg | first1 = MG. | last2 = O'Donnell | first2 = MJ. | last3 = Khatri | first3 = P. | last4 = Lang | first4 = ES. | last5 = Nguyen-Huynh | first5 = MN. | last6 = Schwartz | first6 = NE. | last7 = Sonnenberg | first7 = FA. | last8 = Schulman | first8 = S. | last9 = Vandvik | first9 = PO. | title = Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e601S-36S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2302 | PMID = 22315273 }}</ref><br />
<br />
=====Thrombosis prophylaxis in percutaneous coronary intervention =====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid'''<ref name="Vandvik-2012">{{Cite journal | last1 = Vandvik | first1 = PO. | last2 = Lincoff | first2 = AM. | last3 = Gore | first3 = JM. | last4 = Gutterman | first4 = DD. | last5 = Sonnenberg | first5 = FA. | last6 = Alonso-Coello | first6 = P. | last7 = Akl | first7 = EA. | last8 = Lansberg | first8 = MG. | last9 = Guyatt | first9 = GH. | title = Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e637S-68S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2306 | PMID = 22315274 }}</ref><br />
|offLabelAdultNoGuideSupport======Secondary prevention of femoral artery occlusion after peripheral intervention=====<br />
<ref name="Iida-2013">{{Cite journal | last1 = Iida | first1 = O. | last2 = Yokoi | first2 = H. | last3 = Soga | first3 = Y. | last4 = Inoue | first4 = N. | last5 = Suzuki | first5 = K. | last6 = Yokoi | first6 = Y. | last7 = Kawasaki | first7 = D. | last8 = Zen | first8 = K. | last9 = Urasawa | first9 = K. | title = Cilostazol reduces angiographic restenosis after endovascular therapy for femoropopliteal lesions in the Sufficient Treatment of Peripheral Intervention by Cilostazol study. | journal = Circulation | volume = 127 | issue = 23 | pages = 2307-15 | month = Jun | year = 2013 | doi = 10.1161/CIRCULATIONAHA.112.000711 | PMID = 23652861 }}</ref><br />
<br />
|contraindications=* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
|warnings======Hematologic Adverse Reactions=====<br />
Rare cases have been reported of [[thrombocytopenia ]]or [[leukopenia ]]progressing to [[agranulocytosis ]]when cilostazol was not immediately discontinued. The agranulocytosis, however, was reversible on discontinuation of cilostazol.<br />
<br />
=====Use with Clopidogrel=====<br />
There is limited information with respect to the efficacy or safety of the concurrent use of cilostazol and [[clopidogrel]], a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Although it cannot be determined whether there was an additive effect on bleeding times during concomitant administration with cilostazol and [[clopidogrel]], caution is advised for checking bleeding times during co-administration.<br />
|clinicalTrials=Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol and 134 days for patients on placebo.<br />
<br />
The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with PLETAL 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included [[palpitation ]]and [[diarrhea]], both 1.1% for cilostazol (all doses) versus 0.1% for placebo.<br />
<br />
======Body as a Whole======<br />
*Common:<br />
:*Abdominal pain<br />
:*Back pain<br />
:*Headache <br />
:*Infection<br />
<br />
*Less common:<br />
[[Chills]], face [[edema]], [[fever]], [[generalized edema]], [[malaise]], [[neck rigidity]], [[pelvic pain]], [[retroperitoneal haemorrhage]].<br />
<br />
======Central Nervous System======<br />
<br />
*Common:<br />
:*Dizziness<br />
:*Vertigo<br />
<br />
*Less common:<br />
[[Anxiety]], [[insomnia]], [[neuralgia]].<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
*Common:<br />
:*Abnormal stool<br />
:*Diarrhea<br />
:*Dyspepsia<br />
:*Flatulence<br />
:*Nausea<br />
<br />
*Less common:<br />
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Metabolic & Nutritional======<br />
*Common:<br />
:*Peripheral edema<br />
<br />
*Less common:<br />
Increased [[creatinine]], [[gout]], [[hyperlipemia]], [[hyperuricemia]].<br />
<br />
======Musculoskeletal======<br />
<br />
*Common:<br />
:*Myalgia<br />
<br />
*Less common:<br />
[[Arthralgia]], bone pain, [[bursitis]].<br />
<br />
======Miscellaneous======<br />
Less common adverse reactions:<br />
<br />
*'''Endocrine:''' [[Diabetes mellitus]].<br />
<br />
*'''Hemic and Lymphatic:''' [[Anemia]], [[ecchymosis]],[[ iron deficiency anemia]], [[polycythemia]], [[purpura]].<br />
<br />
*'''Skin and Appendages:''' Dry skin, [[furunculosis]], skin hypertrophy, [[urticaria]].<br />
<br />
*'''Special Senses:''' [[Amblyopia]], [[blindness]], [[conjunctivitis]], [[diplopia]], ear pain, eye haemorrhage, [[retinal haemorrhage]], [[tinnitus]].<br />
<br />
*'''Urogenital:''' [[Albuminuria]], [[cystitis]], [[urinary frequency]], vaginal haemorrhage, vaginitis.<br />
|postmarketing=The following events have been reported spontaneously from worldwide post-marketing experience since the launch of PLETAL in the US.<br />
<br />
======Blood and lymphatic system disorders:======<br />
[[Agranulocytosis]],[[ aplastic anemia]], [[granulocytopenia]], [[pancytopenia]], [[thrombocytopenia]], [[leukopenia]], <br />
[[bleeding tendency]]<br />
<br />
======Cardiac disorders:======<br />
<br />
[[Torsades de pointes]], [[QT prolongation|QTc prolongation]] (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. [[complete atrioventricular block]], c[[ardiac failure ]]and [[bradyarrythmia]], when treated with cilostazol. Cilostazol was used "off label" due to its positive [[chronotropic]] action)<br />
<br />
======Gastrointestinal disorders:======<br />
<br />
*Gastrointestinal haemorrhage<br />
<br />
======General disorders and administration site conditions:======<br />
<br />
*Pain<br />
*[[chest pain]] <br />
*[[hot flushes]]<br />
<br />
======Hepatobiliary disorders:======<br />
<br />
*Hepatic dysfunction/abnormal liver function tests <br />
*[[jaundice]]<br />
<br />
======Injury, poisoning and procedural complications:======<br />
<br />
*Extradural [[haematoma ]] <br />
*Subdural haematoma<br />
<br />
=====Investigations:=====<br />
<br />
*[[Blood glucose]] increased, blood [[uric acid]] increased, [[platelet count]] decreased, [[white blood cell count]] decreased, increase in [[BUN]] (blood urea increased), blood pressure increase<br />
<br />
======Nervous system disorders:======<br />
<br />
*[[Intracranial haemorrhage]] <br />
*[[cerebral haemorrhage]] <br />
*[[cerebrovascular accident]]<br />
<br />
======Respiratory, thoracic and mediastinal disorders:======<br />
<br />
*Pulmonary haemorrhage<br />
*[[ interstitial pneumonia]]<br />
<br />
'''Skin and subcutaneous tissue disorders:'''<br />
<br />
*Haemorrhage subcutaneous, [[pruritus]], skin eruptions including [[Stevens-Johnson syndrome]], skin drug eruption ([[dermatitis medicamentosa]])<br />
<br />
======Vascular disorders:======<br />
<br />
*Subacute [[thrombosis ]](these cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting)<br />
|drugInteractions======Aspirin=====<br />
<br />
*Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of ADP-induced ex vivo platelet aggregation by 22% to 37% when compared to either aspirin or cilostazol alone. Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to cilostazol alone and by 48% compared to aspirin alone. However, short-term co-administration of aspirin with cilostazol had no clinically significant impact on PT, aPTT or bleeding time compared to aspirin alone. <br />
<br />
*Effects of long-term co-administration in the general population are unknown. In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was co-administered with cilostazol to 201 patients. The most frequent doses and mean durations of aspirin therapy were 75 mg to 81 mg daily for 137 days (107 patients) and 325 mg daily for 54 days (85 patients). There was no apparent increase in incidence of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.<br />
<br />
=====Warfarin=====<br />
<br />
The cytochrome P-450 isoenzymes involved in the metabolism of R-warfarin are CYP3A4, CYP1A2 and CYP2C19 and in the metabolism of S-warfarin, CYP2C9. Cilostazol did not inhibit either the metabolism or the pharmacologic effects (PT, aPTT, bleeding time or platelet aggregation) of R- and S-warfarin after a single 25-mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and cilostazol on the pharmacokinetics and pharmacodynamics of both drugs is unknown.<br />
<br />
=====Clopidogrel=====<br />
<br />
Multiple doses of clopidogrel do not significantly increase steady state plasma concentrations of cilostazol.<br />
<br />
=====Inhibitors of CYP3A4=====<br />
<br />
======Strong Inhibitors of CYP3A4======<br />
<br />
A priming dose of [[ketoconazole ]]400 mg (a strong inhibitor of CYP3A4), was given one day prior to co-administration of single doses of [[ketoconazole ]]400 mg and cilostazol 100 mg. This regimen increased cilostazol Cmax by 94% and AUC by 117%. Other strong inhibitors of CYP3A4, such as [[itraconazole]], [[fluconazole]], [[miconazole]], [[fluvoxamine]], [[fluoxetine]], [[nefazodone ]]and [[sertraline]], would be expected to have a similar effect <br />
<br />
======Moderate Inhibitors of CYP3A4======<br />
<br />
*[[Erythromycin ]]and Other [[Macrolide ]]Antibiotics: [[Erythromycin ]]is a moderately strong inhibitor of CYP3A4. Co-administration of erythromycin 500 mg q 8h with a single dose of cilostazol 100 mg increased cilostazol Cmax by 47% and AUC by 73%. Inhibition of cilostazol metabolism by erythromycin increased the AUC of 4´-trans-hydroxy-cilostazol by 141%. Other macrolide antibiotics (e.g., [[clarithromycin]]), but not all (e.g., [[azithromycin]]), would be expected to have a similar effect.<br />
<br />
*Diltiazem: [[Diltiazem]] 180 mg decreased the clearance of cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC increased ~40%.<br />
<br />
*Grapefruit Juice: [[Grapefruit juice]] increased the Cmax of cilostazol by ~50% , but had no effect on AUC.<br />
=====Inhibitors of CYP2C19=====<br />
<br />
[[Omeprazole]]: Co-administration of omeprazole did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%, probably the result of omeprazole’s potent inhibition of CYP2C19 <br />
<br />
=====Quinidine =====<br />
<br />
Concomitant administration of [[quinidine ]]with a single dose of cilostazol 100 mg did not alter cilostazol pharmacokinetics.<br />
<br />
=====Lovastatin=====<br />
<br />
The concomitant administration of [[lovastatin ]]with cilostazol decreases cilostazol Css, max and AUCT by 15%. There is also a decrease, although nonsignificant, in cilostazol metabolite concentrations. Co-administration of cilostazol with lovastatin increases lovastatin and β–hydroxy lovastatin AUC approximately 70%. This is most likely clinically insignificant.<br />
|useInPregnancyFDA=In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
|useInNursing=Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
|useInPed=The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
|useInGeri=Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
|useInGender=The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range.<br />
|useInRenalImpair=Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
|useInHepaticImpair=Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
|othersTitle=Smokers<br />
|useInOthers=Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
|administration=Oral<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability)<br />
|overdose=Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
|drugBox={{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
|mechAction=The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
|structure=*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
|PK=Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
<br />
====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4 dehydro cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4 dehydro cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
|nonClinToxic=====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the<br />
|clinicalStudies=*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
<br />
{|<br />
| [[image:Cilo2.png|400px|thumb]]<br />
|}<br />
<br />
<br />
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
|howSupplied='''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other.<br />
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other.<br />
|NDC=0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
|storage=Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
|manBy=Sandoz Inc.Princeton, NJ 08540<br />
|distBy=Bryant Ranch Prepack<br />
|isPill=Yes<br />
|dosageValue=50<br />
|dosageUnit=mg<br />
|pillImprint=E 123<br />
|pillSize=9<br />
|pillShape=Round<br />
|pillColor=White<br />
|pillScoring=1<br />
|pillImage=http://static.wikidoc.org/0/0e/Cilostazol50mg.jpg<br />
}}<br />
{|class="infobox" style="position: fixed; top: 180px; right: 20px; margin: 0 0 0 0; border: 0; float: right; width: 15%; background: #104E8B; border-radius: 10px 10px 10px 10px;" cellpadding="0" cellspacing="0";<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #104E8B;" | [[{{PAGENAME}}|{{fontcolor|#F8F8FF|{{PAGENAME}}®}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #000000; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|Black Box Warning}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adult Indications and Dosage|{{fontcolor|#F8F8FF|Adult Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pediatric Indications and Dosage|{{fontcolor|#F8F8FF|Pediatric Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Contraindications|{{fontcolor|#F8F8FF|Contraindications}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Warnings|{{fontcolor|#F8F8FF|Warnings}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adverse Reactions|{{fontcolor|#F8F8FF|Adverse Reactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Drug Interactions|{{fontcolor|#F8F8FF|Drug Interactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Use in Specific Populations|{{fontcolor|#F8F8FF|Use in Specific Populations}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Administration and Monitoring|{{fontcolor|#F8F8FF|Administration and Monitoring}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#IV Compatibility|{{fontcolor|#F8F8FF|IV Compatibility}}]]<br />
|-<br />
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|-<br />
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|-<br />
|}<br />
<div style="width: 80%"><br />
__NOTOC__<br />
{{CMG}}<br />
<br />
{{SB}} Cilostazol®, Pletal®<br />
<br />
==Disclaimer==<br />
<br />
'''''WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature. The information provided is not a medical advice or treatment. WikiDoc does not promote any medication or off-label use of drugs. Please read our full disclaimer [[wikidoc:General_disclaimer|{{fontcolor|#FF0000|here}}]].'''''<br />
<br />
==<span style="color:#FF0000; background:#000000;">Black Box Warning</span>==<br />
<br />
FDA Package Insert for {{PAGENAME}} contains no information regarding ''Black Box Warning''.<br />
<br />
{| style="border: 3px solid #696969;"<br />
| style="background: #000000; border: 0px; padding: 20px 20px; width: 800px;" |<br />
<center><br />
<font color="#F8F8FF" style="font-weight: bold;">CONTRAINDICATION</font><br />
</center><br />
<br />
<center><br />
<font color="#F8F8FF" size="1" style="font-style: italic;">See full prescribing information for complete boxed warning.</font><br />
</center><br />
<br />
<font color="#F8F8FF" style="font-weight: bold;"><br />
''{{fontcolor|#FF0000|Condition Name:}}'' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
</font><br />
|}<br />
<br />
==Overview==<br />
<br />
{{PAGENAME}} is a_Phosphodiesterase 3 Inhibitor drug that is FDA approved for the treatment of intermittent claudication. There is a Black Box Warning for this drug as shown <span style="background:#000000;">'''[[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|here}}]]'''</span>. Common adverse reactions include headache, dizziness, palpitation, diarrhea, rhinitis and pharyngitis.<br />
<br />
==Adult Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Adult)===<br />
<br />
=====Intermittent claudication=====<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
<br />
===Off-Label Use and Dosage (Adult)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Secondary prevention of stroke and TIA=====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid'''<ref name="Lansberg-2012">{{Cite journal | last1 = Lansberg | first1 = MG. | last2 = O'Donnell | first2 = MJ. | last3 = Khatri | first3 = P. | last4 = Lang | first4 = ES. | last5 = Nguyen-Huynh | first5 = MN. | last6 = Schwartz | first6 = NE. | last7 = Sonnenberg | first7 = FA. | last8 = Schulman | first8 = S. | last9 = Vandvik | first9 = PO. | title = Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e601S-36S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2302 | PMID = 22315273 }}</ref><br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid''<ref name="Vandvik-2012">{{Cite journal | last1 = Vandvik | first1 = PO. | last2 = Lincoff | first2 = AM. | last3 = Gore | first3 = JM. | last4 = Gutterman | first4 = DD. | last5 = Sonnenberg | first5 = FA. | last6 = Alonso-Coello | first6 = P. | last7 = Akl | first7 = EA. | last8 = Lansberg | first8 = MG. | last9 = Guyatt | first9 = GH. | title = Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e637S-68S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2306 | PMID = 22315274 }}</ref><br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* There is limited information about ''Off-Label Non–Guideline-Supported Use'' of {{PAGENAME}} in adult patients.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Pediatric Indications and Dosage==<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
==Contraindications==<br />
* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
<br />
==Warnings==<br />
<br />
=====Hematologic Adverse Reactions=====<br />
Rare cases have been reported of [[thrombocytopenia ]]or [[leukopenia ]]progressing to [[agranulocytosis ]]when cilostazol was not immediately discontinued. The agranulocytosis, however, was reversible on discontinuation of cilostazol.<br />
<br />
=====Use with Clopidogrel=====<br />
There is limited information with respect to the efficacy or safety of the concurrent use of cilostazol and [[clopidogrel]], a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Although it cannot be determined whether there was an additive effect on bleeding times during concomitant administration with cilostazol and [[clopidogrel]], caution is advised for checking bleeding times during co-administration.<br />
<br />
==Adverse Reactions==<br />
<br />
===Clinical Trials Experience===<br />
Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol and 134 days for patients on placebo.<br />
<br />
The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with PLETAL 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included [[palpitation ]]and [[diarrhea]], both 1.1% for cilostazol (all doses) versus 0.1% for placebo.<br />
<br />
======Body as a Whole======<br />
*Common:<br />
:*Abdominal pain<br />
:*Back pain<br />
:*Headache <br />
:*Infection<br />
<br />
*Less common:<br />
[[Chills]], face [[edema]], [[fever]], [[generalized edema]], [[malaise]], [[neck rigidity]], [[pelvic pain]], [[retroperitoneal haemorrhage]].<br />
<br />
======Central Nervous System======<br />
<br />
*Common:<br />
:*Dizziness<br />
:*Vertigo<br />
<br />
*Less common:<br />
[[Anxiety]], [[insomnia]], [[neuralgia]].<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
*Common:<br />
:*Abnormal stool<br />
:*Diarrhea<br />
:*Dyspepsia<br />
:*Flatulence<br />
:*Nausea<br />
<br />
*Less common:<br />
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Metabolic & Nutritional======<br />
*Common:<br />
:*Peripheral edema<br />
<br />
*Less common:<br />
Increased [[creatinine]], [[gout]], [[hyperlipemia]], [[hyperuricemia]].<br />
<br />
======Musculoskeletal======<br />
<br />
*Common:<br />
:*Myalgia<br />
<br />
*Less common:<br />
[[Arthralgia]], bone pain, [[bursitis]].<br />
<br />
======Miscellaneous======<br />
Less common adverse reactions:<br />
<br />
*'''Endocrine:''' [[Diabetes mellitus]].<br />
<br />
*'''Hemic and Lymphatic:''' [[Anemia]], [[ecchymosis]],[[ iron deficiency anemia]], [[polycythemia]], [[purpura]].<br />
<br />
*'''Skin and Appendages:''' Dry skin, [[furunculosis]], skin hypertrophy, [[urticaria]].<br />
<br />
*'''Special Senses:''' [[Amblyopia]], [[blindness]], [[conjunctivitis]], [[diplopia]], ear pain, eye haemorrhage, [[retinal haemorrhage]], [[tinnitus]].<br />
<br />
*'''Urogenital:''' [[Albuminuria]], [[cystitis]], [[urinary frequency]], vaginal haemorrhage, vaginitis.<br />
<br />
===Postmarketing Experience===<br />
<br />
The following events have been reported spontaneously from worldwide post-marketing experience since the launch of PLETAL in the US.<br />
<br />
======Blood and lymphatic system disorders:======<br />
[[Agranulocytosis]],[[ aplastic anemia]], [[granulocytopenia]], [[pancytopenia]], [[thrombocytopenia]], [[leukopenia]], <br />
[[bleeding tendency]]<br />
<br />
======Cardiac disorders:======<br />
<br />
[[Torsades de pointes]], [[QT prolongation|QTc prolongation]] (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. [[complete atrioventricular block]], c[[ardiac failure ]]and [[bradyarrythmia]], when treated with cilostazol. Cilostazol was used "off label" due to its positive [[chronotropic]] action)<br />
<br />
======Gastrointestinal disorders:======<br />
<br />
*Gastrointestinal haemorrhage<br />
<br />
======General disorders and administration site conditions:======<br />
<br />
*Pain<br />
*[[chest pain]] <br />
*[[hot flushes]]<br />
<br />
======Hepatobiliary disorders:======<br />
<br />
*Hepatic dysfunction/abnormal liver function tests <br />
*[[jaundice]]<br />
<br />
======Injury, poisoning and procedural complications:======<br />
<br />
*Extradural [[haematoma ]] <br />
*Subdural haematoma<br />
<br />
=====Investigations:=====<br />
<br />
*[[Blood glucose]] increased, blood [[uric acid]] increased, [[platelet count]] decreased, [[white blood cell count]] decreased, increase in [[BUN]] (blood urea increased), blood pressure increase<br />
<br />
======Nervous system disorders:======<br />
<br />
*[[Intracranial haemorrhage]] <br />
*[[cerebral haemorrhage]] <br />
*[[cerebrovascular accident]]<br />
<br />
======Respiratory, thoracic and mediastinal disorders:======<br />
<br />
*Pulmonary haemorrhage<br />
*[[ interstitial pneumonia]]<br />
<br />
'''Skin and subcutaneous tissue disorders:'''<br />
<br />
*Haemorrhage subcutaneous, [[pruritus]], skin eruptions including [[Stevens-Johnson syndrome]], skin drug eruption ([[dermatitis medicamentosa]])<br />
<br />
======Vascular disorders:======<br />
<br />
*Subacute [[thrombosis ]](these cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting)<br />
<br />
==Drug Interactions==<br />
<br />
=====Aspirin=====<br />
<br />
*Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of ADP-induced ex vivo platelet aggregation by 22% to 37% when compared to either aspirin or cilostazol alone. Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to cilostazol alone and by 48% compared to aspirin alone. However, short-term co-administration of aspirin with cilostazol had no clinically significant impact on PT, aPTT or bleeding time compared to aspirin alone. <br />
<br />
*Effects of long-term co-administration in the general population are unknown. In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was co-administered with cilostazol to 201 patients. The most frequent doses and mean durations of aspirin therapy were 75 mg to 81 mg daily for 137 days (107 patients) and 325 mg daily for 54 days (85 patients). There was no apparent increase in incidence of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.<br />
<br />
=====Warfarin=====<br />
<br />
The cytochrome P-450 isoenzymes involved in the metabolism of R-warfarin are CYP3A4, CYP1A2 and CYP2C19 and in the metabolism of S-warfarin, CYP2C9. Cilostazol did not inhibit either the metabolism or the pharmacologic effects (PT, aPTT, bleeding time or platelet aggregation) of R- and S-warfarin after a single 25-mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and cilostazol on the pharmacokinetics and pharmacodynamics of both drugs is unknown.<br />
<br />
=====Clopidogrel=====<br />
<br />
Multiple doses of clopidogrel do not significantly increase steady state plasma concentrations of cilostazol.<br />
<br />
=====Inhibitors of CYP3A4=====<br />
<br />
======Strong Inhibitors of CYP3A4======<br />
<br />
A priming dose of [[ketoconazole ]]400 mg (a strong inhibitor of CYP3A4), was given one day prior to co-administration of single doses of [[ketoconazole ]]400 mg and cilostazol 100 mg. This regimen increased cilostazol Cmax by 94% and AUC by 117%. Other strong inhibitors of CYP3A4, such as [[itraconazole]], [[fluconazole]], [[miconazole]], [[fluvoxamine]], [[fluoxetine]], [[nefazodone ]]and [[sertraline]], would be expected to have a similar effect <br />
<br />
======Moderate Inhibitors of CYP3A4======<br />
<br />
*[[Erythromycin ]]and Other [[Macrolide ]]Antibiotics: [[Erythromycin ]]is a moderately strong inhibitor of CYP3A4. Co-administration of erythromycin 500 mg q 8h with a single dose of cilostazol 100 mg increased cilostazol Cmax by 47% and AUC by 73%. Inhibition of cilostazol metabolism by erythromycin increased the AUC of 4´-trans-hydroxy-cilostazol by 141%. Other macrolide antibiotics (e.g., [[clarithromycin]]), but not all (e.g., [[azithromycin]]), would be expected to have a similar effect.<br />
<br />
*Diltiazem: [[Diltiazem]] 180 mg decreased the clearance of cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC increased ~40%.<br />
<br />
*Grapefruit Juice: [[Grapefruit juice]] increased the Cmax of cilostazol by ~50% , but had no effect on AUC.<br />
=====Inhibitors of CYP2C19=====<br />
<br />
[[Omeprazole]]: Co-administration of omeprazole did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%, probably the result of omeprazole’s potent inhibition of CYP2C19 <br />
<br />
=====Quinidine =====<br />
<br />
Concomitant administration of [[quinidine ]]with a single dose of cilostazol 100 mg did not alter cilostazol pharmacokinetics.<br />
<br />
=====Lovastatin=====<br />
<br />
The concomitant administration of [[lovastatin ]]with cilostazol decreases cilostazol Css, max and AUCT by 15%. There is also a decrease, although nonsignificant, in cilostazol metabolite concentrations. Co-administration of cilostazol with lovastatin increases lovastatin and β–hydroxy lovastatin AUC approximately 70%. This is most likely clinically insignificant.<br />
<br />
==Use in Specific Populations==<br />
<br />
====Pregnancy====<br />
<br />
* '''[[Pregnancy category#United States|Pregnancy Category (FDA)]]: C'''<br />
<br />
* '''[[Pregnancy category#Australia|Pregnancy Category (AUS)]]: {{PAGENAME}} is not included in Australian Drug Evaluation Committee (ADEC) Pregnancy Categories.'''<br />
<br />
In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
<br />
====Labor and Delivery====<br />
<br />
FDA package insert doesn't contain any information regarding "'''Labor and Delivery'''"<br />
<br />
====Nursing Mothers====<br />
<br />
Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
<br />
====Pediatric Use====<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
====Geriatric Use====<br />
Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
====Gender====<br />
<br />
The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range<br />
<br />
====Race====<br />
<br />
(Description)<br />
<br />
====Renal Impairment====<br />
<br />
Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
<br />
====Hepatic Impairment====<br />
<br />
Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
<br />
====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the exposure in humans at the MRHD.<br />
<br />
====Immunocompromised Patients====<br />
<br />
(Description)<br />
<br />
====Miscellaneous====<br />
<br />
=====Smokers=====<br />
Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
<br />
==Administration and Monitoring==<br />
<br />
====Administration====<br />
<br />
Oral<br />
<br />
====Monitoring====<br />
FDA package insert does't contain any information regarding "'''Monitoring'''"<br />
<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability).<br />
<br />
==IV Compatibility==<br />
<br />
FDA package insert doesn't contain any information regarding '''IV Compatibility'''<br />
<br />
==Overdosage==<br />
<br />
===Acute Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
<br />
====Management====<br />
<br />
FDA package insert doesn't contain any information regarding "'''Management '''"<br />
<br />
==Pharmacology==<br />
<br />
{{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
<br />
===Mechanism of Action===<br />
<br />
The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
<br />
===Structure===<br />
<br />
*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
<br />
<br />
===Pharmacodynamics===<br />
<br />
(Description)<br />
<br />
===Pharmacokinetics===<br />
<br />
Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
<br />
====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4‑dehydro‑cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4‑dehydro‑cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
<br />
===Nonclinical Toxicology===<br />
<br />
==Clinical Studies==<br />
<br />
*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
<br />
{|<br />
| [[image:Cilo2.png|400px|thumb]]<br />
|}<br />
<br />
<br />
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
<br />
==How Supplied==<br />
<br />
'''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
<br />
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0223-60 bottles of 60 and 0185-0223-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
==Images==<br />
<br />
===Drug Images===<br />
<br />
{|<br />
| [[File:Cilostazol50mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 50 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;123 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
{|<br />
| [[File:Cilostazol100mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 100 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;223 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
===Package and Label Display Panel===<br />
<br />
Sandoz Inc.<br />
Princeton, NJ 08540<br />
OS8128<br />
Rev. 02/13<br />
MF0223REV02/13<br />
Cilostazol 100mg Tablet<br />
<br />
{|<br />
| [[image:Cilostazollabel.jpg|400px|thumb]]<br />
|}<br />
<br />
{|<br />
| [[image:Cilostazollabel1.png|400px|thumb]]<br />
|}<br />
<br />
==Patient Information==<br />
<br />
===Patient Information from FDA===<br />
(sil-OS-tah-zol)<br />
<br />
Please read this leaflet before you start taking cilostazol tablets and each time you renew it in case anything has changed. This leaflet does not replace careful discussions with your doctor. You and your doctor should discuss cilostazol when you start taking it and at regular check-ups. You should follow your doctor’s advice about when to have check-ups.<br />
What is cilostazol for?<br />
Cilostazol may improve the symptoms of patients with a medical condition called intermittent claudication.<br />
What is intermittent claudication?<br />
Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. It occurs because narrowing or blockage of the arteries decreases blood flow to the legs. The decreased blood flow does not supply enough oxygen to the leg muscles during walking, resulting in these painful leg cramps.<br />
<br />
'''What treatments are available for intermittent claudication?'''<br />
<br />
The three main treatments available for intermittent claudication are:<br />
*Exercise. Your doctor may advise an exercise program.<br />
*Medication. Your doctor may prescribe a medication such as cilostazol. (See Who should not take cilostazol tablets?)<br />
*Surgery. Your doctor may recommend a surgical procedure to bypass the blocked segment of the artery. Another procedure is called a percutaneous transluminal angioplasty. In this procedure, a catheter (a flexible tube) is inserted into the artery to reduce the blockage and improve blood flow.<br />
<br />
'''How does cilostazol work?'''<br />
<br />
*The exact way that many drugs work is not well understood. Although how cilostazol works is not completely clear, its main effects are to dilate (widen) the arteries supplying blood to the legs and to decrease the ability of platelets in the blood to stick together. Platelets are particles that circulate in the blood and play a role in clotting.<br />
*Cilostazol may reduce the leg pain that patients with intermittent claudication experience, allowing them to walk farther before their leg pain occurs.<br />
*Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks. If you have not noticed any benefit from cilostazol tablets after 12 weeks you and your doctor may wish to discuss other forms of treatment.<br />
*Sometimes blood vessel disease of the legs causes pain at rest or breakdown of skin in the leg. Cilostazol has not been shown to work in patients with these problems.<br />
<br />
'''Who should not take cilostazol tablets?'''<br />
<br />
*Patients who have congestive heart failure (CHF) must not take cilostazol tablets. The most common symptoms of CHF are shortness of breath and swelling of the legs. However, other conditions may also cause these symptoms. It is important that you discuss with your doctor whether you have CHF.<br />
*Over 1,300 patients took cilostazol in studies that lasted for 3 to 6 months. The mortality rate in these patients was similar to placebo (less than 1%). These studies were too small to be sure there is not some increased risk of dying with longer use or in patients sicker than those in the studies.<br />
<br />
'''How should cilostazol tablets be taken?'''<br />
<br />
*Follow your doctor’s advice about how to take cilostazol tablets.<br />
*You should take cilostazol tablets twice a day, at least one half-hour before or two hours after breakfast and dinner. Take cilostazol tablets at about the same times each day.<br />
*Do not share cilostazol tablets with anyone else. It was prescribed only for you.<br />
*Keep cilostazol tablets and all drugs out of the reach of children.<br />
<br />
'''Can cilostazol tablets be taken with other drugs?'''<br />
<br />
Certain drugs and foods can increase the amount of cilostazol in the blood. Because of this, your doctor may adjust your dose of cilostazol or even stop it if you are taking or are going to take one of the following medications.<br />
Drugs Interacting with Cilostazol<br />
Generic Name (Brand Names)Type of Drug<br />
[[erythromycin]] (such as E.E.S.®, Erythrocin®) Antibiotic<br />
[[ketoconazole]] (Nizoral®), [[itraconazole]] (Sporanox®) Antifungal<br />
[[diltiazem]] (Cardizem®) Antihypertensive<br />
[[omeprazole]] (Prilosec®) Gastric acid reducer<br />
This list does not include every drug that may interact with cilostazol tablets. Therefore, you should tell your doctor about all medications that you are taking, including vitamins, herbal supplements and over-the-counter drugs you can buy without a prescription. You should also check with your doctor before taking a new medication after you have begun cilostazol tablets.<br />
<br />
'''What are the possible side effects of cilostazol tablets?'''<br />
<br />
Cilostazol tablets may cause side effects including headache, diarrhea, abnormal stools, increased heart rate and palpitations.<br />
You should discuss possible side effects with your doctor before taking cilostazol tablets and any time you think you are having a side effect.<br />
This provides only a summary of information about cilostazol tablets. If you have any questions about cilostazol tablets, talk to your doctor.<br />
'''Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.'''<br />
<br />
===Patient Information from NLM===<br />
<br />
For patient information about Cilostazol from NLM, click [[Cilostazol (patient information)|here]].<br />
<br />
==Precautions with Alcohol==<br />
<br />
Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
<br />
==Brand Names==<br />
<br />
Cilostazol®, Platel®.<br />
<br />
==Look-Alike Drug Names==<br />
<br />
* (Paired Confused Name 1a) — (Paired Confused Name 1b)<br />
* (Paired Confused Name 2a) — (Paired Confused Name 2b)<br />
* (Paired Confused Name 3a) — (Paired Confused Name 3b)<br />
<br />
==[http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm Drug Shortage Status]==<br />
<br />
==[http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price Price]==<br />
<br />
==References==<br />
<br />
{{reflist}}<br />
<br />
</div></div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=Cilostazol&diff=962116Cilostazol2014-04-03T02:45:18Z<p>Abdurahman Khalil: </p>
<hr />
<div>{{DrugProjectFormSinglePage<br />
|authorTag={{AK}}<br />
|genericName=Cilostazol<br />
|aOrAn=a<br />
|drugClass=Phosphodiesterase 3 inhibitor<br />
|indication=Intermittent claudication<br />
|hasBlackBoxWarning=Yes<br />
|adverseReactions=headache, dizziness, palpitation, diarrhea, rhinitis and pharyngitis.<br />
|blackBoxWarningTitle=Contraindication<br />
|blackBoxWarningBody=<i><span style="color:#FF0000;">Heart failure</span></i> '' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
|fdaLIADAdult=&lt;h4&gt;Intermittent claudication 1&lt;/h5&gt;<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
|offLabelAdultGuideSupport======Secondary prevention of stroke and TIA=====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid'''<ref name="Lansberg-2012">{{Cite journal | last1 = Lansberg | first1 = MG. | last2 = O'Donnell | first2 = MJ. | last3 = Khatri | first3 = P. | last4 = Lang | first4 = ES. | last5 = Nguyen-Huynh | first5 = MN. | last6 = Schwartz | first6 = NE. | last7 = Sonnenberg | first7 = FA. | last8 = Schulman | first8 = S. | last9 = Vandvik | first9 = PO. | title = Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e601S-36S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2302 | PMID = 22315273 }}</ref><br />
<br />
=====Thrombosis prophylaxis in percutaneous coronary intervention =====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid'''<ref name="Vandvik-2012">{{Cite journal | last1 = Vandvik | first1 = PO. | last2 = Lincoff | first2 = AM. | last3 = Gore | first3 = JM. | last4 = Gutterman | first4 = DD. | last5 = Sonnenberg | first5 = FA. | last6 = Alonso-Coello | first6 = P. | last7 = Akl | first7 = EA. | last8 = Lansberg | first8 = MG. | last9 = Guyatt | first9 = GH. | title = Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e637S-68S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2306 | PMID = 22315274 }}</ref><br />
|contraindications=* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
|warnings======Hematologic Adverse Reactions=====<br />
Rare cases have been reported of [[thrombocytopenia ]]or [[leukopenia ]]progressing to [[agranulocytosis ]]when cilostazol was not immediately discontinued. The agranulocytosis, however, was reversible on discontinuation of cilostazol.<br />
<br />
=====Use with Clopidogrel=====<br />
There is limited information with respect to the efficacy or safety of the concurrent use of cilostazol and [[clopidogrel]], a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Although it cannot be determined whether there was an additive effect on bleeding times during concomitant administration with cilostazol and [[clopidogrel]], caution is advised for checking bleeding times during co-administration.<br />
|clinicalTrials=Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol and 134 days for patients on placebo.<br />
<br />
The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with PLETAL 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included [[palpitation ]]and [[diarrhea]], both 1.1% for cilostazol (all doses) versus 0.1% for placebo.<br />
<br />
======Body as a Whole======<br />
*Common:<br />
:*Abdominal pain<br />
:*Back pain<br />
:*Headache <br />
:*Infection<br />
<br />
*Less common:<br />
[[Chills]], face [[edema]], [[fever]], [[generalized edema]], [[malaise]], [[neck rigidity]], [[pelvic pain]], [[retroperitoneal haemorrhage]].<br />
<br />
======Central Nervous System======<br />
<br />
*Common:<br />
:*Dizziness<br />
:*Vertigo<br />
<br />
*Less common:<br />
[[Anxiety]], [[insomnia]], [[neuralgia]].<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
*Common:<br />
:*Abnormal stool<br />
:*Diarrhea<br />
:*Dyspepsia<br />
:*Flatulence<br />
:*Nausea<br />
<br />
*Less common:<br />
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Metabolic & Nutritional======<br />
*Common:<br />
:*Peripheral edema<br />
<br />
*Less common:<br />
Increased [[creatinine]], [[gout]], [[hyperlipemia]], [[hyperuricemia]].<br />
<br />
======Musculoskeletal======<br />
<br />
*Common:<br />
:*Myalgia<br />
<br />
*Less common:<br />
[[Arthralgia]], bone pain, [[bursitis]].<br />
<br />
======Miscellaneous======<br />
Less common adverse reactions:<br />
<br />
*'''Endocrine:''' [[Diabetes mellitus]].<br />
<br />
*'''Hemic and Lymphatic:''' [[Anemia]], [[ecchymosis]],[[ iron deficiency anemia]], [[polycythemia]], [[purpura]].<br />
<br />
*'''Skin and Appendages:''' Dry skin, [[furunculosis]], skin hypertrophy, [[urticaria]].<br />
<br />
*'''Special Senses:''' [[Amblyopia]], [[blindness]], [[conjunctivitis]], [[diplopia]], ear pain, eye haemorrhage, [[retinal haemorrhage]], [[tinnitus]].<br />
<br />
*'''Urogenital:''' [[Albuminuria]], [[cystitis]], [[urinary frequency]], vaginal haemorrhage, vaginitis.<br />
|postmarketing=The following events have been reported spontaneously from worldwide post-marketing experience since the launch of PLETAL in the US.<br />
<br />
======Blood and lymphatic system disorders:======<br />
[[Agranulocytosis]],[[ aplastic anemia]], [[granulocytopenia]], [[pancytopenia]], [[thrombocytopenia]], [[leukopenia]], <br />
[[bleeding tendency]]<br />
<br />
======Cardiac disorders:======<br />
<br />
[[Torsades de pointes]], [[QT prolongation|QTc prolongation]] (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. [[complete atrioventricular block]], c[[ardiac failure ]]and [[bradyarrythmia]], when treated with cilostazol. Cilostazol was used "off label" due to its positive [[chronotropic]] action)<br />
<br />
======Gastrointestinal disorders:======<br />
<br />
*Gastrointestinal haemorrhage<br />
<br />
======General disorders and administration site conditions:======<br />
<br />
*Pain<br />
*[[chest pain]] <br />
*[[hot flushes]]<br />
<br />
======Hepatobiliary disorders:======<br />
<br />
*Hepatic dysfunction/abnormal liver function tests <br />
*[[jaundice]]<br />
<br />
======Injury, poisoning and procedural complications:======<br />
<br />
*Extradural [[haematoma ]] <br />
*Subdural haematoma<br />
<br />
=====Investigations:=====<br />
<br />
*[[Blood glucose]] increased, blood [[uric acid]] increased, [[platelet count]] decreased, [[white blood cell count]] decreased, increase in [[BUN]] (blood urea increased), blood pressure increase<br />
<br />
======Nervous system disorders:======<br />
<br />
*[[Intracranial haemorrhage]] <br />
*[[cerebral haemorrhage]] <br />
*[[cerebrovascular accident]]<br />
<br />
======Respiratory, thoracic and mediastinal disorders:======<br />
<br />
*Pulmonary haemorrhage<br />
*[[ interstitial pneumonia]]<br />
<br />
'''Skin and subcutaneous tissue disorders:'''<br />
<br />
*Haemorrhage subcutaneous, [[pruritus]], skin eruptions including [[Stevens-Johnson syndrome]], skin drug eruption ([[dermatitis medicamentosa]])<br />
<br />
======Vascular disorders:======<br />
<br />
*Subacute [[thrombosis ]](these cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting)<br />
|drugInteractions======Aspirin=====<br />
<br />
*Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of ADP-induced ex vivo platelet aggregation by 22% to 37% when compared to either aspirin or cilostazol alone. Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to cilostazol alone and by 48% compared to aspirin alone. However, short-term co-administration of aspirin with cilostazol had no clinically significant impact on PT, aPTT or bleeding time compared to aspirin alone. <br />
<br />
*Effects of long-term co-administration in the general population are unknown. In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was co-administered with cilostazol to 201 patients. The most frequent doses and mean durations of aspirin therapy were 75 mg to 81 mg daily for 137 days (107 patients) and 325 mg daily for 54 days (85 patients). There was no apparent increase in incidence of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.<br />
<br />
=====Warfarin=====<br />
<br />
The cytochrome P-450 isoenzymes involved in the metabolism of R-warfarin are CYP3A4, CYP1A2 and CYP2C19 and in the metabolism of S-warfarin, CYP2C9. Cilostazol did not inhibit either the metabolism or the pharmacologic effects (PT, aPTT, bleeding time or platelet aggregation) of R- and S-warfarin after a single 25-mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and cilostazol on the pharmacokinetics and pharmacodynamics of both drugs is unknown.<br />
<br />
=====Clopidogrel=====<br />
<br />
Multiple doses of clopidogrel do not significantly increase steady state plasma concentrations of cilostazol.<br />
<br />
=====Inhibitors of CYP3A4=====<br />
<br />
======Strong Inhibitors of CYP3A4======<br />
<br />
A priming dose of [[ketoconazole ]]400 mg (a strong inhibitor of CYP3A4), was given one day prior to co-administration of single doses of [[ketoconazole ]]400 mg and cilostazol 100 mg. This regimen increased cilostazol Cmax by 94% and AUC by 117%. Other strong inhibitors of CYP3A4, such as [[itraconazole]], [[fluconazole]], [[miconazole]], [[fluvoxamine]], [[fluoxetine]], [[nefazodone ]]and [[sertraline]], would be expected to have a similar effect <br />
<br />
======Moderate Inhibitors of CYP3A4======<br />
<br />
*[[Erythromycin ]]and Other [[Macrolide ]]Antibiotics: [[Erythromycin ]]is a moderately strong inhibitor of CYP3A4. Co-administration of erythromycin 500 mg q 8h with a single dose of cilostazol 100 mg increased cilostazol Cmax by 47% and AUC by 73%. Inhibition of cilostazol metabolism by erythromycin increased the AUC of 4´-trans-hydroxy-cilostazol by 141%. Other macrolide antibiotics (e.g., [[clarithromycin]]), but not all (e.g., [[azithromycin]]), would be expected to have a similar effect.<br />
<br />
*Diltiazem: [[Diltiazem]] 180 mg decreased the clearance of cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC increased ~40%.<br />
<br />
*Grapefruit Juice: [[Grapefruit juice]] increased the Cmax of cilostazol by ~50% , but had no effect on AUC.<br />
=====Inhibitors of CYP2C19=====<br />
<br />
[[Omeprazole]]: Co-administration of omeprazole did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%, probably the result of omeprazole’s potent inhibition of CYP2C19 <br />
<br />
=====Quinidine =====<br />
<br />
Concomitant administration of [[quinidine ]]with a single dose of cilostazol 100 mg did not alter cilostazol pharmacokinetics.<br />
<br />
=====Lovastatin=====<br />
<br />
The concomitant administration of [[lovastatin ]]with cilostazol decreases cilostazol Css, max and AUCT by 15%. There is also a decrease, although nonsignificant, in cilostazol metabolite concentrations. Co-administration of cilostazol with lovastatin increases lovastatin and β–hydroxy lovastatin AUC approximately 70%. This is most likely clinically insignificant.<br />
|useInPregnancyFDA=In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
|useInNursing=Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
|useInPed=The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
|useInGeri=Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
|useInGender=The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range.<br />
|useInRenalImpair=Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
|useInHepaticImpair=Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
|othersTitle=Smokers<br />
|useInOthers=Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
|administration=Oral<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability)<br />
|overdose=Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
|drugBox={{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
|mechAction=The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
|structure=*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
|PK=Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
<br />
====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4 dehydro cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4 dehydro cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
|nonClinToxic=====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the<br />
|clinicalStudies=*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
<br />
{|<br />
| [[image:Cilo2.png|400px|thumb]]<br />
|}<br />
<br />
<br />
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
|howSupplied='''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other.<br />
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other.<br />
|NDC=0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
|storage=Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
|manBy=Sandoz Inc.Princeton, NJ 08540<br />
|distBy=Bryant Ranch Prepack<br />
|isPill=Yes<br />
|dosageValue=50<br />
|dosageUnit=mg<br />
|pillImprint=E 123<br />
|pillSize=9<br />
|pillShape=Round<br />
|pillColor=White<br />
|pillScoring=1<br />
|pillImage=http://static.wikidoc.org/0/0e/Cilostazol50mg.jpg<br />
}}<br />
{|class="infobox" style="position: fixed; top: 180px; right: 20px; margin: 0 0 0 0; border: 0; float: right; width: 15%; background: #104E8B; border-radius: 10px 10px 10px 10px;" cellpadding="0" cellspacing="0";<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #104E8B;" | [[{{PAGENAME}}|{{fontcolor|#F8F8FF|{{PAGENAME}}®}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #000000; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|Black Box Warning}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adult Indications and Dosage|{{fontcolor|#F8F8FF|Adult Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pediatric Indications and Dosage|{{fontcolor|#F8F8FF|Pediatric Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Contraindications|{{fontcolor|#F8F8FF|Contraindications}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Warnings|{{fontcolor|#F8F8FF|Warnings}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adverse Reactions|{{fontcolor|#F8F8FF|Adverse Reactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Drug Interactions|{{fontcolor|#F8F8FF|Drug Interactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Use in Specific Populations|{{fontcolor|#F8F8FF|Use in Specific Populations}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Administration and Monitoring|{{fontcolor|#F8F8FF|Administration and Monitoring}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#IV Compatibility|{{fontcolor|#F8F8FF|IV Compatibility}}]]<br />
|-<br />
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|-<br />
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|-<br />
|}<br />
<div style="width: 80%"><br />
__NOTOC__<br />
{{CMG}}<br />
<br />
{{SB}} Cilostazol®, Pletal®<br />
<br />
==Disclaimer==<br />
<br />
'''''WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature. The information provided is not a medical advice or treatment. WikiDoc does not promote any medication or off-label use of drugs. Please read our full disclaimer [[wikidoc:General_disclaimer|{{fontcolor|#FF0000|here}}]].'''''<br />
<br />
==<span style="color:#FF0000; background:#000000;">Black Box Warning</span>==<br />
<br />
FDA Package Insert for {{PAGENAME}} contains no information regarding ''Black Box Warning''.<br />
<br />
{| style="border: 3px solid #696969;"<br />
| style="background: #000000; border: 0px; padding: 20px 20px; width: 800px;" |<br />
<center><br />
<font color="#F8F8FF" style="font-weight: bold;">CONTRAINDICATION</font><br />
</center><br />
<br />
<center><br />
<font color="#F8F8FF" size="1" style="font-style: italic;">See full prescribing information for complete boxed warning.</font><br />
</center><br />
<br />
<font color="#F8F8FF" style="font-weight: bold;"><br />
''{{fontcolor|#FF0000|Condition Name:}}'' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
</font><br />
|}<br />
<br />
==Overview==<br />
<br />
{{PAGENAME}} is a_Phosphodiesterase 3 Inhibitor drug that is FDA approved for the treatment of intermittent claudication. There is a Black Box Warning for this drug as shown <span style="background:#000000;">'''[[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|here}}]]'''</span>. Common adverse reactions include headache, dizziness, palpitation, diarrhea, rhinitis and pharyngitis.<br />
<br />
==Adult Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Adult)===<br />
<br />
=====Intermittent claudication=====<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
<br />
===Off-Label Use and Dosage (Adult)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Secondary prevention of stroke and TIA=====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid'''<ref name="Lansberg-2012">{{Cite journal | last1 = Lansberg | first1 = MG. | last2 = O'Donnell | first2 = MJ. | last3 = Khatri | first3 = P. | last4 = Lang | first4 = ES. | last5 = Nguyen-Huynh | first5 = MN. | last6 = Schwartz | first6 = NE. | last7 = Sonnenberg | first7 = FA. | last8 = Schulman | first8 = S. | last9 = Vandvik | first9 = PO. | title = Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e601S-36S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2302 | PMID = 22315273 }}</ref><br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid''<ref name="Vandvik-2012">{{Cite journal | last1 = Vandvik | first1 = PO. | last2 = Lincoff | first2 = AM. | last3 = Gore | first3 = JM. | last4 = Gutterman | first4 = DD. | last5 = Sonnenberg | first5 = FA. | last6 = Alonso-Coello | first6 = P. | last7 = Akl | first7 = EA. | last8 = Lansberg | first8 = MG. | last9 = Guyatt | first9 = GH. | title = Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e637S-68S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2306 | PMID = 22315274 }}</ref><br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* There is limited information about ''Off-Label Non–Guideline-Supported Use'' of {{PAGENAME}} in adult patients.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Pediatric Indications and Dosage==<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
==Contraindications==<br />
* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
<br />
==Warnings==<br />
<br />
=====Hematologic Adverse Reactions=====<br />
Rare cases have been reported of [[thrombocytopenia ]]or [[leukopenia ]]progressing to [[agranulocytosis ]]when cilostazol was not immediately discontinued. The agranulocytosis, however, was reversible on discontinuation of cilostazol.<br />
<br />
=====Use with Clopidogrel=====<br />
There is limited information with respect to the efficacy or safety of the concurrent use of cilostazol and [[clopidogrel]], a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Although it cannot be determined whether there was an additive effect on bleeding times during concomitant administration with cilostazol and [[clopidogrel]], caution is advised for checking bleeding times during co-administration.<br />
<br />
==Adverse Reactions==<br />
<br />
===Clinical Trials Experience===<br />
Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol and 134 days for patients on placebo.<br />
<br />
The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with PLETAL 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included [[palpitation ]]and [[diarrhea]], both 1.1% for cilostazol (all doses) versus 0.1% for placebo.<br />
<br />
======Body as a Whole======<br />
*Common:<br />
:*Abdominal pain<br />
:*Back pain<br />
:*Headache <br />
:*Infection<br />
<br />
*Less common:<br />
[[Chills]], face [[edema]], [[fever]], [[generalized edema]], [[malaise]], [[neck rigidity]], [[pelvic pain]], [[retroperitoneal haemorrhage]].<br />
<br />
======Central Nervous System======<br />
<br />
*Common:<br />
:*Dizziness<br />
:*Vertigo<br />
<br />
*Less common:<br />
[[Anxiety]], [[insomnia]], [[neuralgia]].<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
*Common:<br />
:*Abnormal stool<br />
:*Diarrhea<br />
:*Dyspepsia<br />
:*Flatulence<br />
:*Nausea<br />
<br />
*Less common:<br />
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Metabolic & Nutritional======<br />
*Common:<br />
:*Peripheral edema<br />
<br />
*Less common:<br />
Increased [[creatinine]], [[gout]], [[hyperlipemia]], [[hyperuricemia]].<br />
<br />
======Musculoskeletal======<br />
<br />
*Common:<br />
:*Myalgia<br />
<br />
*Less common:<br />
[[Arthralgia]], bone pain, [[bursitis]].<br />
<br />
======Miscellaneous======<br />
Less common adverse reactions:<br />
<br />
*'''Endocrine:''' [[Diabetes mellitus]].<br />
<br />
*'''Hemic and Lymphatic:''' [[Anemia]], [[ecchymosis]],[[ iron deficiency anemia]], [[polycythemia]], [[purpura]].<br />
<br />
*'''Skin and Appendages:''' Dry skin, [[furunculosis]], skin hypertrophy, [[urticaria]].<br />
<br />
*'''Special Senses:''' [[Amblyopia]], [[blindness]], [[conjunctivitis]], [[diplopia]], ear pain, eye haemorrhage, [[retinal haemorrhage]], [[tinnitus]].<br />
<br />
*'''Urogenital:''' [[Albuminuria]], [[cystitis]], [[urinary frequency]], vaginal haemorrhage, vaginitis.<br />
<br />
===Postmarketing Experience===<br />
<br />
The following events have been reported spontaneously from worldwide post-marketing experience since the launch of PLETAL in the US.<br />
<br />
======Blood and lymphatic system disorders:======<br />
[[Agranulocytosis]],[[ aplastic anemia]], [[granulocytopenia]], [[pancytopenia]], [[thrombocytopenia]], [[leukopenia]], <br />
[[bleeding tendency]]<br />
<br />
======Cardiac disorders:======<br />
<br />
[[Torsades de pointes]], [[QT prolongation|QTc prolongation]] (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. [[complete atrioventricular block]], c[[ardiac failure ]]and [[bradyarrythmia]], when treated with cilostazol. Cilostazol was used "off label" due to its positive [[chronotropic]] action)<br />
<br />
======Gastrointestinal disorders:======<br />
<br />
*Gastrointestinal haemorrhage<br />
<br />
======General disorders and administration site conditions:======<br />
<br />
*Pain<br />
*[[chest pain]] <br />
*[[hot flushes]]<br />
<br />
======Hepatobiliary disorders:======<br />
<br />
*Hepatic dysfunction/abnormal liver function tests <br />
*[[jaundice]]<br />
<br />
======Injury, poisoning and procedural complications:======<br />
<br />
*Extradural [[haematoma ]] <br />
*Subdural haematoma<br />
<br />
=====Investigations:=====<br />
<br />
*[[Blood glucose]] increased, blood [[uric acid]] increased, [[platelet count]] decreased, [[white blood cell count]] decreased, increase in [[BUN]] (blood urea increased), blood pressure increase<br />
<br />
======Nervous system disorders:======<br />
<br />
*[[Intracranial haemorrhage]] <br />
*[[cerebral haemorrhage]] <br />
*[[cerebrovascular accident]]<br />
<br />
======Respiratory, thoracic and mediastinal disorders:======<br />
<br />
*Pulmonary haemorrhage<br />
*[[ interstitial pneumonia]]<br />
<br />
'''Skin and subcutaneous tissue disorders:'''<br />
<br />
*Haemorrhage subcutaneous, [[pruritus]], skin eruptions including [[Stevens-Johnson syndrome]], skin drug eruption ([[dermatitis medicamentosa]])<br />
<br />
======Vascular disorders:======<br />
<br />
*Subacute [[thrombosis ]](these cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting)<br />
<br />
==Drug Interactions==<br />
<br />
=====Aspirin=====<br />
<br />
*Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of ADP-induced ex vivo platelet aggregation by 22% to 37% when compared to either aspirin or cilostazol alone. Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to cilostazol alone and by 48% compared to aspirin alone. However, short-term co-administration of aspirin with cilostazol had no clinically significant impact on PT, aPTT or bleeding time compared to aspirin alone. <br />
<br />
*Effects of long-term co-administration in the general population are unknown. In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was co-administered with cilostazol to 201 patients. The most frequent doses and mean durations of aspirin therapy were 75 mg to 81 mg daily for 137 days (107 patients) and 325 mg daily for 54 days (85 patients). There was no apparent increase in incidence of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.<br />
<br />
=====Warfarin=====<br />
<br />
The cytochrome P-450 isoenzymes involved in the metabolism of R-warfarin are CYP3A4, CYP1A2 and CYP2C19 and in the metabolism of S-warfarin, CYP2C9. Cilostazol did not inhibit either the metabolism or the pharmacologic effects (PT, aPTT, bleeding time or platelet aggregation) of R- and S-warfarin after a single 25-mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and cilostazol on the pharmacokinetics and pharmacodynamics of both drugs is unknown.<br />
<br />
=====Clopidogrel=====<br />
<br />
Multiple doses of clopidogrel do not significantly increase steady state plasma concentrations of cilostazol.<br />
<br />
=====Inhibitors of CYP3A4=====<br />
<br />
======Strong Inhibitors of CYP3A4======<br />
<br />
A priming dose of [[ketoconazole ]]400 mg (a strong inhibitor of CYP3A4), was given one day prior to co-administration of single doses of [[ketoconazole ]]400 mg and cilostazol 100 mg. This regimen increased cilostazol Cmax by 94% and AUC by 117%. Other strong inhibitors of CYP3A4, such as [[itraconazole]], [[fluconazole]], [[miconazole]], [[fluvoxamine]], [[fluoxetine]], [[nefazodone ]]and [[sertraline]], would be expected to have a similar effect <br />
<br />
======Moderate Inhibitors of CYP3A4======<br />
<br />
*[[Erythromycin ]]and Other [[Macrolide ]]Antibiotics: [[Erythromycin ]]is a moderately strong inhibitor of CYP3A4. Co-administration of erythromycin 500 mg q 8h with a single dose of cilostazol 100 mg increased cilostazol Cmax by 47% and AUC by 73%. Inhibition of cilostazol metabolism by erythromycin increased the AUC of 4´-trans-hydroxy-cilostazol by 141%. Other macrolide antibiotics (e.g., [[clarithromycin]]), but not all (e.g., [[azithromycin]]), would be expected to have a similar effect.<br />
<br />
*Diltiazem: [[Diltiazem]] 180 mg decreased the clearance of cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC increased ~40%.<br />
<br />
*Grapefruit Juice: [[Grapefruit juice]] increased the Cmax of cilostazol by ~50% , but had no effect on AUC.<br />
=====Inhibitors of CYP2C19=====<br />
<br />
[[Omeprazole]]: Co-administration of omeprazole did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%, probably the result of omeprazole’s potent inhibition of CYP2C19 <br />
<br />
=====Quinidine =====<br />
<br />
Concomitant administration of [[quinidine ]]with a single dose of cilostazol 100 mg did not alter cilostazol pharmacokinetics.<br />
<br />
=====Lovastatin=====<br />
<br />
The concomitant administration of [[lovastatin ]]with cilostazol decreases cilostazol Css, max and AUCT by 15%. There is also a decrease, although nonsignificant, in cilostazol metabolite concentrations. Co-administration of cilostazol with lovastatin increases lovastatin and β–hydroxy lovastatin AUC approximately 70%. This is most likely clinically insignificant.<br />
<br />
==Use in Specific Populations==<br />
<br />
====Pregnancy====<br />
<br />
* '''[[Pregnancy category#United States|Pregnancy Category (FDA)]]: C'''<br />
<br />
* '''[[Pregnancy category#Australia|Pregnancy Category (AUS)]]: {{PAGENAME}} is not included in Australian Drug Evaluation Committee (ADEC) Pregnancy Categories.'''<br />
<br />
In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
<br />
====Labor and Delivery====<br />
<br />
FDA package insert doesn't contain any information regarding "'''Labor and Delivery'''"<br />
<br />
====Nursing Mothers====<br />
<br />
Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
<br />
====Pediatric Use====<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
====Geriatric Use====<br />
Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
====Gender====<br />
<br />
The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range<br />
<br />
====Race====<br />
<br />
(Description)<br />
<br />
====Renal Impairment====<br />
<br />
Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
<br />
====Hepatic Impairment====<br />
<br />
Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
<br />
====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the exposure in humans at the MRHD.<br />
<br />
====Immunocompromised Patients====<br />
<br />
(Description)<br />
<br />
====Miscellaneous====<br />
<br />
=====Smokers=====<br />
Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
<br />
==Administration and Monitoring==<br />
<br />
====Administration====<br />
<br />
Oral<br />
<br />
====Monitoring====<br />
FDA package insert does't contain any information regarding "'''Monitoring'''"<br />
<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability).<br />
<br />
==IV Compatibility==<br />
<br />
FDA package insert doesn't contain any information regarding '''IV Compatibility'''<br />
<br />
==Overdosage==<br />
<br />
===Acute Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
<br />
====Management====<br />
<br />
FDA package insert doesn't contain any information regarding "'''Management '''"<br />
<br />
==Pharmacology==<br />
<br />
{{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
<br />
===Mechanism of Action===<br />
<br />
The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
<br />
===Structure===<br />
<br />
*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
<br />
<br />
===Pharmacodynamics===<br />
<br />
(Description)<br />
<br />
===Pharmacokinetics===<br />
<br />
Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
<br />
====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4‑dehydro‑cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4‑dehydro‑cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
<br />
===Nonclinical Toxicology===<br />
<br />
==Clinical Studies==<br />
<br />
*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
<br />
{|<br />
| [[image:Cilo2.png|400px|thumb]]<br />
|}<br />
<br />
<br />
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
<br />
==How Supplied==<br />
<br />
'''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
<br />
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0223-60 bottles of 60 and 0185-0223-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
==Images==<br />
<br />
===Drug Images===<br />
<br />
{|<br />
| [[File:Cilostazol50mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 50 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;123 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
{|<br />
| [[File:Cilostazol100mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 100 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;223 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
===Package and Label Display Panel===<br />
<br />
Sandoz Inc.<br />
Princeton, NJ 08540<br />
OS8128<br />
Rev. 02/13<br />
MF0223REV02/13<br />
Cilostazol 100mg Tablet<br />
<br />
{|<br />
| [[image:Cilostazollabel.jpg|400px|thumb]]<br />
|}<br />
<br />
{|<br />
| [[image:Cilostazollabel1.png|400px|thumb]]<br />
|}<br />
<br />
==Patient Information==<br />
<br />
===Patient Information from FDA===<br />
(sil-OS-tah-zol)<br />
<br />
Please read this leaflet before you start taking cilostazol tablets and each time you renew it in case anything has changed. This leaflet does not replace careful discussions with your doctor. You and your doctor should discuss cilostazol when you start taking it and at regular check-ups. You should follow your doctor’s advice about when to have check-ups.<br />
What is cilostazol for?<br />
Cilostazol may improve the symptoms of patients with a medical condition called intermittent claudication.<br />
What is intermittent claudication?<br />
Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. It occurs because narrowing or blockage of the arteries decreases blood flow to the legs. The decreased blood flow does not supply enough oxygen to the leg muscles during walking, resulting in these painful leg cramps.<br />
<br />
'''What treatments are available for intermittent claudication?'''<br />
<br />
The three main treatments available for intermittent claudication are:<br />
*Exercise. Your doctor may advise an exercise program.<br />
*Medication. Your doctor may prescribe a medication such as cilostazol. (See Who should not take cilostazol tablets?)<br />
*Surgery. Your doctor may recommend a surgical procedure to bypass the blocked segment of the artery. Another procedure is called a percutaneous transluminal angioplasty. In this procedure, a catheter (a flexible tube) is inserted into the artery to reduce the blockage and improve blood flow.<br />
<br />
'''How does cilostazol work?'''<br />
<br />
*The exact way that many drugs work is not well understood. Although how cilostazol works is not completely clear, its main effects are to dilate (widen) the arteries supplying blood to the legs and to decrease the ability of platelets in the blood to stick together. Platelets are particles that circulate in the blood and play a role in clotting.<br />
*Cilostazol may reduce the leg pain that patients with intermittent claudication experience, allowing them to walk farther before their leg pain occurs.<br />
*Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks. If you have not noticed any benefit from cilostazol tablets after 12 weeks you and your doctor may wish to discuss other forms of treatment.<br />
*Sometimes blood vessel disease of the legs causes pain at rest or breakdown of skin in the leg. Cilostazol has not been shown to work in patients with these problems.<br />
<br />
'''Who should not take cilostazol tablets?'''<br />
<br />
*Patients who have congestive heart failure (CHF) must not take cilostazol tablets. The most common symptoms of CHF are shortness of breath and swelling of the legs. However, other conditions may also cause these symptoms. It is important that you discuss with your doctor whether you have CHF.<br />
*Over 1,300 patients took cilostazol in studies that lasted for 3 to 6 months. The mortality rate in these patients was similar to placebo (less than 1%). These studies were too small to be sure there is not some increased risk of dying with longer use or in patients sicker than those in the studies.<br />
<br />
'''How should cilostazol tablets be taken?'''<br />
<br />
*Follow your doctor’s advice about how to take cilostazol tablets.<br />
*You should take cilostazol tablets twice a day, at least one half-hour before or two hours after breakfast and dinner. Take cilostazol tablets at about the same times each day.<br />
*Do not share cilostazol tablets with anyone else. It was prescribed only for you.<br />
*Keep cilostazol tablets and all drugs out of the reach of children.<br />
<br />
'''Can cilostazol tablets be taken with other drugs?'''<br />
<br />
Certain drugs and foods can increase the amount of cilostazol in the blood. Because of this, your doctor may adjust your dose of cilostazol or even stop it if you are taking or are going to take one of the following medications.<br />
Drugs Interacting with Cilostazol<br />
Generic Name (Brand Names)Type of Drug<br />
[[erythromycin]] (such as E.E.S.®, Erythrocin®) Antibiotic<br />
[[ketoconazole]] (Nizoral®), [[itraconazole]] (Sporanox®) Antifungal<br />
[[diltiazem]] (Cardizem®) Antihypertensive<br />
[[omeprazole]] (Prilosec®) Gastric acid reducer<br />
This list does not include every drug that may interact with cilostazol tablets. Therefore, you should tell your doctor about all medications that you are taking, including vitamins, herbal supplements and over-the-counter drugs you can buy without a prescription. You should also check with your doctor before taking a new medication after you have begun cilostazol tablets.<br />
<br />
'''What are the possible side effects of cilostazol tablets?'''<br />
<br />
Cilostazol tablets may cause side effects including headache, diarrhea, abnormal stools, increased heart rate and palpitations.<br />
You should discuss possible side effects with your doctor before taking cilostazol tablets and any time you think you are having a side effect.<br />
This provides only a summary of information about cilostazol tablets. If you have any questions about cilostazol tablets, talk to your doctor.<br />
'''Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.'''<br />
<br />
===Patient Information from NLM===<br />
<br />
For patient information about Cilostazol from NLM, click [[Cilostazol (patient information)|here]].<br />
<br />
==Precautions with Alcohol==<br />
<br />
Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
<br />
==Brand Names==<br />
<br />
Cilostazol®, Platel®.<br />
<br />
==Look-Alike Drug Names==<br />
<br />
* (Paired Confused Name 1a) — (Paired Confused Name 1b)<br />
* (Paired Confused Name 2a) — (Paired Confused Name 2b)<br />
* (Paired Confused Name 3a) — (Paired Confused Name 3b)<br />
<br />
==[http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm Drug Shortage Status]==<br />
<br />
==[http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price Price]==<br />
<br />
==References==<br />
<br />
{{reflist}}<br />
<br />
</div></div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=Cilostazol&diff=962102Cilostazol2014-04-03T02:06:20Z<p>Abdurahman Khalil: </p>
<hr />
<div>{{DrugProjectFormSinglePage<br />
|authorTag={{AK}}<br />
|genericName=Cilostazol<br />
|aOrAn=a<br />
|drugClass=Phosphodiesterase 3 inhibitor<br />
|indication=Intermittent claudication<br />
|hasBlackBoxWarning=Yes<br />
|adverseReactions=headache, dizziness, palpitation, diarrhea, rhinitis and pharyngitis.<br />
|blackBoxWarningTitle=Contraindication<br />
|blackBoxWarningBody=<i><span style="color:#FF0000;">Heart failure</span></i> '' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
|fdaLIADAdult=&lt;h4&gt;Intermittent claudication 1&lt;/h5&gt;<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
|offLabelAdultGuideSupport======Secondary prevention of stroke and TIA=====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid'''<ref name="Lansberg-2012">{{Cite journal | last1 = Lansberg | first1 = MG. | last2 = O'Donnell | first2 = MJ. | last3 = Khatri | first3 = P. | last4 = Lang | first4 = ES. | last5 = Nguyen-Huynh | first5 = MN. | last6 = Schwartz | first6 = NE. | last7 = Sonnenberg | first7 = FA. | last8 = Schulman | first8 = S. | last9 = Vandvik | first9 = PO. | title = Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e601S-36S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2302 | PMID = 22315273 }}</ref><br />
<br />
=====Thrombosis prophylaxis in percutaneous coronary intervention =====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid'''<ref name="Vandvik-2012">{{Cite journal | last1 = Vandvik | first1 = PO. | last2 = Lincoff | first2 = AM. | last3 = Gore | first3 = JM. | last4 = Gutterman | first4 = DD. | last5 = Sonnenberg | first5 = FA. | last6 = Alonso-Coello | first6 = P. | last7 = Akl | first7 = EA. | last8 = Lansberg | first8 = MG. | last9 = Guyatt | first9 = GH. | title = Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e637S-68S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2306 | PMID = 22315274 }}</ref><br />
|contraindications=* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
|warnings======Hematologic Adverse Reactions=====<br />
Rare cases have been reported of [[thrombocytopenia ]]or [[leukopenia ]]progressing to [[agranulocytosis ]]when cilostazol was not immediately discontinued. The agranulocytosis, however, was reversible on discontinuation of cilostazol.<br />
<br />
=====Use with Clopidogrel=====<br />
There is limited information with respect to the efficacy or safety of the concurrent use of cilostazol and [[clopidogrel]], a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Although it cannot be determined whether there was an additive effect on bleeding times during concomitant administration with cilostazol and [[clopidogrel]], caution is advised for checking bleeding times during co-administration.<br />
|clinicalTrials=Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol and 134 days for patients on placebo.<br />
<br />
The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with PLETAL 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included [[palpitation ]]and [[diarrhea]], both 1.1% for cilostazol (all doses) versus 0.1% for placebo.<br />
<br />
======Body as a Whole======<br />
*Common:<br />
:*Abdominal pain<br />
:*Back pain<br />
:*Headache <br />
:*Infection<br />
<br />
*Less common:<br />
[[Chills]], face [[edema]], [[fever]], [[generalized edema]], [[malaise]], [[neck rigidity]], [[pelvic pain]], [[retroperitoneal haemorrhage]].<br />
<br />
======Central Nervous System======<br />
<br />
*Common:<br />
:*Dizziness<br />
:*Vertigo<br />
<br />
*Less common:<br />
[[Anxiety]], [[insomnia]], [[neuralgia]].<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
*Common:<br />
:*Abnormal stool<br />
:*Diarrhea<br />
:*Dyspepsia<br />
:*Flatulence<br />
:*Nausea<br />
<br />
*Less common:<br />
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Metabolic & Nutritional======<br />
*Common:<br />
:*Peripheral edema<br />
<br />
*Less common:<br />
Increased [[creatinine]], [[gout]], [[hyperlipemia]], [[hyperuricemia]].<br />
<br />
======Musculoskeletal======<br />
<br />
*Common:<br />
:*Myalgia<br />
<br />
*Less common:<br />
[[Arthralgia]], bone pain, [[bursitis]].<br />
<br />
======Miscellaneous======<br />
Less common adverse reactions:<br />
<br />
*'''Endocrine:''' [[Diabetes mellitus]].<br />
<br />
*'''Hemic and Lymphatic:''' [[Anemia]], [[ecchymosis]],[[ iron deficiency anemia]], [[polycythemia]], [[purpura]].<br />
<br />
*'''Skin and Appendages:''' Dry skin, [[furunculosis]], skin hypertrophy, [[urticaria]].<br />
<br />
*'''Special Senses:''' [[Amblyopia]], [[blindness]], [[conjunctivitis]], [[diplopia]], ear pain, eye haemorrhage, [[retinal haemorrhage]], [[tinnitus]].<br />
<br />
*'''Urogenital:''' [[Albuminuria]], [[cystitis]], [[urinary frequency]], vaginal haemorrhage, vaginitis.<br />
|postmarketing=The following events have been reported spontaneously from worldwide post-marketing experience since the launch of PLETAL in the US.<br />
<br />
======Blood and lymphatic system disorders:======<br />
[[Agranulocytosis]],[[ aplastic anemia]], [[granulocytopenia]], [[pancytopenia]], [[thrombocytopenia]], [[leukopenia]], <br />
[[bleeding tendency]]<br />
<br />
======Cardiac disorders:======<br />
<br />
[[Torsades de pointes]], [[QT prolongation|QTc prolongation]] (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. [[complete atrioventricular block]], c[[ardiac failure ]]and [[bradyarrythmia]], when treated with cilostazol. Cilostazol was used "off label" due to its positive [[chronotropic]] action)<br />
<br />
======Gastrointestinal disorders:======<br />
<br />
*Gastrointestinal haemorrhage<br />
<br />
======General disorders and administration site conditions:======<br />
<br />
*Pain<br />
*[[chest pain]] <br />
*[[hot flushes]]<br />
<br />
======Hepatobiliary disorders:======<br />
<br />
*Hepatic dysfunction/abnormal liver function tests <br />
*[[jaundice]]<br />
<br />
======Injury, poisoning and procedural complications:======<br />
<br />
*Extradural [[haematoma ]] <br />
*Subdural haematoma<br />
<br />
=====Investigations:=====<br />
<br />
*[[Blood glucose]] increased, blood [[uric acid]] increased, [[platelet count]] decreased, [[white blood cell count]] decreased, increase in [[BUN]] (blood urea increased), blood pressure increase<br />
<br />
======Nervous system disorders:======<br />
<br />
*[[Intracranial haemorrhage]] <br />
*[[cerebral haemorrhage]] <br />
*[[cerebrovascular accident]]<br />
<br />
======Respiratory, thoracic and mediastinal disorders:======<br />
<br />
*Pulmonary haemorrhage<br />
*[[ interstitial pneumonia]]<br />
<br />
'''Skin and subcutaneous tissue disorders:'''<br />
<br />
*Haemorrhage subcutaneous, [[pruritus]], skin eruptions including [[Stevens-Johnson syndrome]], skin drug eruption ([[dermatitis medicamentosa]])<br />
<br />
======Vascular disorders:======<br />
<br />
*Subacute [[thrombosis ]](these cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting)<br />
|drugInteractions======Aspirin=====<br />
<br />
*Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of ADP-induced ex vivo platelet aggregation by 22% to 37% when compared to either aspirin or cilostazol alone. Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to cilostazol alone and by 48% compared to aspirin alone. However, short-term co-administration of aspirin with cilostazol had no clinically significant impact on PT, aPTT or bleeding time compared to aspirin alone. <br />
<br />
*Effects of long-term co-administration in the general population are unknown. In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was co-administered with cilostazol to 201 patients. The most frequent doses and mean durations of aspirin therapy were 75 mg to 81 mg daily for 137 days (107 patients) and 325 mg daily for 54 days (85 patients). There was no apparent increase in incidence of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.<br />
<br />
=====Warfarin=====<br />
<br />
The cytochrome P-450 isoenzymes involved in the metabolism of R-warfarin are CYP3A4, CYP1A2 and CYP2C19 and in the metabolism of S-warfarin, CYP2C9. Cilostazol did not inhibit either the metabolism or the pharmacologic effects (PT, aPTT, bleeding time or platelet aggregation) of R- and S-warfarin after a single 25-mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and cilostazol on the pharmacokinetics and pharmacodynamics of both drugs is unknown.<br />
<br />
=====Clopidogrel=====<br />
<br />
Multiple doses of clopidogrel do not significantly increase steady state plasma concentrations of cilostazol.<br />
<br />
=====Inhibitors of CYP3A4=====<br />
<br />
======Strong Inhibitors of CYP3A4======<br />
<br />
A priming dose of [[ketoconazole ]]400 mg (a strong inhibitor of CYP3A4), was given one day prior to co-administration of single doses of [[ketoconazole ]]400 mg and cilostazol 100 mg. This regimen increased cilostazol Cmax by 94% and AUC by 117%. Other strong inhibitors of CYP3A4, such as [[itraconazole]], [[fluconazole]], [[miconazole]], [[fluvoxamine]], [[fluoxetine]], [[nefazodone ]]and [[sertraline]], would be expected to have a similar effect <br />
<br />
======Moderate Inhibitors of CYP3A4======<br />
<br />
*[[Erythromycin ]]and Other [[Macrolide ]]Antibiotics: [[Erythromycin ]]is a moderately strong inhibitor of CYP3A4. Co-administration of erythromycin 500 mg q 8h with a single dose of cilostazol 100 mg increased cilostazol Cmax by 47% and AUC by 73%. Inhibition of cilostazol metabolism by erythromycin increased the AUC of 4´-trans-hydroxy-cilostazol by 141%. Other macrolide antibiotics (e.g., [[clarithromycin]]), but not all (e.g., [[azithromycin]]), would be expected to have a similar effect.<br />
<br />
*Diltiazem: [[Diltiazem]] 180 mg decreased the clearance of cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC increased ~40%.<br />
<br />
*Grapefruit Juice: [[Grapefruit juice]] increased the Cmax of cilostazol by ~50% , but had no effect on AUC.<br />
=====Inhibitors of CYP2C19=====<br />
<br />
[[Omeprazole]]: Co-administration of omeprazole did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%, probably the result of omeprazole’s potent inhibition of CYP2C19 <br />
<br />
=====Quinidine =====<br />
<br />
Concomitant administration of [[quinidine ]]with a single dose of cilostazol 100 mg did not alter cilostazol pharmacokinetics.<br />
<br />
=====Lovastatin=====<br />
<br />
The concomitant administration of [[lovastatin ]]with cilostazol decreases cilostazol Css, max and AUCT by 15%. There is also a decrease, although nonsignificant, in cilostazol metabolite concentrations. Co-administration of cilostazol with lovastatin increases lovastatin and β–hydroxy lovastatin AUC approximately 70%. This is most likely clinically insignificant.<br />
|useInPregnancyFDA=In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
|useInNursing=Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
|useInPed=The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
|useInGeri=Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
|useInGender=The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range.<br />
|useInRenalImpair=Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
|useInHepaticImpair=Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
|othersTitle=Smokers<br />
|useInOthers=Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
|administration=Oral<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability)<br />
|overdose=Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
|drugBox={{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
|mechAction=The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
|structure=*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
|PK=Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
<br />
====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4 dehydro cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4 dehydro cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
|nonClinToxic=====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the<br />
|clinicalStudies=*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
<br />
{|<br />
| [[image:Cilo2.png|400px|thumb]]<br />
|}<br />
<br />
<br />
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
|howSupplied='''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other.<br />
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other.<br />
|NDC=0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
|storage=Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
|manBy=Sandoz Inc.Princeton, NJ 08540<br />
|distBy=Bryant Ranch Prepack<br />
|isPill=Yes<br />
|dosageValue=50<br />
|dosageUnit=mg<br />
|pillImprint=E 123<br />
|pillSize=9<br />
|pillShape=Round<br />
|pillColor=White<br />
|pillScoring=1<br />
|pillImage=http://www.wikidoc.org/index.php/File:Cilostazol50mg.jpg<br />
}}<br />
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! style="font-size: 80%; padding: 0 5px; background: #104E8B;" | [[{{PAGENAME}}|{{fontcolor|#F8F8FF|{{PAGENAME}}®}}]]<br />
|-<br />
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|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adult Indications and Dosage|{{fontcolor|#F8F8FF|Adult Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pediatric Indications and Dosage|{{fontcolor|#F8F8FF|Pediatric Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Contraindications|{{fontcolor|#F8F8FF|Contraindications}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Warnings|{{fontcolor|#F8F8FF|Warnings}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adverse Reactions|{{fontcolor|#F8F8FF|Adverse Reactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Drug Interactions|{{fontcolor|#F8F8FF|Drug Interactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Use in Specific Populations|{{fontcolor|#F8F8FF|Use in Specific Populations}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Administration and Monitoring|{{fontcolor|#F8F8FF|Administration and Monitoring}}]]<br />
|-<br />
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|-<br />
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|-<br />
|}<br />
<div style="width: 80%"><br />
__NOTOC__<br />
{{CMG}}<br />
<br />
{{SB}} Cilostazol®, Pletal®<br />
<br />
==Disclaimer==<br />
<br />
'''''WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature. The information provided is not a medical advice or treatment. WikiDoc does not promote any medication or off-label use of drugs. Please read our full disclaimer [[wikidoc:General_disclaimer|{{fontcolor|#FF0000|here}}]].'''''<br />
<br />
==<span style="color:#FF0000; background:#000000;">Black Box Warning</span>==<br />
<br />
FDA Package Insert for {{PAGENAME}} contains no information regarding ''Black Box Warning''.<br />
<br />
{| style="border: 3px solid #696969;"<br />
| style="background: #000000; border: 0px; padding: 20px 20px; width: 800px;" |<br />
<center><br />
<font color="#F8F8FF" style="font-weight: bold;">CONTRAINDICATION</font><br />
</center><br />
<br />
<center><br />
<font color="#F8F8FF" size="1" style="font-style: italic;">See full prescribing information for complete boxed warning.</font><br />
</center><br />
<br />
<font color="#F8F8FF" style="font-weight: bold;"><br />
''{{fontcolor|#FF0000|Condition Name:}}'' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
</font><br />
|}<br />
<br />
==Overview==<br />
<br />
{{PAGENAME}} is a_Phosphodiesterase 3 Inhibitor drug that is FDA approved for the treatment of intermittent claudication. There is a Black Box Warning for this drug as shown <span style="background:#000000;">'''[[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|here}}]]'''</span>. Common adverse reactions include headache, dizziness, palpitation, diarrhea, rhinitis and pharyngitis.<br />
<br />
==Adult Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Adult)===<br />
<br />
=====Intermittent claudication=====<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
<br />
===Off-Label Use and Dosage (Adult)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Secondary prevention of stroke and TIA=====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid'''<ref name="Lansberg-2012">{{Cite journal | last1 = Lansberg | first1 = MG. | last2 = O'Donnell | first2 = MJ. | last3 = Khatri | first3 = P. | last4 = Lang | first4 = ES. | last5 = Nguyen-Huynh | first5 = MN. | last6 = Schwartz | first6 = NE. | last7 = Sonnenberg | first7 = FA. | last8 = Schulman | first8 = S. | last9 = Vandvik | first9 = PO. | title = Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e601S-36S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2302 | PMID = 22315273 }}</ref><br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid''<ref name="Vandvik-2012">{{Cite journal | last1 = Vandvik | first1 = PO. | last2 = Lincoff | first2 = AM. | last3 = Gore | first3 = JM. | last4 = Gutterman | first4 = DD. | last5 = Sonnenberg | first5 = FA. | last6 = Alonso-Coello | first6 = P. | last7 = Akl | first7 = EA. | last8 = Lansberg | first8 = MG. | last9 = Guyatt | first9 = GH. | title = Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e637S-68S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2306 | PMID = 22315274 }}</ref><br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* There is limited information about ''Off-Label Non–Guideline-Supported Use'' of {{PAGENAME}} in adult patients.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Pediatric Indications and Dosage==<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
==Contraindications==<br />
* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
<br />
==Warnings==<br />
<br />
=====Hematologic Adverse Reactions=====<br />
Rare cases have been reported of [[thrombocytopenia ]]or [[leukopenia ]]progressing to [[agranulocytosis ]]when cilostazol was not immediately discontinued. The agranulocytosis, however, was reversible on discontinuation of cilostazol.<br />
<br />
=====Use with Clopidogrel=====<br />
There is limited information with respect to the efficacy or safety of the concurrent use of cilostazol and [[clopidogrel]], a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Although it cannot be determined whether there was an additive effect on bleeding times during concomitant administration with cilostazol and [[clopidogrel]], caution is advised for checking bleeding times during co-administration.<br />
<br />
==Adverse Reactions==<br />
<br />
===Clinical Trials Experience===<br />
Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol and 134 days for patients on placebo.<br />
<br />
The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with PLETAL 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included [[palpitation ]]and [[diarrhea]], both 1.1% for cilostazol (all doses) versus 0.1% for placebo.<br />
<br />
======Body as a Whole======<br />
*Common:<br />
:*Abdominal pain<br />
:*Back pain<br />
:*Headache <br />
:*Infection<br />
<br />
*Less common:<br />
[[Chills]], face [[edema]], [[fever]], [[generalized edema]], [[malaise]], [[neck rigidity]], [[pelvic pain]], [[retroperitoneal haemorrhage]].<br />
<br />
======Central Nervous System======<br />
<br />
*Common:<br />
:*Dizziness<br />
:*Vertigo<br />
<br />
*Less common:<br />
[[Anxiety]], [[insomnia]], [[neuralgia]].<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
*Common:<br />
:*Abnormal stool<br />
:*Diarrhea<br />
:*Dyspepsia<br />
:*Flatulence<br />
:*Nausea<br />
<br />
*Less common:<br />
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Metabolic & Nutritional======<br />
*Common:<br />
:*Peripheral edema<br />
<br />
*Less common:<br />
Increased [[creatinine]], [[gout]], [[hyperlipemia]], [[hyperuricemia]].<br />
<br />
======Musculoskeletal======<br />
<br />
*Common:<br />
:*Myalgia<br />
<br />
*Less common:<br />
[[Arthralgia]], bone pain, [[bursitis]].<br />
<br />
======Miscellaneous======<br />
Less common adverse reactions:<br />
<br />
*'''Endocrine:''' [[Diabetes mellitus]].<br />
<br />
*'''Hemic and Lymphatic:''' [[Anemia]], [[ecchymosis]],[[ iron deficiency anemia]], [[polycythemia]], [[purpura]].<br />
<br />
*'''Skin and Appendages:''' Dry skin, [[furunculosis]], skin hypertrophy, [[urticaria]].<br />
<br />
*'''Special Senses:''' [[Amblyopia]], [[blindness]], [[conjunctivitis]], [[diplopia]], ear pain, eye haemorrhage, [[retinal haemorrhage]], [[tinnitus]].<br />
<br />
*'''Urogenital:''' [[Albuminuria]], [[cystitis]], [[urinary frequency]], vaginal haemorrhage, vaginitis.<br />
<br />
===Postmarketing Experience===<br />
<br />
The following events have been reported spontaneously from worldwide post-marketing experience since the launch of PLETAL in the US.<br />
<br />
======Blood and lymphatic system disorders:======<br />
[[Agranulocytosis]],[[ aplastic anemia]], [[granulocytopenia]], [[pancytopenia]], [[thrombocytopenia]], [[leukopenia]], <br />
[[bleeding tendency]]<br />
<br />
======Cardiac disorders:======<br />
<br />
[[Torsades de pointes]], [[QT prolongation|QTc prolongation]] (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. [[complete atrioventricular block]], c[[ardiac failure ]]and [[bradyarrythmia]], when treated with cilostazol. Cilostazol was used "off label" due to its positive [[chronotropic]] action)<br />
<br />
======Gastrointestinal disorders:======<br />
<br />
*Gastrointestinal haemorrhage<br />
<br />
======General disorders and administration site conditions:======<br />
<br />
*Pain<br />
*[[chest pain]] <br />
*[[hot flushes]]<br />
<br />
======Hepatobiliary disorders:======<br />
<br />
*Hepatic dysfunction/abnormal liver function tests <br />
*[[jaundice]]<br />
<br />
======Injury, poisoning and procedural complications:======<br />
<br />
*Extradural [[haematoma ]] <br />
*Subdural haematoma<br />
<br />
=====Investigations:=====<br />
<br />
*[[Blood glucose]] increased, blood [[uric acid]] increased, [[platelet count]] decreased, [[white blood cell count]] decreased, increase in [[BUN]] (blood urea increased), blood pressure increase<br />
<br />
======Nervous system disorders:======<br />
<br />
*[[Intracranial haemorrhage]] <br />
*[[cerebral haemorrhage]] <br />
*[[cerebrovascular accident]]<br />
<br />
======Respiratory, thoracic and mediastinal disorders:======<br />
<br />
*Pulmonary haemorrhage<br />
*[[ interstitial pneumonia]]<br />
<br />
'''Skin and subcutaneous tissue disorders:'''<br />
<br />
*Haemorrhage subcutaneous, [[pruritus]], skin eruptions including [[Stevens-Johnson syndrome]], skin drug eruption ([[dermatitis medicamentosa]])<br />
<br />
======Vascular disorders:======<br />
<br />
*Subacute [[thrombosis ]](these cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting)<br />
<br />
==Drug Interactions==<br />
<br />
=====Aspirin=====<br />
<br />
*Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of ADP-induced ex vivo platelet aggregation by 22% to 37% when compared to either aspirin or cilostazol alone. Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to cilostazol alone and by 48% compared to aspirin alone. However, short-term co-administration of aspirin with cilostazol had no clinically significant impact on PT, aPTT or bleeding time compared to aspirin alone. <br />
<br />
*Effects of long-term co-administration in the general population are unknown. In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was co-administered with cilostazol to 201 patients. The most frequent doses and mean durations of aspirin therapy were 75 mg to 81 mg daily for 137 days (107 patients) and 325 mg daily for 54 days (85 patients). There was no apparent increase in incidence of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.<br />
<br />
=====Warfarin=====<br />
<br />
The cytochrome P-450 isoenzymes involved in the metabolism of R-warfarin are CYP3A4, CYP1A2 and CYP2C19 and in the metabolism of S-warfarin, CYP2C9. Cilostazol did not inhibit either the metabolism or the pharmacologic effects (PT, aPTT, bleeding time or platelet aggregation) of R- and S-warfarin after a single 25-mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and cilostazol on the pharmacokinetics and pharmacodynamics of both drugs is unknown.<br />
<br />
=====Clopidogrel=====<br />
<br />
Multiple doses of clopidogrel do not significantly increase steady state plasma concentrations of cilostazol.<br />
<br />
=====Inhibitors of CYP3A4=====<br />
<br />
======Strong Inhibitors of CYP3A4======<br />
<br />
A priming dose of [[ketoconazole ]]400 mg (a strong inhibitor of CYP3A4), was given one day prior to co-administration of single doses of [[ketoconazole ]]400 mg and cilostazol 100 mg. This regimen increased cilostazol Cmax by 94% and AUC by 117%. Other strong inhibitors of CYP3A4, such as [[itraconazole]], [[fluconazole]], [[miconazole]], [[fluvoxamine]], [[fluoxetine]], [[nefazodone ]]and [[sertraline]], would be expected to have a similar effect <br />
<br />
======Moderate Inhibitors of CYP3A4======<br />
<br />
*[[Erythromycin ]]and Other [[Macrolide ]]Antibiotics: [[Erythromycin ]]is a moderately strong inhibitor of CYP3A4. Co-administration of erythromycin 500 mg q 8h with a single dose of cilostazol 100 mg increased cilostazol Cmax by 47% and AUC by 73%. Inhibition of cilostazol metabolism by erythromycin increased the AUC of 4´-trans-hydroxy-cilostazol by 141%. Other macrolide antibiotics (e.g., [[clarithromycin]]), but not all (e.g., [[azithromycin]]), would be expected to have a similar effect.<br />
<br />
*Diltiazem: [[Diltiazem]] 180 mg decreased the clearance of cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC increased ~40%.<br />
<br />
*Grapefruit Juice: [[Grapefruit juice]] increased the Cmax of cilostazol by ~50% , but had no effect on AUC.<br />
=====Inhibitors of CYP2C19=====<br />
<br />
[[Omeprazole]]: Co-administration of omeprazole did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%, probably the result of omeprazole’s potent inhibition of CYP2C19 <br />
<br />
=====Quinidine =====<br />
<br />
Concomitant administration of [[quinidine ]]with a single dose of cilostazol 100 mg did not alter cilostazol pharmacokinetics.<br />
<br />
=====Lovastatin=====<br />
<br />
The concomitant administration of [[lovastatin ]]with cilostazol decreases cilostazol Css, max and AUCT by 15%. There is also a decrease, although nonsignificant, in cilostazol metabolite concentrations. Co-administration of cilostazol with lovastatin increases lovastatin and β–hydroxy lovastatin AUC approximately 70%. This is most likely clinically insignificant.<br />
<br />
==Use in Specific Populations==<br />
<br />
====Pregnancy====<br />
<br />
* '''[[Pregnancy category#United States|Pregnancy Category (FDA)]]: C'''<br />
<br />
* '''[[Pregnancy category#Australia|Pregnancy Category (AUS)]]: {{PAGENAME}} is not included in Australian Drug Evaluation Committee (ADEC) Pregnancy Categories.'''<br />
<br />
In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
<br />
====Labor and Delivery====<br />
<br />
FDA package insert doesn't contain any information regarding "'''Labor and Delivery'''"<br />
<br />
====Nursing Mothers====<br />
<br />
Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
<br />
====Pediatric Use====<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
====Geriatric Use====<br />
Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
====Gender====<br />
<br />
The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range<br />
<br />
====Race====<br />
<br />
(Description)<br />
<br />
====Renal Impairment====<br />
<br />
Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
<br />
====Hepatic Impairment====<br />
<br />
Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
<br />
====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the exposure in humans at the MRHD.<br />
<br />
====Immunocompromised Patients====<br />
<br />
(Description)<br />
<br />
====Miscellaneous====<br />
<br />
=====Smokers=====<br />
Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
<br />
==Administration and Monitoring==<br />
<br />
====Administration====<br />
<br />
Oral<br />
<br />
====Monitoring====<br />
FDA package insert does't contain any information regarding "'''Monitoring'''"<br />
<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability).<br />
<br />
==IV Compatibility==<br />
<br />
FDA package insert doesn't contain any information regarding '''IV Compatibility'''<br />
<br />
==Overdosage==<br />
<br />
===Acute Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
<br />
====Management====<br />
<br />
FDA package insert doesn't contain any information regarding "'''Management '''"<br />
<br />
==Pharmacology==<br />
<br />
{{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
<br />
===Mechanism of Action===<br />
<br />
The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
<br />
===Structure===<br />
<br />
*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
<br />
<br />
===Pharmacodynamics===<br />
<br />
(Description)<br />
<br />
===Pharmacokinetics===<br />
<br />
Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
<br />
====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4‑dehydro‑cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4‑dehydro‑cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
<br />
===Nonclinical Toxicology===<br />
<br />
==Clinical Studies==<br />
<br />
*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
<br />
{|<br />
| [[image:Cilo2.png|400px|thumb]]<br />
|}<br />
<br />
<br />
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
<br />
==How Supplied==<br />
<br />
'''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
<br />
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0223-60 bottles of 60 and 0185-0223-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
==Images==<br />
<br />
===Drug Images===<br />
<br />
{|<br />
| [[File:Cilostazol50mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 50 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;123 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
{|<br />
| [[File:Cilostazol100mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 100 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;223 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
===Package and Label Display Panel===<br />
<br />
Sandoz Inc.<br />
Princeton, NJ 08540<br />
OS8128<br />
Rev. 02/13<br />
MF0223REV02/13<br />
Cilostazol 100mg Tablet<br />
<br />
{|<br />
| [[image:Cilostazollabel.jpg|400px|thumb]]<br />
|}<br />
<br />
{|<br />
| [[image:Cilostazollabel1.png|400px|thumb]]<br />
|}<br />
<br />
==Patient Information==<br />
<br />
===Patient Information from FDA===<br />
(sil-OS-tah-zol)<br />
<br />
Please read this leaflet before you start taking cilostazol tablets and each time you renew it in case anything has changed. This leaflet does not replace careful discussions with your doctor. You and your doctor should discuss cilostazol when you start taking it and at regular check-ups. You should follow your doctor’s advice about when to have check-ups.<br />
What is cilostazol for?<br />
Cilostazol may improve the symptoms of patients with a medical condition called intermittent claudication.<br />
What is intermittent claudication?<br />
Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. It occurs because narrowing or blockage of the arteries decreases blood flow to the legs. The decreased blood flow does not supply enough oxygen to the leg muscles during walking, resulting in these painful leg cramps.<br />
<br />
'''What treatments are available for intermittent claudication?'''<br />
<br />
The three main treatments available for intermittent claudication are:<br />
*Exercise. Your doctor may advise an exercise program.<br />
*Medication. Your doctor may prescribe a medication such as cilostazol. (See Who should not take cilostazol tablets?)<br />
*Surgery. Your doctor may recommend a surgical procedure to bypass the blocked segment of the artery. Another procedure is called a percutaneous transluminal angioplasty. In this procedure, a catheter (a flexible tube) is inserted into the artery to reduce the blockage and improve blood flow.<br />
<br />
'''How does cilostazol work?'''<br />
<br />
*The exact way that many drugs work is not well understood. Although how cilostazol works is not completely clear, its main effects are to dilate (widen) the arteries supplying blood to the legs and to decrease the ability of platelets in the blood to stick together. Platelets are particles that circulate in the blood and play a role in clotting.<br />
*Cilostazol may reduce the leg pain that patients with intermittent claudication experience, allowing them to walk farther before their leg pain occurs.<br />
*Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks. If you have not noticed any benefit from cilostazol tablets after 12 weeks you and your doctor may wish to discuss other forms of treatment.<br />
*Sometimes blood vessel disease of the legs causes pain at rest or breakdown of skin in the leg. Cilostazol has not been shown to work in patients with these problems.<br />
<br />
'''Who should not take cilostazol tablets?'''<br />
<br />
*Patients who have congestive heart failure (CHF) must not take cilostazol tablets. The most common symptoms of CHF are shortness of breath and swelling of the legs. However, other conditions may also cause these symptoms. It is important that you discuss with your doctor whether you have CHF.<br />
*Over 1,300 patients took cilostazol in studies that lasted for 3 to 6 months. The mortality rate in these patients was similar to placebo (less than 1%). These studies were too small to be sure there is not some increased risk of dying with longer use or in patients sicker than those in the studies.<br />
<br />
'''How should cilostazol tablets be taken?'''<br />
<br />
*Follow your doctor’s advice about how to take cilostazol tablets.<br />
*You should take cilostazol tablets twice a day, at least one half-hour before or two hours after breakfast and dinner. Take cilostazol tablets at about the same times each day.<br />
*Do not share cilostazol tablets with anyone else. It was prescribed only for you.<br />
*Keep cilostazol tablets and all drugs out of the reach of children.<br />
<br />
'''Can cilostazol tablets be taken with other drugs?'''<br />
<br />
Certain drugs and foods can increase the amount of cilostazol in the blood. Because of this, your doctor may adjust your dose of cilostazol or even stop it if you are taking or are going to take one of the following medications.<br />
Drugs Interacting with Cilostazol<br />
Generic Name (Brand Names)Type of Drug<br />
[[erythromycin]] (such as E.E.S.®, Erythrocin®) Antibiotic<br />
[[ketoconazole]] (Nizoral®), [[itraconazole]] (Sporanox®) Antifungal<br />
[[diltiazem]] (Cardizem®) Antihypertensive<br />
[[omeprazole]] (Prilosec®) Gastric acid reducer<br />
This list does not include every drug that may interact with cilostazol tablets. Therefore, you should tell your doctor about all medications that you are taking, including vitamins, herbal supplements and over-the-counter drugs you can buy without a prescription. You should also check with your doctor before taking a new medication after you have begun cilostazol tablets.<br />
<br />
'''What are the possible side effects of cilostazol tablets?'''<br />
<br />
Cilostazol tablets may cause side effects including headache, diarrhea, abnormal stools, increased heart rate and palpitations.<br />
You should discuss possible side effects with your doctor before taking cilostazol tablets and any time you think you are having a side effect.<br />
This provides only a summary of information about cilostazol tablets. If you have any questions about cilostazol tablets, talk to your doctor.<br />
'''Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.'''<br />
<br />
===Patient Information from NLM===<br />
<br />
For patient information about Cilostazol from NLM, click [[Cilostazol (patient information)|here]].<br />
<br />
==Precautions with Alcohol==<br />
<br />
Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
<br />
==Brand Names==<br />
<br />
Cilostazol®, Platel®.<br />
<br />
==Look-Alike Drug Names==<br />
<br />
* (Paired Confused Name 1a) — (Paired Confused Name 1b)<br />
* (Paired Confused Name 2a) — (Paired Confused Name 2b)<br />
* (Paired Confused Name 3a) — (Paired Confused Name 3b)<br />
<br />
==[http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm Drug Shortage Status]==<br />
<br />
==[http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price Price]==<br />
<br />
==References==<br />
<br />
{{reflist}}<br />
<br />
</div></div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=Cilostazol&diff=962100Cilostazol2014-04-03T02:02:08Z<p>Abdurahman Khalil: </p>
<hr />
<div>{{DrugProjectFormSinglePage<br />
|authorTag={{AK}}<br />
|genericName=Cilostazol<br />
|aOrAn=a<br />
|drugClass=Phosphodiesterase 3 inhibitor<br />
|indication=Intermittent claudication<br />
|hasBlackBoxWarning=Yes<br />
|adverseReactions=headache, dizziness, palpitation, diarrhea, rhinitis and pharyngitis.<br />
|blackBoxWarningTitle=Contraindication<br />
|blackBoxWarningBody=<i><span style="color:#FF0000;">Heart failure</span></i> '' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
|fdaLIADAdult=&lt;h4&gt;Intermittent claudication 1&lt;/h5&gt;<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
|offLabelAdultGuideSupport======Secondary prevention of stroke and TIA=====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid'''<ref name="Lansberg-2012">{{Cite journal | last1 = Lansberg | first1 = MG. | last2 = O'Donnell | first2 = MJ. | last3 = Khatri | first3 = P. | last4 = Lang | first4 = ES. | last5 = Nguyen-Huynh | first5 = MN. | last6 = Schwartz | first6 = NE. | last7 = Sonnenberg | first7 = FA. | last8 = Schulman | first8 = S. | last9 = Vandvik | first9 = PO. | title = Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e601S-36S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2302 | PMID = 22315273 }}</ref><br />
<br />
=====Thrombosis prophylaxis in percutaneous coronary intervention =====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid'''<ref name="Vandvik-2012">{{Cite journal | last1 = Vandvik | first1 = PO. | last2 = Lincoff | first2 = AM. | last3 = Gore | first3 = JM. | last4 = Gutterman | first4 = DD. | last5 = Sonnenberg | first5 = FA. | last6 = Alonso-Coello | first6 = P. | last7 = Akl | first7 = EA. | last8 = Lansberg | first8 = MG. | last9 = Guyatt | first9 = GH. | title = Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e637S-68S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2306 | PMID = 22315274 }}</ref><br />
|contraindications=* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
|warnings======Hematologic Adverse Reactions=====<br />
Rare cases have been reported of [[thrombocytopenia ]]or [[leukopenia ]]progressing to [[agranulocytosis ]]when cilostazol was not immediately discontinued. The agranulocytosis, however, was reversible on discontinuation of cilostazol.<br />
<br />
=====Use with Clopidogrel=====<br />
There is limited information with respect to the efficacy or safety of the concurrent use of cilostazol and [[clopidogrel]], a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Although it cannot be determined whether there was an additive effect on bleeding times during concomitant administration with cilostazol and [[clopidogrel]], caution is advised for checking bleeding times during co-administration.<br />
|clinicalTrials=Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol and 134 days for patients on placebo.<br />
<br />
The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with PLETAL 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included [[palpitation ]]and [[diarrhea]], both 1.1% for cilostazol (all doses) versus 0.1% for placebo.<br />
<br />
======Body as a Whole======<br />
*Common:<br />
:*Abdominal pain<br />
:*Back pain<br />
:*Headache <br />
:*Infection<br />
<br />
*Less common:<br />
[[Chills]], face [[edema]], [[fever]], [[generalized edema]], [[malaise]], [[neck rigidity]], [[pelvic pain]], [[retroperitoneal haemorrhage]].<br />
<br />
======Central Nervous System======<br />
<br />
*Common:<br />
:*Dizziness<br />
:*Vertigo<br />
<br />
*Less common:<br />
[[Anxiety]], [[insomnia]], [[neuralgia]].<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
*Common:<br />
:*Abnormal stool<br />
:*Diarrhea<br />
:*Dyspepsia<br />
:*Flatulence<br />
:*Nausea<br />
<br />
*Less common:<br />
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Metabolic & Nutritional======<br />
*Common:<br />
:*Peripheral edema<br />
<br />
*Less common:<br />
Increased [[creatinine]], [[gout]], [[hyperlipemia]], [[hyperuricemia]].<br />
<br />
======Musculoskeletal======<br />
<br />
*Common:<br />
:*Myalgia<br />
<br />
*Less common:<br />
[[Arthralgia]], bone pain, [[bursitis]].<br />
<br />
======Miscellaneous======<br />
Less common adverse reactions:<br />
<br />
*'''Endocrine:''' [[Diabetes mellitus]].<br />
<br />
*'''Hemic and Lymphatic:''' [[Anemia]], [[ecchymosis]],[[ iron deficiency anemia]], [[polycythemia]], [[purpura]].<br />
<br />
*'''Skin and Appendages:''' Dry skin, [[furunculosis]], skin hypertrophy, [[urticaria]].<br />
<br />
*'''Special Senses:''' [[Amblyopia]], [[blindness]], [[conjunctivitis]], [[diplopia]], ear pain, eye haemorrhage, [[retinal haemorrhage]], [[tinnitus]].<br />
<br />
*'''Urogenital:''' [[Albuminuria]], [[cystitis]], [[urinary frequency]], vaginal haemorrhage, vaginitis.<br />
|postmarketing=The following events have been reported spontaneously from worldwide post-marketing experience since the launch of PLETAL in the US.<br />
<br />
======Blood and lymphatic system disorders:======<br />
[[Agranulocytosis]],[[ aplastic anemia]], [[granulocytopenia]], [[pancytopenia]], [[thrombocytopenia]], [[leukopenia]], <br />
[[bleeding tendency]]<br />
<br />
======Cardiac disorders:======<br />
<br />
[[Torsades de pointes]], [[QT prolongation|QTc prolongation]] (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. [[complete atrioventricular block]], c[[ardiac failure ]]and [[bradyarrythmia]], when treated with cilostazol. Cilostazol was used "off label" due to its positive [[chronotropic]] action)<br />
<br />
======Gastrointestinal disorders:======<br />
<br />
*Gastrointestinal haemorrhage<br />
<br />
======General disorders and administration site conditions:======<br />
<br />
*Pain<br />
*[[chest pain]] <br />
*[[hot flushes]]<br />
<br />
======Hepatobiliary disorders:======<br />
<br />
*Hepatic dysfunction/abnormal liver function tests <br />
*[[jaundice]]<br />
<br />
======Injury, poisoning and procedural complications:======<br />
<br />
*Extradural [[haematoma ]] <br />
*Subdural haematoma<br />
<br />
=====Investigations:=====<br />
<br />
*[[Blood glucose]] increased, blood [[uric acid]] increased, [[platelet count]] decreased, [[white blood cell count]] decreased, increase in [[BUN]] (blood urea increased), blood pressure increase<br />
<br />
======Nervous system disorders:======<br />
<br />
*[[Intracranial haemorrhage]] <br />
*[[cerebral haemorrhage]] <br />
*[[cerebrovascular accident]]<br />
<br />
======Respiratory, thoracic and mediastinal disorders:======<br />
<br />
*Pulmonary haemorrhage<br />
*[[ interstitial pneumonia]]<br />
<br />
'''Skin and subcutaneous tissue disorders:'''<br />
<br />
*Haemorrhage subcutaneous, [[pruritus]], skin eruptions including [[Stevens-Johnson syndrome]], skin drug eruption ([[dermatitis medicamentosa]])<br />
<br />
======Vascular disorders:======<br />
<br />
*Subacute [[thrombosis ]](these cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting)<br />
|drugInteractions======Aspirin=====<br />
<br />
*Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of ADP-induced ex vivo platelet aggregation by 22% to 37% when compared to either aspirin or cilostazol alone. Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to cilostazol alone and by 48% compared to aspirin alone. However, short-term co-administration of aspirin with cilostazol had no clinically significant impact on PT, aPTT or bleeding time compared to aspirin alone. <br />
<br />
*Effects of long-term co-administration in the general population are unknown. In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was co-administered with cilostazol to 201 patients. The most frequent doses and mean durations of aspirin therapy were 75 mg to 81 mg daily for 137 days (107 patients) and 325 mg daily for 54 days (85 patients). There was no apparent increase in incidence of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.<br />
<br />
=====Warfarin=====<br />
<br />
The cytochrome P-450 isoenzymes involved in the metabolism of R-warfarin are CYP3A4, CYP1A2 and CYP2C19 and in the metabolism of S-warfarin, CYP2C9. Cilostazol did not inhibit either the metabolism or the pharmacologic effects (PT, aPTT, bleeding time or platelet aggregation) of R- and S-warfarin after a single 25-mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and cilostazol on the pharmacokinetics and pharmacodynamics of both drugs is unknown.<br />
<br />
=====Clopidogrel=====<br />
<br />
Multiple doses of clopidogrel do not significantly increase steady state plasma concentrations of cilostazol.<br />
<br />
=====Inhibitors of CYP3A4=====<br />
<br />
======Strong Inhibitors of CYP3A4======<br />
<br />
A priming dose of [[ketoconazole ]]400 mg (a strong inhibitor of CYP3A4), was given one day prior to co-administration of single doses of [[ketoconazole ]]400 mg and cilostazol 100 mg. This regimen increased cilostazol Cmax by 94% and AUC by 117%. Other strong inhibitors of CYP3A4, such as [[itraconazole]], [[fluconazole]], [[miconazole]], [[fluvoxamine]], [[fluoxetine]], [[nefazodone ]]and [[sertraline]], would be expected to have a similar effect <br />
<br />
======Moderate Inhibitors of CYP3A4======<br />
<br />
*[[Erythromycin ]]and Other [[Macrolide ]]Antibiotics: [[Erythromycin ]]is a moderately strong inhibitor of CYP3A4. Co-administration of erythromycin 500 mg q 8h with a single dose of cilostazol 100 mg increased cilostazol Cmax by 47% and AUC by 73%. Inhibition of cilostazol metabolism by erythromycin increased the AUC of 4´-trans-hydroxy-cilostazol by 141%. Other macrolide antibiotics (e.g., [[clarithromycin]]), but not all (e.g., [[azithromycin]]), would be expected to have a similar effect.<br />
<br />
*Diltiazem: [[Diltiazem]] 180 mg decreased the clearance of cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC increased ~40%.<br />
<br />
*Grapefruit Juice: [[Grapefruit juice]] increased the Cmax of cilostazol by ~50% , but had no effect on AUC.<br />
=====Inhibitors of CYP2C19=====<br />
<br />
[[Omeprazole]]: Co-administration of omeprazole did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%, probably the result of omeprazole’s potent inhibition of CYP2C19 <br />
<br />
=====Quinidine =====<br />
<br />
Concomitant administration of [[quinidine ]]with a single dose of cilostazol 100 mg did not alter cilostazol pharmacokinetics.<br />
<br />
=====Lovastatin=====<br />
<br />
The concomitant administration of [[lovastatin ]]with cilostazol decreases cilostazol Css, max and AUCT by 15%. There is also a decrease, although nonsignificant, in cilostazol metabolite concentrations. Co-administration of cilostazol with lovastatin increases lovastatin and β–hydroxy lovastatin AUC approximately 70%. This is most likely clinically insignificant.<br />
|useInPregnancyFDA=In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
|useInNursing=Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
|useInPed=The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
|useInGeri=Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
|useInGender=The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range.<br />
|useInRenalImpair=Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
|useInHepaticImpair=Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
|othersTitle=Smokers<br />
|useInOthers=Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
|administration=Oral<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability)<br />
|overdose=Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
|drugBox={{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
|mechAction=The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
|structure=*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
|PK=Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
<br />
====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4 dehydro cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4 dehydro cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
|nonClinToxic=====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the<br />
|clinicalStudies=*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
<br />
{|<br />
| [[image:Cilo2.png|400px|thumb]]<br />
|}<br />
<br />
<br />
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
|howSupplied='''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other.<br />
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other.<br />
|NDC=0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
|storage=Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
|manBy=Sandoz Inc.Princeton, NJ 08540<br />
|distBy=Bryant Ranch Prepack<br />
|isPill=Yes<br />
|pillImprint=E 123 <br />
|pillSize=9 <br />
|pillShape=Round<br />
|pillColor=White<br />
|pillScoring=1<br />
|pillImage=http://static.wikidoc.org/0/0e/Cilostazol50mg.jpg<br />
}}<br />
{|class="infobox" style="position: fixed; top: 180px; right: 20px; margin: 0 0 0 0; border: 0; float: right; width: 15%; background: #104E8B; border-radius: 10px 10px 10px 10px;" cellpadding="0" cellspacing="0";<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #104E8B;" | [[{{PAGENAME}}|{{fontcolor|#F8F8FF|{{PAGENAME}}®}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #000000; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|Black Box Warning}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adult Indications and Dosage|{{fontcolor|#F8F8FF|Adult Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pediatric Indications and Dosage|{{fontcolor|#F8F8FF|Pediatric Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Contraindications|{{fontcolor|#F8F8FF|Contraindications}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Warnings|{{fontcolor|#F8F8FF|Warnings}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adverse Reactions|{{fontcolor|#F8F8FF|Adverse Reactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Drug Interactions|{{fontcolor|#F8F8FF|Drug Interactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Use in Specific Populations|{{fontcolor|#F8F8FF|Use in Specific Populations}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Administration and Monitoring|{{fontcolor|#F8F8FF|Administration and Monitoring}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#IV Compatibility|{{fontcolor|#F8F8FF|IV Compatibility}}]]<br />
|-<br />
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|-<br />
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|-<br />
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|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#How Supplied|{{fontcolor|#F8F8FF|How Supplied}}]]<br />
|-<br />
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|-<br />
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|-<br />
|}<br />
<div style="width: 80%"><br />
__NOTOC__<br />
{{CMG}}<br />
<br />
{{SB}} Cilostazol®, Pletal®<br />
<br />
==Disclaimer==<br />
<br />
'''''WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature. The information provided is not a medical advice or treatment. WikiDoc does not promote any medication or off-label use of drugs. Please read our full disclaimer [[wikidoc:General_disclaimer|{{fontcolor|#FF0000|here}}]].'''''<br />
<br />
==<span style="color:#FF0000; background:#000000;">Black Box Warning</span>==<br />
<br />
FDA Package Insert for {{PAGENAME}} contains no information regarding ''Black Box Warning''.<br />
<br />
{| style="border: 3px solid #696969;"<br />
| style="background: #000000; border: 0px; padding: 20px 20px; width: 800px;" |<br />
<center><br />
<font color="#F8F8FF" style="font-weight: bold;">CONTRAINDICATION</font><br />
</center><br />
<br />
<center><br />
<font color="#F8F8FF" size="1" style="font-style: italic;">See full prescribing information for complete boxed warning.</font><br />
</center><br />
<br />
<font color="#F8F8FF" style="font-weight: bold;"><br />
''{{fontcolor|#FF0000|Condition Name:}}'' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
</font><br />
|}<br />
<br />
==Overview==<br />
<br />
{{PAGENAME}} is a_Phosphodiesterase 3 Inhibitor drug that is FDA approved for the treatment of intermittent claudication. There is a Black Box Warning for this drug as shown <span style="background:#000000;">'''[[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|here}}]]'''</span>. Common adverse reactions include headache, dizziness, palpitation, diarrhea, rhinitis and pharyngitis.<br />
<br />
==Adult Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Adult)===<br />
<br />
=====Intermittent claudication=====<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
<br />
===Off-Label Use and Dosage (Adult)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Secondary prevention of stroke and TIA=====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid'''<ref name="Lansberg-2012">{{Cite journal | last1 = Lansberg | first1 = MG. | last2 = O'Donnell | first2 = MJ. | last3 = Khatri | first3 = P. | last4 = Lang | first4 = ES. | last5 = Nguyen-Huynh | first5 = MN. | last6 = Schwartz | first6 = NE. | last7 = Sonnenberg | first7 = FA. | last8 = Schulman | first8 = S. | last9 = Vandvik | first9 = PO. | title = Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e601S-36S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2302 | PMID = 22315273 }}</ref><br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid''<ref name="Vandvik-2012">{{Cite journal | last1 = Vandvik | first1 = PO. | last2 = Lincoff | first2 = AM. | last3 = Gore | first3 = JM. | last4 = Gutterman | first4 = DD. | last5 = Sonnenberg | first5 = FA. | last6 = Alonso-Coello | first6 = P. | last7 = Akl | first7 = EA. | last8 = Lansberg | first8 = MG. | last9 = Guyatt | first9 = GH. | title = Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e637S-68S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2306 | PMID = 22315274 }}</ref><br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* There is limited information about ''Off-Label Non–Guideline-Supported Use'' of {{PAGENAME}} in adult patients.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Pediatric Indications and Dosage==<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
==Contraindications==<br />
* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
<br />
==Warnings==<br />
<br />
=====Hematologic Adverse Reactions=====<br />
Rare cases have been reported of [[thrombocytopenia ]]or [[leukopenia ]]progressing to [[agranulocytosis ]]when cilostazol was not immediately discontinued. The agranulocytosis, however, was reversible on discontinuation of cilostazol.<br />
<br />
=====Use with Clopidogrel=====<br />
There is limited information with respect to the efficacy or safety of the concurrent use of cilostazol and [[clopidogrel]], a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Although it cannot be determined whether there was an additive effect on bleeding times during concomitant administration with cilostazol and [[clopidogrel]], caution is advised for checking bleeding times during co-administration.<br />
<br />
==Adverse Reactions==<br />
<br />
===Clinical Trials Experience===<br />
Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol and 134 days for patients on placebo.<br />
<br />
The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with PLETAL 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included [[palpitation ]]and [[diarrhea]], both 1.1% for cilostazol (all doses) versus 0.1% for placebo.<br />
<br />
======Body as a Whole======<br />
*Common:<br />
:*Abdominal pain<br />
:*Back pain<br />
:*Headache <br />
:*Infection<br />
<br />
*Less common:<br />
[[Chills]], face [[edema]], [[fever]], [[generalized edema]], [[malaise]], [[neck rigidity]], [[pelvic pain]], [[retroperitoneal haemorrhage]].<br />
<br />
======Central Nervous System======<br />
<br />
*Common:<br />
:*Dizziness<br />
:*Vertigo<br />
<br />
*Less common:<br />
[[Anxiety]], [[insomnia]], [[neuralgia]].<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
*Common:<br />
:*Abnormal stool<br />
:*Diarrhea<br />
:*Dyspepsia<br />
:*Flatulence<br />
:*Nausea<br />
<br />
*Less common:<br />
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Metabolic & Nutritional======<br />
*Common:<br />
:*Peripheral edema<br />
<br />
*Less common:<br />
Increased [[creatinine]], [[gout]], [[hyperlipemia]], [[hyperuricemia]].<br />
<br />
======Musculoskeletal======<br />
<br />
*Common:<br />
:*Myalgia<br />
<br />
*Less common:<br />
[[Arthralgia]], bone pain, [[bursitis]].<br />
<br />
======Miscellaneous======<br />
Less common adverse reactions:<br />
<br />
*'''Endocrine:''' [[Diabetes mellitus]].<br />
<br />
*'''Hemic and Lymphatic:''' [[Anemia]], [[ecchymosis]],[[ iron deficiency anemia]], [[polycythemia]], [[purpura]].<br />
<br />
*'''Skin and Appendages:''' Dry skin, [[furunculosis]], skin hypertrophy, [[urticaria]].<br />
<br />
*'''Special Senses:''' [[Amblyopia]], [[blindness]], [[conjunctivitis]], [[diplopia]], ear pain, eye haemorrhage, [[retinal haemorrhage]], [[tinnitus]].<br />
<br />
*'''Urogenital:''' [[Albuminuria]], [[cystitis]], [[urinary frequency]], vaginal haemorrhage, vaginitis.<br />
<br />
===Postmarketing Experience===<br />
<br />
The following events have been reported spontaneously from worldwide post-marketing experience since the launch of PLETAL in the US.<br />
<br />
======Blood and lymphatic system disorders:======<br />
[[Agranulocytosis]],[[ aplastic anemia]], [[granulocytopenia]], [[pancytopenia]], [[thrombocytopenia]], [[leukopenia]], <br />
[[bleeding tendency]]<br />
<br />
======Cardiac disorders:======<br />
<br />
[[Torsades de pointes]], [[QT prolongation|QTc prolongation]] (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. [[complete atrioventricular block]], c[[ardiac failure ]]and [[bradyarrythmia]], when treated with cilostazol. Cilostazol was used "off label" due to its positive [[chronotropic]] action)<br />
<br />
======Gastrointestinal disorders:======<br />
<br />
*Gastrointestinal haemorrhage<br />
<br />
======General disorders and administration site conditions:======<br />
<br />
*Pain<br />
*[[chest pain]] <br />
*[[hot flushes]]<br />
<br />
======Hepatobiliary disorders:======<br />
<br />
*Hepatic dysfunction/abnormal liver function tests <br />
*[[jaundice]]<br />
<br />
======Injury, poisoning and procedural complications:======<br />
<br />
*Extradural [[haematoma ]] <br />
*Subdural haematoma<br />
<br />
=====Investigations:=====<br />
<br />
*[[Blood glucose]] increased, blood [[uric acid]] increased, [[platelet count]] decreased, [[white blood cell count]] decreased, increase in [[BUN]] (blood urea increased), blood pressure increase<br />
<br />
======Nervous system disorders:======<br />
<br />
*[[Intracranial haemorrhage]] <br />
*[[cerebral haemorrhage]] <br />
*[[cerebrovascular accident]]<br />
<br />
======Respiratory, thoracic and mediastinal disorders:======<br />
<br />
*Pulmonary haemorrhage<br />
*[[ interstitial pneumonia]]<br />
<br />
'''Skin and subcutaneous tissue disorders:'''<br />
<br />
*Haemorrhage subcutaneous, [[pruritus]], skin eruptions including [[Stevens-Johnson syndrome]], skin drug eruption ([[dermatitis medicamentosa]])<br />
<br />
======Vascular disorders:======<br />
<br />
*Subacute [[thrombosis ]](these cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting)<br />
<br />
==Drug Interactions==<br />
<br />
=====Aspirin=====<br />
<br />
*Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of ADP-induced ex vivo platelet aggregation by 22% to 37% when compared to either aspirin or cilostazol alone. Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to cilostazol alone and by 48% compared to aspirin alone. However, short-term co-administration of aspirin with cilostazol had no clinically significant impact on PT, aPTT or bleeding time compared to aspirin alone. <br />
<br />
*Effects of long-term co-administration in the general population are unknown. In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was co-administered with cilostazol to 201 patients. The most frequent doses and mean durations of aspirin therapy were 75 mg to 81 mg daily for 137 days (107 patients) and 325 mg daily for 54 days (85 patients). There was no apparent increase in incidence of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.<br />
<br />
=====Warfarin=====<br />
<br />
The cytochrome P-450 isoenzymes involved in the metabolism of R-warfarin are CYP3A4, CYP1A2 and CYP2C19 and in the metabolism of S-warfarin, CYP2C9. Cilostazol did not inhibit either the metabolism or the pharmacologic effects (PT, aPTT, bleeding time or platelet aggregation) of R- and S-warfarin after a single 25-mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and cilostazol on the pharmacokinetics and pharmacodynamics of both drugs is unknown.<br />
<br />
=====Clopidogrel=====<br />
<br />
Multiple doses of clopidogrel do not significantly increase steady state plasma concentrations of cilostazol.<br />
<br />
=====Inhibitors of CYP3A4=====<br />
<br />
======Strong Inhibitors of CYP3A4======<br />
<br />
A priming dose of [[ketoconazole ]]400 mg (a strong inhibitor of CYP3A4), was given one day prior to co-administration of single doses of [[ketoconazole ]]400 mg and cilostazol 100 mg. This regimen increased cilostazol Cmax by 94% and AUC by 117%. Other strong inhibitors of CYP3A4, such as [[itraconazole]], [[fluconazole]], [[miconazole]], [[fluvoxamine]], [[fluoxetine]], [[nefazodone ]]and [[sertraline]], would be expected to have a similar effect <br />
<br />
======Moderate Inhibitors of CYP3A4======<br />
<br />
*[[Erythromycin ]]and Other [[Macrolide ]]Antibiotics: [[Erythromycin ]]is a moderately strong inhibitor of CYP3A4. Co-administration of erythromycin 500 mg q 8h with a single dose of cilostazol 100 mg increased cilostazol Cmax by 47% and AUC by 73%. Inhibition of cilostazol metabolism by erythromycin increased the AUC of 4´-trans-hydroxy-cilostazol by 141%. Other macrolide antibiotics (e.g., [[clarithromycin]]), but not all (e.g., [[azithromycin]]), would be expected to have a similar effect.<br />
<br />
*Diltiazem: [[Diltiazem]] 180 mg decreased the clearance of cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC increased ~40%.<br />
<br />
*Grapefruit Juice: [[Grapefruit juice]] increased the Cmax of cilostazol by ~50% , but had no effect on AUC.<br />
=====Inhibitors of CYP2C19=====<br />
<br />
[[Omeprazole]]: Co-administration of omeprazole did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%, probably the result of omeprazole’s potent inhibition of CYP2C19 <br />
<br />
=====Quinidine =====<br />
<br />
Concomitant administration of [[quinidine ]]with a single dose of cilostazol 100 mg did not alter cilostazol pharmacokinetics.<br />
<br />
=====Lovastatin=====<br />
<br />
The concomitant administration of [[lovastatin ]]with cilostazol decreases cilostazol Css, max and AUCT by 15%. There is also a decrease, although nonsignificant, in cilostazol metabolite concentrations. Co-administration of cilostazol with lovastatin increases lovastatin and β–hydroxy lovastatin AUC approximately 70%. This is most likely clinically insignificant.<br />
<br />
==Use in Specific Populations==<br />
<br />
====Pregnancy====<br />
<br />
* '''[[Pregnancy category#United States|Pregnancy Category (FDA)]]: C'''<br />
<br />
* '''[[Pregnancy category#Australia|Pregnancy Category (AUS)]]: {{PAGENAME}} is not included in Australian Drug Evaluation Committee (ADEC) Pregnancy Categories.'''<br />
<br />
In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
<br />
====Labor and Delivery====<br />
<br />
FDA package insert doesn't contain any information regarding "'''Labor and Delivery'''"<br />
<br />
====Nursing Mothers====<br />
<br />
Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
<br />
====Pediatric Use====<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
====Geriatric Use====<br />
Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
====Gender====<br />
<br />
The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range<br />
<br />
====Race====<br />
<br />
(Description)<br />
<br />
====Renal Impairment====<br />
<br />
Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
<br />
====Hepatic Impairment====<br />
<br />
Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
<br />
====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the exposure in humans at the MRHD.<br />
<br />
====Immunocompromised Patients====<br />
<br />
(Description)<br />
<br />
====Miscellaneous====<br />
<br />
=====Smokers=====<br />
Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
<br />
==Administration and Monitoring==<br />
<br />
====Administration====<br />
<br />
Oral<br />
<br />
====Monitoring====<br />
FDA package insert does't contain any information regarding "'''Monitoring'''"<br />
<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability).<br />
<br />
==IV Compatibility==<br />
<br />
FDA package insert doesn't contain any information regarding '''IV Compatibility'''<br />
<br />
==Overdosage==<br />
<br />
===Acute Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
<br />
====Management====<br />
<br />
FDA package insert doesn't contain any information regarding "'''Management '''"<br />
<br />
==Pharmacology==<br />
<br />
{{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
<br />
===Mechanism of Action===<br />
<br />
The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
<br />
===Structure===<br />
<br />
*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
<br />
<br />
===Pharmacodynamics===<br />
<br />
(Description)<br />
<br />
===Pharmacokinetics===<br />
<br />
Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
<br />
====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4‑dehydro‑cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4‑dehydro‑cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
<br />
===Nonclinical Toxicology===<br />
<br />
==Clinical Studies==<br />
<br />
*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
<br />
{|<br />
| [[image:Cilo2.png|400px|thumb]]<br />
|}<br />
<br />
<br />
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
<br />
==How Supplied==<br />
<br />
'''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
<br />
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0223-60 bottles of 60 and 0185-0223-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
==Images==<br />
<br />
===Drug Images===<br />
<br />
{|<br />
| [[File:Cilostazol50mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 50 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;123 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
{|<br />
| [[File:Cilostazol100mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 100 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;223 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
===Package and Label Display Panel===<br />
<br />
Sandoz Inc.<br />
Princeton, NJ 08540<br />
OS8128<br />
Rev. 02/13<br />
MF0223REV02/13<br />
Cilostazol 100mg Tablet<br />
<br />
{|<br />
| [[image:Cilostazollabel.jpg|400px|thumb]]<br />
|}<br />
<br />
{|<br />
| [[image:Cilostazollabel1.png|400px|thumb]]<br />
|}<br />
<br />
==Patient Information==<br />
<br />
===Patient Information from FDA===<br />
(sil-OS-tah-zol)<br />
<br />
Please read this leaflet before you start taking cilostazol tablets and each time you renew it in case anything has changed. This leaflet does not replace careful discussions with your doctor. You and your doctor should discuss cilostazol when you start taking it and at regular check-ups. You should follow your doctor’s advice about when to have check-ups.<br />
What is cilostazol for?<br />
Cilostazol may improve the symptoms of patients with a medical condition called intermittent claudication.<br />
What is intermittent claudication?<br />
Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. It occurs because narrowing or blockage of the arteries decreases blood flow to the legs. The decreased blood flow does not supply enough oxygen to the leg muscles during walking, resulting in these painful leg cramps.<br />
<br />
'''What treatments are available for intermittent claudication?'''<br />
<br />
The three main treatments available for intermittent claudication are:<br />
*Exercise. Your doctor may advise an exercise program.<br />
*Medication. Your doctor may prescribe a medication such as cilostazol. (See Who should not take cilostazol tablets?)<br />
*Surgery. Your doctor may recommend a surgical procedure to bypass the blocked segment of the artery. Another procedure is called a percutaneous transluminal angioplasty. In this procedure, a catheter (a flexible tube) is inserted into the artery to reduce the blockage and improve blood flow.<br />
<br />
'''How does cilostazol work?'''<br />
<br />
*The exact way that many drugs work is not well understood. Although how cilostazol works is not completely clear, its main effects are to dilate (widen) the arteries supplying blood to the legs and to decrease the ability of platelets in the blood to stick together. Platelets are particles that circulate in the blood and play a role in clotting.<br />
*Cilostazol may reduce the leg pain that patients with intermittent claudication experience, allowing them to walk farther before their leg pain occurs.<br />
*Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks. If you have not noticed any benefit from cilostazol tablets after 12 weeks you and your doctor may wish to discuss other forms of treatment.<br />
*Sometimes blood vessel disease of the legs causes pain at rest or breakdown of skin in the leg. Cilostazol has not been shown to work in patients with these problems.<br />
<br />
'''Who should not take cilostazol tablets?'''<br />
<br />
*Patients who have congestive heart failure (CHF) must not take cilostazol tablets. The most common symptoms of CHF are shortness of breath and swelling of the legs. However, other conditions may also cause these symptoms. It is important that you discuss with your doctor whether you have CHF.<br />
*Over 1,300 patients took cilostazol in studies that lasted for 3 to 6 months. The mortality rate in these patients was similar to placebo (less than 1%). These studies were too small to be sure there is not some increased risk of dying with longer use or in patients sicker than those in the studies.<br />
<br />
'''How should cilostazol tablets be taken?'''<br />
<br />
*Follow your doctor’s advice about how to take cilostazol tablets.<br />
*You should take cilostazol tablets twice a day, at least one half-hour before or two hours after breakfast and dinner. Take cilostazol tablets at about the same times each day.<br />
*Do not share cilostazol tablets with anyone else. It was prescribed only for you.<br />
*Keep cilostazol tablets and all drugs out of the reach of children.<br />
<br />
'''Can cilostazol tablets be taken with other drugs?'''<br />
<br />
Certain drugs and foods can increase the amount of cilostazol in the blood. Because of this, your doctor may adjust your dose of cilostazol or even stop it if you are taking or are going to take one of the following medications.<br />
Drugs Interacting with Cilostazol<br />
Generic Name (Brand Names)Type of Drug<br />
[[erythromycin]] (such as E.E.S.®, Erythrocin®) Antibiotic<br />
[[ketoconazole]] (Nizoral®), [[itraconazole]] (Sporanox®) Antifungal<br />
[[diltiazem]] (Cardizem®) Antihypertensive<br />
[[omeprazole]] (Prilosec®) Gastric acid reducer<br />
This list does not include every drug that may interact with cilostazol tablets. Therefore, you should tell your doctor about all medications that you are taking, including vitamins, herbal supplements and over-the-counter drugs you can buy without a prescription. You should also check with your doctor before taking a new medication after you have begun cilostazol tablets.<br />
<br />
'''What are the possible side effects of cilostazol tablets?'''<br />
<br />
Cilostazol tablets may cause side effects including headache, diarrhea, abnormal stools, increased heart rate and palpitations.<br />
You should discuss possible side effects with your doctor before taking cilostazol tablets and any time you think you are having a side effect.<br />
This provides only a summary of information about cilostazol tablets. If you have any questions about cilostazol tablets, talk to your doctor.<br />
'''Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.'''<br />
<br />
===Patient Information from NLM===<br />
<br />
For patient information about Cilostazol from NLM, click [[Cilostazol (patient information)|here]].<br />
<br />
==Precautions with Alcohol==<br />
<br />
Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
<br />
==Brand Names==<br />
<br />
Cilostazol®, Platel®.<br />
<br />
==Look-Alike Drug Names==<br />
<br />
* (Paired Confused Name 1a) — (Paired Confused Name 1b)<br />
* (Paired Confused Name 2a) — (Paired Confused Name 2b)<br />
* (Paired Confused Name 3a) — (Paired Confused Name 3b)<br />
<br />
==[http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm Drug Shortage Status]==<br />
<br />
==[http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price Price]==<br />
<br />
==References==<br />
<br />
{{reflist}}<br />
<br />
</div></div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=Cilostazol&diff=962086Cilostazol2014-04-03T01:16:49Z<p>Abdurahman Khalil: </p>
<hr />
<div>{{DrugProjectFormSinglePage<br />
|authorTag={{AK}}<br />
|genericName=Cilostazol<br />
|aOrAn=a<br />
|drugClass=Phosphodiesterase 3 inhibitor<br />
|indication=Intermittent claudication<br />
|hasBlackBoxWarning=Yes<br />
|adverseReactions=headache, dizziness, palpitation, diarrhea, rhinitis and pharyngitis.<br />
|blackBoxWarningTitle=Contraindication<br />
|blackBoxWarningBody=<i><span style="color:#FF0000;">Heart failure</span></i> '' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
|fdaLIADAdult=&lt;h4&gt;Intermittent claudication 1&lt;/h5&gt;<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
|offLabelAdultGuideSupport======Secondary prevention of stroke and TIA=====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid'''<ref name="Lansberg-2012">{{Cite journal | last1 = Lansberg | first1 = MG. | last2 = O'Donnell | first2 = MJ. | last3 = Khatri | first3 = P. | last4 = Lang | first4 = ES. | last5 = Nguyen-Huynh | first5 = MN. | last6 = Schwartz | first6 = NE. | last7 = Sonnenberg | first7 = FA. | last8 = Schulman | first8 = S. | last9 = Vandvik | first9 = PO. | title = Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e601S-36S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2302 | PMID = 22315273 }}</ref><br />
<br />
=====Thrombosis prophylaxis in percutaneous coronary intervention =====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid'''<ref name="Vandvik-2012">{{Cite journal | last1 = Vandvik | first1 = PO. | last2 = Lincoff | first2 = AM. | last3 = Gore | first3 = JM. | last4 = Gutterman | first4 = DD. | last5 = Sonnenberg | first5 = FA. | last6 = Alonso-Coello | first6 = P. | last7 = Akl | first7 = EA. | last8 = Lansberg | first8 = MG. | last9 = Guyatt | first9 = GH. | title = Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e637S-68S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2306 | PMID = 22315274 }}</ref><br />
|contraindications=* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
|warnings======Hematologic Adverse Reactions=====<br />
Rare cases have been reported of [[thrombocytopenia ]]or [[leukopenia ]]progressing to [[agranulocytosis ]]when cilostazol was not immediately discontinued. The agranulocytosis, however, was reversible on discontinuation of cilostazol.<br />
<br />
=====Use with Clopidogrel=====<br />
There is limited information with respect to the efficacy or safety of the concurrent use of cilostazol and [[clopidogrel]], a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Although it cannot be determined whether there was an additive effect on bleeding times during concomitant administration with cilostazol and [[clopidogrel]], caution is advised for checking bleeding times during co-administration.<br />
|clinicalTrials=Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol and 134 days for patients on placebo.<br />
<br />
The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with PLETAL 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included [[palpitation ]]and [[diarrhea]], both 1.1% for cilostazol (all doses) versus 0.1% for placebo.<br />
<br />
======Body as a Whole======<br />
*Common:<br />
:*Abdominal pain<br />
:*Back pain<br />
:*Headache <br />
:*Infection<br />
<br />
*Less common:<br />
[[Chills]], face [[edema]], [[fever]], [[generalized edema]], [[malaise]], [[neck rigidity]], [[pelvic pain]], [[retroperitoneal haemorrhage]].<br />
<br />
======Central Nervous System======<br />
<br />
*Common:<br />
:*Dizziness<br />
:*Vertigo<br />
<br />
*Less common:<br />
[[Anxiety]], [[insomnia]], [[neuralgia]].<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
*Common:<br />
:*Abnormal stool<br />
:*Diarrhea<br />
:*Dyspepsia<br />
:*Flatulence<br />
:*Nausea<br />
<br />
*Less common:<br />
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Metabolic & Nutritional======<br />
*Common:<br />
:*Peripheral edema<br />
<br />
*Less common:<br />
Increased [[creatinine]], [[gout]], [[hyperlipemia]], [[hyperuricemia]].<br />
<br />
======Musculoskeletal======<br />
<br />
*Common:<br />
:*Myalgia<br />
<br />
*Less common:<br />
[[Arthralgia]], bone pain, [[bursitis]].<br />
<br />
======Miscellaneous======<br />
Less common adverse reactions:<br />
<br />
*'''Endocrine:''' [[Diabetes mellitus]].<br />
<br />
*'''Hemic and Lymphatic:''' [[Anemia]], [[ecchymosis]],[[ iron deficiency anemia]], [[polycythemia]], [[purpura]].<br />
<br />
*'''Skin and Appendages:''' Dry skin, [[furunculosis]], skin hypertrophy, [[urticaria]].<br />
<br />
*'''Special Senses:''' [[Amblyopia]], [[blindness]], [[conjunctivitis]], [[diplopia]], ear pain, eye haemorrhage, [[retinal haemorrhage]], [[tinnitus]].<br />
<br />
*'''Urogenital:''' [[Albuminuria]], [[cystitis]], [[urinary frequency]], vaginal haemorrhage, vaginitis.<br />
|postmarketing=The following events have been reported spontaneously from worldwide post-marketing experience since the launch of PLETAL in the US.<br />
<br />
======Blood and lymphatic system disorders:======<br />
[[Agranulocytosis]],[[ aplastic anemia]], [[granulocytopenia]], [[pancytopenia]], [[thrombocytopenia]], [[leukopenia]], <br />
[[bleeding tendency]]<br />
<br />
======Cardiac disorders:======<br />
<br />
[[Torsades de pointes]], [[QT prolongation|QTc prolongation]] (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. [[complete atrioventricular block]], c[[ardiac failure ]]and [[bradyarrythmia]], when treated with cilostazol. Cilostazol was used "off label" due to its positive [[chronotropic]] action)<br />
<br />
======Gastrointestinal disorders:======<br />
<br />
*Gastrointestinal haemorrhage<br />
<br />
======General disorders and administration site conditions:======<br />
<br />
*Pain<br />
*[[chest pain]] <br />
*[[hot flushes]]<br />
<br />
======Hepatobiliary disorders:======<br />
<br />
*Hepatic dysfunction/abnormal liver function tests <br />
*[[jaundice]]<br />
<br />
======Injury, poisoning and procedural complications:======<br />
<br />
*Extradural [[haematoma ]] <br />
*Subdural haematoma<br />
<br />
=====Investigations:=====<br />
<br />
*[[Blood glucose]] increased, blood [[uric acid]] increased, [[platelet count]] decreased, [[white blood cell count]] decreased, increase in [[BUN]] (blood urea increased), blood pressure increase<br />
<br />
======Nervous system disorders:======<br />
<br />
*[[Intracranial haemorrhage]] <br />
*[[cerebral haemorrhage]] <br />
*[[cerebrovascular accident]]<br />
<br />
======Respiratory, thoracic and mediastinal disorders:======<br />
<br />
*Pulmonary haemorrhage<br />
*[[ interstitial pneumonia]]<br />
<br />
'''Skin and subcutaneous tissue disorders:'''<br />
<br />
*Haemorrhage subcutaneous, [[pruritus]], skin eruptions including [[Stevens-Johnson syndrome]], skin drug eruption ([[dermatitis medicamentosa]])<br />
<br />
======Vascular disorders:======<br />
<br />
*Subacute [[thrombosis ]](these cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting)<br />
|drugInteractions======Aspirin=====<br />
<br />
*Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of ADP-induced ex vivo platelet aggregation by 22% to 37% when compared to either aspirin or cilostazol alone. Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to cilostazol alone and by 48% compared to aspirin alone. However, short-term co-administration of aspirin with cilostazol had no clinically significant impact on PT, aPTT or bleeding time compared to aspirin alone. <br />
<br />
*Effects of long-term co-administration in the general population are unknown. In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was co-administered with cilostazol to 201 patients. The most frequent doses and mean durations of aspirin therapy were 75 mg to 81 mg daily for 137 days (107 patients) and 325 mg daily for 54 days (85 patients). There was no apparent increase in incidence of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.<br />
<br />
=====Warfarin=====<br />
<br />
The cytochrome P-450 isoenzymes involved in the metabolism of R-warfarin are CYP3A4, CYP1A2 and CYP2C19 and in the metabolism of S-warfarin, CYP2C9. Cilostazol did not inhibit either the metabolism or the pharmacologic effects (PT, aPTT, bleeding time or platelet aggregation) of R- and S-warfarin after a single 25-mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and cilostazol on the pharmacokinetics and pharmacodynamics of both drugs is unknown.<br />
<br />
=====Clopidogrel=====<br />
<br />
Multiple doses of clopidogrel do not significantly increase steady state plasma concentrations of cilostazol.<br />
<br />
=====Inhibitors of CYP3A4=====<br />
<br />
======Strong Inhibitors of CYP3A4======<br />
<br />
A priming dose of [[ketoconazole ]]400 mg (a strong inhibitor of CYP3A4), was given one day prior to co-administration of single doses of [[ketoconazole ]]400 mg and cilostazol 100 mg. This regimen increased cilostazol Cmax by 94% and AUC by 117%. Other strong inhibitors of CYP3A4, such as [[itraconazole]], [[fluconazole]], [[miconazole]], [[fluvoxamine]], [[fluoxetine]], [[nefazodone ]]and [[sertraline]], would be expected to have a similar effect <br />
<br />
======Moderate Inhibitors of CYP3A4======<br />
<br />
*[[Erythromycin ]]and Other [[Macrolide ]]Antibiotics: [[Erythromycin ]]is a moderately strong inhibitor of CYP3A4. Co-administration of erythromycin 500 mg q 8h with a single dose of cilostazol 100 mg increased cilostazol Cmax by 47% and AUC by 73%. Inhibition of cilostazol metabolism by erythromycin increased the AUC of 4´-trans-hydroxy-cilostazol by 141%. Other macrolide antibiotics (e.g., [[clarithromycin]]), but not all (e.g., [[azithromycin]]), would be expected to have a similar effect.<br />
<br />
*Diltiazem: [[Diltiazem]] 180 mg decreased the clearance of cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC increased ~40%.<br />
<br />
*Grapefruit Juice: [[Grapefruit juice]] increased the Cmax of cilostazol by ~50% , but had no effect on AUC.<br />
=====Inhibitors of CYP2C19=====<br />
<br />
[[Omeprazole]]: Co-administration of omeprazole did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%, probably the result of omeprazole’s potent inhibition of CYP2C19 <br />
<br />
=====Quinidine =====<br />
<br />
Concomitant administration of [[quinidine ]]with a single dose of cilostazol 100 mg did not alter cilostazol pharmacokinetics.<br />
<br />
=====Lovastatin=====<br />
<br />
The concomitant administration of [[lovastatin ]]with cilostazol decreases cilostazol Css, max and AUCT by 15%. There is also a decrease, although nonsignificant, in cilostazol metabolite concentrations. Co-administration of cilostazol with lovastatin increases lovastatin and β–hydroxy lovastatin AUC approximately 70%. This is most likely clinically insignificant.<br />
|useInPregnancyFDA=In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
|useInNursing=Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
|useInPed=The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
|useInGeri=Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
|useInGender=The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range.<br />
|useInRenalImpair=Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
|useInHepaticImpair=Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
|othersTitle=Smokers<br />
|useInOthers=Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
|administration=Oral<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability)<br />
|overdose=Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
|drugBox={{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
|mechAction=The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
|structure=*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
|PK=Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
<br />
====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4 dehydro cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4 dehydro cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
|nonClinToxic=====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the<br />
|clinicalStudies=*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
<br />
{|<br />
| [[image:Cilo2.png|400px|thumb]]<br />
|}<br />
<br />
<br />
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
|howSupplied='''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other.<br />
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other.<br />
|NDC=0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
|storage=Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
|manBy=Sandoz Inc.Princeton, NJ 08540<br />
|distBy=Bryant Ranch Prepack<br />
|isPill=Yes<br />
}}<br />
{|class="infobox" style="position: fixed; top: 180px; right: 20px; margin: 0 0 0 0; border: 0; float: right; width: 15%; background: #104E8B; border-radius: 10px 10px 10px 10px;" cellpadding="0" cellspacing="0";<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #104E8B;" | [[{{PAGENAME}}|{{fontcolor|#F8F8FF|{{PAGENAME}}®}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #000000; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|Black Box Warning}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adult Indications and Dosage|{{fontcolor|#F8F8FF|Adult Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pediatric Indications and Dosage|{{fontcolor|#F8F8FF|Pediatric Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Contraindications|{{fontcolor|#F8F8FF|Contraindications}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Warnings|{{fontcolor|#F8F8FF|Warnings}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adverse Reactions|{{fontcolor|#F8F8FF|Adverse Reactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Drug Interactions|{{fontcolor|#F8F8FF|Drug Interactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Use in Specific Populations|{{fontcolor|#F8F8FF|Use in Specific Populations}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Administration and Monitoring|{{fontcolor|#F8F8FF|Administration and Monitoring}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#IV Compatibility|{{fontcolor|#F8F8FF|IV Compatibility}}]]<br />
|-<br />
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|-<br />
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|-<br />
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|-<br />
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|-<br />
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|-<br />
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|-<br />
|}<br />
<div style="width: 80%"><br />
__NOTOC__<br />
{{CMG}}<br />
<br />
{{SB}} Cilostazol®, Pletal®<br />
<br />
==Disclaimer==<br />
<br />
'''''WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature. The information provided is not a medical advice or treatment. WikiDoc does not promote any medication or off-label use of drugs. Please read our full disclaimer [[wikidoc:General_disclaimer|{{fontcolor|#FF0000|here}}]].'''''<br />
<br />
==<span style="color:#FF0000; background:#000000;">Black Box Warning</span>==<br />
<br />
FDA Package Insert for {{PAGENAME}} contains no information regarding ''Black Box Warning''.<br />
<br />
{| style="border: 3px solid #696969;"<br />
| style="background: #000000; border: 0px; padding: 20px 20px; width: 800px;" |<br />
<center><br />
<font color="#F8F8FF" style="font-weight: bold;">CONTRAINDICATION</font><br />
</center><br />
<br />
<center><br />
<font color="#F8F8FF" size="1" style="font-style: italic;">See full prescribing information for complete boxed warning.</font><br />
</center><br />
<br />
<font color="#F8F8FF" style="font-weight: bold;"><br />
''{{fontcolor|#FF0000|Condition Name:}}'' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
</font><br />
|}<br />
<br />
==Overview==<br />
<br />
{{PAGENAME}} is a_Phosphodiesterase 3 Inhibitor drug that is FDA approved for the treatment of intermittent claudication. There is a Black Box Warning for this drug as shown <span style="background:#000000;">'''[[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|here}}]]'''</span>. Common adverse reactions include headache, dizziness, palpitation, diarrhea, rhinitis and pharyngitis.<br />
<br />
==Adult Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Adult)===<br />
<br />
=====Intermittent claudication=====<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
<br />
===Off-Label Use and Dosage (Adult)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Secondary prevention of stroke and TIA=====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid'''<ref name="Lansberg-2012">{{Cite journal | last1 = Lansberg | first1 = MG. | last2 = O'Donnell | first2 = MJ. | last3 = Khatri | first3 = P. | last4 = Lang | first4 = ES. | last5 = Nguyen-Huynh | first5 = MN. | last6 = Schwartz | first6 = NE. | last7 = Sonnenberg | first7 = FA. | last8 = Schulman | first8 = S. | last9 = Vandvik | first9 = PO. | title = Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e601S-36S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2302 | PMID = 22315273 }}</ref><br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid''<ref name="Vandvik-2012">{{Cite journal | last1 = Vandvik | first1 = PO. | last2 = Lincoff | first2 = AM. | last3 = Gore | first3 = JM. | last4 = Gutterman | first4 = DD. | last5 = Sonnenberg | first5 = FA. | last6 = Alonso-Coello | first6 = P. | last7 = Akl | first7 = EA. | last8 = Lansberg | first8 = MG. | last9 = Guyatt | first9 = GH. | title = Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e637S-68S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2306 | PMID = 22315274 }}</ref><br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* There is limited information about ''Off-Label Non–Guideline-Supported Use'' of {{PAGENAME}} in adult patients.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Pediatric Indications and Dosage==<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
==Contraindications==<br />
* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
<br />
==Warnings==<br />
<br />
=====Hematologic Adverse Reactions=====<br />
Rare cases have been reported of [[thrombocytopenia ]]or [[leukopenia ]]progressing to [[agranulocytosis ]]when cilostazol was not immediately discontinued. The agranulocytosis, however, was reversible on discontinuation of cilostazol.<br />
<br />
=====Use with Clopidogrel=====<br />
There is limited information with respect to the efficacy or safety of the concurrent use of cilostazol and [[clopidogrel]], a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Although it cannot be determined whether there was an additive effect on bleeding times during concomitant administration with cilostazol and [[clopidogrel]], caution is advised for checking bleeding times during co-administration.<br />
<br />
==Adverse Reactions==<br />
<br />
===Clinical Trials Experience===<br />
Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol and 134 days for patients on placebo.<br />
<br />
The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with PLETAL 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included [[palpitation ]]and [[diarrhea]], both 1.1% for cilostazol (all doses) versus 0.1% for placebo.<br />
<br />
======Body as a Whole======<br />
*Common:<br />
:*Abdominal pain<br />
:*Back pain<br />
:*Headache <br />
:*Infection<br />
<br />
*Less common:<br />
[[Chills]], face [[edema]], [[fever]], [[generalized edema]], [[malaise]], [[neck rigidity]], [[pelvic pain]], [[retroperitoneal haemorrhage]].<br />
<br />
======Central Nervous System======<br />
<br />
*Common:<br />
:*Dizziness<br />
:*Vertigo<br />
<br />
*Less common:<br />
[[Anxiety]], [[insomnia]], [[neuralgia]].<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
*Common:<br />
:*Abnormal stool<br />
:*Diarrhea<br />
:*Dyspepsia<br />
:*Flatulence<br />
:*Nausea<br />
<br />
*Less common:<br />
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Metabolic & Nutritional======<br />
*Common:<br />
:*Peripheral edema<br />
<br />
*Less common:<br />
Increased [[creatinine]], [[gout]], [[hyperlipemia]], [[hyperuricemia]].<br />
<br />
======Musculoskeletal======<br />
<br />
*Common:<br />
:*Myalgia<br />
<br />
*Less common:<br />
[[Arthralgia]], bone pain, [[bursitis]].<br />
<br />
======Miscellaneous======<br />
Less common adverse reactions:<br />
<br />
*'''Endocrine:''' [[Diabetes mellitus]].<br />
<br />
*'''Hemic and Lymphatic:''' [[Anemia]], [[ecchymosis]],[[ iron deficiency anemia]], [[polycythemia]], [[purpura]].<br />
<br />
*'''Skin and Appendages:''' Dry skin, [[furunculosis]], skin hypertrophy, [[urticaria]].<br />
<br />
*'''Special Senses:''' [[Amblyopia]], [[blindness]], [[conjunctivitis]], [[diplopia]], ear pain, eye haemorrhage, [[retinal haemorrhage]], [[tinnitus]].<br />
<br />
*'''Urogenital:''' [[Albuminuria]], [[cystitis]], [[urinary frequency]], vaginal haemorrhage, vaginitis.<br />
<br />
===Postmarketing Experience===<br />
<br />
The following events have been reported spontaneously from worldwide post-marketing experience since the launch of PLETAL in the US.<br />
<br />
======Blood and lymphatic system disorders:======<br />
[[Agranulocytosis]],[[ aplastic anemia]], [[granulocytopenia]], [[pancytopenia]], [[thrombocytopenia]], [[leukopenia]], <br />
[[bleeding tendency]]<br />
<br />
======Cardiac disorders:======<br />
<br />
[[Torsades de pointes]], [[QT prolongation|QTc prolongation]] (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. [[complete atrioventricular block]], c[[ardiac failure ]]and [[bradyarrythmia]], when treated with cilostazol. Cilostazol was used "off label" due to its positive [[chronotropic]] action)<br />
<br />
======Gastrointestinal disorders:======<br />
<br />
*Gastrointestinal haemorrhage<br />
<br />
======General disorders and administration site conditions:======<br />
<br />
*Pain<br />
*[[chest pain]] <br />
*[[hot flushes]]<br />
<br />
======Hepatobiliary disorders:======<br />
<br />
*Hepatic dysfunction/abnormal liver function tests <br />
*[[jaundice]]<br />
<br />
======Injury, poisoning and procedural complications:======<br />
<br />
*Extradural [[haematoma ]] <br />
*Subdural haematoma<br />
<br />
=====Investigations:=====<br />
<br />
*[[Blood glucose]] increased, blood [[uric acid]] increased, [[platelet count]] decreased, [[white blood cell count]] decreased, increase in [[BUN]] (blood urea increased), blood pressure increase<br />
<br />
======Nervous system disorders:======<br />
<br />
*[[Intracranial haemorrhage]] <br />
*[[cerebral haemorrhage]] <br />
*[[cerebrovascular accident]]<br />
<br />
======Respiratory, thoracic and mediastinal disorders:======<br />
<br />
*Pulmonary haemorrhage<br />
*[[ interstitial pneumonia]]<br />
<br />
'''Skin and subcutaneous tissue disorders:'''<br />
<br />
*Haemorrhage subcutaneous, [[pruritus]], skin eruptions including [[Stevens-Johnson syndrome]], skin drug eruption ([[dermatitis medicamentosa]])<br />
<br />
======Vascular disorders:======<br />
<br />
*Subacute [[thrombosis ]](these cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting)<br />
<br />
==Drug Interactions==<br />
<br />
=====Aspirin=====<br />
<br />
*Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of ADP-induced ex vivo platelet aggregation by 22% to 37% when compared to either aspirin or cilostazol alone. Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to cilostazol alone and by 48% compared to aspirin alone. However, short-term co-administration of aspirin with cilostazol had no clinically significant impact on PT, aPTT or bleeding time compared to aspirin alone. <br />
<br />
*Effects of long-term co-administration in the general population are unknown. In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was co-administered with cilostazol to 201 patients. The most frequent doses and mean durations of aspirin therapy were 75 mg to 81 mg daily for 137 days (107 patients) and 325 mg daily for 54 days (85 patients). There was no apparent increase in incidence of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.<br />
<br />
=====Warfarin=====<br />
<br />
The cytochrome P-450 isoenzymes involved in the metabolism of R-warfarin are CYP3A4, CYP1A2 and CYP2C19 and in the metabolism of S-warfarin, CYP2C9. Cilostazol did not inhibit either the metabolism or the pharmacologic effects (PT, aPTT, bleeding time or platelet aggregation) of R- and S-warfarin after a single 25-mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and cilostazol on the pharmacokinetics and pharmacodynamics of both drugs is unknown.<br />
<br />
=====Clopidogrel=====<br />
<br />
Multiple doses of clopidogrel do not significantly increase steady state plasma concentrations of cilostazol.<br />
<br />
=====Inhibitors of CYP3A4=====<br />
<br />
======Strong Inhibitors of CYP3A4======<br />
<br />
A priming dose of [[ketoconazole ]]400 mg (a strong inhibitor of CYP3A4), was given one day prior to co-administration of single doses of [[ketoconazole ]]400 mg and cilostazol 100 mg. This regimen increased cilostazol Cmax by 94% and AUC by 117%. Other strong inhibitors of CYP3A4, such as [[itraconazole]], [[fluconazole]], [[miconazole]], [[fluvoxamine]], [[fluoxetine]], [[nefazodone ]]and [[sertraline]], would be expected to have a similar effect <br />
<br />
======Moderate Inhibitors of CYP3A4======<br />
<br />
*[[Erythromycin ]]and Other [[Macrolide ]]Antibiotics: [[Erythromycin ]]is a moderately strong inhibitor of CYP3A4. Co-administration of erythromycin 500 mg q 8h with a single dose of cilostazol 100 mg increased cilostazol Cmax by 47% and AUC by 73%. Inhibition of cilostazol metabolism by erythromycin increased the AUC of 4´-trans-hydroxy-cilostazol by 141%. Other macrolide antibiotics (e.g., [[clarithromycin]]), but not all (e.g., [[azithromycin]]), would be expected to have a similar effect.<br />
<br />
*Diltiazem: [[Diltiazem]] 180 mg decreased the clearance of cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC increased ~40%.<br />
<br />
*Grapefruit Juice: [[Grapefruit juice]] increased the Cmax of cilostazol by ~50% , but had no effect on AUC.<br />
=====Inhibitors of CYP2C19=====<br />
<br />
[[Omeprazole]]: Co-administration of omeprazole did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%, probably the result of omeprazole’s potent inhibition of CYP2C19 <br />
<br />
=====Quinidine =====<br />
<br />
Concomitant administration of [[quinidine ]]with a single dose of cilostazol 100 mg did not alter cilostazol pharmacokinetics.<br />
<br />
=====Lovastatin=====<br />
<br />
The concomitant administration of [[lovastatin ]]with cilostazol decreases cilostazol Css, max and AUCT by 15%. There is also a decrease, although nonsignificant, in cilostazol metabolite concentrations. Co-administration of cilostazol with lovastatin increases lovastatin and β–hydroxy lovastatin AUC approximately 70%. This is most likely clinically insignificant.<br />
<br />
==Use in Specific Populations==<br />
<br />
====Pregnancy====<br />
<br />
* '''[[Pregnancy category#United States|Pregnancy Category (FDA)]]: C'''<br />
<br />
* '''[[Pregnancy category#Australia|Pregnancy Category (AUS)]]: {{PAGENAME}} is not included in Australian Drug Evaluation Committee (ADEC) Pregnancy Categories.'''<br />
<br />
In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
<br />
====Labor and Delivery====<br />
<br />
FDA package insert doesn't contain any information regarding "'''Labor and Delivery'''"<br />
<br />
====Nursing Mothers====<br />
<br />
Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
<br />
====Pediatric Use====<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
====Geriatric Use====<br />
Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
====Gender====<br />
<br />
The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range<br />
<br />
====Race====<br />
<br />
(Description)<br />
<br />
====Renal Impairment====<br />
<br />
Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
<br />
====Hepatic Impairment====<br />
<br />
Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
<br />
====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the exposure in humans at the MRHD.<br />
<br />
====Immunocompromised Patients====<br />
<br />
(Description)<br />
<br />
====Miscellaneous====<br />
<br />
=====Smokers=====<br />
Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
<br />
==Administration and Monitoring==<br />
<br />
====Administration====<br />
<br />
Oral<br />
<br />
====Monitoring====<br />
FDA package insert does't contain any information regarding "'''Monitoring'''"<br />
<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability).<br />
<br />
==IV Compatibility==<br />
<br />
FDA package insert doesn't contain any information regarding '''IV Compatibility'''<br />
<br />
==Overdosage==<br />
<br />
===Acute Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
<br />
====Management====<br />
<br />
FDA package insert doesn't contain any information regarding "'''Management '''"<br />
<br />
==Pharmacology==<br />
<br />
{{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
<br />
===Mechanism of Action===<br />
<br />
The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
<br />
===Structure===<br />
<br />
*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
<br />
<br />
===Pharmacodynamics===<br />
<br />
(Description)<br />
<br />
===Pharmacokinetics===<br />
<br />
Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
<br />
====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4‑dehydro‑cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4‑dehydro‑cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
<br />
===Nonclinical Toxicology===<br />
<br />
==Clinical Studies==<br />
<br />
*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
<br />
{|<br />
| [[image:Cilo2.png|400px|thumb]]<br />
|}<br />
<br />
<br />
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
<br />
==How Supplied==<br />
<br />
'''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
<br />
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0223-60 bottles of 60 and 0185-0223-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
==Images==<br />
<br />
===Drug Images===<br />
<br />
{|<br />
| [[File:Cilostazol50mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 50 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;123 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
{|<br />
| [[File:Cilostazol100mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 100 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;223 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
===Package and Label Display Panel===<br />
<br />
Sandoz Inc.<br />
Princeton, NJ 08540<br />
OS8128<br />
Rev. 02/13<br />
MF0223REV02/13<br />
Cilostazol 100mg Tablet<br />
<br />
{|<br />
| [[image:Cilostazollabel.jpg|400px|thumb]]<br />
|}<br />
<br />
{|<br />
| [[image:Cilostazollabel1.png|400px|thumb]]<br />
|}<br />
<br />
==Patient Information==<br />
<br />
===Patient Information from FDA===<br />
(sil-OS-tah-zol)<br />
<br />
Please read this leaflet before you start taking cilostazol tablets and each time you renew it in case anything has changed. This leaflet does not replace careful discussions with your doctor. You and your doctor should discuss cilostazol when you start taking it and at regular check-ups. You should follow your doctor’s advice about when to have check-ups.<br />
What is cilostazol for?<br />
Cilostazol may improve the symptoms of patients with a medical condition called intermittent claudication.<br />
What is intermittent claudication?<br />
Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. It occurs because narrowing or blockage of the arteries decreases blood flow to the legs. The decreased blood flow does not supply enough oxygen to the leg muscles during walking, resulting in these painful leg cramps.<br />
<br />
'''What treatments are available for intermittent claudication?'''<br />
<br />
The three main treatments available for intermittent claudication are:<br />
*Exercise. Your doctor may advise an exercise program.<br />
*Medication. Your doctor may prescribe a medication such as cilostazol. (See Who should not take cilostazol tablets?)<br />
*Surgery. Your doctor may recommend a surgical procedure to bypass the blocked segment of the artery. Another procedure is called a percutaneous transluminal angioplasty. In this procedure, a catheter (a flexible tube) is inserted into the artery to reduce the blockage and improve blood flow.<br />
<br />
'''How does cilostazol work?'''<br />
<br />
*The exact way that many drugs work is not well understood. Although how cilostazol works is not completely clear, its main effects are to dilate (widen) the arteries supplying blood to the legs and to decrease the ability of platelets in the blood to stick together. Platelets are particles that circulate in the blood and play a role in clotting.<br />
*Cilostazol may reduce the leg pain that patients with intermittent claudication experience, allowing them to walk farther before their leg pain occurs.<br />
*Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks. If you have not noticed any benefit from cilostazol tablets after 12 weeks you and your doctor may wish to discuss other forms of treatment.<br />
*Sometimes blood vessel disease of the legs causes pain at rest or breakdown of skin in the leg. Cilostazol has not been shown to work in patients with these problems.<br />
<br />
'''Who should not take cilostazol tablets?'''<br />
<br />
*Patients who have congestive heart failure (CHF) must not take cilostazol tablets. The most common symptoms of CHF are shortness of breath and swelling of the legs. However, other conditions may also cause these symptoms. It is important that you discuss with your doctor whether you have CHF.<br />
*Over 1,300 patients took cilostazol in studies that lasted for 3 to 6 months. The mortality rate in these patients was similar to placebo (less than 1%). These studies were too small to be sure there is not some increased risk of dying with longer use or in patients sicker than those in the studies.<br />
<br />
'''How should cilostazol tablets be taken?'''<br />
<br />
*Follow your doctor’s advice about how to take cilostazol tablets.<br />
*You should take cilostazol tablets twice a day, at least one half-hour before or two hours after breakfast and dinner. Take cilostazol tablets at about the same times each day.<br />
*Do not share cilostazol tablets with anyone else. It was prescribed only for you.<br />
*Keep cilostazol tablets and all drugs out of the reach of children.<br />
<br />
'''Can cilostazol tablets be taken with other drugs?'''<br />
<br />
Certain drugs and foods can increase the amount of cilostazol in the blood. Because of this, your doctor may adjust your dose of cilostazol or even stop it if you are taking or are going to take one of the following medications.<br />
Drugs Interacting with Cilostazol<br />
Generic Name (Brand Names)Type of Drug<br />
[[erythromycin]] (such as E.E.S.®, Erythrocin®) Antibiotic<br />
[[ketoconazole]] (Nizoral®), [[itraconazole]] (Sporanox®) Antifungal<br />
[[diltiazem]] (Cardizem®) Antihypertensive<br />
[[omeprazole]] (Prilosec®) Gastric acid reducer<br />
This list does not include every drug that may interact with cilostazol tablets. Therefore, you should tell your doctor about all medications that you are taking, including vitamins, herbal supplements and over-the-counter drugs you can buy without a prescription. You should also check with your doctor before taking a new medication after you have begun cilostazol tablets.<br />
<br />
'''What are the possible side effects of cilostazol tablets?'''<br />
<br />
Cilostazol tablets may cause side effects including headache, diarrhea, abnormal stools, increased heart rate and palpitations.<br />
You should discuss possible side effects with your doctor before taking cilostazol tablets and any time you think you are having a side effect.<br />
This provides only a summary of information about cilostazol tablets. If you have any questions about cilostazol tablets, talk to your doctor.<br />
'''Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.'''<br />
<br />
===Patient Information from NLM===<br />
<br />
For patient information about Cilostazol from NLM, click [[Cilostazol (patient information)|here]].<br />
<br />
==Precautions with Alcohol==<br />
<br />
Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
<br />
==Brand Names==<br />
<br />
Cilostazol®, Platel®.<br />
<br />
==Look-Alike Drug Names==<br />
<br />
* (Paired Confused Name 1a) — (Paired Confused Name 1b)<br />
* (Paired Confused Name 2a) — (Paired Confused Name 2b)<br />
* (Paired Confused Name 3a) — (Paired Confused Name 3b)<br />
<br />
==[http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm Drug Shortage Status]==<br />
<br />
==[http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price Price]==<br />
<br />
==References==<br />
<br />
{{reflist}}<br />
<br />
</div></div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=Cilostazol&diff=962081Cilostazol2014-04-03T00:47:51Z<p>Abdurahman Khalil: </p>
<hr />
<div>{{DrugProjectFormSinglePage<br />
|authorTag={{AK}}<br />
|genericName=Cilostazol<br />
|aOrAn=a<br />
|drugClass=Phosphodiesterase 3 inhibitor<br />
|indication=Intermittent claudication<br />
|hasBlackBoxWarning=Yes<br />
|adverseReactions=*headache<br />
*dizziness <br />
*palpitation <br />
*diarrhea, <br />
*rhinitis <br />
*pharyngitis.<br />
|blackBoxWarningTitle=Contraindication<br />
|blackBoxWarningBody=<i><span style="color:#FF0000;">Heart failure</span></i> '' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
|fdaLIADAdult=&lt;h4&gt;Intermittent claudication 1&lt;/h5&gt;<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
|offLabelAdultGuideSupport======Secondary prevention of stroke and TIA=====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid'''<ref name="Lansberg-2012">{{Cite journal | last1 = Lansberg | first1 = MG. | last2 = O'Donnell | first2 = MJ. | last3 = Khatri | first3 = P. | last4 = Lang | first4 = ES. | last5 = Nguyen-Huynh | first5 = MN. | last6 = Schwartz | first6 = NE. | last7 = Sonnenberg | first7 = FA. | last8 = Schulman | first8 = S. | last9 = Vandvik | first9 = PO. | title = Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e601S-36S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2302 | PMID = 22315273 }}</ref><br />
<br />
=====Thrombosis prophylaxis in percutaneous coronary intervention =====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid'''<ref name="Vandvik-2012">{{Cite journal | last1 = Vandvik | first1 = PO. | last2 = Lincoff | first2 = AM. | last3 = Gore | first3 = JM. | last4 = Gutterman | first4 = DD. | last5 = Sonnenberg | first5 = FA. | last6 = Alonso-Coello | first6 = P. | last7 = Akl | first7 = EA. | last8 = Lansberg | first8 = MG. | last9 = Guyatt | first9 = GH. | title = Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e637S-68S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2306 | PMID = 22315274 }}</ref><br />
|contraindications=* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
|warnings======Hematologic Adverse Reactions=====<br />
Rare cases have been reported of [[thrombocytopenia ]]or [[leukopenia ]]progressing to [[agranulocytosis ]]when cilostazol was not immediately discontinued. The agranulocytosis, however, was reversible on discontinuation of cilostazol.<br />
<br />
=====Use with Clopidogrel=====<br />
There is limited information with respect to the efficacy or safety of the concurrent use of cilostazol and [[clopidogrel]], a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Although it cannot be determined whether there was an additive effect on bleeding times during concomitant administration with cilostazol and [[clopidogrel]], caution is advised for checking bleeding times during co-administration.<br />
|clinicalTrials=Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol and 134 days for patients on placebo.<br />
<br />
The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with PLETAL 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included [[palpitation ]]and [[diarrhea]], both 1.1% for cilostazol (all doses) versus 0.1% for placebo.<br />
<br />
======Body as a Whole======<br />
*Common:<br />
:*Abdominal pain<br />
:*Back pain<br />
:*Headache <br />
:*Infection<br />
<br />
*Less common:<br />
[[Chills]], face [[edema]], [[fever]], [[generalized edema]], [[malaise]], [[neck rigidity]], [[pelvic pain]], [[retroperitoneal haemorrhage]].<br />
<br />
======Central Nervous System======<br />
<br />
*Common:<br />
:*Dizziness<br />
:*Vertigo<br />
<br />
*Less common:<br />
[[Anxiety]], [[insomnia]], [[neuralgia]].<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
*Common:<br />
:*Abnormal stool<br />
:*Diarrhea<br />
:*Dyspepsia<br />
:*Flatulence<br />
:*Nausea<br />
<br />
*Less common:<br />
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Metabolic & Nutritional======<br />
*Common:<br />
:*Peripheral edema<br />
<br />
*Less common:<br />
Increased [[creatinine]], [[gout]], [[hyperlipemia]], [[hyperuricemia]].<br />
<br />
======Musculoskeletal======<br />
<br />
*Common:<br />
:*Myalgia<br />
<br />
*Less common:<br />
[[Arthralgia]], bone pain, [[bursitis]].<br />
<br />
======Miscellaneous======<br />
Less common adverse reactions:<br />
<br />
*'''Endocrine:''' [[Diabetes mellitus]].<br />
<br />
*'''Hemic and Lymphatic:''' [[Anemia]], [[ecchymosis]],[[ iron deficiency anemia]], [[polycythemia]], [[purpura]].<br />
<br />
*'''Skin and Appendages:''' Dry skin, [[furunculosis]], skin hypertrophy, [[urticaria]].<br />
<br />
*'''Special Senses:''' [[Amblyopia]], [[blindness]], [[conjunctivitis]], [[diplopia]], ear pain, eye haemorrhage, [[retinal haemorrhage]], [[tinnitus]].<br />
<br />
*'''Urogenital:''' [[Albuminuria]], [[cystitis]], [[urinary frequency]], vaginal haemorrhage, vaginitis.<br />
|postmarketing=The following events have been reported spontaneously from worldwide post-marketing experience since the launch of PLETAL in the US.<br />
<br />
======Blood and lymphatic system disorders:======<br />
[[Agranulocytosis]],[[ aplastic anemia]], [[granulocytopenia]], [[pancytopenia]], [[thrombocytopenia]], [[leukopenia]], <br />
[[bleeding tendency]]<br />
<br />
======Cardiac disorders:======<br />
<br />
[[Torsades de pointes]], [[QT prolongation|QTc prolongation]] (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. [[complete atrioventricular block]], c[[ardiac failure ]]and [[bradyarrythmia]], when treated with cilostazol. Cilostazol was used "off label" due to its positive [[chronotropic]] action)<br />
<br />
======Gastrointestinal disorders:======<br />
<br />
*Gastrointestinal haemorrhage<br />
<br />
======General disorders and administration site conditions:======<br />
<br />
*Pain<br />
*[[chest pain]] <br />
*[[hot flushes]]<br />
<br />
======Hepatobiliary disorders:======<br />
<br />
*Hepatic dysfunction/abnormal liver function tests <br />
*[[jaundice]]<br />
<br />
======Injury, poisoning and procedural complications:======<br />
<br />
*Extradural [[haematoma ]] <br />
*Subdural haematoma<br />
<br />
=====Investigations:=====<br />
<br />
*[[Blood glucose]] increased, blood [[uric acid]] increased, [[platelet count]] decreased, [[white blood cell count]] decreased, increase in [[BUN]] (blood urea increased), blood pressure increase<br />
<br />
======Nervous system disorders:======<br />
<br />
*[[Intracranial haemorrhage]] <br />
*[[cerebral haemorrhage]] <br />
*[[cerebrovascular accident]]<br />
<br />
======Respiratory, thoracic and mediastinal disorders:======<br />
<br />
*Pulmonary haemorrhage<br />
*[[ interstitial pneumonia]]<br />
<br />
'''Skin and subcutaneous tissue disorders:'''<br />
<br />
*Haemorrhage subcutaneous, [[pruritus]], skin eruptions including [[Stevens-Johnson syndrome]], skin drug eruption ([[dermatitis medicamentosa]])<br />
<br />
======Vascular disorders:======<br />
<br />
*Subacute [[thrombosis ]](these cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting)<br />
|drugInteractions======Aspirin=====<br />
<br />
*Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of ADP-induced ex vivo platelet aggregation by 22% to 37% when compared to either aspirin or cilostazol alone. Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to cilostazol alone and by 48% compared to aspirin alone. However, short-term co-administration of aspirin with cilostazol had no clinically significant impact on PT, aPTT or bleeding time compared to aspirin alone. <br />
<br />
*Effects of long-term co-administration in the general population are unknown. In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was co-administered with cilostazol to 201 patients. The most frequent doses and mean durations of aspirin therapy were 75 mg to 81 mg daily for 137 days (107 patients) and 325 mg daily for 54 days (85 patients). There was no apparent increase in incidence of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.<br />
<br />
=====Warfarin=====<br />
<br />
The cytochrome P-450 isoenzymes involved in the metabolism of R-warfarin are CYP3A4, CYP1A2 and CYP2C19 and in the metabolism of S-warfarin, CYP2C9. Cilostazol did not inhibit either the metabolism or the pharmacologic effects (PT, aPTT, bleeding time or platelet aggregation) of R- and S-warfarin after a single 25-mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and cilostazol on the pharmacokinetics and pharmacodynamics of both drugs is unknown.<br />
<br />
=====Clopidogrel=====<br />
<br />
Multiple doses of clopidogrel do not significantly increase steady state plasma concentrations of cilostazol.<br />
<br />
=====Inhibitors of CYP3A4=====<br />
<br />
======Strong Inhibitors of CYP3A4======<br />
<br />
A priming dose of [[ketoconazole ]]400 mg (a strong inhibitor of CYP3A4), was given one day prior to co-administration of single doses of [[ketoconazole ]]400 mg and cilostazol 100 mg. This regimen increased cilostazol Cmax by 94% and AUC by 117%. Other strong inhibitors of CYP3A4, such as [[itraconazole]], [[fluconazole]], [[miconazole]], [[fluvoxamine]], [[fluoxetine]], [[nefazodone ]]and [[sertraline]], would be expected to have a similar effect <br />
<br />
======Moderate Inhibitors of CYP3A4======<br />
<br />
*[[Erythromycin ]]and Other [[Macrolide ]]Antibiotics: [[Erythromycin ]]is a moderately strong inhibitor of CYP3A4. Co-administration of erythromycin 500 mg q 8h with a single dose of cilostazol 100 mg increased cilostazol Cmax by 47% and AUC by 73%. Inhibition of cilostazol metabolism by erythromycin increased the AUC of 4´-trans-hydroxy-cilostazol by 141%. Other macrolide antibiotics (e.g., [[clarithromycin]]), but not all (e.g., [[azithromycin]]), would be expected to have a similar effect.<br />
<br />
*Diltiazem: [[Diltiazem]] 180 mg decreased the clearance of cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC increased ~40%.<br />
<br />
*Grapefruit Juice: [[Grapefruit juice]] increased the Cmax of cilostazol by ~50% , but had no effect on AUC.<br />
=====Inhibitors of CYP2C19=====<br />
<br />
[[Omeprazole]]: Co-administration of omeprazole did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%, probably the result of omeprazole’s potent inhibition of CYP2C19 <br />
<br />
=====Quinidine =====<br />
<br />
Concomitant administration of [[quinidine ]]with a single dose of cilostazol 100 mg did not alter cilostazol pharmacokinetics.<br />
<br />
=====Lovastatin=====<br />
<br />
The concomitant administration of [[lovastatin ]]with cilostazol decreases cilostazol Css, max and AUCT by 15%. There is also a decrease, although nonsignificant, in cilostazol metabolite concentrations. Co-administration of cilostazol with lovastatin increases lovastatin and β–hydroxy lovastatin AUC approximately 70%. This is most likely clinically insignificant.<br />
|useInPregnancyFDA=In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
|useInNursing=Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
|useInPed=The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
|useInGeri=Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
|useInGender=The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range.<br />
|useInRenalImpair=Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
|useInHepaticImpair=Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
|othersTitle=Smokers<br />
|useInOthers=Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
|administration=Oral<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability)<br />
|overdose=Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
|drugBox={{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
|mechAction=The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
|structure=*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
|PK=Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
<br />
====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4 dehydro cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4 dehydro cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
|nonClinToxic=====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the<br />
|clinicalStudies=*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
<br />
{|<br />
| [[image:Cilo2.png|400px|thumb]]<br />
|}<br />
<br />
<br />
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
|howSupplied='''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other.<br />
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other.<br />
|NDC=0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
|storage=Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
|manBy=Sandoz Inc.Princeton, NJ 08540<br />
|distBy=Bryant Ranch Prepack<br />
|isPill=Yes<br />
}}<br />
{|class="infobox" style="position: fixed; top: 180px; right: 20px; margin: 0 0 0 0; border: 0; float: right; width: 15%; background: #104E8B; border-radius: 10px 10px 10px 10px;" cellpadding="0" cellspacing="0";<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #104E8B;" | [[{{PAGENAME}}|{{fontcolor|#F8F8FF|{{PAGENAME}}®}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #000000; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|Black Box Warning}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adult Indications and Dosage|{{fontcolor|#F8F8FF|Adult Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pediatric Indications and Dosage|{{fontcolor|#F8F8FF|Pediatric Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Contraindications|{{fontcolor|#F8F8FF|Contraindications}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Warnings|{{fontcolor|#F8F8FF|Warnings}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adverse Reactions|{{fontcolor|#F8F8FF|Adverse Reactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Drug Interactions|{{fontcolor|#F8F8FF|Drug Interactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Use in Specific Populations|{{fontcolor|#F8F8FF|Use in Specific Populations}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Administration and Monitoring|{{fontcolor|#F8F8FF|Administration and Monitoring}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#IV Compatibility|{{fontcolor|#F8F8FF|IV Compatibility}}]]<br />
|-<br />
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|-<br />
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|-<br />
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|-<br />
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|-<br />
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|-<br />
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|-<br />
|}<br />
<div style="width: 80%"><br />
__NOTOC__<br />
{{CMG}}<br />
<br />
{{SB}} Cilostazol®, Pletal®<br />
<br />
==Disclaimer==<br />
<br />
'''''WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature. The information provided is not a medical advice or treatment. WikiDoc does not promote any medication or off-label use of drugs. Please read our full disclaimer [[wikidoc:General_disclaimer|{{fontcolor|#FF0000|here}}]].'''''<br />
<br />
==<span style="color:#FF0000; background:#000000;">Black Box Warning</span>==<br />
<br />
FDA Package Insert for {{PAGENAME}} contains no information regarding ''Black Box Warning''.<br />
<br />
{| style="border: 3px solid #696969;"<br />
| style="background: #000000; border: 0px; padding: 20px 20px; width: 800px;" |<br />
<center><br />
<font color="#F8F8FF" style="font-weight: bold;">CONTRAINDICATION</font><br />
</center><br />
<br />
<center><br />
<font color="#F8F8FF" size="1" style="font-style: italic;">See full prescribing information for complete boxed warning.</font><br />
</center><br />
<br />
<font color="#F8F8FF" style="font-weight: bold;"><br />
''{{fontcolor|#FF0000|Condition Name:}}'' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
</font><br />
|}<br />
<br />
==Overview==<br />
<br />
{{PAGENAME}} is a_Phosphodiesterase 3 Inhibitor drug that is FDA approved for the treatment of intermittent claudication. There is a Black Box Warning for this drug as shown <span style="background:#000000;">'''[[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|here}}]]'''</span>. Common adverse reactions include headache, dizziness, palpitation, diarrhea, rhinitis and pharyngitis.<br />
<br />
==Adult Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Adult)===<br />
<br />
=====Intermittent claudication=====<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
<br />
===Off-Label Use and Dosage (Adult)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Secondary prevention of stroke and TIA=====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid'''<ref name="Lansberg-2012">{{Cite journal | last1 = Lansberg | first1 = MG. | last2 = O'Donnell | first2 = MJ. | last3 = Khatri | first3 = P. | last4 = Lang | first4 = ES. | last5 = Nguyen-Huynh | first5 = MN. | last6 = Schwartz | first6 = NE. | last7 = Sonnenberg | first7 = FA. | last8 = Schulman | first8 = S. | last9 = Vandvik | first9 = PO. | title = Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e601S-36S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2302 | PMID = 22315273 }}</ref><br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid''<ref name="Vandvik-2012">{{Cite journal | last1 = Vandvik | first1 = PO. | last2 = Lincoff | first2 = AM. | last3 = Gore | first3 = JM. | last4 = Gutterman | first4 = DD. | last5 = Sonnenberg | first5 = FA. | last6 = Alonso-Coello | first6 = P. | last7 = Akl | first7 = EA. | last8 = Lansberg | first8 = MG. | last9 = Guyatt | first9 = GH. | title = Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e637S-68S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2306 | PMID = 22315274 }}</ref><br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* There is limited information about ''Off-Label Non–Guideline-Supported Use'' of {{PAGENAME}} in adult patients.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Pediatric Indications and Dosage==<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
==Contraindications==<br />
* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
<br />
==Warnings==<br />
<br />
=====Hematologic Adverse Reactions=====<br />
Rare cases have been reported of [[thrombocytopenia ]]or [[leukopenia ]]progressing to [[agranulocytosis ]]when cilostazol was not immediately discontinued. The agranulocytosis, however, was reversible on discontinuation of cilostazol.<br />
<br />
=====Use with Clopidogrel=====<br />
There is limited information with respect to the efficacy or safety of the concurrent use of cilostazol and [[clopidogrel]], a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Although it cannot be determined whether there was an additive effect on bleeding times during concomitant administration with cilostazol and [[clopidogrel]], caution is advised for checking bleeding times during co-administration.<br />
<br />
==Adverse Reactions==<br />
<br />
===Clinical Trials Experience===<br />
Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol and 134 days for patients on placebo.<br />
<br />
The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with PLETAL 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included [[palpitation ]]and [[diarrhea]], both 1.1% for cilostazol (all doses) versus 0.1% for placebo.<br />
<br />
======Body as a Whole======<br />
*Common:<br />
:*Abdominal pain<br />
:*Back pain<br />
:*Headache <br />
:*Infection<br />
<br />
*Less common:<br />
[[Chills]], face [[edema]], [[fever]], [[generalized edema]], [[malaise]], [[neck rigidity]], [[pelvic pain]], [[retroperitoneal haemorrhage]].<br />
<br />
======Central Nervous System======<br />
<br />
*Common:<br />
:*Dizziness<br />
:*Vertigo<br />
<br />
*Less common:<br />
[[Anxiety]], [[insomnia]], [[neuralgia]].<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
*Common:<br />
:*Abnormal stool<br />
:*Diarrhea<br />
:*Dyspepsia<br />
:*Flatulence<br />
:*Nausea<br />
<br />
*Less common:<br />
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Metabolic & Nutritional======<br />
*Common:<br />
:*Peripheral edema<br />
<br />
*Less common:<br />
Increased [[creatinine]], [[gout]], [[hyperlipemia]], [[hyperuricemia]].<br />
<br />
======Musculoskeletal======<br />
<br />
*Common:<br />
:*Myalgia<br />
<br />
*Less common:<br />
[[Arthralgia]], bone pain, [[bursitis]].<br />
<br />
======Miscellaneous======<br />
Less common adverse reactions:<br />
<br />
*'''Endocrine:''' [[Diabetes mellitus]].<br />
<br />
*'''Hemic and Lymphatic:''' [[Anemia]], [[ecchymosis]],[[ iron deficiency anemia]], [[polycythemia]], [[purpura]].<br />
<br />
*'''Skin and Appendages:''' Dry skin, [[furunculosis]], skin hypertrophy, [[urticaria]].<br />
<br />
*'''Special Senses:''' [[Amblyopia]], [[blindness]], [[conjunctivitis]], [[diplopia]], ear pain, eye haemorrhage, [[retinal haemorrhage]], [[tinnitus]].<br />
<br />
*'''Urogenital:''' [[Albuminuria]], [[cystitis]], [[urinary frequency]], vaginal haemorrhage, vaginitis.<br />
<br />
===Postmarketing Experience===<br />
<br />
The following events have been reported spontaneously from worldwide post-marketing experience since the launch of PLETAL in the US.<br />
<br />
======Blood and lymphatic system disorders:======<br />
[[Agranulocytosis]],[[ aplastic anemia]], [[granulocytopenia]], [[pancytopenia]], [[thrombocytopenia]], [[leukopenia]], <br />
[[bleeding tendency]]<br />
<br />
======Cardiac disorders:======<br />
<br />
[[Torsades de pointes]], [[QT prolongation|QTc prolongation]] (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. [[complete atrioventricular block]], c[[ardiac failure ]]and [[bradyarrythmia]], when treated with cilostazol. Cilostazol was used "off label" due to its positive [[chronotropic]] action)<br />
<br />
======Gastrointestinal disorders:======<br />
<br />
*Gastrointestinal haemorrhage<br />
<br />
======General disorders and administration site conditions:======<br />
<br />
*Pain<br />
*[[chest pain]] <br />
*[[hot flushes]]<br />
<br />
======Hepatobiliary disorders:======<br />
<br />
*Hepatic dysfunction/abnormal liver function tests <br />
*[[jaundice]]<br />
<br />
======Injury, poisoning and procedural complications:======<br />
<br />
*Extradural [[haematoma ]] <br />
*Subdural haematoma<br />
<br />
=====Investigations:=====<br />
<br />
*[[Blood glucose]] increased, blood [[uric acid]] increased, [[platelet count]] decreased, [[white blood cell count]] decreased, increase in [[BUN]] (blood urea increased), blood pressure increase<br />
<br />
======Nervous system disorders:======<br />
<br />
*[[Intracranial haemorrhage]] <br />
*[[cerebral haemorrhage]] <br />
*[[cerebrovascular accident]]<br />
<br />
======Respiratory, thoracic and mediastinal disorders:======<br />
<br />
*Pulmonary haemorrhage<br />
*[[ interstitial pneumonia]]<br />
<br />
'''Skin and subcutaneous tissue disorders:'''<br />
<br />
*Haemorrhage subcutaneous, [[pruritus]], skin eruptions including [[Stevens-Johnson syndrome]], skin drug eruption ([[dermatitis medicamentosa]])<br />
<br />
======Vascular disorders:======<br />
<br />
*Subacute [[thrombosis ]](these cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting)<br />
<br />
==Drug Interactions==<br />
<br />
=====Aspirin=====<br />
<br />
*Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of ADP-induced ex vivo platelet aggregation by 22% to 37% when compared to either aspirin or cilostazol alone. Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to cilostazol alone and by 48% compared to aspirin alone. However, short-term co-administration of aspirin with cilostazol had no clinically significant impact on PT, aPTT or bleeding time compared to aspirin alone. <br />
<br />
*Effects of long-term co-administration in the general population are unknown. In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was co-administered with cilostazol to 201 patients. The most frequent doses and mean durations of aspirin therapy were 75 mg to 81 mg daily for 137 days (107 patients) and 325 mg daily for 54 days (85 patients). There was no apparent increase in incidence of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.<br />
<br />
=====Warfarin=====<br />
<br />
The cytochrome P-450 isoenzymes involved in the metabolism of R-warfarin are CYP3A4, CYP1A2 and CYP2C19 and in the metabolism of S-warfarin, CYP2C9. Cilostazol did not inhibit either the metabolism or the pharmacologic effects (PT, aPTT, bleeding time or platelet aggregation) of R- and S-warfarin after a single 25-mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and cilostazol on the pharmacokinetics and pharmacodynamics of both drugs is unknown.<br />
<br />
=====Clopidogrel=====<br />
<br />
Multiple doses of clopidogrel do not significantly increase steady state plasma concentrations of cilostazol.<br />
<br />
=====Inhibitors of CYP3A4=====<br />
<br />
======Strong Inhibitors of CYP3A4======<br />
<br />
A priming dose of [[ketoconazole ]]400 mg (a strong inhibitor of CYP3A4), was given one day prior to co-administration of single doses of [[ketoconazole ]]400 mg and cilostazol 100 mg. This regimen increased cilostazol Cmax by 94% and AUC by 117%. Other strong inhibitors of CYP3A4, such as [[itraconazole]], [[fluconazole]], [[miconazole]], [[fluvoxamine]], [[fluoxetine]], [[nefazodone ]]and [[sertraline]], would be expected to have a similar effect <br />
<br />
======Moderate Inhibitors of CYP3A4======<br />
<br />
*[[Erythromycin ]]and Other [[Macrolide ]]Antibiotics: [[Erythromycin ]]is a moderately strong inhibitor of CYP3A4. Co-administration of erythromycin 500 mg q 8h with a single dose of cilostazol 100 mg increased cilostazol Cmax by 47% and AUC by 73%. Inhibition of cilostazol metabolism by erythromycin increased the AUC of 4´-trans-hydroxy-cilostazol by 141%. Other macrolide antibiotics (e.g., [[clarithromycin]]), but not all (e.g., [[azithromycin]]), would be expected to have a similar effect.<br />
<br />
*Diltiazem: [[Diltiazem]] 180 mg decreased the clearance of cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC increased ~40%.<br />
<br />
*Grapefruit Juice: [[Grapefruit juice]] increased the Cmax of cilostazol by ~50% , but had no effect on AUC.<br />
=====Inhibitors of CYP2C19=====<br />
<br />
[[Omeprazole]]: Co-administration of omeprazole did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%, probably the result of omeprazole’s potent inhibition of CYP2C19 <br />
<br />
=====Quinidine =====<br />
<br />
Concomitant administration of [[quinidine ]]with a single dose of cilostazol 100 mg did not alter cilostazol pharmacokinetics.<br />
<br />
=====Lovastatin=====<br />
<br />
The concomitant administration of [[lovastatin ]]with cilostazol decreases cilostazol Css, max and AUCT by 15%. There is also a decrease, although nonsignificant, in cilostazol metabolite concentrations. Co-administration of cilostazol with lovastatin increases lovastatin and β–hydroxy lovastatin AUC approximately 70%. This is most likely clinically insignificant.<br />
<br />
==Use in Specific Populations==<br />
<br />
====Pregnancy====<br />
<br />
* '''[[Pregnancy category#United States|Pregnancy Category (FDA)]]: C'''<br />
<br />
* '''[[Pregnancy category#Australia|Pregnancy Category (AUS)]]: {{PAGENAME}} is not included in Australian Drug Evaluation Committee (ADEC) Pregnancy Categories.'''<br />
<br />
In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
<br />
====Labor and Delivery====<br />
<br />
FDA package insert doesn't contain any information regarding "'''Labor and Delivery'''"<br />
<br />
====Nursing Mothers====<br />
<br />
Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
<br />
====Pediatric Use====<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
====Geriatric Use====<br />
Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
====Gender====<br />
<br />
The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range<br />
<br />
====Race====<br />
<br />
(Description)<br />
<br />
====Renal Impairment====<br />
<br />
Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
<br />
====Hepatic Impairment====<br />
<br />
Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
<br />
====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the exposure in humans at the MRHD.<br />
<br />
====Immunocompromised Patients====<br />
<br />
(Description)<br />
<br />
====Miscellaneous====<br />
<br />
=====Smokers=====<br />
Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
<br />
==Administration and Monitoring==<br />
<br />
====Administration====<br />
<br />
Oral<br />
<br />
====Monitoring====<br />
FDA package insert does't contain any information regarding "'''Monitoring'''"<br />
<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability).<br />
<br />
==IV Compatibility==<br />
<br />
FDA package insert doesn't contain any information regarding '''IV Compatibility'''<br />
<br />
==Overdosage==<br />
<br />
===Acute Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
<br />
====Management====<br />
<br />
FDA package insert doesn't contain any information regarding "'''Management '''"<br />
<br />
==Pharmacology==<br />
<br />
{{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
<br />
===Mechanism of Action===<br />
<br />
The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
<br />
===Structure===<br />
<br />
*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
<br />
<br />
===Pharmacodynamics===<br />
<br />
(Description)<br />
<br />
===Pharmacokinetics===<br />
<br />
Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
<br />
====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4‑dehydro‑cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4‑dehydro‑cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
<br />
===Nonclinical Toxicology===<br />
<br />
==Clinical Studies==<br />
<br />
*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
<br />
{|<br />
| [[image:Cilo2.png|400px|thumb]]<br />
|}<br />
<br />
<br />
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
<br />
==How Supplied==<br />
<br />
'''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
<br />
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0223-60 bottles of 60 and 0185-0223-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
==Images==<br />
<br />
===Drug Images===<br />
<br />
{|<br />
| [[File:Cilostazol50mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 50 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;123 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
{|<br />
| [[File:Cilostazol100mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 100 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;223 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
===Package and Label Display Panel===<br />
<br />
Sandoz Inc.<br />
Princeton, NJ 08540<br />
OS8128<br />
Rev. 02/13<br />
MF0223REV02/13<br />
Cilostazol 100mg Tablet<br />
<br />
{|<br />
| [[image:Cilostazollabel.jpg|400px|thumb]]<br />
|}<br />
<br />
{|<br />
| [[image:Cilostazollabel1.png|400px|thumb]]<br />
|}<br />
<br />
==Patient Information==<br />
<br />
===Patient Information from FDA===<br />
(sil-OS-tah-zol)<br />
<br />
Please read this leaflet before you start taking cilostazol tablets and each time you renew it in case anything has changed. This leaflet does not replace careful discussions with your doctor. You and your doctor should discuss cilostazol when you start taking it and at regular check-ups. You should follow your doctor’s advice about when to have check-ups.<br />
What is cilostazol for?<br />
Cilostazol may improve the symptoms of patients with a medical condition called intermittent claudication.<br />
What is intermittent claudication?<br />
Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. It occurs because narrowing or blockage of the arteries decreases blood flow to the legs. The decreased blood flow does not supply enough oxygen to the leg muscles during walking, resulting in these painful leg cramps.<br />
<br />
'''What treatments are available for intermittent claudication?'''<br />
<br />
The three main treatments available for intermittent claudication are:<br />
*Exercise. Your doctor may advise an exercise program.<br />
*Medication. Your doctor may prescribe a medication such as cilostazol. (See Who should not take cilostazol tablets?)<br />
*Surgery. Your doctor may recommend a surgical procedure to bypass the blocked segment of the artery. Another procedure is called a percutaneous transluminal angioplasty. In this procedure, a catheter (a flexible tube) is inserted into the artery to reduce the blockage and improve blood flow.<br />
<br />
'''How does cilostazol work?'''<br />
<br />
*The exact way that many drugs work is not well understood. Although how cilostazol works is not completely clear, its main effects are to dilate (widen) the arteries supplying blood to the legs and to decrease the ability of platelets in the blood to stick together. Platelets are particles that circulate in the blood and play a role in clotting.<br />
*Cilostazol may reduce the leg pain that patients with intermittent claudication experience, allowing them to walk farther before their leg pain occurs.<br />
*Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks. If you have not noticed any benefit from cilostazol tablets after 12 weeks you and your doctor may wish to discuss other forms of treatment.<br />
*Sometimes blood vessel disease of the legs causes pain at rest or breakdown of skin in the leg. Cilostazol has not been shown to work in patients with these problems.<br />
<br />
'''Who should not take cilostazol tablets?'''<br />
<br />
*Patients who have congestive heart failure (CHF) must not take cilostazol tablets. The most common symptoms of CHF are shortness of breath and swelling of the legs. However, other conditions may also cause these symptoms. It is important that you discuss with your doctor whether you have CHF.<br />
*Over 1,300 patients took cilostazol in studies that lasted for 3 to 6 months. The mortality rate in these patients was similar to placebo (less than 1%). These studies were too small to be sure there is not some increased risk of dying with longer use or in patients sicker than those in the studies.<br />
<br />
'''How should cilostazol tablets be taken?'''<br />
<br />
*Follow your doctor’s advice about how to take cilostazol tablets.<br />
*You should take cilostazol tablets twice a day, at least one half-hour before or two hours after breakfast and dinner. Take cilostazol tablets at about the same times each day.<br />
*Do not share cilostazol tablets with anyone else. It was prescribed only for you.<br />
*Keep cilostazol tablets and all drugs out of the reach of children.<br />
<br />
'''Can cilostazol tablets be taken with other drugs?'''<br />
<br />
Certain drugs and foods can increase the amount of cilostazol in the blood. Because of this, your doctor may adjust your dose of cilostazol or even stop it if you are taking or are going to take one of the following medications.<br />
Drugs Interacting with Cilostazol<br />
Generic Name (Brand Names)Type of Drug<br />
[[erythromycin]] (such as E.E.S.®, Erythrocin®) Antibiotic<br />
[[ketoconazole]] (Nizoral®), [[itraconazole]] (Sporanox®) Antifungal<br />
[[diltiazem]] (Cardizem®) Antihypertensive<br />
[[omeprazole]] (Prilosec®) Gastric acid reducer<br />
This list does not include every drug that may interact with cilostazol tablets. Therefore, you should tell your doctor about all medications that you are taking, including vitamins, herbal supplements and over-the-counter drugs you can buy without a prescription. You should also check with your doctor before taking a new medication after you have begun cilostazol tablets.<br />
<br />
'''What are the possible side effects of cilostazol tablets?'''<br />
<br />
Cilostazol tablets may cause side effects including headache, diarrhea, abnormal stools, increased heart rate and palpitations.<br />
You should discuss possible side effects with your doctor before taking cilostazol tablets and any time you think you are having a side effect.<br />
This provides only a summary of information about cilostazol tablets. If you have any questions about cilostazol tablets, talk to your doctor.<br />
'''Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.'''<br />
<br />
===Patient Information from NLM===<br />
<br />
For patient information about Cilostazol from NLM, click [[Cilostazol (patient information)|here]].<br />
<br />
==Precautions with Alcohol==<br />
<br />
Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
<br />
==Brand Names==<br />
<br />
Cilostazol®, Platel®.<br />
<br />
==Look-Alike Drug Names==<br />
<br />
* (Paired Confused Name 1a) — (Paired Confused Name 1b)<br />
* (Paired Confused Name 2a) — (Paired Confused Name 2b)<br />
* (Paired Confused Name 3a) — (Paired Confused Name 3b)<br />
<br />
==[http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm Drug Shortage Status]==<br />
<br />
==[http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price Price]==<br />
<br />
==References==<br />
<br />
{{reflist}}<br />
<br />
</div></div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=Cilostazol&diff=962080Cilostazol2014-04-03T00:45:25Z<p>Abdurahman Khalil: </p>
<hr />
<div>{{DrugProjectFormSinglePage<br />
|authorTag={{AK}}<br />
|genericName=Cilostazol<br />
|aOrAn=a<br />
|drugClass=Phosphodiesterase 3 inhibitor<br />
|indication=Intermittent claudication<br />
|hasBlackBoxWarning=Yes<br />
|adverseReactions=*headache<br />
*dizziness <br />
*palpitation <br />
*diarrhea, <br />
*rhinitis <br />
*pharyngitis.<br />
|blackBoxWarningTitle=Contraindication<br />
|blackBoxWarningBody=<i><span style="color:#FF0000;">Heart failure</span></i> '' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
|fdaLIADAdult=&lt;h4&gt;Intermittent claudication 1&lt;/h5&gt;<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
|offLabelAdultGuideSupport======Secondary prevention of stroke and TIA=====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid'''<ref name="Lansberg-2012">{{Cite journal | last1 = Lansberg | first1 = MG. | last2 = O'Donnell | first2 = MJ. | last3 = Khatri | first3 = P. | last4 = Lang | first4 = ES. | last5 = Nguyen-Huynh | first5 = MN. | last6 = Schwartz | first6 = NE. | last7 = Sonnenberg | first7 = FA. | last8 = Schulman | first8 = S. | last9 = Vandvik | first9 = PO. | title = Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e601S-36S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2302 | PMID = 22315273 }}</ref><br />
<br />
=====Thrombosis prophylaxis in percutaneous coronary intervention =====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid'''<ref name="Vandvik-2012">{{Cite journal | last1 = Vandvik | first1 = PO. | last2 = Lincoff | first2 = AM. | last3 = Gore | first3 = JM. | last4 = Gutterman | first4 = DD. | last5 = Sonnenberg | first5 = FA. | last6 = Alonso-Coello | first6 = P. | last7 = Akl | first7 = EA. | last8 = Lansberg | first8 = MG. | last9 = Guyatt | first9 = GH. | title = Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e637S-68S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2306 | PMID = 22315274 }}</ref><br />
|contraindications=* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
|warnings======Hematologic Adverse Reactions=====<br />
Rare cases have been reported of [[thrombocytopenia ]]or [[leukopenia ]]progressing to [[agranulocytosis ]]when cilostazol was not immediately discontinued. The agranulocytosis, however, was reversible on discontinuation of cilostazol.<br />
<br />
=====Use with Clopidogrel=====<br />
There is limited information with respect to the efficacy or safety of the concurrent use of cilostazol and [[clopidogrel]], a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Although it cannot be determined whether there was an additive effect on bleeding times during concomitant administration with cilostazol and [[clopidogrel]], caution is advised for checking bleeding times during co-administration.<br />
|clinicalTrials=Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol and 134 days for patients on placebo.<br />
<br />
The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with PLETAL 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included [[palpitation ]]and [[diarrhea]], both 1.1% for cilostazol (all doses) versus 0.1% for placebo.<br />
<br />
======Body as a Whole======<br />
*Common:<br />
:*Abdominal pain<br />
:*Back pain<br />
:*Headache <br />
:*Infection<br />
<br />
*Less common:<br />
[[Chills]], face [[edema]], [[fever]], [[generalized edema]], [[malaise]], [[neck rigidity]], [[pelvic pain]], [[retroperitoneal haemorrhage]].<br />
<br />
======Central Nervous System======<br />
<br />
*Common:<br />
:*Dizziness<br />
:*Vertigo<br />
<br />
*Less common:<br />
[[Anxiety]], [[insomnia]], [[neuralgia]].<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
*Common:<br />
:*Abnormal stool<br />
:*Diarrhea<br />
:*Dyspepsia<br />
:*Flatulence<br />
:*Nausea<br />
<br />
*Less common:<br />
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Metabolic & Nutritional======<br />
*Common:<br />
:*Peripheral edema<br />
<br />
*Less common:<br />
Increased [[creatinine]], [[gout]], [[hyperlipemia]], [[hyperuricemia]].<br />
<br />
======Musculoskeletal======<br />
<br />
*Common:<br />
:*Myalgia<br />
<br />
*Less common:<br />
[[Arthralgia]], bone pain, [[bursitis]].<br />
<br />
======Miscellaneous======<br />
Less common adverse reactions:<br />
<br />
*'''Endocrine:''' [[Diabetes mellitus]].<br />
<br />
*'''Hemic and Lymphatic:''' [[Anemia]], [[ecchymosis]],[[ iron deficiency anemia]], [[polycythemia]], [[purpura]].<br />
<br />
*'''Skin and Appendages:''' Dry skin, [[furunculosis]], skin hypertrophy, [[urticaria]].<br />
<br />
*'''Special Senses:''' [[Amblyopia]], [[blindness]], [[conjunctivitis]], [[diplopia]], ear pain, eye haemorrhage, [[retinal haemorrhage]], [[tinnitus]].<br />
<br />
*'''Urogenital:''' [[Albuminuria]], [[cystitis]], [[urinary frequency]], vaginal haemorrhage, vaginitis.<br />
|postmarketing=The following events have been reported spontaneously from worldwide post-marketing experience since the launch of PLETAL in the US.<br />
<br />
======Blood and lymphatic system disorders:======<br />
[[Agranulocytosis]],[[ aplastic anemia]], [[granulocytopenia]], [[pancytopenia]], [[thrombocytopenia]], [[leukopenia]], <br />
[[bleeding tendency]]<br />
<br />
======Cardiac disorders:======<br />
<br />
[[Torsades de pointes]], [[QT prolongation|QTc prolongation]] (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. [[complete atrioventricular block]], c[[ardiac failure ]]and [[bradyarrythmia]], when treated with cilostazol. Cilostazol was used "off label" due to its positive [[chronotropic]] action)<br />
<br />
======Gastrointestinal disorders:======<br />
<br />
*Gastrointestinal haemorrhage<br />
<br />
======General disorders and administration site conditions:======<br />
<br />
*Pain<br />
*[[chest pain]] <br />
*[[hot flushes]]<br />
<br />
======Hepatobiliary disorders:======<br />
<br />
*Hepatic dysfunction/abnormal liver function tests <br />
*[[jaundice]]<br />
<br />
======Injury, poisoning and procedural complications:======<br />
<br />
*Extradural [[haematoma ]] <br />
*Subdural haematoma<br />
<br />
=====Investigations:=====<br />
<br />
*[[Blood glucose]] increased, blood [[uric acid]] increased, [[platelet count]] decreased, [[white blood cell count]] decreased, increase in [[BUN]] (blood urea increased), blood pressure increase<br />
<br />
======Nervous system disorders:======<br />
<br />
*[[Intracranial haemorrhage]] <br />
*[[cerebral haemorrhage]] <br />
*[[cerebrovascular accident]]<br />
<br />
======Respiratory, thoracic and mediastinal disorders:======<br />
<br />
*Pulmonary haemorrhage<br />
*[[ interstitial pneumonia]]<br />
<br />
'''Skin and subcutaneous tissue disorders:'''<br />
<br />
*Haemorrhage subcutaneous, [[pruritus]], skin eruptions including [[Stevens-Johnson syndrome]], skin drug eruption ([[dermatitis medicamentosa]])<br />
<br />
======Vascular disorders:======<br />
<br />
*Subacute [[thrombosis ]](these cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting)<br />
|drugInteractions======Aspirin=====<br />
<br />
*Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of ADP-induced ex vivo platelet aggregation by 22% to 37% when compared to either aspirin or cilostazol alone. Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to cilostazol alone and by 48% compared to aspirin alone. However, short-term co-administration of aspirin with cilostazol had no clinically significant impact on PT, aPTT or bleeding time compared to aspirin alone. <br />
<br />
*Effects of long-term co-administration in the general population are unknown. In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was co-administered with cilostazol to 201 patients. The most frequent doses and mean durations of aspirin therapy were 75 mg to 81 mg daily for 137 days (107 patients) and 325 mg daily for 54 days (85 patients). There was no apparent increase in incidence of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.<br />
<br />
=====Warfarin=====<br />
<br />
The cytochrome P-450 isoenzymes involved in the metabolism of R-warfarin are CYP3A4, CYP1A2 and CYP2C19 and in the metabolism of S-warfarin, CYP2C9. Cilostazol did not inhibit either the metabolism or the pharmacologic effects (PT, aPTT, bleeding time or platelet aggregation) of R- and S-warfarin after a single 25-mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and cilostazol on the pharmacokinetics and pharmacodynamics of both drugs is unknown.<br />
<br />
=====Clopidogrel=====<br />
<br />
Multiple doses of clopidogrel do not significantly increase steady state plasma concentrations of cilostazol.<br />
<br />
=====Inhibitors of CYP3A4=====<br />
<br />
======Strong Inhibitors of CYP3A4======<br />
<br />
A priming dose of [[ketoconazole ]]400 mg (a strong inhibitor of CYP3A4), was given one day prior to co-administration of single doses of [[ketoconazole ]]400 mg and cilostazol 100 mg. This regimen increased cilostazol Cmax by 94% and AUC by 117%. Other strong inhibitors of CYP3A4, such as [[itraconazole]], [[fluconazole]], [[miconazole]], [[fluvoxamine]], [[fluoxetine]], [[nefazodone ]]and [[sertraline]], would be expected to have a similar effect <br />
<br />
======Moderate Inhibitors of CYP3A4======<br />
<br />
*[[Erythromycin ]]and Other [[Macrolide ]]Antibiotics: [[Erythromycin ]]is a moderately strong inhibitor of CYP3A4. Co-administration of erythromycin 500 mg q 8h with a single dose of cilostazol 100 mg increased cilostazol Cmax by 47% and AUC by 73%. Inhibition of cilostazol metabolism by erythromycin increased the AUC of 4´-trans-hydroxy-cilostazol by 141%. Other macrolide antibiotics (e.g., [[clarithromycin]]), but not all (e.g., [[azithromycin]]), would be expected to have a similar effect.<br />
<br />
*Diltiazem: [[Diltiazem]] 180 mg decreased the clearance of cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC increased ~40%.<br />
<br />
*Grapefruit Juice: [[Grapefruit juice]] increased the Cmax of cilostazol by ~50% , but had no effect on AUC.<br />
=====Inhibitors of CYP2C19=====<br />
<br />
[[Omeprazole]]: Co-administration of omeprazole did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%, probably the result of omeprazole’s potent inhibition of CYP2C19 <br />
<br />
=====Quinidine =====<br />
<br />
Concomitant administration of [[quinidine ]]with a single dose of cilostazol 100 mg did not alter cilostazol pharmacokinetics.<br />
<br />
=====Lovastatin=====<br />
<br />
The concomitant administration of [[lovastatin ]]with cilostazol decreases cilostazol Css, max and AUCT by 15%. There is also a decrease, although nonsignificant, in cilostazol metabolite concentrations. Co-administration of cilostazol with lovastatin increases lovastatin and β–hydroxy lovastatin AUC approximately 70%. This is most likely clinically insignificant.<br />
|useInPregnancyFDA=* '''[[Pregnancy category#United States|Pregnancy Category (FDA)]]: C'''<br />
<br />
In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
|useInNursing=Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
|useInPed=The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
|useInGeri=Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
|useInGender=The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range.<br />
|useInRenalImpair=Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
|useInHepaticImpair=Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
|othersTitle=Smokers<br />
|useInOthers=Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
|administration=Oral<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability)<br />
|overdose=Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
|drugBox={{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
|mechAction=The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
|structure=*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
|PK=Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
<br />
====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4 dehydro cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4 dehydro cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
|nonClinToxic=====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the<br />
|clinicalStudies=*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
<br />
{|<br />
| [[image:Cilo2.png|400px|thumb]]<br />
|}<br />
<br />
<br />
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
|howSupplied='''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other.<br />
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other.<br />
|NDC= 0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
|storage=Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
|manBy=Sandoz Inc.Princeton, NJ 08540<br />
|distBy=Bryant Ranch Prepack<br />
|isPill=Yes<br />
}}<br />
{|class="infobox" style="position: fixed; top: 180px; right: 20px; margin: 0 0 0 0; border: 0; float: right; width: 15%; background: #104E8B; border-radius: 10px 10px 10px 10px;" cellpadding="0" cellspacing="0";<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #104E8B;" | [[{{PAGENAME}}|{{fontcolor|#F8F8FF|{{PAGENAME}}®}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #000000; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|Black Box Warning}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adult Indications and Dosage|{{fontcolor|#F8F8FF|Adult Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pediatric Indications and Dosage|{{fontcolor|#F8F8FF|Pediatric Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Contraindications|{{fontcolor|#F8F8FF|Contraindications}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Warnings|{{fontcolor|#F8F8FF|Warnings}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adverse Reactions|{{fontcolor|#F8F8FF|Adverse Reactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Drug Interactions|{{fontcolor|#F8F8FF|Drug Interactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Use in Specific Populations|{{fontcolor|#F8F8FF|Use in Specific Populations}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Administration and Monitoring|{{fontcolor|#F8F8FF|Administration and Monitoring}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#IV Compatibility|{{fontcolor|#F8F8FF|IV Compatibility}}]]<br />
|-<br />
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|-<br />
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|-<br />
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|-<br />
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|-<br />
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|-<br />
|}<br />
<div style="width: 80%"><br />
__NOTOC__<br />
{{CMG}}<br />
<br />
{{SB}} Cilostazol®, Pletal®<br />
<br />
==Disclaimer==<br />
<br />
'''''WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature. The information provided is not a medical advice or treatment. WikiDoc does not promote any medication or off-label use of drugs. Please read our full disclaimer [[wikidoc:General_disclaimer|{{fontcolor|#FF0000|here}}]].'''''<br />
<br />
==<span style="color:#FF0000; background:#000000;">Black Box Warning</span>==<br />
<br />
FDA Package Insert for {{PAGENAME}} contains no information regarding ''Black Box Warning''.<br />
<br />
{| style="border: 3px solid #696969;"<br />
| style="background: #000000; border: 0px; padding: 20px 20px; width: 800px;" |<br />
<center><br />
<font color="#F8F8FF" style="font-weight: bold;">CONTRAINDICATION</font><br />
</center><br />
<br />
<center><br />
<font color="#F8F8FF" size="1" style="font-style: italic;">See full prescribing information for complete boxed warning.</font><br />
</center><br />
<br />
<font color="#F8F8FF" style="font-weight: bold;"><br />
''{{fontcolor|#FF0000|Condition Name:}}'' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
</font><br />
|}<br />
<br />
==Overview==<br />
<br />
{{PAGENAME}} is a_Phosphodiesterase 3 Inhibitor drug that is FDA approved for the treatment of intermittent claudication. There is a Black Box Warning for this drug as shown <span style="background:#000000;">'''[[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|here}}]]'''</span>. Common adverse reactions include headache, dizziness, palpitation, diarrhea, rhinitis and pharyngitis.<br />
<br />
==Adult Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Adult)===<br />
<br />
=====Intermittent claudication=====<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
<br />
===Off-Label Use and Dosage (Adult)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Secondary prevention of stroke and TIA=====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid'''<ref name="Lansberg-2012">{{Cite journal | last1 = Lansberg | first1 = MG. | last2 = O'Donnell | first2 = MJ. | last3 = Khatri | first3 = P. | last4 = Lang | first4 = ES. | last5 = Nguyen-Huynh | first5 = MN. | last6 = Schwartz | first6 = NE. | last7 = Sonnenberg | first7 = FA. | last8 = Schulman | first8 = S. | last9 = Vandvik | first9 = PO. | title = Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e601S-36S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2302 | PMID = 22315273 }}</ref><br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid''<ref name="Vandvik-2012">{{Cite journal | last1 = Vandvik | first1 = PO. | last2 = Lincoff | first2 = AM. | last3 = Gore | first3 = JM. | last4 = Gutterman | first4 = DD. | last5 = Sonnenberg | first5 = FA. | last6 = Alonso-Coello | first6 = P. | last7 = Akl | first7 = EA. | last8 = Lansberg | first8 = MG. | last9 = Guyatt | first9 = GH. | title = Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e637S-68S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2306 | PMID = 22315274 }}</ref><br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* There is limited information about ''Off-Label Non–Guideline-Supported Use'' of {{PAGENAME}} in adult patients.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Pediatric Indications and Dosage==<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
==Contraindications==<br />
* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
<br />
==Warnings==<br />
<br />
=====Hematologic Adverse Reactions=====<br />
Rare cases have been reported of [[thrombocytopenia ]]or [[leukopenia ]]progressing to [[agranulocytosis ]]when cilostazol was not immediately discontinued. The agranulocytosis, however, was reversible on discontinuation of cilostazol.<br />
<br />
=====Use with Clopidogrel=====<br />
There is limited information with respect to the efficacy or safety of the concurrent use of cilostazol and [[clopidogrel]], a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Although it cannot be determined whether there was an additive effect on bleeding times during concomitant administration with cilostazol and [[clopidogrel]], caution is advised for checking bleeding times during co-administration.<br />
<br />
==Adverse Reactions==<br />
<br />
===Clinical Trials Experience===<br />
Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol and 134 days for patients on placebo.<br />
<br />
The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with PLETAL 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included [[palpitation ]]and [[diarrhea]], both 1.1% for cilostazol (all doses) versus 0.1% for placebo.<br />
<br />
======Body as a Whole======<br />
*Common:<br />
:*Abdominal pain<br />
:*Back pain<br />
:*Headache <br />
:*Infection<br />
<br />
*Less common:<br />
[[Chills]], face [[edema]], [[fever]], [[generalized edema]], [[malaise]], [[neck rigidity]], [[pelvic pain]], [[retroperitoneal haemorrhage]].<br />
<br />
======Central Nervous System======<br />
<br />
*Common:<br />
:*Dizziness<br />
:*Vertigo<br />
<br />
*Less common:<br />
[[Anxiety]], [[insomnia]], [[neuralgia]].<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
*Common:<br />
:*Abnormal stool<br />
:*Diarrhea<br />
:*Dyspepsia<br />
:*Flatulence<br />
:*Nausea<br />
<br />
*Less common:<br />
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Metabolic & Nutritional======<br />
*Common:<br />
:*Peripheral edema<br />
<br />
*Less common:<br />
Increased [[creatinine]], [[gout]], [[hyperlipemia]], [[hyperuricemia]].<br />
<br />
======Musculoskeletal======<br />
<br />
*Common:<br />
:*Myalgia<br />
<br />
*Less common:<br />
[[Arthralgia]], bone pain, [[bursitis]].<br />
<br />
======Miscellaneous======<br />
Less common adverse reactions:<br />
<br />
*'''Endocrine:''' [[Diabetes mellitus]].<br />
<br />
*'''Hemic and Lymphatic:''' [[Anemia]], [[ecchymosis]],[[ iron deficiency anemia]], [[polycythemia]], [[purpura]].<br />
<br />
*'''Skin and Appendages:''' Dry skin, [[furunculosis]], skin hypertrophy, [[urticaria]].<br />
<br />
*'''Special Senses:''' [[Amblyopia]], [[blindness]], [[conjunctivitis]], [[diplopia]], ear pain, eye haemorrhage, [[retinal haemorrhage]], [[tinnitus]].<br />
<br />
*'''Urogenital:''' [[Albuminuria]], [[cystitis]], [[urinary frequency]], vaginal haemorrhage, vaginitis.<br />
<br />
===Postmarketing Experience===<br />
<br />
The following events have been reported spontaneously from worldwide post-marketing experience since the launch of PLETAL in the US.<br />
<br />
======Blood and lymphatic system disorders:======<br />
[[Agranulocytosis]],[[ aplastic anemia]], [[granulocytopenia]], [[pancytopenia]], [[thrombocytopenia]], [[leukopenia]], <br />
[[bleeding tendency]]<br />
<br />
======Cardiac disorders:======<br />
<br />
[[Torsades de pointes]], [[QT prolongation|QTc prolongation]] (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. [[complete atrioventricular block]], c[[ardiac failure ]]and [[bradyarrythmia]], when treated with cilostazol. Cilostazol was used "off label" due to its positive [[chronotropic]] action)<br />
<br />
======Gastrointestinal disorders:======<br />
<br />
*Gastrointestinal haemorrhage<br />
<br />
======General disorders and administration site conditions:======<br />
<br />
*Pain<br />
*[[chest pain]] <br />
*[[hot flushes]]<br />
<br />
======Hepatobiliary disorders:======<br />
<br />
*Hepatic dysfunction/abnormal liver function tests <br />
*[[jaundice]]<br />
<br />
======Injury, poisoning and procedural complications:======<br />
<br />
*Extradural [[haematoma ]] <br />
*Subdural haematoma<br />
<br />
=====Investigations:=====<br />
<br />
*[[Blood glucose]] increased, blood [[uric acid]] increased, [[platelet count]] decreased, [[white blood cell count]] decreased, increase in [[BUN]] (blood urea increased), blood pressure increase<br />
<br />
======Nervous system disorders:======<br />
<br />
*[[Intracranial haemorrhage]] <br />
*[[cerebral haemorrhage]] <br />
*[[cerebrovascular accident]]<br />
<br />
======Respiratory, thoracic and mediastinal disorders:======<br />
<br />
*Pulmonary haemorrhage<br />
*[[ interstitial pneumonia]]<br />
<br />
'''Skin and subcutaneous tissue disorders:'''<br />
<br />
*Haemorrhage subcutaneous, [[pruritus]], skin eruptions including [[Stevens-Johnson syndrome]], skin drug eruption ([[dermatitis medicamentosa]])<br />
<br />
======Vascular disorders:======<br />
<br />
*Subacute [[thrombosis ]](these cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting)<br />
<br />
==Drug Interactions==<br />
<br />
=====Aspirin=====<br />
<br />
*Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of ADP-induced ex vivo platelet aggregation by 22% to 37% when compared to either aspirin or cilostazol alone. Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to cilostazol alone and by 48% compared to aspirin alone. However, short-term co-administration of aspirin with cilostazol had no clinically significant impact on PT, aPTT or bleeding time compared to aspirin alone. <br />
<br />
*Effects of long-term co-administration in the general population are unknown. In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was co-administered with cilostazol to 201 patients. The most frequent doses and mean durations of aspirin therapy were 75 mg to 81 mg daily for 137 days (107 patients) and 325 mg daily for 54 days (85 patients). There was no apparent increase in incidence of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.<br />
<br />
=====Warfarin=====<br />
<br />
The cytochrome P-450 isoenzymes involved in the metabolism of R-warfarin are CYP3A4, CYP1A2 and CYP2C19 and in the metabolism of S-warfarin, CYP2C9. Cilostazol did not inhibit either the metabolism or the pharmacologic effects (PT, aPTT, bleeding time or platelet aggregation) of R- and S-warfarin after a single 25-mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and cilostazol on the pharmacokinetics and pharmacodynamics of both drugs is unknown.<br />
<br />
=====Clopidogrel=====<br />
<br />
Multiple doses of clopidogrel do not significantly increase steady state plasma concentrations of cilostazol.<br />
<br />
=====Inhibitors of CYP3A4=====<br />
<br />
======Strong Inhibitors of CYP3A4======<br />
<br />
A priming dose of [[ketoconazole ]]400 mg (a strong inhibitor of CYP3A4), was given one day prior to co-administration of single doses of [[ketoconazole ]]400 mg and cilostazol 100 mg. This regimen increased cilostazol Cmax by 94% and AUC by 117%. Other strong inhibitors of CYP3A4, such as [[itraconazole]], [[fluconazole]], [[miconazole]], [[fluvoxamine]], [[fluoxetine]], [[nefazodone ]]and [[sertraline]], would be expected to have a similar effect <br />
<br />
======Moderate Inhibitors of CYP3A4======<br />
<br />
*[[Erythromycin ]]and Other [[Macrolide ]]Antibiotics: [[Erythromycin ]]is a moderately strong inhibitor of CYP3A4. Co-administration of erythromycin 500 mg q 8h with a single dose of cilostazol 100 mg increased cilostazol Cmax by 47% and AUC by 73%. Inhibition of cilostazol metabolism by erythromycin increased the AUC of 4´-trans-hydroxy-cilostazol by 141%. Other macrolide antibiotics (e.g., [[clarithromycin]]), but not all (e.g., [[azithromycin]]), would be expected to have a similar effect.<br />
<br />
*Diltiazem: [[Diltiazem]] 180 mg decreased the clearance of cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC increased ~40%.<br />
<br />
*Grapefruit Juice: [[Grapefruit juice]] increased the Cmax of cilostazol by ~50% , but had no effect on AUC.<br />
=====Inhibitors of CYP2C19=====<br />
<br />
[[Omeprazole]]: Co-administration of omeprazole did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%, probably the result of omeprazole’s potent inhibition of CYP2C19 <br />
<br />
=====Quinidine =====<br />
<br />
Concomitant administration of [[quinidine ]]with a single dose of cilostazol 100 mg did not alter cilostazol pharmacokinetics.<br />
<br />
=====Lovastatin=====<br />
<br />
The concomitant administration of [[lovastatin ]]with cilostazol decreases cilostazol Css, max and AUCT by 15%. There is also a decrease, although nonsignificant, in cilostazol metabolite concentrations. Co-administration of cilostazol with lovastatin increases lovastatin and β–hydroxy lovastatin AUC approximately 70%. This is most likely clinically insignificant.<br />
<br />
==Use in Specific Populations==<br />
<br />
====Pregnancy====<br />
<br />
* '''[[Pregnancy category#United States|Pregnancy Category (FDA)]]: C'''<br />
<br />
* '''[[Pregnancy category#Australia|Pregnancy Category (AUS)]]: {{PAGENAME}} is not included in Australian Drug Evaluation Committee (ADEC) Pregnancy Categories.'''<br />
<br />
In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
<br />
====Labor and Delivery====<br />
<br />
FDA package insert doesn't contain any information regarding "'''Labor and Delivery'''"<br />
<br />
====Nursing Mothers====<br />
<br />
Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
<br />
====Pediatric Use====<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
====Geriatric Use====<br />
Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
====Gender====<br />
<br />
The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range<br />
<br />
====Race====<br />
<br />
(Description)<br />
<br />
====Renal Impairment====<br />
<br />
Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
<br />
====Hepatic Impairment====<br />
<br />
Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
<br />
====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the exposure in humans at the MRHD.<br />
<br />
====Immunocompromised Patients====<br />
<br />
(Description)<br />
<br />
====Miscellaneous====<br />
<br />
=====Smokers=====<br />
Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
<br />
==Administration and Monitoring==<br />
<br />
====Administration====<br />
<br />
Oral<br />
<br />
====Monitoring====<br />
FDA package insert does't contain any information regarding "'''Monitoring'''"<br />
<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability).<br />
<br />
==IV Compatibility==<br />
<br />
FDA package insert doesn't contain any information regarding '''IV Compatibility'''<br />
<br />
==Overdosage==<br />
<br />
===Acute Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
<br />
====Management====<br />
<br />
FDA package insert doesn't contain any information regarding "'''Management '''"<br />
<br />
==Pharmacology==<br />
<br />
{{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
<br />
===Mechanism of Action===<br />
<br />
The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
<br />
===Structure===<br />
<br />
*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
<br />
<br />
===Pharmacodynamics===<br />
<br />
(Description)<br />
<br />
===Pharmacokinetics===<br />
<br />
Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
<br />
====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4‑dehydro‑cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4‑dehydro‑cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
<br />
===Nonclinical Toxicology===<br />
<br />
==Clinical Studies==<br />
<br />
*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
<br />
{|<br />
| [[image:Cilo2.png|400px|thumb]]<br />
|}<br />
<br />
<br />
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
<br />
==How Supplied==<br />
<br />
'''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
<br />
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0223-60 bottles of 60 and 0185-0223-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
==Images==<br />
<br />
===Drug Images===<br />
<br />
{|<br />
| [[File:Cilostazol50mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 50 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;123 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
{|<br />
| [[File:Cilostazol100mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 100 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;223 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
===Package and Label Display Panel===<br />
<br />
Sandoz Inc.<br />
Princeton, NJ 08540<br />
OS8128<br />
Rev. 02/13<br />
MF0223REV02/13<br />
Cilostazol 100mg Tablet<br />
<br />
{|<br />
| [[image:Cilostazollabel.jpg|400px|thumb]]<br />
|}<br />
<br />
{|<br />
| [[image:Cilostazollabel1.png|400px|thumb]]<br />
|}<br />
<br />
==Patient Information==<br />
<br />
===Patient Information from FDA===<br />
(sil-OS-tah-zol)<br />
<br />
Please read this leaflet before you start taking cilostazol tablets and each time you renew it in case anything has changed. This leaflet does not replace careful discussions with your doctor. You and your doctor should discuss cilostazol when you start taking it and at regular check-ups. You should follow your doctor’s advice about when to have check-ups.<br />
What is cilostazol for?<br />
Cilostazol may improve the symptoms of patients with a medical condition called intermittent claudication.<br />
What is intermittent claudication?<br />
Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. It occurs because narrowing or blockage of the arteries decreases blood flow to the legs. The decreased blood flow does not supply enough oxygen to the leg muscles during walking, resulting in these painful leg cramps.<br />
<br />
'''What treatments are available for intermittent claudication?'''<br />
<br />
The three main treatments available for intermittent claudication are:<br />
*Exercise. Your doctor may advise an exercise program.<br />
*Medication. Your doctor may prescribe a medication such as cilostazol. (See Who should not take cilostazol tablets?)<br />
*Surgery. Your doctor may recommend a surgical procedure to bypass the blocked segment of the artery. Another procedure is called a percutaneous transluminal angioplasty. In this procedure, a catheter (a flexible tube) is inserted into the artery to reduce the blockage and improve blood flow.<br />
<br />
'''How does cilostazol work?'''<br />
<br />
*The exact way that many drugs work is not well understood. Although how cilostazol works is not completely clear, its main effects are to dilate (widen) the arteries supplying blood to the legs and to decrease the ability of platelets in the blood to stick together. Platelets are particles that circulate in the blood and play a role in clotting.<br />
*Cilostazol may reduce the leg pain that patients with intermittent claudication experience, allowing them to walk farther before their leg pain occurs.<br />
*Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks. If you have not noticed any benefit from cilostazol tablets after 12 weeks you and your doctor may wish to discuss other forms of treatment.<br />
*Sometimes blood vessel disease of the legs causes pain at rest or breakdown of skin in the leg. Cilostazol has not been shown to work in patients with these problems.<br />
<br />
'''Who should not take cilostazol tablets?'''<br />
<br />
*Patients who have congestive heart failure (CHF) must not take cilostazol tablets. The most common symptoms of CHF are shortness of breath and swelling of the legs. However, other conditions may also cause these symptoms. It is important that you discuss with your doctor whether you have CHF.<br />
*Over 1,300 patients took cilostazol in studies that lasted for 3 to 6 months. The mortality rate in these patients was similar to placebo (less than 1%). These studies were too small to be sure there is not some increased risk of dying with longer use or in patients sicker than those in the studies.<br />
<br />
'''How should cilostazol tablets be taken?'''<br />
<br />
*Follow your doctor’s advice about how to take cilostazol tablets.<br />
*You should take cilostazol tablets twice a day, at least one half-hour before or two hours after breakfast and dinner. Take cilostazol tablets at about the same times each day.<br />
*Do not share cilostazol tablets with anyone else. It was prescribed only for you.<br />
*Keep cilostazol tablets and all drugs out of the reach of children.<br />
<br />
'''Can cilostazol tablets be taken with other drugs?'''<br />
<br />
Certain drugs and foods can increase the amount of cilostazol in the blood. Because of this, your doctor may adjust your dose of cilostazol or even stop it if you are taking or are going to take one of the following medications.<br />
Drugs Interacting with Cilostazol<br />
Generic Name (Brand Names)Type of Drug<br />
[[erythromycin]] (such as E.E.S.®, Erythrocin®) Antibiotic<br />
[[ketoconazole]] (Nizoral®), [[itraconazole]] (Sporanox®) Antifungal<br />
[[diltiazem]] (Cardizem®) Antihypertensive<br />
[[omeprazole]] (Prilosec®) Gastric acid reducer<br />
This list does not include every drug that may interact with cilostazol tablets. Therefore, you should tell your doctor about all medications that you are taking, including vitamins, herbal supplements and over-the-counter drugs you can buy without a prescription. You should also check with your doctor before taking a new medication after you have begun cilostazol tablets.<br />
<br />
'''What are the possible side effects of cilostazol tablets?'''<br />
<br />
Cilostazol tablets may cause side effects including headache, diarrhea, abnormal stools, increased heart rate and palpitations.<br />
You should discuss possible side effects with your doctor before taking cilostazol tablets and any time you think you are having a side effect.<br />
This provides only a summary of information about cilostazol tablets. If you have any questions about cilostazol tablets, talk to your doctor.<br />
'''Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.'''<br />
<br />
===Patient Information from NLM===<br />
<br />
For patient information about Cilostazol from NLM, click [[Cilostazol (patient information)|here]].<br />
<br />
==Precautions with Alcohol==<br />
<br />
Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
<br />
==Brand Names==<br />
<br />
Cilostazol®, Platel®.<br />
<br />
==Look-Alike Drug Names==<br />
<br />
* (Paired Confused Name 1a) — (Paired Confused Name 1b)<br />
* (Paired Confused Name 2a) — (Paired Confused Name 2b)<br />
* (Paired Confused Name 3a) — (Paired Confused Name 3b)<br />
<br />
==[http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm Drug Shortage Status]==<br />
<br />
==[http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price Price]==<br />
<br />
==References==<br />
<br />
{{reflist}}<br />
<br />
</div></div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=Cilostazol&diff=962075Cilostazol2014-04-03T00:36:12Z<p>Abdurahman Khalil: </p>
<hr />
<div>{{DrugProjectFormSinglePage<br />
|authorTag={{AK}}<br />
|genericName=Cilostazol<br />
|aOrAn=a<br />
|drugClass=Phosphodiesterase 3 inhibitor<br />
|indication=Intermittent claudication<br />
|hasBlackBoxWarning=Yes<br />
|adverseReactions=*headache<br />
*dizziness <br />
*palpitation <br />
*diarrhea, <br />
*rhinitis <br />
*pharyngitis.<br />
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:Contraindication</span></i> '' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
|fdaLIADAdult=&lt;h4&gt;Intermittent claudication 1&lt;/h5&gt;<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
<br />
|offLabelAdultGuideSupport=<br />
=====Secondary prevention of stroke and TIA=====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid'''<ref name="Lansberg-2012">{{Cite journal | last1 = Lansberg | first1 = MG. | last2 = O'Donnell | first2 = MJ. | last3 = Khatri | first3 = P. | last4 = Lang | first4 = ES. | last5 = Nguyen-Huynh | first5 = MN. | last6 = Schwartz | first6 = NE. | last7 = Sonnenberg | first7 = FA. | last8 = Schulman | first8 = S. | last9 = Vandvik | first9 = PO. | title = Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e601S-36S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2302 | PMID = 22315273 }}</ref><br />
<br />
=====Thrombosis prophylaxis in percutaneous coronary intervention =====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid''<ref name="Vandvik-2012">{{Cite journal | last1 = Vandvik | first1 = PO. | last2 = Lincoff | first2 = AM. | last3 = Gore | first3 = JM. | last4 = Gutterman | first4 = DD. | last5 = Sonnenberg | first5 = FA. | last6 = Alonso-Coello | first6 = P. | last7 = Akl | first7 = EA. | last8 = Lansberg | first8 = MG. | last9 = Guyatt | first9 = GH. | title = Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e637S-68S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2306 | PMID = 22315274 }}</ref><br />
<br />
|contraindications=* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
<br />
|warnings=<br />
=====Hematologic Adverse Reactions=====<br />
Rare cases have been reported of [[thrombocytopenia ]]or [[leukopenia ]]progressing to [[agranulocytosis ]]when cilostazol was not immediately discontinued. The agranulocytosis, however, was reversible on discontinuation of cilostazol.<br />
<br />
=====Use with Clopidogrel=====<br />
There is limited information with respect to the efficacy or safety of the concurrent use of cilostazol and [[clopidogrel]], a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Although it cannot be determined whether there was an additive effect on bleeding times during concomitant administration with cilostazol and [[clopidogrel]], caution is advised for checking bleeding times during co-administration.<br />
<br />
|clinicalTrials=Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol and 134 days for patients on placebo.<br />
<br />
The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with PLETAL 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included [[palpitation ]]and [[diarrhea]], both 1.1% for cilostazol (all doses) versus 0.1% for placebo.<br />
<br />
======Body as a Whole======<br />
*Common:<br />
:*Abdominal pain<br />
:*Back pain<br />
:*Headache <br />
:*Infection<br />
<br />
*Less common:<br />
[[Chills]], face [[edema]], [[fever]], [[generalized edema]], [[malaise]], [[neck rigidity]], [[pelvic pain]], [[retroperitoneal haemorrhage]].<br />
<br />
======Central Nervous System======<br />
<br />
*Common:<br />
:*Dizziness<br />
:*Vertigo<br />
<br />
*Less common:<br />
[[Anxiety]], [[insomnia]], [[neuralgia]].<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
*Common:<br />
:*Abnormal stool<br />
:*Diarrhea<br />
:*Dyspepsia<br />
:*Flatulence<br />
:*Nausea<br />
<br />
*Less common:<br />
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Metabolic & Nutritional======<br />
*Common:<br />
:*Peripheral edema<br />
<br />
*Less common:<br />
Increased [[creatinine]], [[gout]], [[hyperlipemia]], [[hyperuricemia]].<br />
<br />
======Musculoskeletal======<br />
<br />
*Common:<br />
:*Myalgia<br />
<br />
*Less common:<br />
[[Arthralgia]], bone pain, [[bursitis]].<br />
<br />
======Miscellaneous======<br />
Less common adverse reactions:<br />
<br />
*'''Endocrine:''' [[Diabetes mellitus]].<br />
<br />
*'''Hemic and Lymphatic:''' [[Anemia]], [[ecchymosis]],[[ iron deficiency anemia]], [[polycythemia]], [[purpura]].<br />
<br />
*'''Skin and Appendages:''' Dry skin, [[furunculosis]], skin hypertrophy, [[urticaria]].<br />
<br />
*'''Special Senses:''' [[Amblyopia]], [[blindness]], [[conjunctivitis]], [[diplopia]], ear pain, eye haemorrhage, [[retinal haemorrhage]], [[tinnitus]].<br />
<br />
*'''Urogenital:''' [[Albuminuria]], [[cystitis]], [[urinary frequency]], vaginal haemorrhage, vaginitis.<br />
<br />
<br />
|postmarketing=The following events have been reported spontaneously from worldwide post-marketing experience since the launch of PLETAL in the US.<br />
<br />
======Blood and lymphatic system disorders:======<br />
[[Agranulocytosis]],[[ aplastic anemia]], [[granulocytopenia]], [[pancytopenia]], [[thrombocytopenia]], [[leukopenia]], <br />
[[bleeding tendency]]<br />
<br />
======Cardiac disorders:======<br />
<br />
[[Torsades de pointes]], [[QT prolongation|QTc prolongation]] (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. [[complete atrioventricular block]], c[[ardiac failure ]]and [[bradyarrythmia]], when treated with cilostazol. Cilostazol was used "off label" due to its positive [[chronotropic]] action)<br />
<br />
======Gastrointestinal disorders:======<br />
<br />
*Gastrointestinal haemorrhage<br />
<br />
======General disorders and administration site conditions:======<br />
<br />
*Pain<br />
*[[chest pain]] <br />
*[[hot flushes]]<br />
<br />
======Hepatobiliary disorders:======<br />
<br />
*Hepatic dysfunction/abnormal liver function tests <br />
*[[jaundice]]<br />
<br />
======Injury, poisoning and procedural complications:======<br />
<br />
*Extradural [[haematoma ]] <br />
*Subdural haematoma<br />
<br />
=====Investigations:=====<br />
<br />
*[[Blood glucose]] increased, blood [[uric acid]] increased, [[platelet count]] decreased, [[white blood cell count]] decreased, increase in [[BUN]] (blood urea increased), blood pressure increase<br />
<br />
======Nervous system disorders:======<br />
<br />
*[[Intracranial haemorrhage]] <br />
*[[cerebral haemorrhage]] <br />
*[[cerebrovascular accident]]<br />
<br />
======Respiratory, thoracic and mediastinal disorders:======<br />
<br />
*Pulmonary haemorrhage<br />
*[[ interstitial pneumonia]]<br />
<br />
'''Skin and subcutaneous tissue disorders:'''<br />
<br />
*Haemorrhage subcutaneous, [[pruritus]], skin eruptions including [[Stevens-Johnson syndrome]], skin drug eruption ([[dermatitis medicamentosa]])<br />
<br />
======Vascular disorders:======<br />
<br />
*Subacute [[thrombosis ]](these cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting)<br />
<br />
|drugInteractions======Aspirin=====<br />
<br />
*Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of ADP-induced ex vivo platelet aggregation by 22% to 37% when compared to either aspirin or cilostazol alone. Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to cilostazol alone and by 48% compared to aspirin alone. However, short-term co-administration of aspirin with cilostazol had no clinically significant impact on PT, aPTT or bleeding time compared to aspirin alone. <br />
<br />
*Effects of long-term co-administration in the general population are unknown. In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was co-administered with cilostazol to 201 patients. The most frequent doses and mean durations of aspirin therapy were 75 mg to 81 mg daily for 137 days (107 patients) and 325 mg daily for 54 days (85 patients). There was no apparent increase in incidence of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.<br />
<br />
=====Warfarin=====<br />
<br />
The cytochrome P-450 isoenzymes involved in the metabolism of R-warfarin are CYP3A4, CYP1A2 and CYP2C19 and in the metabolism of S-warfarin, CYP2C9. Cilostazol did not inhibit either the metabolism or the pharmacologic effects (PT, aPTT, bleeding time or platelet aggregation) of R- and S-warfarin after a single 25-mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and cilostazol on the pharmacokinetics and pharmacodynamics of both drugs is unknown.<br />
<br />
=====Clopidogrel=====<br />
<br />
Multiple doses of clopidogrel do not significantly increase steady state plasma concentrations of cilostazol.<br />
<br />
=====Inhibitors of CYP3A4=====<br />
<br />
======Strong Inhibitors of CYP3A4======<br />
<br />
A priming dose of [[ketoconazole ]]400 mg (a strong inhibitor of CYP3A4), was given one day prior to co-administration of single doses of [[ketoconazole ]]400 mg and cilostazol 100 mg. This regimen increased cilostazol Cmax by 94% and AUC by 117%. Other strong inhibitors of CYP3A4, such as [[itraconazole]], [[fluconazole]], [[miconazole]], [[fluvoxamine]], [[fluoxetine]], [[nefazodone ]]and [[sertraline]], would be expected to have a similar effect <br />
<br />
======Moderate Inhibitors of CYP3A4======<br />
<br />
*[[Erythromycin ]]and Other [[Macrolide ]]Antibiotics: [[Erythromycin ]]is a moderately strong inhibitor of CYP3A4. Co-administration of erythromycin 500 mg q 8h with a single dose of cilostazol 100 mg increased cilostazol Cmax by 47% and AUC by 73%. Inhibition of cilostazol metabolism by erythromycin increased the AUC of 4´-trans-hydroxy-cilostazol by 141%. Other macrolide antibiotics (e.g., [[clarithromycin]]), but not all (e.g., [[azithromycin]]), would be expected to have a similar effect.<br />
<br />
*Diltiazem: [[Diltiazem]] 180 mg decreased the clearance of cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC increased ~40%.<br />
<br />
*Grapefruit Juice: [[Grapefruit juice]] increased the Cmax of cilostazol by ~50% , but had no effect on AUC.<br />
=====Inhibitors of CYP2C19=====<br />
<br />
[[Omeprazole]]: Co-administration of omeprazole did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%, probably the result of omeprazole’s potent inhibition of CYP2C19 <br />
<br />
=====Quinidine =====<br />
<br />
Concomitant administration of [[quinidine ]]with a single dose of cilostazol 100 mg did not alter cilostazol pharmacokinetics.<br />
<br />
=====Lovastatin=====<br />
<br />
The concomitant administration of [[lovastatin ]]with cilostazol decreases cilostazol Css, max and AUCT by 15%. There is also a decrease, although nonsignificant, in cilostazol metabolite concentrations. Co-administration of cilostazol with lovastatin increases lovastatin and β–hydroxy lovastatin AUC approximately 70%. This is most likely clinically insignificant.<br />
<br />
|useInPregnancyFDA=* '''[[Pregnancy category#United States|Pregnancy Category (FDA)]]: C'''<br />
<br />
In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
<br />
|useInNursing=Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
|useInPed=The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
|useInGeri=Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
|useInGender=The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range.<br />
|useInRenalImpair=<br />
Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
<br />
|useInHepaticImpair=Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
<br />
|othersTitle=Smokers<br />
|useInOthers=Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
|administration=Oral<br />
<br />
<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability)<br />
<br />
|overdose=Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
|drugBox=<br />
<br />
{{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
<br />
|mechAction=The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
<br />
|structure=*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
<br />
|PK=Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
<br />
====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4 dehydro cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4 dehydro cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
<br />
|nonClinToxic=====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the <br />
|clinicalStudies=*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
<br />
{|<br />
| [[image:Cilo2.png|400px|thumb]]<br />
|}<br />
<br />
<br />
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
<br />
|howSupplied='''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other and supplied as:<br />
|NDC=): 0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
|storage=Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
|manBy= Sandoz Inc.Princeton, NJ 08540<br />
|distBy=Bryant Ranch Prepack<br />
}}<br />
{|class="infobox" style="position: fixed; top: 180px; right: 20px; margin: 0 0 0 0; border: 0; float: right; width: 15%; background: #104E8B; border-radius: 10px 10px 10px 10px;" cellpadding="0" cellspacing="0";<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #104E8B;" | [[{{PAGENAME}}|{{fontcolor|#F8F8FF|{{PAGENAME}}®}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #000000; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|Black Box Warning}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adult Indications and Dosage|{{fontcolor|#F8F8FF|Adult Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pediatric Indications and Dosage|{{fontcolor|#F8F8FF|Pediatric Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Contraindications|{{fontcolor|#F8F8FF|Contraindications}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Warnings|{{fontcolor|#F8F8FF|Warnings}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adverse Reactions|{{fontcolor|#F8F8FF|Adverse Reactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Drug Interactions|{{fontcolor|#F8F8FF|Drug Interactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Use in Specific Populations|{{fontcolor|#F8F8FF|Use in Specific Populations}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Administration and Monitoring|{{fontcolor|#F8F8FF|Administration and Monitoring}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#IV Compatibility|{{fontcolor|#F8F8FF|IV Compatibility}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Overdosage|{{fontcolor|#F8F8FF|Overdosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pharmacology|{{fontcolor|#F8F8FF|Pharmacology}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Clinical Studies|{{fontcolor|#F8F8FF|Clinical Studies}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#How Supplied|{{fontcolor|#F8F8FF|How Supplied}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Images|{{fontcolor|#F8F8FF|Images}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Patient Information|{{fontcolor|#F8F8FF|Patient information}}]]<br />
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Precautions with Alcohol|{{fontcolor|#F8F8FF|Precautions with Alcohol}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Brand Names|{{fontcolor|#F8F8FF|Brand Names}}]]<br />
|-<br />
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|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm {{fontcolor|#F8F8FF|Drug Shortage Status}}]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price {{fontcolor|#F8F8FF|Price}}]<br />
|-<br />
|}<br />
<div style="width: 80%"><br />
__NOTOC__<br />
{{CMG}}<br />
<br />
{{SB}} Cilostazol®, Pletal®<br />
<br />
==Disclaimer==<br />
<br />
'''''WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature. The information provided is not a medical advice or treatment. WikiDoc does not promote any medication or off-label use of drugs. Please read our full disclaimer [[wikidoc:General_disclaimer|{{fontcolor|#FF0000|here}}]].'''''<br />
<br />
==<span style="color:#FF0000; background:#000000;">Black Box Warning</span>==<br />
<br />
FDA Package Insert for {{PAGENAME}} contains no information regarding ''Black Box Warning''.<br />
<br />
{| style="border: 3px solid #696969;"<br />
| style="background: #000000; border: 0px; padding: 20px 20px; width: 800px;" |<br />
<center><br />
<font color="#F8F8FF" style="font-weight: bold;">CONTRAINDICATION</font><br />
</center><br />
<br />
<center><br />
<font color="#F8F8FF" size="1" style="font-style: italic;">See full prescribing information for complete boxed warning.</font><br />
</center><br />
<br />
<font color="#F8F8FF" style="font-weight: bold;"><br />
''{{fontcolor|#FF0000|Condition Name:}}'' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
</font><br />
|}<br />
<br />
==Overview==<br />
<br />
{{PAGENAME}} is a_Phosphodiesterase 3 Inhibitor drug that is FDA approved for the treatment of intermittent claudication. There is a Black Box Warning for this drug as shown <span style="background:#000000;">'''[[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|here}}]]'''</span>. Common adverse reactions include headache, dizziness, palpitation, diarrhea, rhinitis and pharyngitis.<br />
<br />
==Adult Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Adult)===<br />
<br />
=====Intermittent claudication=====<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
<br />
===Off-Label Use and Dosage (Adult)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Secondary prevention of stroke and TIA=====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid'''<ref name="Lansberg-2012">{{Cite journal | last1 = Lansberg | first1 = MG. | last2 = O'Donnell | first2 = MJ. | last3 = Khatri | first3 = P. | last4 = Lang | first4 = ES. | last5 = Nguyen-Huynh | first5 = MN. | last6 = Schwartz | first6 = NE. | last7 = Sonnenberg | first7 = FA. | last8 = Schulman | first8 = S. | last9 = Vandvik | first9 = PO. | title = Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e601S-36S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2302 | PMID = 22315273 }}</ref><br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid''<ref name="Vandvik-2012">{{Cite journal | last1 = Vandvik | first1 = PO. | last2 = Lincoff | first2 = AM. | last3 = Gore | first3 = JM. | last4 = Gutterman | first4 = DD. | last5 = Sonnenberg | first5 = FA. | last6 = Alonso-Coello | first6 = P. | last7 = Akl | first7 = EA. | last8 = Lansberg | first8 = MG. | last9 = Guyatt | first9 = GH. | title = Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e637S-68S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2306 | PMID = 22315274 }}</ref><br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* There is limited information about ''Off-Label Non–Guideline-Supported Use'' of {{PAGENAME}} in adult patients.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Pediatric Indications and Dosage==<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
==Contraindications==<br />
* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
<br />
==Warnings==<br />
<br />
=====Hematologic Adverse Reactions=====<br />
Rare cases have been reported of [[thrombocytopenia ]]or [[leukopenia ]]progressing to [[agranulocytosis ]]when cilostazol was not immediately discontinued. The agranulocytosis, however, was reversible on discontinuation of cilostazol.<br />
<br />
=====Use with Clopidogrel=====<br />
There is limited information with respect to the efficacy or safety of the concurrent use of cilostazol and [[clopidogrel]], a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Although it cannot be determined whether there was an additive effect on bleeding times during concomitant administration with cilostazol and [[clopidogrel]], caution is advised for checking bleeding times during co-administration.<br />
<br />
==Adverse Reactions==<br />
<br />
===Clinical Trials Experience===<br />
Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol and 134 days for patients on placebo.<br />
<br />
The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with PLETAL 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included [[palpitation ]]and [[diarrhea]], both 1.1% for cilostazol (all doses) versus 0.1% for placebo.<br />
<br />
======Body as a Whole======<br />
*Common:<br />
:*Abdominal pain<br />
:*Back pain<br />
:*Headache <br />
:*Infection<br />
<br />
*Less common:<br />
[[Chills]], face [[edema]], [[fever]], [[generalized edema]], [[malaise]], [[neck rigidity]], [[pelvic pain]], [[retroperitoneal haemorrhage]].<br />
<br />
======Central Nervous System======<br />
<br />
*Common:<br />
:*Dizziness<br />
:*Vertigo<br />
<br />
*Less common:<br />
[[Anxiety]], [[insomnia]], [[neuralgia]].<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
*Common:<br />
:*Abnormal stool<br />
:*Diarrhea<br />
:*Dyspepsia<br />
:*Flatulence<br />
:*Nausea<br />
<br />
*Less common:<br />
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Metabolic & Nutritional======<br />
*Common:<br />
:*Peripheral edema<br />
<br />
*Less common:<br />
Increased [[creatinine]], [[gout]], [[hyperlipemia]], [[hyperuricemia]].<br />
<br />
======Musculoskeletal======<br />
<br />
*Common:<br />
:*Myalgia<br />
<br />
*Less common:<br />
[[Arthralgia]], bone pain, [[bursitis]].<br />
<br />
======Miscellaneous======<br />
Less common adverse reactions:<br />
<br />
*'''Endocrine:''' [[Diabetes mellitus]].<br />
<br />
*'''Hemic and Lymphatic:''' [[Anemia]], [[ecchymosis]],[[ iron deficiency anemia]], [[polycythemia]], [[purpura]].<br />
<br />
*'''Skin and Appendages:''' Dry skin, [[furunculosis]], skin hypertrophy, [[urticaria]].<br />
<br />
*'''Special Senses:''' [[Amblyopia]], [[blindness]], [[conjunctivitis]], [[diplopia]], ear pain, eye haemorrhage, [[retinal haemorrhage]], [[tinnitus]].<br />
<br />
*'''Urogenital:''' [[Albuminuria]], [[cystitis]], [[urinary frequency]], vaginal haemorrhage, vaginitis.<br />
<br />
===Postmarketing Experience===<br />
<br />
The following events have been reported spontaneously from worldwide post-marketing experience since the launch of PLETAL in the US.<br />
<br />
======Blood and lymphatic system disorders:======<br />
[[Agranulocytosis]],[[ aplastic anemia]], [[granulocytopenia]], [[pancytopenia]], [[thrombocytopenia]], [[leukopenia]], <br />
[[bleeding tendency]]<br />
<br />
======Cardiac disorders:======<br />
<br />
[[Torsades de pointes]], [[QT prolongation|QTc prolongation]] (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. [[complete atrioventricular block]], c[[ardiac failure ]]and [[bradyarrythmia]], when treated with cilostazol. Cilostazol was used "off label" due to its positive [[chronotropic]] action)<br />
<br />
======Gastrointestinal disorders:======<br />
<br />
*Gastrointestinal haemorrhage<br />
<br />
======General disorders and administration site conditions:======<br />
<br />
*Pain<br />
*[[chest pain]] <br />
*[[hot flushes]]<br />
<br />
======Hepatobiliary disorders:======<br />
<br />
*Hepatic dysfunction/abnormal liver function tests <br />
*[[jaundice]]<br />
<br />
======Injury, poisoning and procedural complications:======<br />
<br />
*Extradural [[haematoma ]] <br />
*Subdural haematoma<br />
<br />
=====Investigations:=====<br />
<br />
*[[Blood glucose]] increased, blood [[uric acid]] increased, [[platelet count]] decreased, [[white blood cell count]] decreased, increase in [[BUN]] (blood urea increased), blood pressure increase<br />
<br />
======Nervous system disorders:======<br />
<br />
*[[Intracranial haemorrhage]] <br />
*[[cerebral haemorrhage]] <br />
*[[cerebrovascular accident]]<br />
<br />
======Respiratory, thoracic and mediastinal disorders:======<br />
<br />
*Pulmonary haemorrhage<br />
*[[ interstitial pneumonia]]<br />
<br />
'''Skin and subcutaneous tissue disorders:'''<br />
<br />
*Haemorrhage subcutaneous, [[pruritus]], skin eruptions including [[Stevens-Johnson syndrome]], skin drug eruption ([[dermatitis medicamentosa]])<br />
<br />
======Vascular disorders:======<br />
<br />
*Subacute [[thrombosis ]](these cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting)<br />
<br />
==Drug Interactions==<br />
<br />
=====Aspirin=====<br />
<br />
*Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of ADP-induced ex vivo platelet aggregation by 22% to 37% when compared to either aspirin or cilostazol alone. Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to cilostazol alone and by 48% compared to aspirin alone. However, short-term co-administration of aspirin with cilostazol had no clinically significant impact on PT, aPTT or bleeding time compared to aspirin alone. <br />
<br />
*Effects of long-term co-administration in the general population are unknown. In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was co-administered with cilostazol to 201 patients. The most frequent doses and mean durations of aspirin therapy were 75 mg to 81 mg daily for 137 days (107 patients) and 325 mg daily for 54 days (85 patients). There was no apparent increase in incidence of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.<br />
<br />
=====Warfarin=====<br />
<br />
The cytochrome P-450 isoenzymes involved in the metabolism of R-warfarin are CYP3A4, CYP1A2 and CYP2C19 and in the metabolism of S-warfarin, CYP2C9. Cilostazol did not inhibit either the metabolism or the pharmacologic effects (PT, aPTT, bleeding time or platelet aggregation) of R- and S-warfarin after a single 25-mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and cilostazol on the pharmacokinetics and pharmacodynamics of both drugs is unknown.<br />
<br />
=====Clopidogrel=====<br />
<br />
Multiple doses of clopidogrel do not significantly increase steady state plasma concentrations of cilostazol.<br />
<br />
=====Inhibitors of CYP3A4=====<br />
<br />
======Strong Inhibitors of CYP3A4======<br />
<br />
A priming dose of [[ketoconazole ]]400 mg (a strong inhibitor of CYP3A4), was given one day prior to co-administration of single doses of [[ketoconazole ]]400 mg and cilostazol 100 mg. This regimen increased cilostazol Cmax by 94% and AUC by 117%. Other strong inhibitors of CYP3A4, such as [[itraconazole]], [[fluconazole]], [[miconazole]], [[fluvoxamine]], [[fluoxetine]], [[nefazodone ]]and [[sertraline]], would be expected to have a similar effect <br />
<br />
======Moderate Inhibitors of CYP3A4======<br />
<br />
*[[Erythromycin ]]and Other [[Macrolide ]]Antibiotics: [[Erythromycin ]]is a moderately strong inhibitor of CYP3A4. Co-administration of erythromycin 500 mg q 8h with a single dose of cilostazol 100 mg increased cilostazol Cmax by 47% and AUC by 73%. Inhibition of cilostazol metabolism by erythromycin increased the AUC of 4´-trans-hydroxy-cilostazol by 141%. Other macrolide antibiotics (e.g., [[clarithromycin]]), but not all (e.g., [[azithromycin]]), would be expected to have a similar effect.<br />
<br />
*Diltiazem: [[Diltiazem]] 180 mg decreased the clearance of cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC increased ~40%.<br />
<br />
*Grapefruit Juice: [[Grapefruit juice]] increased the Cmax of cilostazol by ~50% , but had no effect on AUC.<br />
=====Inhibitors of CYP2C19=====<br />
<br />
[[Omeprazole]]: Co-administration of omeprazole did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%, probably the result of omeprazole’s potent inhibition of CYP2C19 <br />
<br />
=====Quinidine =====<br />
<br />
Concomitant administration of [[quinidine ]]with a single dose of cilostazol 100 mg did not alter cilostazol pharmacokinetics.<br />
<br />
=====Lovastatin=====<br />
<br />
The concomitant administration of [[lovastatin ]]with cilostazol decreases cilostazol Css, max and AUCT by 15%. There is also a decrease, although nonsignificant, in cilostazol metabolite concentrations. Co-administration of cilostazol with lovastatin increases lovastatin and β–hydroxy lovastatin AUC approximately 70%. This is most likely clinically insignificant.<br />
<br />
==Use in Specific Populations==<br />
<br />
====Pregnancy====<br />
<br />
* '''[[Pregnancy category#United States|Pregnancy Category (FDA)]]: C'''<br />
<br />
* '''[[Pregnancy category#Australia|Pregnancy Category (AUS)]]: {{PAGENAME}} is not included in Australian Drug Evaluation Committee (ADEC) Pregnancy Categories.'''<br />
<br />
In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
<br />
====Labor and Delivery====<br />
<br />
FDA package insert doesn't contain any information regarding "'''Labor and Delivery'''"<br />
<br />
====Nursing Mothers====<br />
<br />
Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
<br />
====Pediatric Use====<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
====Geriatric Use====<br />
Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
====Gender====<br />
<br />
The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range<br />
<br />
====Race====<br />
<br />
(Description)<br />
<br />
====Renal Impairment====<br />
<br />
Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
<br />
====Hepatic Impairment====<br />
<br />
Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
<br />
====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the exposure in humans at the MRHD.<br />
<br />
====Immunocompromised Patients====<br />
<br />
(Description)<br />
<br />
====Miscellaneous====<br />
<br />
=====Smokers=====<br />
Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
<br />
==Administration and Monitoring==<br />
<br />
====Administration====<br />
<br />
Oral<br />
<br />
====Monitoring====<br />
FDA package insert does't contain any information regarding "'''Monitoring'''"<br />
<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability).<br />
<br />
==IV Compatibility==<br />
<br />
FDA package insert doesn't contain any information regarding '''IV Compatibility'''<br />
<br />
==Overdosage==<br />
<br />
===Acute Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
<br />
====Management====<br />
<br />
FDA package insert doesn't contain any information regarding "'''Management '''"<br />
<br />
==Pharmacology==<br />
<br />
{{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
<br />
===Mechanism of Action===<br />
<br />
The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
<br />
===Structure===<br />
<br />
*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
<br />
<br />
===Pharmacodynamics===<br />
<br />
(Description)<br />
<br />
===Pharmacokinetics===<br />
<br />
Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
<br />
====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4‑dehydro‑cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4‑dehydro‑cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
<br />
===Nonclinical Toxicology===<br />
<br />
==Clinical Studies==<br />
<br />
*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
<br />
{|<br />
| [[image:Cilo2.png|400px|thumb]]<br />
|}<br />
<br />
<br />
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
<br />
==How Supplied==<br />
<br />
'''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
<br />
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0223-60 bottles of 60 and 0185-0223-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
==Images==<br />
<br />
===Drug Images===<br />
<br />
{|<br />
| [[File:Cilostazol50mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 50 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;123 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
{|<br />
| [[File:Cilostazol100mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 100 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;223 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
===Package and Label Display Panel===<br />
<br />
Sandoz Inc.<br />
Princeton, NJ 08540<br />
OS8128<br />
Rev. 02/13<br />
MF0223REV02/13<br />
Cilostazol 100mg Tablet<br />
<br />
{|<br />
| [[image:Cilostazollabel.jpg|400px|thumb]]<br />
|}<br />
<br />
{|<br />
| [[image:Cilostazollabel1.png|400px|thumb]]<br />
|}<br />
<br />
==Patient Information==<br />
<br />
===Patient Information from FDA===<br />
(sil-OS-tah-zol)<br />
<br />
Please read this leaflet before you start taking cilostazol tablets and each time you renew it in case anything has changed. This leaflet does not replace careful discussions with your doctor. You and your doctor should discuss cilostazol when you start taking it and at regular check-ups. You should follow your doctor’s advice about when to have check-ups.<br />
What is cilostazol for?<br />
Cilostazol may improve the symptoms of patients with a medical condition called intermittent claudication.<br />
What is intermittent claudication?<br />
Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. It occurs because narrowing or blockage of the arteries decreases blood flow to the legs. The decreased blood flow does not supply enough oxygen to the leg muscles during walking, resulting in these painful leg cramps.<br />
<br />
'''What treatments are available for intermittent claudication?'''<br />
<br />
The three main treatments available for intermittent claudication are:<br />
*Exercise. Your doctor may advise an exercise program.<br />
*Medication. Your doctor may prescribe a medication such as cilostazol. (See Who should not take cilostazol tablets?)<br />
*Surgery. Your doctor may recommend a surgical procedure to bypass the blocked segment of the artery. Another procedure is called a percutaneous transluminal angioplasty. In this procedure, a catheter (a flexible tube) is inserted into the artery to reduce the blockage and improve blood flow.<br />
<br />
'''How does cilostazol work?'''<br />
<br />
*The exact way that many drugs work is not well understood. Although how cilostazol works is not completely clear, its main effects are to dilate (widen) the arteries supplying blood to the legs and to decrease the ability of platelets in the blood to stick together. Platelets are particles that circulate in the blood and play a role in clotting.<br />
*Cilostazol may reduce the leg pain that patients with intermittent claudication experience, allowing them to walk farther before their leg pain occurs.<br />
*Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks. If you have not noticed any benefit from cilostazol tablets after 12 weeks you and your doctor may wish to discuss other forms of treatment.<br />
*Sometimes blood vessel disease of the legs causes pain at rest or breakdown of skin in the leg. Cilostazol has not been shown to work in patients with these problems.<br />
<br />
'''Who should not take cilostazol tablets?'''<br />
<br />
*Patients who have congestive heart failure (CHF) must not take cilostazol tablets. The most common symptoms of CHF are shortness of breath and swelling of the legs. However, other conditions may also cause these symptoms. It is important that you discuss with your doctor whether you have CHF.<br />
*Over 1,300 patients took cilostazol in studies that lasted for 3 to 6 months. The mortality rate in these patients was similar to placebo (less than 1%). These studies were too small to be sure there is not some increased risk of dying with longer use or in patients sicker than those in the studies.<br />
<br />
'''How should cilostazol tablets be taken?'''<br />
<br />
*Follow your doctor’s advice about how to take cilostazol tablets.<br />
*You should take cilostazol tablets twice a day, at least one half-hour before or two hours after breakfast and dinner. Take cilostazol tablets at about the same times each day.<br />
*Do not share cilostazol tablets with anyone else. It was prescribed only for you.<br />
*Keep cilostazol tablets and all drugs out of the reach of children.<br />
<br />
'''Can cilostazol tablets be taken with other drugs?'''<br />
<br />
Certain drugs and foods can increase the amount of cilostazol in the blood. Because of this, your doctor may adjust your dose of cilostazol or even stop it if you are taking or are going to take one of the following medications.<br />
Drugs Interacting with Cilostazol<br />
Generic Name (Brand Names)Type of Drug<br />
[[erythromycin]] (such as E.E.S.®, Erythrocin®) Antibiotic<br />
[[ketoconazole]] (Nizoral®), [[itraconazole]] (Sporanox®) Antifungal<br />
[[diltiazem]] (Cardizem®) Antihypertensive<br />
[[omeprazole]] (Prilosec®) Gastric acid reducer<br />
This list does not include every drug that may interact with cilostazol tablets. Therefore, you should tell your doctor about all medications that you are taking, including vitamins, herbal supplements and over-the-counter drugs you can buy without a prescription. You should also check with your doctor before taking a new medication after you have begun cilostazol tablets.<br />
<br />
'''What are the possible side effects of cilostazol tablets?'''<br />
<br />
Cilostazol tablets may cause side effects including headache, diarrhea, abnormal stools, increased heart rate and palpitations.<br />
You should discuss possible side effects with your doctor before taking cilostazol tablets and any time you think you are having a side effect.<br />
This provides only a summary of information about cilostazol tablets. If you have any questions about cilostazol tablets, talk to your doctor.<br />
'''Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.'''<br />
<br />
===Patient Information from NLM===<br />
<br />
For patient information about Cilostazol from NLM, click [[Cilostazol (patient information)|here]].<br />
<br />
==Precautions with Alcohol==<br />
<br />
Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
<br />
==Brand Names==<br />
<br />
Cilostazol®, Platel®.<br />
<br />
==Look-Alike Drug Names==<br />
<br />
* (Paired Confused Name 1a) — (Paired Confused Name 1b)<br />
* (Paired Confused Name 2a) — (Paired Confused Name 2b)<br />
* (Paired Confused Name 3a) — (Paired Confused Name 3b)<br />
<br />
==[http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm Drug Shortage Status]==<br />
<br />
==[http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price Price]==<br />
<br />
==References==<br />
<br />
{{reflist}}<br />
<br />
</div></div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=Cilostazol&diff=962068Cilostazol2014-04-03T00:02:34Z<p>Abdurahman Khalil: </p>
<hr />
<div>{{DrugProjectFormSinglePage<br />
|authorTag={{AK}}<br />
|genericName=Cilostazol<br />
|aOrAn=a<br />
|drugClass=Phosphodiesterase 3 inhibitor<br />
|indication=Intermittent claudication<br />
|hasBlackBoxWarning=Yes<br />
|adverseReactions=*headache<br />
*dizziness <br />
*palpitation <br />
*diarrhea, <br />
*rhinitis <br />
*pharyngitis.<br />
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)<br />
|fdaLIADAdult=&lt;h4&gt;Condition 1&lt;/h5&gt;<br />
<br />
* Dosing Information<br />
<br />
:: (Dosage)<br />
}}<br />
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|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adult Indications and Dosage|{{fontcolor|#F8F8FF|Adult Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pediatric Indications and Dosage|{{fontcolor|#F8F8FF|Pediatric Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Contraindications|{{fontcolor|#F8F8FF|Contraindications}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Warnings|{{fontcolor|#F8F8FF|Warnings}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adverse Reactions|{{fontcolor|#F8F8FF|Adverse Reactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Drug Interactions|{{fontcolor|#F8F8FF|Drug Interactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Use in Specific Populations|{{fontcolor|#F8F8FF|Use in Specific Populations}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Administration and Monitoring|{{fontcolor|#F8F8FF|Administration and Monitoring}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#IV Compatibility|{{fontcolor|#F8F8FF|IV Compatibility}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Overdosage|{{fontcolor|#F8F8FF|Overdosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pharmacology|{{fontcolor|#F8F8FF|Pharmacology}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Clinical Studies|{{fontcolor|#F8F8FF|Clinical Studies}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#How Supplied|{{fontcolor|#F8F8FF|How Supplied}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Images|{{fontcolor|#F8F8FF|Images}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Patient Information|{{fontcolor|#F8F8FF|Patient information}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Precautions with Alcohol|{{fontcolor|#F8F8FF|Precautions with Alcohol}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Brand Names|{{fontcolor|#F8F8FF|Brand Names}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Look-Alike Drug Names|{{fontcolor|#F8F8FF|Look-Alike Drug Names}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm {{fontcolor|#F8F8FF|Drug Shortage Status}}]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price {{fontcolor|#F8F8FF|Price}}]<br />
|-<br />
|}<br />
<div style="width: 80%"><br />
__NOTOC__<br />
{{CMG}}<br />
<br />
{{SB}} Cilostazol®, Pletal®<br />
<br />
==Disclaimer==<br />
<br />
'''''WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature. The information provided is not a medical advice or treatment. WikiDoc does not promote any medication or off-label use of drugs. Please read our full disclaimer [[wikidoc:General_disclaimer|{{fontcolor|#FF0000|here}}]].'''''<br />
<br />
==<span style="color:#FF0000; background:#000000;">Black Box Warning</span>==<br />
<br />
FDA Package Insert for {{PAGENAME}} contains no information regarding ''Black Box Warning''.<br />
<br />
{| style="border: 3px solid #696969;"<br />
| style="background: #000000; border: 0px; padding: 20px 20px; width: 800px;" |<br />
<center><br />
<font color="#F8F8FF" style="font-weight: bold;">CONTRAINDICATION</font><br />
</center><br />
<br />
<center><br />
<font color="#F8F8FF" size="1" style="font-style: italic;">See full prescribing information for complete boxed warning.</font><br />
</center><br />
<br />
<font color="#F8F8FF" style="font-weight: bold;"><br />
''{{fontcolor|#FF0000|Condition Name:}}'' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
</font><br />
|}<br />
<br />
==Overview==<br />
<br />
{{PAGENAME}} is a_Phosphodiesterase 3 Inhibitor drug that is FDA approved for the treatment of intermittent claudication. There is a Black Box Warning for this drug as shown <span style="background:#000000;">'''[[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|here}}]]'''</span>. Common adverse reactions include headache, dizziness, palpitation, diarrhea, rhinitis and pharyngitis.<br />
<br />
==Adult Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Adult)===<br />
<br />
=====Intermittent claudication=====<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
<br />
===Off-Label Use and Dosage (Adult)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Secondary prevention of stroke and TIA=====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid'''<ref name="Lansberg-2012">{{Cite journal | last1 = Lansberg | first1 = MG. | last2 = O'Donnell | first2 = MJ. | last3 = Khatri | first3 = P. | last4 = Lang | first4 = ES. | last5 = Nguyen-Huynh | first5 = MN. | last6 = Schwartz | first6 = NE. | last7 = Sonnenberg | first7 = FA. | last8 = Schulman | first8 = S. | last9 = Vandvik | first9 = PO. | title = Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e601S-36S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2302 | PMID = 22315273 }}</ref><br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid''<ref name="Vandvik-2012">{{Cite journal | last1 = Vandvik | first1 = PO. | last2 = Lincoff | first2 = AM. | last3 = Gore | first3 = JM. | last4 = Gutterman | first4 = DD. | last5 = Sonnenberg | first5 = FA. | last6 = Alonso-Coello | first6 = P. | last7 = Akl | first7 = EA. | last8 = Lansberg | first8 = MG. | last9 = Guyatt | first9 = GH. | title = Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e637S-68S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2306 | PMID = 22315274 }}</ref><br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* There is limited information about ''Off-Label Non–Guideline-Supported Use'' of {{PAGENAME}} in adult patients.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Pediatric Indications and Dosage==<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
==Contraindications==<br />
* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
<br />
==Warnings==<br />
<br />
=====Hematologic Adverse Reactions=====<br />
Rare cases have been reported of [[thrombocytopenia ]]or [[leukopenia ]]progressing to [[agranulocytosis ]]when cilostazol was not immediately discontinued. The agranulocytosis, however, was reversible on discontinuation of cilostazol.<br />
<br />
=====Use with Clopidogrel=====<br />
There is limited information with respect to the efficacy or safety of the concurrent use of cilostazol and [[clopidogrel]], a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Although it cannot be determined whether there was an additive effect on bleeding times during concomitant administration with cilostazol and [[clopidogrel]], caution is advised for checking bleeding times during co-administration.<br />
<br />
==Adverse Reactions==<br />
<br />
===Clinical Trials Experience===<br />
Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol and 134 days for patients on placebo.<br />
<br />
The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with PLETAL 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included [[palpitation ]]and [[diarrhea]], both 1.1% for cilostazol (all doses) versus 0.1% for placebo.<br />
<br />
======Body as a Whole======<br />
*Common:<br />
:*Abdominal pain<br />
:*Back pain<br />
:*Headache <br />
:*Infection<br />
<br />
*Less common:<br />
[[Chills]], face [[edema]], [[fever]], [[generalized edema]], [[malaise]], [[neck rigidity]], [[pelvic pain]], [[retroperitoneal haemorrhage]].<br />
<br />
======Central Nervous System======<br />
<br />
*Common:<br />
:*Dizziness<br />
:*Vertigo<br />
<br />
*Less common:<br />
[[Anxiety]], [[insomnia]], [[neuralgia]].<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
*Common:<br />
:*Abnormal stool<br />
:*Diarrhea<br />
:*Dyspepsia<br />
:*Flatulence<br />
:*Nausea<br />
<br />
*Less common:<br />
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Metabolic & Nutritional======<br />
*Common:<br />
:*Peripheral edema<br />
<br />
*Less common:<br />
Increased [[creatinine]], [[gout]], [[hyperlipemia]], [[hyperuricemia]].<br />
<br />
======Musculoskeletal======<br />
<br />
*Common:<br />
:*Myalgia<br />
<br />
*Less common:<br />
[[Arthralgia]], bone pain, [[bursitis]].<br />
<br />
======Miscellaneous======<br />
Less common adverse reactions:<br />
<br />
*'''Endocrine:''' [[Diabetes mellitus]].<br />
<br />
*'''Hemic and Lymphatic:''' [[Anemia]], [[ecchymosis]],[[ iron deficiency anemia]], [[polycythemia]], [[purpura]].<br />
<br />
*'''Skin and Appendages:''' Dry skin, [[furunculosis]], skin hypertrophy, [[urticaria]].<br />
<br />
*'''Special Senses:''' [[Amblyopia]], [[blindness]], [[conjunctivitis]], [[diplopia]], ear pain, eye haemorrhage, [[retinal haemorrhage]], [[tinnitus]].<br />
<br />
*'''Urogenital:''' [[Albuminuria]], [[cystitis]], [[urinary frequency]], vaginal haemorrhage, vaginitis.<br />
<br />
===Postmarketing Experience===<br />
<br />
The following events have been reported spontaneously from worldwide post-marketing experience since the launch of PLETAL in the US.<br />
<br />
======Blood and lymphatic system disorders:======<br />
[[Agranulocytosis]],[[ aplastic anemia]], [[granulocytopenia]], [[pancytopenia]], [[thrombocytopenia]], [[leukopenia]], <br />
[[bleeding tendency]]<br />
<br />
======Cardiac disorders:======<br />
<br />
[[Torsades de pointes]], [[QT prolongation|QTc prolongation]] (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. [[complete atrioventricular block]], c[[ardiac failure ]]and [[bradyarrythmia]], when treated with cilostazol. Cilostazol was used "off label" due to its positive [[chronotropic]] action)<br />
<br />
======Gastrointestinal disorders:======<br />
<br />
*Gastrointestinal haemorrhage<br />
<br />
======General disorders and administration site conditions:======<br />
<br />
*Pain<br />
*[[chest pain]] <br />
*[[hot flushes]]<br />
<br />
======Hepatobiliary disorders:======<br />
<br />
*Hepatic dysfunction/abnormal liver function tests <br />
*[[jaundice]]<br />
<br />
======Injury, poisoning and procedural complications:======<br />
<br />
*Extradural [[haematoma ]] <br />
*Subdural haematoma<br />
<br />
=====Investigations:=====<br />
<br />
*[[Blood glucose]] increased, blood [[uric acid]] increased, [[platelet count]] decreased, [[white blood cell count]] decreased, increase in [[BUN]] (blood urea increased), blood pressure increase<br />
<br />
======Nervous system disorders:======<br />
<br />
*[[Intracranial haemorrhage]] <br />
*[[cerebral haemorrhage]] <br />
*[[cerebrovascular accident]]<br />
<br />
======Respiratory, thoracic and mediastinal disorders:======<br />
<br />
*Pulmonary haemorrhage<br />
*[[ interstitial pneumonia]]<br />
<br />
'''Skin and subcutaneous tissue disorders:'''<br />
<br />
*Haemorrhage subcutaneous, [[pruritus]], skin eruptions including [[Stevens-Johnson syndrome]], skin drug eruption ([[dermatitis medicamentosa]])<br />
<br />
======Vascular disorders:======<br />
<br />
*Subacute [[thrombosis ]](these cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting)<br />
<br />
==Drug Interactions==<br />
<br />
=====Aspirin=====<br />
<br />
*Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of ADP-induced ex vivo platelet aggregation by 22% to 37% when compared to either aspirin or cilostazol alone. Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to cilostazol alone and by 48% compared to aspirin alone. However, short-term co-administration of aspirin with cilostazol had no clinically significant impact on PT, aPTT or bleeding time compared to aspirin alone. <br />
<br />
*Effects of long-term co-administration in the general population are unknown. In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was co-administered with cilostazol to 201 patients. The most frequent doses and mean durations of aspirin therapy were 75 mg to 81 mg daily for 137 days (107 patients) and 325 mg daily for 54 days (85 patients). There was no apparent increase in incidence of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.<br />
<br />
=====Warfarin=====<br />
<br />
The cytochrome P-450 isoenzymes involved in the metabolism of R-warfarin are CYP3A4, CYP1A2 and CYP2C19 and in the metabolism of S-warfarin, CYP2C9. Cilostazol did not inhibit either the metabolism or the pharmacologic effects (PT, aPTT, bleeding time or platelet aggregation) of R- and S-warfarin after a single 25-mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and cilostazol on the pharmacokinetics and pharmacodynamics of both drugs is unknown.<br />
<br />
=====Clopidogrel=====<br />
<br />
Multiple doses of clopidogrel do not significantly increase steady state plasma concentrations of cilostazol.<br />
<br />
=====Inhibitors of CYP3A4=====<br />
<br />
======Strong Inhibitors of CYP3A4======<br />
<br />
A priming dose of [[ketoconazole ]]400 mg (a strong inhibitor of CYP3A4), was given one day prior to co-administration of single doses of [[ketoconazole ]]400 mg and cilostazol 100 mg. This regimen increased cilostazol Cmax by 94% and AUC by 117%. Other strong inhibitors of CYP3A4, such as [[itraconazole]], [[fluconazole]], [[miconazole]], [[fluvoxamine]], [[fluoxetine]], [[nefazodone ]]and [[sertraline]], would be expected to have a similar effect <br />
<br />
======Moderate Inhibitors of CYP3A4======<br />
<br />
*[[Erythromycin ]]and Other [[Macrolide ]]Antibiotics: [[Erythromycin ]]is a moderately strong inhibitor of CYP3A4. Co-administration of erythromycin 500 mg q 8h with a single dose of cilostazol 100 mg increased cilostazol Cmax by 47% and AUC by 73%. Inhibition of cilostazol metabolism by erythromycin increased the AUC of 4´-trans-hydroxy-cilostazol by 141%. Other macrolide antibiotics (e.g., [[clarithromycin]]), but not all (e.g., [[azithromycin]]), would be expected to have a similar effect.<br />
<br />
*Diltiazem: [[Diltiazem]] 180 mg decreased the clearance of cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC increased ~40%.<br />
<br />
*Grapefruit Juice: [[Grapefruit juice]] increased the Cmax of cilostazol by ~50% , but had no effect on AUC.<br />
=====Inhibitors of CYP2C19=====<br />
<br />
[[Omeprazole]]: Co-administration of omeprazole did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%, probably the result of omeprazole’s potent inhibition of CYP2C19 <br />
<br />
=====Quinidine =====<br />
<br />
Concomitant administration of [[quinidine ]]with a single dose of cilostazol 100 mg did not alter cilostazol pharmacokinetics.<br />
<br />
=====Lovastatin=====<br />
<br />
The concomitant administration of [[lovastatin ]]with cilostazol decreases cilostazol Css, max and AUCT by 15%. There is also a decrease, although nonsignificant, in cilostazol metabolite concentrations. Co-administration of cilostazol with lovastatin increases lovastatin and β–hydroxy lovastatin AUC approximately 70%. This is most likely clinically insignificant.<br />
<br />
==Use in Specific Populations==<br />
<br />
====Pregnancy====<br />
<br />
* '''[[Pregnancy category#United States|Pregnancy Category (FDA)]]: C'''<br />
<br />
* '''[[Pregnancy category#Australia|Pregnancy Category (AUS)]]: {{PAGENAME}} is not included in Australian Drug Evaluation Committee (ADEC) Pregnancy Categories.'''<br />
<br />
In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
<br />
====Labor and Delivery====<br />
<br />
FDA package insert doesn't contain any information regarding "'''Labor and Delivery'''"<br />
<br />
====Nursing Mothers====<br />
<br />
Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
<br />
====Pediatric Use====<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
====Geriatric Use====<br />
Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
====Gender====<br />
<br />
The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range<br />
<br />
====Race====<br />
<br />
(Description)<br />
<br />
====Renal Impairment====<br />
<br />
Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
<br />
====Hepatic Impairment====<br />
<br />
Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
<br />
====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the exposure in humans at the MRHD.<br />
<br />
====Immunocompromised Patients====<br />
<br />
(Description)<br />
<br />
====Miscellaneous====<br />
<br />
=====Smokers=====<br />
Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
<br />
==Administration and Monitoring==<br />
<br />
====Administration====<br />
<br />
Oral<br />
<br />
====Monitoring====<br />
FDA package insert does't contain any information regarding "'''Monitoring'''"<br />
<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability).<br />
<br />
==IV Compatibility==<br />
<br />
FDA package insert doesn't contain any information regarding '''IV Compatibility'''<br />
<br />
==Overdosage==<br />
<br />
===Acute Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
<br />
====Management====<br />
<br />
FDA package insert doesn't contain any information regarding "'''Management '''"<br />
<br />
==Pharmacology==<br />
<br />
{{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
<br />
===Mechanism of Action===<br />
<br />
The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
<br />
===Structure===<br />
<br />
*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
<br />
<br />
===Pharmacodynamics===<br />
<br />
(Description)<br />
<br />
===Pharmacokinetics===<br />
<br />
Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
<br />
====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4‑dehydro‑cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4‑dehydro‑cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
<br />
===Nonclinical Toxicology===<br />
<br />
==Clinical Studies==<br />
<br />
*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
<br />
{|<br />
| [[image:Cilo2.png|400px|thumb]]<br />
|}<br />
<br />
<br />
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
<br />
==How Supplied==<br />
<br />
'''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
<br />
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0223-60 bottles of 60 and 0185-0223-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
==Images==<br />
<br />
===Drug Images===<br />
<br />
{|<br />
| [[File:Cilostazol50mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 50 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;123 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
{|<br />
| [[File:Cilostazol100mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 100 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;223 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
===Package and Label Display Panel===<br />
<br />
Sandoz Inc.<br />
Princeton, NJ 08540<br />
OS8128<br />
Rev. 02/13<br />
MF0223REV02/13<br />
Cilostazol 100mg Tablet<br />
<br />
{|<br />
| [[image:Cilostazollabel.jpg|400px|thumb]]<br />
|}<br />
<br />
{|<br />
| [[image:Cilostazollabel1.png|400px|thumb]]<br />
|}<br />
<br />
==Patient Information==<br />
<br />
===Patient Information from FDA===<br />
(sil-OS-tah-zol)<br />
<br />
Please read this leaflet before you start taking cilostazol tablets and each time you renew it in case anything has changed. This leaflet does not replace careful discussions with your doctor. You and your doctor should discuss cilostazol when you start taking it and at regular check-ups. You should follow your doctor’s advice about when to have check-ups.<br />
What is cilostazol for?<br />
Cilostazol may improve the symptoms of patients with a medical condition called intermittent claudication.<br />
What is intermittent claudication?<br />
Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. It occurs because narrowing or blockage of the arteries decreases blood flow to the legs. The decreased blood flow does not supply enough oxygen to the leg muscles during walking, resulting in these painful leg cramps.<br />
<br />
'''What treatments are available for intermittent claudication?'''<br />
<br />
The three main treatments available for intermittent claudication are:<br />
*Exercise. Your doctor may advise an exercise program.<br />
*Medication. Your doctor may prescribe a medication such as cilostazol. (See Who should not take cilostazol tablets?)<br />
*Surgery. Your doctor may recommend a surgical procedure to bypass the blocked segment of the artery. Another procedure is called a percutaneous transluminal angioplasty. In this procedure, a catheter (a flexible tube) is inserted into the artery to reduce the blockage and improve blood flow.<br />
<br />
'''How does cilostazol work?'''<br />
<br />
*The exact way that many drugs work is not well understood. Although how cilostazol works is not completely clear, its main effects are to dilate (widen) the arteries supplying blood to the legs and to decrease the ability of platelets in the blood to stick together. Platelets are particles that circulate in the blood and play a role in clotting.<br />
*Cilostazol may reduce the leg pain that patients with intermittent claudication experience, allowing them to walk farther before their leg pain occurs.<br />
*Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks. If you have not noticed any benefit from cilostazol tablets after 12 weeks you and your doctor may wish to discuss other forms of treatment.<br />
*Sometimes blood vessel disease of the legs causes pain at rest or breakdown of skin in the leg. Cilostazol has not been shown to work in patients with these problems.<br />
<br />
'''Who should not take cilostazol tablets?'''<br />
<br />
*Patients who have congestive heart failure (CHF) must not take cilostazol tablets. The most common symptoms of CHF are shortness of breath and swelling of the legs. However, other conditions may also cause these symptoms. It is important that you discuss with your doctor whether you have CHF.<br />
*Over 1,300 patients took cilostazol in studies that lasted for 3 to 6 months. The mortality rate in these patients was similar to placebo (less than 1%). These studies were too small to be sure there is not some increased risk of dying with longer use or in patients sicker than those in the studies.<br />
<br />
'''How should cilostazol tablets be taken?'''<br />
<br />
*Follow your doctor’s advice about how to take cilostazol tablets.<br />
*You should take cilostazol tablets twice a day, at least one half-hour before or two hours after breakfast and dinner. Take cilostazol tablets at about the same times each day.<br />
*Do not share cilostazol tablets with anyone else. It was prescribed only for you.<br />
*Keep cilostazol tablets and all drugs out of the reach of children.<br />
<br />
'''Can cilostazol tablets be taken with other drugs?'''<br />
<br />
Certain drugs and foods can increase the amount of cilostazol in the blood. Because of this, your doctor may adjust your dose of cilostazol or even stop it if you are taking or are going to take one of the following medications.<br />
Drugs Interacting with Cilostazol<br />
Generic Name (Brand Names)Type of Drug<br />
[[erythromycin]] (such as E.E.S.®, Erythrocin®) Antibiotic<br />
[[ketoconazole]] (Nizoral®), [[itraconazole]] (Sporanox®) Antifungal<br />
[[diltiazem]] (Cardizem®) Antihypertensive<br />
[[omeprazole]] (Prilosec®) Gastric acid reducer<br />
This list does not include every drug that may interact with cilostazol tablets. Therefore, you should tell your doctor about all medications that you are taking, including vitamins, herbal supplements and over-the-counter drugs you can buy without a prescription. You should also check with your doctor before taking a new medication after you have begun cilostazol tablets.<br />
<br />
'''What are the possible side effects of cilostazol tablets?'''<br />
<br />
Cilostazol tablets may cause side effects including headache, diarrhea, abnormal stools, increased heart rate and palpitations.<br />
You should discuss possible side effects with your doctor before taking cilostazol tablets and any time you think you are having a side effect.<br />
This provides only a summary of information about cilostazol tablets. If you have any questions about cilostazol tablets, talk to your doctor.<br />
'''Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.'''<br />
<br />
===Patient Information from NLM===<br />
<br />
For patient information about Cilostazol from NLM, click [[Cilostazol (patient information)|here]].<br />
<br />
==Precautions with Alcohol==<br />
<br />
Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
<br />
==Brand Names==<br />
<br />
Cilostazol®, Platel®.<br />
<br />
==Look-Alike Drug Names==<br />
<br />
* (Paired Confused Name 1a) — (Paired Confused Name 1b)<br />
* (Paired Confused Name 2a) — (Paired Confused Name 2b)<br />
* (Paired Confused Name 3a) — (Paired Confused Name 3b)<br />
<br />
==[http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm Drug Shortage Status]==<br />
<br />
==[http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price Price]==<br />
<br />
==References==<br />
<br />
{{reflist}}<br />
<br />
</div></div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=Cilostazol&diff=962065Cilostazol2014-04-02T23:41:07Z<p>Abdurahman Khalil: /* Off-Label Use and Dosage (Adult) */</p>
<hr />
<div>{|class="infobox" style="position: fixed; top: 180px; right: 20px; margin: 0 0 0 0; border: 0; float: right; width: 15%; background: #104E8B; border-radius: 10px 10px 10px 10px;" cellpadding="0" cellspacing="0";<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #104E8B;" | [[{{PAGENAME}}|{{fontcolor|#F8F8FF|{{PAGENAME}}®}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #000000; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|Black Box Warning}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adult Indications and Dosage|{{fontcolor|#F8F8FF|Adult Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pediatric Indications and Dosage|{{fontcolor|#F8F8FF|Pediatric Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Contraindications|{{fontcolor|#F8F8FF|Contraindications}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Warnings|{{fontcolor|#F8F8FF|Warnings}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adverse Reactions|{{fontcolor|#F8F8FF|Adverse Reactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Drug Interactions|{{fontcolor|#F8F8FF|Drug Interactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Use in Specific Populations|{{fontcolor|#F8F8FF|Use in Specific Populations}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Administration and Monitoring|{{fontcolor|#F8F8FF|Administration and Monitoring}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#IV Compatibility|{{fontcolor|#F8F8FF|IV Compatibility}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Overdosage|{{fontcolor|#F8F8FF|Overdosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pharmacology|{{fontcolor|#F8F8FF|Pharmacology}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Clinical Studies|{{fontcolor|#F8F8FF|Clinical Studies}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#How Supplied|{{fontcolor|#F8F8FF|How Supplied}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Images|{{fontcolor|#F8F8FF|Images}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Patient Information|{{fontcolor|#F8F8FF|Patient information}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Precautions with Alcohol|{{fontcolor|#F8F8FF|Precautions with Alcohol}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Brand Names|{{fontcolor|#F8F8FF|Brand Names}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Look-Alike Drug Names|{{fontcolor|#F8F8FF|Look-Alike Drug Names}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm {{fontcolor|#F8F8FF|Drug Shortage Status}}]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price {{fontcolor|#F8F8FF|Price}}]<br />
|-<br />
|}<br />
<div style="width: 80%"><br />
__NOTOC__<br />
{{CMG}}<br />
<br />
{{SB}} Cilostazol®, Pletal®<br />
<br />
==Disclaimer==<br />
<br />
'''''WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature. The information provided is not a medical advice or treatment. WikiDoc does not promote any medication or off-label use of drugs. Please read our full disclaimer [[wikidoc:General_disclaimer|{{fontcolor|#FF0000|here}}]].'''''<br />
<br />
==<span style="color:#FF0000; background:#000000;">Black Box Warning</span>==<br />
<br />
FDA Package Insert for {{PAGENAME}} contains no information regarding ''Black Box Warning''.<br />
<br />
{| style="border: 3px solid #696969;"<br />
| style="background: #000000; border: 0px; padding: 20px 20px; width: 800px;" |<br />
<center><br />
<font color="#F8F8FF" style="font-weight: bold;">CONTRAINDICATION</font><br />
</center><br />
<br />
<center><br />
<font color="#F8F8FF" size="1" style="font-style: italic;">See full prescribing information for complete boxed warning.</font><br />
</center><br />
<br />
<font color="#F8F8FF" style="font-weight: bold;"><br />
''{{fontcolor|#FF0000|Condition Name:}}'' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
</font><br />
|}<br />
<br />
==Overview==<br />
<br />
{{PAGENAME}} is a_Phosphodiesterase 3 Inhibitor drug that is FDA approved for the treatment of intermittent claudication. There is a Black Box Warning for this drug as shown <span style="background:#000000;">'''[[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|here}}]]'''</span>. Common adverse reactions include headache, dizziness, palpitation, diarrhea, rhinitis and pharyngitis.<br />
<br />
==Adult Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Adult)===<br />
<br />
=====Intermittent claudication=====<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
<br />
===Off-Label Use and Dosage (Adult)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Secondary prevention of stroke and TIA=====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid'''<ref name="Lansberg-2012">{{Cite journal | last1 = Lansberg | first1 = MG. | last2 = O'Donnell | first2 = MJ. | last3 = Khatri | first3 = P. | last4 = Lang | first4 = ES. | last5 = Nguyen-Huynh | first5 = MN. | last6 = Schwartz | first6 = NE. | last7 = Sonnenberg | first7 = FA. | last8 = Schulman | first8 = S. | last9 = Vandvik | first9 = PO. | title = Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e601S-36S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2302 | PMID = 22315273 }}</ref><br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid''<ref name="Vandvik-2012">{{Cite journal | last1 = Vandvik | first1 = PO. | last2 = Lincoff | first2 = AM. | last3 = Gore | first3 = JM. | last4 = Gutterman | first4 = DD. | last5 = Sonnenberg | first5 = FA. | last6 = Alonso-Coello | first6 = P. | last7 = Akl | first7 = EA. | last8 = Lansberg | first8 = MG. | last9 = Guyatt | first9 = GH. | title = Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e637S-68S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2306 | PMID = 22315274 }}</ref><br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* There is limited information about ''Off-Label Non–Guideline-Supported Use'' of {{PAGENAME}} in adult patients.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Pediatric Indications and Dosage==<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
==Contraindications==<br />
* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
<br />
==Warnings==<br />
<br />
=====Hematologic Adverse Reactions=====<br />
Rare cases have been reported of [[thrombocytopenia ]]or [[leukopenia ]]progressing to [[agranulocytosis ]]when cilostazol was not immediately discontinued. The agranulocytosis, however, was reversible on discontinuation of cilostazol.<br />
<br />
=====Use with Clopidogrel=====<br />
There is limited information with respect to the efficacy or safety of the concurrent use of cilostazol and [[clopidogrel]], a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Although it cannot be determined whether there was an additive effect on bleeding times during concomitant administration with cilostazol and [[clopidogrel]], caution is advised for checking bleeding times during co-administration.<br />
<br />
==Adverse Reactions==<br />
<br />
===Clinical Trials Experience===<br />
Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol and 134 days for patients on placebo.<br />
<br />
The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with PLETAL 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included [[palpitation ]]and [[diarrhea]], both 1.1% for cilostazol (all doses) versus 0.1% for placebo.<br />
<br />
======Body as a Whole======<br />
*Common:<br />
:*Abdominal pain<br />
:*Back pain<br />
:*Headache <br />
:*Infection<br />
<br />
*Less common:<br />
[[Chills]], face [[edema]], [[fever]], [[generalized edema]], [[malaise]], [[neck rigidity]], [[pelvic pain]], [[retroperitoneal haemorrhage]].<br />
<br />
======Central Nervous System======<br />
<br />
*Common:<br />
:*Dizziness<br />
:*Vertigo<br />
<br />
*Less common:<br />
[[Anxiety]], [[insomnia]], [[neuralgia]].<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
*Common:<br />
:*Abnormal stool<br />
:*Diarrhea<br />
:*Dyspepsia<br />
:*Flatulence<br />
:*Nausea<br />
<br />
*Less common:<br />
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Metabolic & Nutritional======<br />
*Common:<br />
:*Peripheral edema<br />
<br />
*Less common:<br />
Increased [[creatinine]], [[gout]], [[hyperlipemia]], [[hyperuricemia]].<br />
<br />
======Musculoskeletal======<br />
<br />
*Common:<br />
:*Myalgia<br />
<br />
*Less common:<br />
[[Arthralgia]], bone pain, [[bursitis]].<br />
<br />
======Miscellaneous======<br />
Less common adverse reactions:<br />
<br />
*'''Endocrine:''' [[Diabetes mellitus]].<br />
<br />
*'''Hemic and Lymphatic:''' [[Anemia]], [[ecchymosis]],[[ iron deficiency anemia]], [[polycythemia]], [[purpura]].<br />
<br />
*'''Skin and Appendages:''' Dry skin, [[furunculosis]], skin hypertrophy, [[urticaria]].<br />
<br />
*'''Special Senses:''' [[Amblyopia]], [[blindness]], [[conjunctivitis]], [[diplopia]], ear pain, eye haemorrhage, [[retinal haemorrhage]], [[tinnitus]].<br />
<br />
*'''Urogenital:''' [[Albuminuria]], [[cystitis]], [[urinary frequency]], vaginal haemorrhage, vaginitis.<br />
<br />
===Postmarketing Experience===<br />
<br />
The following events have been reported spontaneously from worldwide post-marketing experience since the launch of PLETAL in the US.<br />
<br />
======Blood and lymphatic system disorders:======<br />
[[Agranulocytosis]],[[ aplastic anemia]], [[granulocytopenia]], [[pancytopenia]], [[thrombocytopenia]], [[leukopenia]], <br />
[[bleeding tendency]]<br />
<br />
======Cardiac disorders:======<br />
<br />
[[Torsades de pointes]], [[QT prolongation|QTc prolongation]] (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. [[complete atrioventricular block]], c[[ardiac failure ]]and [[bradyarrythmia]], when treated with cilostazol. Cilostazol was used "off label" due to its positive [[chronotropic]] action)<br />
<br />
======Gastrointestinal disorders:======<br />
<br />
*Gastrointestinal haemorrhage<br />
<br />
======General disorders and administration site conditions:======<br />
<br />
*Pain<br />
*[[chest pain]] <br />
*[[hot flushes]]<br />
<br />
======Hepatobiliary disorders:======<br />
<br />
*Hepatic dysfunction/abnormal liver function tests <br />
*[[jaundice]]<br />
<br />
======Injury, poisoning and procedural complications:======<br />
<br />
*Extradural [[haematoma ]] <br />
*Subdural haematoma<br />
<br />
=====Investigations:=====<br />
<br />
*[[Blood glucose]] increased, blood [[uric acid]] increased, [[platelet count]] decreased, [[white blood cell count]] decreased, increase in [[BUN]] (blood urea increased), blood pressure increase<br />
<br />
======Nervous system disorders:======<br />
<br />
*[[Intracranial haemorrhage]] <br />
*[[cerebral haemorrhage]] <br />
*[[cerebrovascular accident]]<br />
<br />
======Respiratory, thoracic and mediastinal disorders:======<br />
<br />
*Pulmonary haemorrhage<br />
*[[ interstitial pneumonia]]<br />
<br />
'''Skin and subcutaneous tissue disorders:'''<br />
<br />
*Haemorrhage subcutaneous, [[pruritus]], skin eruptions including [[Stevens-Johnson syndrome]], skin drug eruption ([[dermatitis medicamentosa]])<br />
<br />
======Vascular disorders:======<br />
<br />
*Subacute [[thrombosis ]](these cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting)<br />
<br />
==Drug Interactions==<br />
<br />
=====Aspirin=====<br />
<br />
*Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of ADP-induced ex vivo platelet aggregation by 22% to 37% when compared to either aspirin or cilostazol alone. Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to cilostazol alone and by 48% compared to aspirin alone. However, short-term co-administration of aspirin with cilostazol had no clinically significant impact on PT, aPTT or bleeding time compared to aspirin alone. <br />
<br />
*Effects of long-term co-administration in the general population are unknown. In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was co-administered with cilostazol to 201 patients. The most frequent doses and mean durations of aspirin therapy were 75 mg to 81 mg daily for 137 days (107 patients) and 325 mg daily for 54 days (85 patients). There was no apparent increase in incidence of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.<br />
<br />
=====Warfarin=====<br />
<br />
The cytochrome P-450 isoenzymes involved in the metabolism of R-warfarin are CYP3A4, CYP1A2 and CYP2C19 and in the metabolism of S-warfarin, CYP2C9. Cilostazol did not inhibit either the metabolism or the pharmacologic effects (PT, aPTT, bleeding time or platelet aggregation) of R- and S-warfarin after a single 25-mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and cilostazol on the pharmacokinetics and pharmacodynamics of both drugs is unknown.<br />
<br />
=====Clopidogrel=====<br />
<br />
Multiple doses of clopidogrel do not significantly increase steady state plasma concentrations of cilostazol.<br />
<br />
=====Inhibitors of CYP3A4=====<br />
<br />
======Strong Inhibitors of CYP3A4======<br />
<br />
A priming dose of [[ketoconazole ]]400 mg (a strong inhibitor of CYP3A4), was given one day prior to co-administration of single doses of [[ketoconazole ]]400 mg and cilostazol 100 mg. This regimen increased cilostazol Cmax by 94% and AUC by 117%. Other strong inhibitors of CYP3A4, such as [[itraconazole]], [[fluconazole]], [[miconazole]], [[fluvoxamine]], [[fluoxetine]], [[nefazodone ]]and [[sertraline]], would be expected to have a similar effect <br />
<br />
======Moderate Inhibitors of CYP3A4======<br />
<br />
*[[Erythromycin ]]and Other [[Macrolide ]]Antibiotics: [[Erythromycin ]]is a moderately strong inhibitor of CYP3A4. Co-administration of erythromycin 500 mg q 8h with a single dose of cilostazol 100 mg increased cilostazol Cmax by 47% and AUC by 73%. Inhibition of cilostazol metabolism by erythromycin increased the AUC of 4´-trans-hydroxy-cilostazol by 141%. Other macrolide antibiotics (e.g., [[clarithromycin]]), but not all (e.g., [[azithromycin]]), would be expected to have a similar effect.<br />
<br />
*Diltiazem: [[Diltiazem]] 180 mg decreased the clearance of cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC increased ~40%.<br />
<br />
*Grapefruit Juice: [[Grapefruit juice]] increased the Cmax of cilostazol by ~50% , but had no effect on AUC.<br />
=====Inhibitors of CYP2C19=====<br />
<br />
[[Omeprazole]]: Co-administration of omeprazole did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%, probably the result of omeprazole’s potent inhibition of CYP2C19 <br />
<br />
=====Quinidine =====<br />
<br />
Concomitant administration of [[quinidine ]]with a single dose of cilostazol 100 mg did not alter cilostazol pharmacokinetics.<br />
<br />
=====Lovastatin=====<br />
<br />
The concomitant administration of [[lovastatin ]]with cilostazol decreases cilostazol Css, max and AUCT by 15%. There is also a decrease, although nonsignificant, in cilostazol metabolite concentrations. Co-administration of cilostazol with lovastatin increases lovastatin and β–hydroxy lovastatin AUC approximately 70%. This is most likely clinically insignificant.<br />
<br />
==Use in Specific Populations==<br />
<br />
====Pregnancy====<br />
<br />
* '''[[Pregnancy category#United States|Pregnancy Category (FDA)]]: C'''<br />
<br />
* '''[[Pregnancy category#Australia|Pregnancy Category (AUS)]]: {{PAGENAME}} is not included in Australian Drug Evaluation Committee (ADEC) Pregnancy Categories.'''<br />
<br />
In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
<br />
====Labor and Delivery====<br />
<br />
FDA package insert doesn't contain any information regarding "'''Labor and Delivery'''"<br />
<br />
====Nursing Mothers====<br />
<br />
Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
<br />
====Pediatric Use====<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
====Geriatric Use====<br />
Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
====Gender====<br />
<br />
The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range<br />
<br />
====Race====<br />
<br />
(Description)<br />
<br />
====Renal Impairment====<br />
<br />
Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
<br />
====Hepatic Impairment====<br />
<br />
Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
<br />
====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the exposure in humans at the MRHD.<br />
<br />
====Immunocompromised Patients====<br />
<br />
(Description)<br />
<br />
====Miscellaneous====<br />
<br />
=====Smokers=====<br />
Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
<br />
==Administration and Monitoring==<br />
<br />
====Administration====<br />
<br />
Oral<br />
<br />
====Monitoring====<br />
FDA package insert does't contain any information regarding "'''Monitoring'''"<br />
<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability).<br />
<br />
==IV Compatibility==<br />
<br />
FDA package insert doesn't contain any information regarding '''IV Compatibility'''<br />
<br />
==Overdosage==<br />
<br />
===Acute Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
<br />
====Management====<br />
<br />
FDA package insert doesn't contain any information regarding "'''Management '''"<br />
<br />
==Pharmacology==<br />
<br />
{{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
<br />
===Mechanism of Action===<br />
<br />
The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
<br />
===Structure===<br />
<br />
*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
<br />
<br />
===Pharmacodynamics===<br />
<br />
(Description)<br />
<br />
===Pharmacokinetics===<br />
<br />
Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
<br />
====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4‑dehydro‑cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4‑dehydro‑cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
<br />
===Nonclinical Toxicology===<br />
<br />
==Clinical Studies==<br />
<br />
*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
<br />
{|<br />
| [[image:Cilo2.png|400px|thumb]]<br />
|}<br />
<br />
<br />
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
<br />
==How Supplied==<br />
<br />
'''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
<br />
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0223-60 bottles of 60 and 0185-0223-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
==Images==<br />
<br />
===Drug Images===<br />
<br />
{|<br />
| [[File:Cilostazol50mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 50 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;123 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
{|<br />
| [[File:Cilostazol100mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 100 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;223 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
===Package and Label Display Panel===<br />
<br />
Sandoz Inc.<br />
Princeton, NJ 08540<br />
OS8128<br />
Rev. 02/13<br />
MF0223REV02/13<br />
Cilostazol 100mg Tablet<br />
<br />
{|<br />
| [[image:Cilostazollabel.jpg|400px|thumb]]<br />
|}<br />
<br />
{|<br />
| [[image:Cilostazollabel1.png|400px|thumb]]<br />
|}<br />
<br />
==Patient Information==<br />
<br />
===Patient Information from FDA===<br />
(sil-OS-tah-zol)<br />
<br />
Please read this leaflet before you start taking cilostazol tablets and each time you renew it in case anything has changed. This leaflet does not replace careful discussions with your doctor. You and your doctor should discuss cilostazol when you start taking it and at regular check-ups. You should follow your doctor’s advice about when to have check-ups.<br />
What is cilostazol for?<br />
Cilostazol may improve the symptoms of patients with a medical condition called intermittent claudication.<br />
What is intermittent claudication?<br />
Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. It occurs because narrowing or blockage of the arteries decreases blood flow to the legs. The decreased blood flow does not supply enough oxygen to the leg muscles during walking, resulting in these painful leg cramps.<br />
<br />
'''What treatments are available for intermittent claudication?'''<br />
<br />
The three main treatments available for intermittent claudication are:<br />
*Exercise. Your doctor may advise an exercise program.<br />
*Medication. Your doctor may prescribe a medication such as cilostazol. (See Who should not take cilostazol tablets?)<br />
*Surgery. Your doctor may recommend a surgical procedure to bypass the blocked segment of the artery. Another procedure is called a percutaneous transluminal angioplasty. In this procedure, a catheter (a flexible tube) is inserted into the artery to reduce the blockage and improve blood flow.<br />
<br />
'''How does cilostazol work?'''<br />
<br />
*The exact way that many drugs work is not well understood. Although how cilostazol works is not completely clear, its main effects are to dilate (widen) the arteries supplying blood to the legs and to decrease the ability of platelets in the blood to stick together. Platelets are particles that circulate in the blood and play a role in clotting.<br />
*Cilostazol may reduce the leg pain that patients with intermittent claudication experience, allowing them to walk farther before their leg pain occurs.<br />
*Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks. If you have not noticed any benefit from cilostazol tablets after 12 weeks you and your doctor may wish to discuss other forms of treatment.<br />
*Sometimes blood vessel disease of the legs causes pain at rest or breakdown of skin in the leg. Cilostazol has not been shown to work in patients with these problems.<br />
<br />
'''Who should not take cilostazol tablets?'''<br />
<br />
*Patients who have congestive heart failure (CHF) must not take cilostazol tablets. The most common symptoms of CHF are shortness of breath and swelling of the legs. However, other conditions may also cause these symptoms. It is important that you discuss with your doctor whether you have CHF.<br />
*Over 1,300 patients took cilostazol in studies that lasted for 3 to 6 months. The mortality rate in these patients was similar to placebo (less than 1%). These studies were too small to be sure there is not some increased risk of dying with longer use or in patients sicker than those in the studies.<br />
<br />
'''How should cilostazol tablets be taken?'''<br />
<br />
*Follow your doctor’s advice about how to take cilostazol tablets.<br />
*You should take cilostazol tablets twice a day, at least one half-hour before or two hours after breakfast and dinner. Take cilostazol tablets at about the same times each day.<br />
*Do not share cilostazol tablets with anyone else. It was prescribed only for you.<br />
*Keep cilostazol tablets and all drugs out of the reach of children.<br />
<br />
'''Can cilostazol tablets be taken with other drugs?'''<br />
<br />
Certain drugs and foods can increase the amount of cilostazol in the blood. Because of this, your doctor may adjust your dose of cilostazol or even stop it if you are taking or are going to take one of the following medications.<br />
Drugs Interacting with Cilostazol<br />
Generic Name (Brand Names)Type of Drug<br />
[[erythromycin]] (such as E.E.S.®, Erythrocin®) Antibiotic<br />
[[ketoconazole]] (Nizoral®), [[itraconazole]] (Sporanox®) Antifungal<br />
[[diltiazem]] (Cardizem®) Antihypertensive<br />
[[omeprazole]] (Prilosec®) Gastric acid reducer<br />
This list does not include every drug that may interact with cilostazol tablets. Therefore, you should tell your doctor about all medications that you are taking, including vitamins, herbal supplements and over-the-counter drugs you can buy without a prescription. You should also check with your doctor before taking a new medication after you have begun cilostazol tablets.<br />
<br />
'''What are the possible side effects of cilostazol tablets?'''<br />
<br />
Cilostazol tablets may cause side effects including headache, diarrhea, abnormal stools, increased heart rate and palpitations.<br />
You should discuss possible side effects with your doctor before taking cilostazol tablets and any time you think you are having a side effect.<br />
This provides only a summary of information about cilostazol tablets. If you have any questions about cilostazol tablets, talk to your doctor.<br />
'''Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.'''<br />
<br />
===Patient Information from NLM===<br />
<br />
For patient information about Cilostazol from NLM, click [[Cilostazol (patient information)|here]].<br />
<br />
==Precautions with Alcohol==<br />
<br />
Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
<br />
==Brand Names==<br />
<br />
Cilostazol®, Platel®.<br />
<br />
==Look-Alike Drug Names==<br />
<br />
* (Paired Confused Name 1a) — (Paired Confused Name 1b)<br />
* (Paired Confused Name 2a) — (Paired Confused Name 2b)<br />
* (Paired Confused Name 3a) — (Paired Confused Name 3b)<br />
<br />
==[http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm Drug Shortage Status]==<br />
<br />
==[http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price Price]==<br />
<br />
==References==<br />
<br />
{{reflist}}<br />
<br />
</div></div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=Cilostazol&diff=961914Cilostazol2014-04-02T18:54:57Z<p>Abdurahman Khalil: /* FDA-Labeled Indications and Dosage (Adult) */</p>
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! style="font-size: 80%; padding: 0 5px; background: #104E8B;" | [[{{PAGENAME}}|{{fontcolor|#F8F8FF|{{PAGENAME}}®}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #000000; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|Black Box Warning}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adult Indications and Dosage|{{fontcolor|#F8F8FF|Adult Indications and Dosage}}]]<br />
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pediatric Indications and Dosage|{{fontcolor|#F8F8FF|Pediatric Indications and Dosage}}]]<br />
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Contraindications|{{fontcolor|#F8F8FF|Contraindications}}]]<br />
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Warnings|{{fontcolor|#F8F8FF|Warnings}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adverse Reactions|{{fontcolor|#F8F8FF|Adverse Reactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Drug Interactions|{{fontcolor|#F8F8FF|Drug Interactions}}]]<br />
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Use in Specific Populations|{{fontcolor|#F8F8FF|Use in Specific Populations}}]]<br />
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Administration and Monitoring|{{fontcolor|#F8F8FF|Administration and Monitoring}}]]<br />
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<div style="width: 80%"><br />
__NOTOC__<br />
{{CMG}}<br />
<br />
{{SB}} Cilostazol®, Pletal®<br />
<br />
==Disclaimer==<br />
<br />
'''''WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature. The information provided is not a medical advice or treatment. WikiDoc does not promote any medication or off-label use of drugs. Please read our full disclaimer [[wikidoc:General_disclaimer|{{fontcolor|#FF0000|here}}]].'''''<br />
<br />
==<span style="color:#FF0000; background:#000000;">Black Box Warning</span>==<br />
<br />
FDA Package Insert for {{PAGENAME}} contains no information regarding ''Black Box Warning''.<br />
<br />
{| style="border: 3px solid #696969;"<br />
| style="background: #000000; border: 0px; padding: 20px 20px; width: 800px;" |<br />
<center><br />
<font color="#F8F8FF" style="font-weight: bold;">CONTRAINDICATION</font><br />
</center><br />
<br />
<center><br />
<font color="#F8F8FF" size="1" style="font-style: italic;">See full prescribing information for complete boxed warning.</font><br />
</center><br />
<br />
<font color="#F8F8FF" style="font-weight: bold;"><br />
''{{fontcolor|#FF0000|Condition Name:}}'' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
</font><br />
|}<br />
<br />
==Overview==<br />
<br />
{{PAGENAME}} is a_Phosphodiesterase 3 Inhibitor drug that is FDA approved for the treatment of intermittent claudication. There is a Black Box Warning for this drug as shown <span style="background:#000000;">'''[[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|here}}]]'''</span>. Common adverse reactions include headache, dizziness, palpitation, diarrhea, rhinitis and pharyngitis.<br />
<br />
==Adult Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Adult)===<br />
<br />
=====Intermittent claudication=====<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
<br />
===Off-Label Use and Dosage (Adult)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Secondary prevention of stroke and TIA=====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid'''<ref name="Lansberg-2012">{{Cite journal | last1 = Lansberg | first1 = MG. | last2 = O'Donnell | first2 = MJ. | last3 = Khatri | first3 = P. | last4 = Lang | first4 = ES. | last5 = Nguyen-Huynh | first5 = MN. | last6 = Schwartz | first6 = NE. | last7 = Sonnenberg | first7 = FA. | last8 = Schulman | first8 = S. | last9 = Vandvik | first9 = PO. | title = Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e601S-36S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2302 | PMID = 22315273 }}</ref><br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<ref name="Vandvik-2012">{{Cite journal | last1 = Vandvik | first1 = PO. | last2 = Lincoff | first2 = AM. | last3 = Gore | first3 = JM. | last4 = Gutterman | first4 = DD. | last5 = Sonnenberg | first5 = FA. | last6 = Alonso-Coello | first6 = P. | last7 = Akl | first7 = EA. | last8 = Lansberg | first8 = MG. | last9 = Guyatt | first9 = GH. | title = Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e637S-68S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2306 | PMID = 22315274 }}</ref><br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* There is limited information about ''Off-Label Non–Guideline-Supported Use'' of {{PAGENAME}} in adult patients.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Pediatric Indications and Dosage==<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
==Contraindications==<br />
* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
<br />
==Warnings==<br />
<br />
=====Hematologic Adverse Reactions=====<br />
Rare cases have been reported of [[thrombocytopenia ]]or [[leukopenia ]]progressing to [[agranulocytosis ]]when cilostazol was not immediately discontinued. The agranulocytosis, however, was reversible on discontinuation of cilostazol.<br />
<br />
=====Use with Clopidogrel=====<br />
There is limited information with respect to the efficacy or safety of the concurrent use of cilostazol and [[clopidogrel]], a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Although it cannot be determined whether there was an additive effect on bleeding times during concomitant administration with cilostazol and [[clopidogrel]], caution is advised for checking bleeding times during co-administration.<br />
<br />
==Adverse Reactions==<br />
<br />
===Clinical Trials Experience===<br />
Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol and 134 days for patients on placebo.<br />
<br />
The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with PLETAL 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included [[palpitation ]]and [[diarrhea]], both 1.1% for cilostazol (all doses) versus 0.1% for placebo.<br />
<br />
======Body as a Whole======<br />
*Common:<br />
:*Abdominal pain<br />
:*Back pain<br />
:*Headache <br />
:*Infection<br />
<br />
*Less common:<br />
[[Chills]], face [[edema]], [[fever]], [[generalized edema]], [[malaise]], [[neck rigidity]], [[pelvic pain]], [[retroperitoneal haemorrhage]].<br />
<br />
======Central Nervous System======<br />
<br />
*Common:<br />
:*Dizziness<br />
:*Vertigo<br />
<br />
*Less common:<br />
[[Anxiety]], [[insomnia]], [[neuralgia]].<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
*Common:<br />
:*Abnormal stool<br />
:*Diarrhea<br />
:*Dyspepsia<br />
:*Flatulence<br />
:*Nausea<br />
<br />
*Less common:<br />
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Metabolic & Nutritional======<br />
*Common:<br />
:*Peripheral edema<br />
<br />
*Less common:<br />
Increased [[creatinine]], [[gout]], [[hyperlipemia]], [[hyperuricemia]].<br />
<br />
======Musculoskeletal======<br />
<br />
*Common:<br />
:*Myalgia<br />
<br />
*Less common:<br />
[[Arthralgia]], bone pain, [[bursitis]].<br />
<br />
======Miscellaneous======<br />
Less common adverse reactions:<br />
<br />
*'''Endocrine:''' [[Diabetes mellitus]].<br />
<br />
*'''Hemic and Lymphatic:''' [[Anemia]], [[ecchymosis]],[[ iron deficiency anemia]], [[polycythemia]], [[purpura]].<br />
<br />
*'''Skin and Appendages:''' Dry skin, [[furunculosis]], skin hypertrophy, [[urticaria]].<br />
<br />
*'''Special Senses:''' [[Amblyopia]], [[blindness]], [[conjunctivitis]], [[diplopia]], ear pain, eye haemorrhage, [[retinal haemorrhage]], [[tinnitus]].<br />
<br />
*'''Urogenital:''' [[Albuminuria]], [[cystitis]], [[urinary frequency]], vaginal haemorrhage, vaginitis.<br />
<br />
===Postmarketing Experience===<br />
<br />
The following events have been reported spontaneously from worldwide post-marketing experience since the launch of PLETAL in the US.<br />
<br />
======Blood and lymphatic system disorders:======<br />
[[Agranulocytosis]],[[ aplastic anemia]], [[granulocytopenia]], [[pancytopenia]], [[thrombocytopenia]], [[leukopenia]], <br />
[[bleeding tendency]]<br />
<br />
======Cardiac disorders:======<br />
<br />
[[Torsades de pointes]], [[QT prolongation|QTc prolongation]] (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. [[complete atrioventricular block]], c[[ardiac failure ]]and [[bradyarrythmia]], when treated with cilostazol. Cilostazol was used "off label" due to its positive [[chronotropic]] action)<br />
<br />
======Gastrointestinal disorders:======<br />
<br />
*Gastrointestinal haemorrhage<br />
<br />
======General disorders and administration site conditions:======<br />
<br />
*Pain<br />
*[[chest pain]] <br />
*[[hot flushes]]<br />
<br />
======Hepatobiliary disorders:======<br />
<br />
*Hepatic dysfunction/abnormal liver function tests <br />
*[[jaundice]]<br />
<br />
======Injury, poisoning and procedural complications:======<br />
<br />
*Extradural [[haematoma ]] <br />
*Subdural haematoma<br />
<br />
=====Investigations:=====<br />
<br />
*[[Blood glucose]] increased, blood [[uric acid]] increased, [[platelet count]] decreased, [[white blood cell count]] decreased, increase in [[BUN]] (blood urea increased), blood pressure increase<br />
<br />
======Nervous system disorders:======<br />
<br />
*[[Intracranial haemorrhage]] <br />
*[[cerebral haemorrhage]] <br />
*[[cerebrovascular accident]]<br />
<br />
======Respiratory, thoracic and mediastinal disorders:======<br />
<br />
*Pulmonary haemorrhage<br />
*[[ interstitial pneumonia]]<br />
<br />
'''Skin and subcutaneous tissue disorders:'''<br />
<br />
*Haemorrhage subcutaneous, [[pruritus]], skin eruptions including [[Stevens-Johnson syndrome]], skin drug eruption ([[dermatitis medicamentosa]])<br />
<br />
======Vascular disorders:======<br />
<br />
*Subacute [[thrombosis ]](these cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting)<br />
<br />
==Drug Interactions==<br />
<br />
=====Aspirin=====<br />
<br />
*Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of ADP-induced ex vivo platelet aggregation by 22% to 37% when compared to either aspirin or cilostazol alone. Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to cilostazol alone and by 48% compared to aspirin alone. However, short-term co-administration of aspirin with cilostazol had no clinically significant impact on PT, aPTT or bleeding time compared to aspirin alone. <br />
<br />
*Effects of long-term co-administration in the general population are unknown. In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was co-administered with cilostazol to 201 patients. The most frequent doses and mean durations of aspirin therapy were 75 mg to 81 mg daily for 137 days (107 patients) and 325 mg daily for 54 days (85 patients). There was no apparent increase in incidence of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.<br />
<br />
=====Warfarin=====<br />
<br />
The cytochrome P-450 isoenzymes involved in the metabolism of R-warfarin are CYP3A4, CYP1A2 and CYP2C19 and in the metabolism of S-warfarin, CYP2C9. Cilostazol did not inhibit either the metabolism or the pharmacologic effects (PT, aPTT, bleeding time or platelet aggregation) of R- and S-warfarin after a single 25-mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and cilostazol on the pharmacokinetics and pharmacodynamics of both drugs is unknown.<br />
<br />
=====Clopidogrel=====<br />
<br />
Multiple doses of clopidogrel do not significantly increase steady state plasma concentrations of cilostazol.<br />
<br />
=====Inhibitors of CYP3A4=====<br />
<br />
======Strong Inhibitors of CYP3A4======<br />
<br />
A priming dose of [[ketoconazole ]]400 mg (a strong inhibitor of CYP3A4), was given one day prior to co-administration of single doses of [[ketoconazole ]]400 mg and cilostazol 100 mg. This regimen increased cilostazol Cmax by 94% and AUC by 117%. Other strong inhibitors of CYP3A4, such as [[itraconazole]], [[fluconazole]], [[miconazole]], [[fluvoxamine]], [[fluoxetine]], [[nefazodone ]]and [[sertraline]], would be expected to have a similar effect <br />
<br />
======Moderate Inhibitors of CYP3A4======<br />
<br />
*[[Erythromycin ]]and Other [[Macrolide ]]Antibiotics: [[Erythromycin ]]is a moderately strong inhibitor of CYP3A4. Co-administration of erythromycin 500 mg q 8h with a single dose of cilostazol 100 mg increased cilostazol Cmax by 47% and AUC by 73%. Inhibition of cilostazol metabolism by erythromycin increased the AUC of 4´-trans-hydroxy-cilostazol by 141%. Other macrolide antibiotics (e.g., [[clarithromycin]]), but not all (e.g., [[azithromycin]]), would be expected to have a similar effect.<br />
<br />
*Diltiazem: [[Diltiazem]] 180 mg decreased the clearance of cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC increased ~40%.<br />
<br />
*Grapefruit Juice: [[Grapefruit juice]] increased the Cmax of cilostazol by ~50% , but had no effect on AUC.<br />
=====Inhibitors of CYP2C19=====<br />
<br />
[[Omeprazole]]: Co-administration of omeprazole did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%, probably the result of omeprazole’s potent inhibition of CYP2C19 <br />
<br />
=====Quinidine =====<br />
<br />
Concomitant administration of [[quinidine ]]with a single dose of cilostazol 100 mg did not alter cilostazol pharmacokinetics.<br />
<br />
=====Lovastatin=====<br />
<br />
The concomitant administration of [[lovastatin ]]with cilostazol decreases cilostazol Css, max and AUCT by 15%. There is also a decrease, although nonsignificant, in cilostazol metabolite concentrations. Co-administration of cilostazol with lovastatin increases lovastatin and β–hydroxy lovastatin AUC approximately 70%. This is most likely clinically insignificant.<br />
<br />
==Use in Specific Populations==<br />
<br />
====Pregnancy====<br />
<br />
* '''[[Pregnancy category#United States|Pregnancy Category (FDA)]]: C'''<br />
<br />
* '''[[Pregnancy category#Australia|Pregnancy Category (AUS)]]: {{PAGENAME}} is not included in Australian Drug Evaluation Committee (ADEC) Pregnancy Categories.'''<br />
<br />
In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
<br />
====Labor and Delivery====<br />
<br />
FDA package insert doesn't contain any information regarding "'''Labor and Delivery'''"<br />
<br />
====Nursing Mothers====<br />
<br />
Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
<br />
====Pediatric Use====<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
====Geriatric Use====<br />
Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
====Gender====<br />
<br />
The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range<br />
<br />
====Race====<br />
<br />
(Description)<br />
<br />
====Renal Impairment====<br />
<br />
Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
<br />
====Hepatic Impairment====<br />
<br />
Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
<br />
====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the exposure in humans at the MRHD.<br />
<br />
====Immunocompromised Patients====<br />
<br />
(Description)<br />
<br />
====Miscellaneous====<br />
<br />
=====Smokers=====<br />
Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
<br />
==Administration and Monitoring==<br />
<br />
====Administration====<br />
<br />
Oral<br />
<br />
====Monitoring====<br />
FDA package insert does't contain any information regarding "'''Monitoring'''"<br />
<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability).<br />
<br />
==IV Compatibility==<br />
<br />
FDA package insert doesn't contain any information regarding '''IV Compatibility'''<br />
<br />
==Overdosage==<br />
<br />
===Acute Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
<br />
====Management====<br />
<br />
FDA package insert doesn't contain any information regarding "'''Management '''"<br />
<br />
==Pharmacology==<br />
<br />
{{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
<br />
===Mechanism of Action===<br />
<br />
The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
<br />
===Structure===<br />
<br />
*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
<br />
<br />
===Pharmacodynamics===<br />
<br />
(Description)<br />
<br />
===Pharmacokinetics===<br />
<br />
Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
<br />
====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4‑dehydro‑cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4‑dehydro‑cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
<br />
===Nonclinical Toxicology===<br />
<br />
==Clinical Studies==<br />
<br />
*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
<br />
{|<br />
| [[image:Cilo2.png|400px|thumb]]<br />
|}<br />
<br />
<br />
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
<br />
==How Supplied==<br />
<br />
'''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
<br />
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0223-60 bottles of 60 and 0185-0223-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
==Images==<br />
<br />
===Drug Images===<br />
<br />
{|<br />
| [[File:Cilostazol50mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 50 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;123 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
{|<br />
| [[File:Cilostazol100mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 100 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;223 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
===Package and Label Display Panel===<br />
<br />
Sandoz Inc.<br />
Princeton, NJ 08540<br />
OS8128<br />
Rev. 02/13<br />
MF0223REV02/13<br />
Cilostazol 100mg Tablet<br />
<br />
{|<br />
| [[image:Cilostazollabel.jpg|400px|thumb]]<br />
|}<br />
<br />
{|<br />
| [[image:Cilostazollabel1.png|400px|thumb]]<br />
|}<br />
<br />
==Patient Information==<br />
<br />
===Patient Information from FDA===<br />
(sil-OS-tah-zol)<br />
<br />
Please read this leaflet before you start taking cilostazol tablets and each time you renew it in case anything has changed. This leaflet does not replace careful discussions with your doctor. You and your doctor should discuss cilostazol when you start taking it and at regular check-ups. You should follow your doctor’s advice about when to have check-ups.<br />
What is cilostazol for?<br />
Cilostazol may improve the symptoms of patients with a medical condition called intermittent claudication.<br />
What is intermittent claudication?<br />
Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. It occurs because narrowing or blockage of the arteries decreases blood flow to the legs. The decreased blood flow does not supply enough oxygen to the leg muscles during walking, resulting in these painful leg cramps.<br />
<br />
'''What treatments are available for intermittent claudication?'''<br />
<br />
The three main treatments available for intermittent claudication are:<br />
*Exercise. Your doctor may advise an exercise program.<br />
*Medication. Your doctor may prescribe a medication such as cilostazol. (See Who should not take cilostazol tablets?)<br />
*Surgery. Your doctor may recommend a surgical procedure to bypass the blocked segment of the artery. Another procedure is called a percutaneous transluminal angioplasty. In this procedure, a catheter (a flexible tube) is inserted into the artery to reduce the blockage and improve blood flow.<br />
<br />
'''How does cilostazol work?'''<br />
<br />
*The exact way that many drugs work is not well understood. Although how cilostazol works is not completely clear, its main effects are to dilate (widen) the arteries supplying blood to the legs and to decrease the ability of platelets in the blood to stick together. Platelets are particles that circulate in the blood and play a role in clotting.<br />
*Cilostazol may reduce the leg pain that patients with intermittent claudication experience, allowing them to walk farther before their leg pain occurs.<br />
*Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks. If you have not noticed any benefit from cilostazol tablets after 12 weeks you and your doctor may wish to discuss other forms of treatment.<br />
*Sometimes blood vessel disease of the legs causes pain at rest or breakdown of skin in the leg. Cilostazol has not been shown to work in patients with these problems.<br />
<br />
'''Who should not take cilostazol tablets?'''<br />
<br />
*Patients who have congestive heart failure (CHF) must not take cilostazol tablets. The most common symptoms of CHF are shortness of breath and swelling of the legs. However, other conditions may also cause these symptoms. It is important that you discuss with your doctor whether you have CHF.<br />
*Over 1,300 patients took cilostazol in studies that lasted for 3 to 6 months. The mortality rate in these patients was similar to placebo (less than 1%). These studies were too small to be sure there is not some increased risk of dying with longer use or in patients sicker than those in the studies.<br />
<br />
'''How should cilostazol tablets be taken?'''<br />
<br />
*Follow your doctor’s advice about how to take cilostazol tablets.<br />
*You should take cilostazol tablets twice a day, at least one half-hour before or two hours after breakfast and dinner. Take cilostazol tablets at about the same times each day.<br />
*Do not share cilostazol tablets with anyone else. It was prescribed only for you.<br />
*Keep cilostazol tablets and all drugs out of the reach of children.<br />
<br />
'''Can cilostazol tablets be taken with other drugs?'''<br />
<br />
Certain drugs and foods can increase the amount of cilostazol in the blood. Because of this, your doctor may adjust your dose of cilostazol or even stop it if you are taking or are going to take one of the following medications.<br />
Drugs Interacting with Cilostazol<br />
Generic Name (Brand Names)Type of Drug<br />
[[erythromycin]] (such as E.E.S.®, Erythrocin®) Antibiotic<br />
[[ketoconazole]] (Nizoral®), [[itraconazole]] (Sporanox®) Antifungal<br />
[[diltiazem]] (Cardizem®) Antihypertensive<br />
[[omeprazole]] (Prilosec®) Gastric acid reducer<br />
This list does not include every drug that may interact with cilostazol tablets. Therefore, you should tell your doctor about all medications that you are taking, including vitamins, herbal supplements and over-the-counter drugs you can buy without a prescription. You should also check with your doctor before taking a new medication after you have begun cilostazol tablets.<br />
<br />
'''What are the possible side effects of cilostazol tablets?'''<br />
<br />
Cilostazol tablets may cause side effects including headache, diarrhea, abnormal stools, increased heart rate and palpitations.<br />
You should discuss possible side effects with your doctor before taking cilostazol tablets and any time you think you are having a side effect.<br />
This provides only a summary of information about cilostazol tablets. If you have any questions about cilostazol tablets, talk to your doctor.<br />
'''Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.'''<br />
<br />
===Patient Information from NLM===<br />
<br />
For patient information about Cilostazol from NLM, click [[Cilostazol (patient information)|here]].<br />
<br />
==Precautions with Alcohol==<br />
<br />
Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
<br />
==Brand Names==<br />
<br />
Cilostazol®, Platel®.<br />
<br />
==Look-Alike Drug Names==<br />
<br />
* (Paired Confused Name 1a) — (Paired Confused Name 1b)<br />
* (Paired Confused Name 2a) — (Paired Confused Name 2b)<br />
* (Paired Confused Name 3a) — (Paired Confused Name 3b)<br />
<br />
==[http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm Drug Shortage Status]==<br />
<br />
==[http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price Price]==<br />
<br />
==References==<br />
<br />
{{reflist}}<br />
<br />
</div></div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=Cilostazol&diff=961910Cilostazol2014-04-02T18:48:04Z<p>Abdurahman Khalil: /* Condition 2 */</p>
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! style="font-size: 80%; padding: 0 5px; background: #000000; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|Black Box Warning}}]]<br />
|-<br />
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|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Warnings|{{fontcolor|#F8F8FF|Warnings}}]]<br />
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adverse Reactions|{{fontcolor|#F8F8FF|Adverse Reactions}}]]<br />
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Administration and Monitoring|{{fontcolor|#F8F8FF|Administration and Monitoring}}]]<br />
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#IV Compatibility|{{fontcolor|#F8F8FF|IV Compatibility}}]]<br />
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<div style="width: 80%"><br />
__NOTOC__<br />
{{CMG}}<br />
<br />
{{SB}} Cilostazol®, Pletal®<br />
<br />
==Disclaimer==<br />
<br />
'''''WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature. The information provided is not a medical advice or treatment. WikiDoc does not promote any medication or off-label use of drugs. Please read our full disclaimer [[wikidoc:General_disclaimer|{{fontcolor|#FF0000|here}}]].'''''<br />
<br />
==<span style="color:#FF0000; background:#000000;">Black Box Warning</span>==<br />
<br />
FDA Package Insert for {{PAGENAME}} contains no information regarding ''Black Box Warning''.<br />
<br />
{| style="border: 3px solid #696969;"<br />
| style="background: #000000; border: 0px; padding: 20px 20px; width: 800px;" |<br />
<center><br />
<font color="#F8F8FF" style="font-weight: bold;">CONTRAINDICATION</font><br />
</center><br />
<br />
<center><br />
<font color="#F8F8FF" size="1" style="font-style: italic;">See full prescribing information for complete boxed warning.</font><br />
</center><br />
<br />
<font color="#F8F8FF" style="font-weight: bold;"><br />
''{{fontcolor|#FF0000|Condition Name:}}'' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
</font><br />
|}<br />
<br />
==Overview==<br />
<br />
{{PAGENAME}} is a_Phosphodiesterase 3 Inhibitor drug that is FDA approved for the treatment of intermittent claudication. There is a Black Box Warning for this drug as shown <span style="background:#000000;">'''[[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|here}}]]'''</span>. Common adverse reactions include headache, dizziness, palpitation, diarrhea, rhinitis and pharyngitis.<br />
<br />
==Adult Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Adult)===<br />
<br />
=====Intermittent claudication=====<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
===Off-Label Use and Dosage (Adult)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Secondary prevention of stroke and TIA=====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid'''<ref name="Lansberg-2012">{{Cite journal | last1 = Lansberg | first1 = MG. | last2 = O'Donnell | first2 = MJ. | last3 = Khatri | first3 = P. | last4 = Lang | first4 = ES. | last5 = Nguyen-Huynh | first5 = MN. | last6 = Schwartz | first6 = NE. | last7 = Sonnenberg | first7 = FA. | last8 = Schulman | first8 = S. | last9 = Vandvik | first9 = PO. | title = Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e601S-36S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2302 | PMID = 22315273 }}</ref><br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<ref name="Vandvik-2012">{{Cite journal | last1 = Vandvik | first1 = PO. | last2 = Lincoff | first2 = AM. | last3 = Gore | first3 = JM. | last4 = Gutterman | first4 = DD. | last5 = Sonnenberg | first5 = FA. | last6 = Alonso-Coello | first6 = P. | last7 = Akl | first7 = EA. | last8 = Lansberg | first8 = MG. | last9 = Guyatt | first9 = GH. | title = Primary and secondary prevention of cardiovascular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e637S-68S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2306 | PMID = 22315274 }}</ref><br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* There is limited information about ''Off-Label Non–Guideline-Supported Use'' of {{PAGENAME}} in adult patients.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Pediatric Indications and Dosage==<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
==Contraindications==<br />
* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
<br />
==Warnings==<br />
<br />
=====Hematologic Adverse Reactions=====<br />
Rare cases have been reported of [[thrombocytopenia ]]or [[leukopenia ]]progressing to [[agranulocytosis ]]when cilostazol was not immediately discontinued. The agranulocytosis, however, was reversible on discontinuation of cilostazol.<br />
<br />
=====Use with Clopidogrel=====<br />
There is limited information with respect to the efficacy or safety of the concurrent use of cilostazol and [[clopidogrel]], a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Although it cannot be determined whether there was an additive effect on bleeding times during concomitant administration with cilostazol and [[clopidogrel]], caution is advised for checking bleeding times during co-administration.<br />
<br />
==Adverse Reactions==<br />
<br />
===Clinical Trials Experience===<br />
Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol and 134 days for patients on placebo.<br />
<br />
The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with PLETAL 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included [[palpitation ]]and [[diarrhea]], both 1.1% for cilostazol (all doses) versus 0.1% for placebo.<br />
<br />
======Body as a Whole======<br />
*Common:<br />
:*Abdominal pain<br />
:*Back pain<br />
:*Headache <br />
:*Infection<br />
<br />
*Less common:<br />
[[Chills]], face [[edema]], [[fever]], [[generalized edema]], [[malaise]], [[neck rigidity]], [[pelvic pain]], [[retroperitoneal haemorrhage]].<br />
<br />
======Central Nervous System======<br />
<br />
*Common:<br />
:*Dizziness<br />
:*Vertigo<br />
<br />
*Less common:<br />
[[Anxiety]], [[insomnia]], [[neuralgia]].<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
*Common:<br />
:*Abnormal stool<br />
:*Diarrhea<br />
:*Dyspepsia<br />
:*Flatulence<br />
:*Nausea<br />
<br />
*Less common:<br />
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Metabolic & Nutritional======<br />
*Common:<br />
:*Peripheral edema<br />
<br />
*Less common:<br />
Increased [[creatinine]], [[gout]], [[hyperlipemia]], [[hyperuricemia]].<br />
<br />
======Musculoskeletal======<br />
<br />
*Common:<br />
:*Myalgia<br />
<br />
*Less common:<br />
[[Arthralgia]], bone pain, [[bursitis]].<br />
<br />
======Miscellaneous======<br />
Less common adverse reactions:<br />
<br />
*'''Endocrine:''' [[Diabetes mellitus]].<br />
<br />
*'''Hemic and Lymphatic:''' [[Anemia]], [[ecchymosis]],[[ iron deficiency anemia]], [[polycythemia]], [[purpura]].<br />
<br />
*'''Skin and Appendages:''' Dry skin, [[furunculosis]], skin hypertrophy, [[urticaria]].<br />
<br />
*'''Special Senses:''' [[Amblyopia]], [[blindness]], [[conjunctivitis]], [[diplopia]], ear pain, eye haemorrhage, [[retinal haemorrhage]], [[tinnitus]].<br />
<br />
*'''Urogenital:''' [[Albuminuria]], [[cystitis]], [[urinary frequency]], vaginal haemorrhage, vaginitis.<br />
<br />
===Postmarketing Experience===<br />
<br />
The following events have been reported spontaneously from worldwide post-marketing experience since the launch of PLETAL in the US.<br />
<br />
======Blood and lymphatic system disorders:======<br />
[[Agranulocytosis]],[[ aplastic anemia]], [[granulocytopenia]], [[pancytopenia]], [[thrombocytopenia]], [[leukopenia]], <br />
[[bleeding tendency]]<br />
<br />
======Cardiac disorders:======<br />
<br />
[[Torsades de pointes]], [[QT prolongation|QTc prolongation]] (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. [[complete atrioventricular block]], c[[ardiac failure ]]and [[bradyarrythmia]], when treated with cilostazol. Cilostazol was used "off label" due to its positive [[chronotropic]] action)<br />
<br />
======Gastrointestinal disorders:======<br />
<br />
*Gastrointestinal haemorrhage<br />
<br />
======General disorders and administration site conditions:======<br />
<br />
*Pain<br />
*[[chest pain]] <br />
*[[hot flushes]]<br />
<br />
======Hepatobiliary disorders:======<br />
<br />
*Hepatic dysfunction/abnormal liver function tests <br />
*[[jaundice]]<br />
<br />
======Injury, poisoning and procedural complications:======<br />
<br />
*Extradural [[haematoma ]] <br />
*Subdural haematoma<br />
<br />
=====Investigations:=====<br />
<br />
*[[Blood glucose]] increased, blood [[uric acid]] increased, [[platelet count]] decreased, [[white blood cell count]] decreased, increase in [[BUN]] (blood urea increased), blood pressure increase<br />
<br />
======Nervous system disorders:======<br />
<br />
*[[Intracranial haemorrhage]] <br />
*[[cerebral haemorrhage]] <br />
*[[cerebrovascular accident]]<br />
<br />
======Respiratory, thoracic and mediastinal disorders:======<br />
<br />
*Pulmonary haemorrhage<br />
*[[ interstitial pneumonia]]<br />
<br />
'''Skin and subcutaneous tissue disorders:'''<br />
<br />
*Haemorrhage subcutaneous, [[pruritus]], skin eruptions including [[Stevens-Johnson syndrome]], skin drug eruption ([[dermatitis medicamentosa]])<br />
<br />
======Vascular disorders:======<br />
<br />
*Subacute [[thrombosis ]](these cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting)<br />
<br />
==Drug Interactions==<br />
<br />
=====Aspirin=====<br />
<br />
*Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of ADP-induced ex vivo platelet aggregation by 22% to 37% when compared to either aspirin or cilostazol alone. Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to cilostazol alone and by 48% compared to aspirin alone. However, short-term co-administration of aspirin with cilostazol had no clinically significant impact on PT, aPTT or bleeding time compared to aspirin alone. <br />
<br />
*Effects of long-term co-administration in the general population are unknown. In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was co-administered with cilostazol to 201 patients. The most frequent doses and mean durations of aspirin therapy were 75 mg to 81 mg daily for 137 days (107 patients) and 325 mg daily for 54 days (85 patients). There was no apparent increase in incidence of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.<br />
<br />
=====Warfarin=====<br />
<br />
The cytochrome P-450 isoenzymes involved in the metabolism of R-warfarin are CYP3A4, CYP1A2 and CYP2C19 and in the metabolism of S-warfarin, CYP2C9. Cilostazol did not inhibit either the metabolism or the pharmacologic effects (PT, aPTT, bleeding time or platelet aggregation) of R- and S-warfarin after a single 25-mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and cilostazol on the pharmacokinetics and pharmacodynamics of both drugs is unknown.<br />
<br />
=====Clopidogrel=====<br />
<br />
Multiple doses of clopidogrel do not significantly increase steady state plasma concentrations of cilostazol.<br />
<br />
=====Inhibitors of CYP3A4=====<br />
<br />
======Strong Inhibitors of CYP3A4======<br />
<br />
A priming dose of [[ketoconazole ]]400 mg (a strong inhibitor of CYP3A4), was given one day prior to co-administration of single doses of [[ketoconazole ]]400 mg and cilostazol 100 mg. This regimen increased cilostazol Cmax by 94% and AUC by 117%. Other strong inhibitors of CYP3A4, such as [[itraconazole]], [[fluconazole]], [[miconazole]], [[fluvoxamine]], [[fluoxetine]], [[nefazodone ]]and [[sertraline]], would be expected to have a similar effect <br />
<br />
======Moderate Inhibitors of CYP3A4======<br />
<br />
*[[Erythromycin ]]and Other [[Macrolide ]]Antibiotics: [[Erythromycin ]]is a moderately strong inhibitor of CYP3A4. Co-administration of erythromycin 500 mg q 8h with a single dose of cilostazol 100 mg increased cilostazol Cmax by 47% and AUC by 73%. Inhibition of cilostazol metabolism by erythromycin increased the AUC of 4´-trans-hydroxy-cilostazol by 141%. Other macrolide antibiotics (e.g., [[clarithromycin]]), but not all (e.g., [[azithromycin]]), would be expected to have a similar effect.<br />
<br />
*Diltiazem: [[Diltiazem]] 180 mg decreased the clearance of cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC increased ~40%.<br />
<br />
*Grapefruit Juice: [[Grapefruit juice]] increased the Cmax of cilostazol by ~50% , but had no effect on AUC.<br />
=====Inhibitors of CYP2C19=====<br />
<br />
[[Omeprazole]]: Co-administration of omeprazole did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%, probably the result of omeprazole’s potent inhibition of CYP2C19 <br />
<br />
=====Quinidine =====<br />
<br />
Concomitant administration of [[quinidine ]]with a single dose of cilostazol 100 mg did not alter cilostazol pharmacokinetics.<br />
<br />
=====Lovastatin=====<br />
<br />
The concomitant administration of [[lovastatin ]]with cilostazol decreases cilostazol Css, max and AUCT by 15%. There is also a decrease, although nonsignificant, in cilostazol metabolite concentrations. Co-administration of cilostazol with lovastatin increases lovastatin and β–hydroxy lovastatin AUC approximately 70%. This is most likely clinically insignificant.<br />
<br />
==Use in Specific Populations==<br />
<br />
====Pregnancy====<br />
<br />
* '''[[Pregnancy category#United States|Pregnancy Category (FDA)]]: C'''<br />
<br />
* '''[[Pregnancy category#Australia|Pregnancy Category (AUS)]]: {{PAGENAME}} is not included in Australian Drug Evaluation Committee (ADEC) Pregnancy Categories.'''<br />
<br />
In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
<br />
====Labor and Delivery====<br />
<br />
FDA package insert doesn't contain any information regarding "'''Labor and Delivery'''"<br />
<br />
====Nursing Mothers====<br />
<br />
Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
<br />
====Pediatric Use====<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
====Geriatric Use====<br />
Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
====Gender====<br />
<br />
The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range<br />
<br />
====Race====<br />
<br />
(Description)<br />
<br />
====Renal Impairment====<br />
<br />
Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
<br />
====Hepatic Impairment====<br />
<br />
Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
<br />
====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the exposure in humans at the MRHD.<br />
<br />
====Immunocompromised Patients====<br />
<br />
(Description)<br />
<br />
====Miscellaneous====<br />
<br />
=====Smokers=====<br />
Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
<br />
==Administration and Monitoring==<br />
<br />
====Administration====<br />
<br />
Oral<br />
<br />
====Monitoring====<br />
FDA package insert does't contain any information regarding "'''Monitoring'''"<br />
<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability).<br />
<br />
==IV Compatibility==<br />
<br />
FDA package insert doesn't contain any information regarding '''IV Compatibility'''<br />
<br />
==Overdosage==<br />
<br />
===Acute Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
<br />
====Management====<br />
<br />
FDA package insert doesn't contain any information regarding "'''Management '''"<br />
<br />
==Pharmacology==<br />
<br />
{{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
<br />
===Mechanism of Action===<br />
<br />
The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
<br />
===Structure===<br />
<br />
*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
<br />
<br />
===Pharmacodynamics===<br />
<br />
(Description)<br />
<br />
===Pharmacokinetics===<br />
<br />
Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
<br />
====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4‑dehydro‑cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4‑dehydro‑cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
<br />
===Nonclinical Toxicology===<br />
<br />
==Clinical Studies==<br />
<br />
*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
<br />
{|<br />
| [[image:Cilo2.png|400px|thumb]]<br />
|}<br />
<br />
<br />
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
<br />
==How Supplied==<br />
<br />
'''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
<br />
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0223-60 bottles of 60 and 0185-0223-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
==Images==<br />
<br />
===Drug Images===<br />
<br />
{|<br />
| [[File:Cilostazol50mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 50 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;123 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
{|<br />
| [[File:Cilostazol100mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 100 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;223 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
===Package and Label Display Panel===<br />
<br />
Sandoz Inc.<br />
Princeton, NJ 08540<br />
OS8128<br />
Rev. 02/13<br />
MF0223REV02/13<br />
Cilostazol 100mg Tablet<br />
<br />
{|<br />
| [[image:Cilostazollabel.jpg|400px|thumb]]<br />
|}<br />
<br />
{|<br />
| [[image:Cilostazollabel1.png|400px|thumb]]<br />
|}<br />
<br />
==Patient Information==<br />
<br />
===Patient Information from FDA===<br />
(sil-OS-tah-zol)<br />
<br />
Please read this leaflet before you start taking cilostazol tablets and each time you renew it in case anything has changed. This leaflet does not replace careful discussions with your doctor. You and your doctor should discuss cilostazol when you start taking it and at regular check-ups. You should follow your doctor’s advice about when to have check-ups.<br />
What is cilostazol for?<br />
Cilostazol may improve the symptoms of patients with a medical condition called intermittent claudication.<br />
What is intermittent claudication?<br />
Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. It occurs because narrowing or blockage of the arteries decreases blood flow to the legs. The decreased blood flow does not supply enough oxygen to the leg muscles during walking, resulting in these painful leg cramps.<br />
<br />
'''What treatments are available for intermittent claudication?'''<br />
<br />
The three main treatments available for intermittent claudication are:<br />
*Exercise. Your doctor may advise an exercise program.<br />
*Medication. Your doctor may prescribe a medication such as cilostazol. (See Who should not take cilostazol tablets?)<br />
*Surgery. Your doctor may recommend a surgical procedure to bypass the blocked segment of the artery. Another procedure is called a percutaneous transluminal angioplasty. In this procedure, a catheter (a flexible tube) is inserted into the artery to reduce the blockage and improve blood flow.<br />
<br />
'''How does cilostazol work?'''<br />
<br />
*The exact way that many drugs work is not well understood. Although how cilostazol works is not completely clear, its main effects are to dilate (widen) the arteries supplying blood to the legs and to decrease the ability of platelets in the blood to stick together. Platelets are particles that circulate in the blood and play a role in clotting.<br />
*Cilostazol may reduce the leg pain that patients with intermittent claudication experience, allowing them to walk farther before their leg pain occurs.<br />
*Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks. If you have not noticed any benefit from cilostazol tablets after 12 weeks you and your doctor may wish to discuss other forms of treatment.<br />
*Sometimes blood vessel disease of the legs causes pain at rest or breakdown of skin in the leg. Cilostazol has not been shown to work in patients with these problems.<br />
<br />
'''Who should not take cilostazol tablets?'''<br />
<br />
*Patients who have congestive heart failure (CHF) must not take cilostazol tablets. The most common symptoms of CHF are shortness of breath and swelling of the legs. However, other conditions may also cause these symptoms. It is important that you discuss with your doctor whether you have CHF.<br />
*Over 1,300 patients took cilostazol in studies that lasted for 3 to 6 months. The mortality rate in these patients was similar to placebo (less than 1%). These studies were too small to be sure there is not some increased risk of dying with longer use or in patients sicker than those in the studies.<br />
<br />
'''How should cilostazol tablets be taken?'''<br />
<br />
*Follow your doctor’s advice about how to take cilostazol tablets.<br />
*You should take cilostazol tablets twice a day, at least one half-hour before or two hours after breakfast and dinner. Take cilostazol tablets at about the same times each day.<br />
*Do not share cilostazol tablets with anyone else. It was prescribed only for you.<br />
*Keep cilostazol tablets and all drugs out of the reach of children.<br />
<br />
'''Can cilostazol tablets be taken with other drugs?'''<br />
<br />
Certain drugs and foods can increase the amount of cilostazol in the blood. Because of this, your doctor may adjust your dose of cilostazol or even stop it if you are taking or are going to take one of the following medications.<br />
Drugs Interacting with Cilostazol<br />
Generic Name (Brand Names)Type of Drug<br />
[[erythromycin]] (such as E.E.S.®, Erythrocin®) Antibiotic<br />
[[ketoconazole]] (Nizoral®), [[itraconazole]] (Sporanox®) Antifungal<br />
[[diltiazem]] (Cardizem®) Antihypertensive<br />
[[omeprazole]] (Prilosec®) Gastric acid reducer<br />
This list does not include every drug that may interact with cilostazol tablets. Therefore, you should tell your doctor about all medications that you are taking, including vitamins, herbal supplements and over-the-counter drugs you can buy without a prescription. You should also check with your doctor before taking a new medication after you have begun cilostazol tablets.<br />
<br />
'''What are the possible side effects of cilostazol tablets?'''<br />
<br />
Cilostazol tablets may cause side effects including headache, diarrhea, abnormal stools, increased heart rate and palpitations.<br />
You should discuss possible side effects with your doctor before taking cilostazol tablets and any time you think you are having a side effect.<br />
This provides only a summary of information about cilostazol tablets. If you have any questions about cilostazol tablets, talk to your doctor.<br />
'''Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.'''<br />
<br />
===Patient Information from NLM===<br />
<br />
For patient information about Cilostazol from NLM, click [[Cilostazol (patient information)|here]].<br />
<br />
==Precautions with Alcohol==<br />
<br />
Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
<br />
==Brand Names==<br />
<br />
Cilostazol®, Platel®.<br />
<br />
==Look-Alike Drug Names==<br />
<br />
* (Paired Confused Name 1a) — (Paired Confused Name 1b)<br />
* (Paired Confused Name 2a) — (Paired Confused Name 2b)<br />
* (Paired Confused Name 3a) — (Paired Confused Name 3b)<br />
<br />
==[http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm Drug Shortage Status]==<br />
<br />
==[http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price Price]==<br />
<br />
==References==<br />
<br />
{{reflist}}<br />
<br />
</div></div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=Cilostazol&diff=961895Cilostazol2014-04-02T18:27:06Z<p>Abdurahman Khalil: /* Secondary prevention of stroke and TIA */</p>
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|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm {{fontcolor|#F8F8FF|Drug Shortage Status}}]<br />
|-<br />
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|-<br />
|}<br />
<div style="width: 80%"><br />
__NOTOC__<br />
{{CMG}}<br />
<br />
{{SB}} Cilostazol®, Pletal®<br />
<br />
==Disclaimer==<br />
<br />
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==<span style="color:#FF0000; background:#000000;">Black Box Warning</span>==<br />
<br />
FDA Package Insert for {{PAGENAME}} contains no information regarding ''Black Box Warning''.<br />
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<center><br />
<font color="#F8F8FF" style="font-weight: bold;">CONTRAINDICATION</font><br />
</center><br />
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<font color="#F8F8FF" size="1" style="font-style: italic;">See full prescribing information for complete boxed warning.</font><br />
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<br />
<font color="#F8F8FF" style="font-weight: bold;"><br />
''{{fontcolor|#FF0000|Condition Name:}}'' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
</font><br />
|}<br />
<br />
==Overview==<br />
<br />
{{PAGENAME}} is a_Phosphodiesterase 3 Inhibitor drug that is FDA approved for the treatment of intermittent claudication. There is a Black Box Warning for this drug as shown <span style="background:#000000;">'''[[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|here}}]]'''</span>. Common adverse reactions include headache, dizziness, palpitation, diarrhea, rhinitis and pharyngitis.<br />
<br />
==Adult Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Adult)===<br />
<br />
=====Intermittent claudication=====<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
===Off-Label Use and Dosage (Adult)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Secondary prevention of stroke and TIA=====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO bid'''<ref name="Lansberg-2012">{{Cite journal | last1 = Lansberg | first1 = MG. | last2 = O'Donnell | first2 = MJ. | last3 = Khatri | first3 = P. | last4 = Lang | first4 = ES. | last5 = Nguyen-Huynh | first5 = MN. | last6 = Schwartz | first6 = NE. | last7 = Sonnenberg | first7 = FA. | last8 = Schulman | first8 = S. | last9 = Vandvik | first9 = PO. | title = Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e601S-36S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2302 | PMID = 22315273 }}</ref><br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* There is limited information about ''Off-Label Non–Guideline-Supported Use'' of {{PAGENAME}} in adult patients.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Pediatric Indications and Dosage==<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
==Contraindications==<br />
* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
<br />
==Warnings==<br />
<br />
=====Hematologic Adverse Reactions=====<br />
Rare cases have been reported of [[thrombocytopenia ]]or [[leukopenia ]]progressing to [[agranulocytosis ]]when cilostazol was not immediately discontinued. The agranulocytosis, however, was reversible on discontinuation of cilostazol.<br />
<br />
=====Use with Clopidogrel=====<br />
There is limited information with respect to the efficacy or safety of the concurrent use of cilostazol and [[clopidogrel]], a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Although it cannot be determined whether there was an additive effect on bleeding times during concomitant administration with cilostazol and [[clopidogrel]], caution is advised for checking bleeding times during co-administration.<br />
<br />
==Adverse Reactions==<br />
<br />
===Clinical Trials Experience===<br />
Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol and 134 days for patients on placebo.<br />
<br />
The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with PLETAL 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included [[palpitation ]]and [[diarrhea]], both 1.1% for cilostazol (all doses) versus 0.1% for placebo.<br />
<br />
======Body as a Whole======<br />
*Common:<br />
:*Abdominal pain<br />
:*Back pain<br />
:*Headache <br />
:*Infection<br />
<br />
*Less common:<br />
[[Chills]], face [[edema]], [[fever]], [[generalized edema]], [[malaise]], [[neck rigidity]], [[pelvic pain]], [[retroperitoneal haemorrhage]].<br />
<br />
======Central Nervous System======<br />
<br />
*Common:<br />
:*Dizziness<br />
:*Vertigo<br />
<br />
*Less common:<br />
[[Anxiety]], [[insomnia]], [[neuralgia]].<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
*Common:<br />
:*Abnormal stool<br />
:*Diarrhea<br />
:*Dyspepsia<br />
:*Flatulence<br />
:*Nausea<br />
<br />
*Less common:<br />
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Metabolic & Nutritional======<br />
*Common:<br />
:*Peripheral edema<br />
<br />
*Less common:<br />
Increased [[creatinine]], [[gout]], [[hyperlipemia]], [[hyperuricemia]].<br />
<br />
======Musculoskeletal======<br />
<br />
*Common:<br />
:*Myalgia<br />
<br />
*Less common:<br />
[[Arthralgia]], bone pain, [[bursitis]].<br />
<br />
======Miscellaneous======<br />
Less common adverse reactions:<br />
<br />
*'''Endocrine:''' [[Diabetes mellitus]].<br />
<br />
*'''Hemic and Lymphatic:''' [[Anemia]], [[ecchymosis]],[[ iron deficiency anemia]], [[polycythemia]], [[purpura]].<br />
<br />
*'''Skin and Appendages:''' Dry skin, [[furunculosis]], skin hypertrophy, [[urticaria]].<br />
<br />
*'''Special Senses:''' [[Amblyopia]], [[blindness]], [[conjunctivitis]], [[diplopia]], ear pain, eye haemorrhage, [[retinal haemorrhage]], [[tinnitus]].<br />
<br />
*'''Urogenital:''' [[Albuminuria]], [[cystitis]], [[urinary frequency]], vaginal haemorrhage, vaginitis.<br />
<br />
===Postmarketing Experience===<br />
<br />
The following events have been reported spontaneously from worldwide post-marketing experience since the launch of PLETAL in the US.<br />
<br />
======Blood and lymphatic system disorders:======<br />
[[Agranulocytosis]],[[ aplastic anemia]], [[granulocytopenia]], [[pancytopenia]], [[thrombocytopenia]], [[leukopenia]], <br />
[[bleeding tendency]]<br />
<br />
======Cardiac disorders:======<br />
<br />
[[Torsades de pointes]], [[QT prolongation|QTc prolongation]] (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. [[complete atrioventricular block]], c[[ardiac failure ]]and [[bradyarrythmia]], when treated with cilostazol. Cilostazol was used "off label" due to its positive [[chronotropic]] action)<br />
<br />
======Gastrointestinal disorders:======<br />
<br />
*Gastrointestinal haemorrhage<br />
<br />
======General disorders and administration site conditions:======<br />
<br />
*Pain<br />
*[[chest pain]] <br />
*[[hot flushes]]<br />
<br />
======Hepatobiliary disorders:======<br />
<br />
*Hepatic dysfunction/abnormal liver function tests <br />
*[[jaundice]]<br />
<br />
======Injury, poisoning and procedural complications:======<br />
<br />
*Extradural [[haematoma ]] <br />
*Subdural haematoma<br />
<br />
=====Investigations:=====<br />
<br />
*[[Blood glucose]] increased, blood [[uric acid]] increased, [[platelet count]] decreased, [[white blood cell count]] decreased, increase in [[BUN]] (blood urea increased), blood pressure increase<br />
<br />
======Nervous system disorders:======<br />
<br />
*[[Intracranial haemorrhage]] <br />
*[[cerebral haemorrhage]] <br />
*[[cerebrovascular accident]]<br />
<br />
======Respiratory, thoracic and mediastinal disorders:======<br />
<br />
*Pulmonary haemorrhage<br />
*[[ interstitial pneumonia]]<br />
<br />
'''Skin and subcutaneous tissue disorders:'''<br />
<br />
*Haemorrhage subcutaneous, [[pruritus]], skin eruptions including [[Stevens-Johnson syndrome]], skin drug eruption ([[dermatitis medicamentosa]])<br />
<br />
======Vascular disorders:======<br />
<br />
*Subacute [[thrombosis ]](these cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting)<br />
<br />
==Drug Interactions==<br />
<br />
=====Aspirin=====<br />
<br />
*Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of ADP-induced ex vivo platelet aggregation by 22% to 37% when compared to either aspirin or cilostazol alone. Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to cilostazol alone and by 48% compared to aspirin alone. However, short-term co-administration of aspirin with cilostazol had no clinically significant impact on PT, aPTT or bleeding time compared to aspirin alone. <br />
<br />
*Effects of long-term co-administration in the general population are unknown. In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was co-administered with cilostazol to 201 patients. The most frequent doses and mean durations of aspirin therapy were 75 mg to 81 mg daily for 137 days (107 patients) and 325 mg daily for 54 days (85 patients). There was no apparent increase in incidence of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.<br />
<br />
=====Warfarin=====<br />
<br />
The cytochrome P-450 isoenzymes involved in the metabolism of R-warfarin are CYP3A4, CYP1A2 and CYP2C19 and in the metabolism of S-warfarin, CYP2C9. Cilostazol did not inhibit either the metabolism or the pharmacologic effects (PT, aPTT, bleeding time or platelet aggregation) of R- and S-warfarin after a single 25-mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and cilostazol on the pharmacokinetics and pharmacodynamics of both drugs is unknown.<br />
<br />
=====Clopidogrel=====<br />
<br />
Multiple doses of clopidogrel do not significantly increase steady state plasma concentrations of cilostazol.<br />
<br />
=====Inhibitors of CYP3A4=====<br />
<br />
======Strong Inhibitors of CYP3A4======<br />
<br />
A priming dose of [[ketoconazole ]]400 mg (a strong inhibitor of CYP3A4), was given one day prior to co-administration of single doses of [[ketoconazole ]]400 mg and cilostazol 100 mg. This regimen increased cilostazol Cmax by 94% and AUC by 117%. Other strong inhibitors of CYP3A4, such as [[itraconazole]], [[fluconazole]], [[miconazole]], [[fluvoxamine]], [[fluoxetine]], [[nefazodone ]]and [[sertraline]], would be expected to have a similar effect <br />
<br />
======Moderate Inhibitors of CYP3A4======<br />
<br />
*[[Erythromycin ]]and Other [[Macrolide ]]Antibiotics: [[Erythromycin ]]is a moderately strong inhibitor of CYP3A4. Co-administration of erythromycin 500 mg q 8h with a single dose of cilostazol 100 mg increased cilostazol Cmax by 47% and AUC by 73%. Inhibition of cilostazol metabolism by erythromycin increased the AUC of 4´-trans-hydroxy-cilostazol by 141%. Other macrolide antibiotics (e.g., [[clarithromycin]]), but not all (e.g., [[azithromycin]]), would be expected to have a similar effect.<br />
<br />
*Diltiazem: [[Diltiazem]] 180 mg decreased the clearance of cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC increased ~40%.<br />
<br />
*Grapefruit Juice: [[Grapefruit juice]] increased the Cmax of cilostazol by ~50% , but had no effect on AUC.<br />
=====Inhibitors of CYP2C19=====<br />
<br />
[[Omeprazole]]: Co-administration of omeprazole did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%, probably the result of omeprazole’s potent inhibition of CYP2C19 <br />
<br />
=====Quinidine =====<br />
<br />
Concomitant administration of [[quinidine ]]with a single dose of cilostazol 100 mg did not alter cilostazol pharmacokinetics.<br />
<br />
=====Lovastatin=====<br />
<br />
The concomitant administration of [[lovastatin ]]with cilostazol decreases cilostazol Css, max and AUCT by 15%. There is also a decrease, although nonsignificant, in cilostazol metabolite concentrations. Co-administration of cilostazol with lovastatin increases lovastatin and β–hydroxy lovastatin AUC approximately 70%. This is most likely clinically insignificant.<br />
<br />
==Use in Specific Populations==<br />
<br />
====Pregnancy====<br />
<br />
* '''[[Pregnancy category#United States|Pregnancy Category (FDA)]]: C'''<br />
<br />
* '''[[Pregnancy category#Australia|Pregnancy Category (AUS)]]: {{PAGENAME}} is not included in Australian Drug Evaluation Committee (ADEC) Pregnancy Categories.'''<br />
<br />
In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
<br />
====Labor and Delivery====<br />
<br />
FDA package insert doesn't contain any information regarding "'''Labor and Delivery'''"<br />
<br />
====Nursing Mothers====<br />
<br />
Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
<br />
====Pediatric Use====<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
====Geriatric Use====<br />
Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
====Gender====<br />
<br />
The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range<br />
<br />
====Race====<br />
<br />
(Description)<br />
<br />
====Renal Impairment====<br />
<br />
Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
<br />
====Hepatic Impairment====<br />
<br />
Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
<br />
====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the exposure in humans at the MRHD.<br />
<br />
====Immunocompromised Patients====<br />
<br />
(Description)<br />
<br />
====Miscellaneous====<br />
<br />
=====Smokers=====<br />
Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
<br />
==Administration and Monitoring==<br />
<br />
====Administration====<br />
<br />
Oral<br />
<br />
====Monitoring====<br />
FDA package insert does't contain any information regarding "'''Monitoring'''"<br />
<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability).<br />
<br />
==IV Compatibility==<br />
<br />
FDA package insert doesn't contain any information regarding '''IV Compatibility'''<br />
<br />
==Overdosage==<br />
<br />
===Acute Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
<br />
====Management====<br />
<br />
FDA package insert doesn't contain any information regarding "'''Management '''"<br />
<br />
==Pharmacology==<br />
<br />
{{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
<br />
===Mechanism of Action===<br />
<br />
The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
<br />
===Structure===<br />
<br />
*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
<br />
<br />
===Pharmacodynamics===<br />
<br />
(Description)<br />
<br />
===Pharmacokinetics===<br />
<br />
Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
<br />
====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4‑dehydro‑cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4‑dehydro‑cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
<br />
===Nonclinical Toxicology===<br />
<br />
==Clinical Studies==<br />
<br />
*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
<br />
{|<br />
| [[image:Cilo2.png|400px|thumb]]<br />
|}<br />
<br />
<br />
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
<br />
==How Supplied==<br />
<br />
'''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
<br />
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0223-60 bottles of 60 and 0185-0223-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
==Images==<br />
<br />
===Drug Images===<br />
<br />
{|<br />
| [[File:Cilostazol50mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 50 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;123 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
{|<br />
| [[File:Cilostazol100mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 100 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;223 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
===Package and Label Display Panel===<br />
<br />
Sandoz Inc.<br />
Princeton, NJ 08540<br />
OS8128<br />
Rev. 02/13<br />
MF0223REV02/13<br />
Cilostazol 100mg Tablet<br />
<br />
{|<br />
| [[image:Cilostazollabel.jpg|400px|thumb]]<br />
|}<br />
<br />
{|<br />
| [[image:Cilostazollabel1.png|400px|thumb]]<br />
|}<br />
<br />
==Patient Information==<br />
<br />
===Patient Information from FDA===<br />
(sil-OS-tah-zol)<br />
<br />
Please read this leaflet before you start taking cilostazol tablets and each time you renew it in case anything has changed. This leaflet does not replace careful discussions with your doctor. You and your doctor should discuss cilostazol when you start taking it and at regular check-ups. You should follow your doctor’s advice about when to have check-ups.<br />
What is cilostazol for?<br />
Cilostazol may improve the symptoms of patients with a medical condition called intermittent claudication.<br />
What is intermittent claudication?<br />
Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. It occurs because narrowing or blockage of the arteries decreases blood flow to the legs. The decreased blood flow does not supply enough oxygen to the leg muscles during walking, resulting in these painful leg cramps.<br />
<br />
'''What treatments are available for intermittent claudication?'''<br />
<br />
The three main treatments available for intermittent claudication are:<br />
*Exercise. Your doctor may advise an exercise program.<br />
*Medication. Your doctor may prescribe a medication such as cilostazol. (See Who should not take cilostazol tablets?)<br />
*Surgery. Your doctor may recommend a surgical procedure to bypass the blocked segment of the artery. Another procedure is called a percutaneous transluminal angioplasty. In this procedure, a catheter (a flexible tube) is inserted into the artery to reduce the blockage and improve blood flow.<br />
<br />
'''How does cilostazol work?'''<br />
<br />
*The exact way that many drugs work is not well understood. Although how cilostazol works is not completely clear, its main effects are to dilate (widen) the arteries supplying blood to the legs and to decrease the ability of platelets in the blood to stick together. Platelets are particles that circulate in the blood and play a role in clotting.<br />
*Cilostazol may reduce the leg pain that patients with intermittent claudication experience, allowing them to walk farther before their leg pain occurs.<br />
*Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks. If you have not noticed any benefit from cilostazol tablets after 12 weeks you and your doctor may wish to discuss other forms of treatment.<br />
*Sometimes blood vessel disease of the legs causes pain at rest or breakdown of skin in the leg. Cilostazol has not been shown to work in patients with these problems.<br />
<br />
'''Who should not take cilostazol tablets?'''<br />
<br />
*Patients who have congestive heart failure (CHF) must not take cilostazol tablets. The most common symptoms of CHF are shortness of breath and swelling of the legs. However, other conditions may also cause these symptoms. It is important that you discuss with your doctor whether you have CHF.<br />
*Over 1,300 patients took cilostazol in studies that lasted for 3 to 6 months. The mortality rate in these patients was similar to placebo (less than 1%). These studies were too small to be sure there is not some increased risk of dying with longer use or in patients sicker than those in the studies.<br />
<br />
'''How should cilostazol tablets be taken?'''<br />
<br />
*Follow your doctor’s advice about how to take cilostazol tablets.<br />
*You should take cilostazol tablets twice a day, at least one half-hour before or two hours after breakfast and dinner. Take cilostazol tablets at about the same times each day.<br />
*Do not share cilostazol tablets with anyone else. It was prescribed only for you.<br />
*Keep cilostazol tablets and all drugs out of the reach of children.<br />
<br />
'''Can cilostazol tablets be taken with other drugs?'''<br />
<br />
Certain drugs and foods can increase the amount of cilostazol in the blood. Because of this, your doctor may adjust your dose of cilostazol or even stop it if you are taking or are going to take one of the following medications.<br />
Drugs Interacting with Cilostazol<br />
Generic Name (Brand Names)Type of Drug<br />
[[erythromycin]] (such as E.E.S.®, Erythrocin®) Antibiotic<br />
[[ketoconazole]] (Nizoral®), [[itraconazole]] (Sporanox®) Antifungal<br />
[[diltiazem]] (Cardizem®) Antihypertensive<br />
[[omeprazole]] (Prilosec®) Gastric acid reducer<br />
This list does not include every drug that may interact with cilostazol tablets. Therefore, you should tell your doctor about all medications that you are taking, including vitamins, herbal supplements and over-the-counter drugs you can buy without a prescription. You should also check with your doctor before taking a new medication after you have begun cilostazol tablets.<br />
<br />
'''What are the possible side effects of cilostazol tablets?'''<br />
<br />
Cilostazol tablets may cause side effects including headache, diarrhea, abnormal stools, increased heart rate and palpitations.<br />
You should discuss possible side effects with your doctor before taking cilostazol tablets and any time you think you are having a side effect.<br />
This provides only a summary of information about cilostazol tablets. If you have any questions about cilostazol tablets, talk to your doctor.<br />
'''Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.'''<br />
<br />
===Patient Information from NLM===<br />
<br />
For patient information about Cilostazol from NLM, click [[Cilostazol (patient information)|here]].<br />
<br />
==Precautions with Alcohol==<br />
<br />
Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
<br />
==Brand Names==<br />
<br />
Cilostazol®, Platel®.<br />
<br />
==Look-Alike Drug Names==<br />
<br />
* (Paired Confused Name 1a) — (Paired Confused Name 1b)<br />
* (Paired Confused Name 2a) — (Paired Confused Name 2b)<br />
* (Paired Confused Name 3a) — (Paired Confused Name 3b)<br />
<br />
==[http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm Drug Shortage Status]==<br />
<br />
==[http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price Price]==<br />
<br />
==References==<br />
<br />
{{reflist}}<br />
<br />
</div></div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=Cilostazol&diff=961885Cilostazol2014-04-02T18:14:05Z<p>Abdurahman Khalil: /* Condition 1 */</p>
<hr />
<div>{|class="infobox" style="position: fixed; top: 180px; right: 20px; margin: 0 0 0 0; border: 0; float: right; width: 15%; background: #104E8B; border-radius: 10px 10px 10px 10px;" cellpadding="0" cellspacing="0";<br />
|-<br />
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|-<br />
! style="font-size: 80%; padding: 0 5px; background: #000000; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|Black Box Warning}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adult Indications and Dosage|{{fontcolor|#F8F8FF|Adult Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pediatric Indications and Dosage|{{fontcolor|#F8F8FF|Pediatric Indications and Dosage}}]]<br />
|-<br />
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|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Warnings|{{fontcolor|#F8F8FF|Warnings}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adverse Reactions|{{fontcolor|#F8F8FF|Adverse Reactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Drug Interactions|{{fontcolor|#F8F8FF|Drug Interactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Use in Specific Populations|{{fontcolor|#F8F8FF|Use in Specific Populations}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Administration and Monitoring|{{fontcolor|#F8F8FF|Administration and Monitoring}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#IV Compatibility|{{fontcolor|#F8F8FF|IV Compatibility}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Overdosage|{{fontcolor|#F8F8FF|Overdosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pharmacology|{{fontcolor|#F8F8FF|Pharmacology}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Clinical Studies|{{fontcolor|#F8F8FF|Clinical Studies}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#How Supplied|{{fontcolor|#F8F8FF|How Supplied}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Images|{{fontcolor|#F8F8FF|Images}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Patient Information|{{fontcolor|#F8F8FF|Patient information}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Precautions with Alcohol|{{fontcolor|#F8F8FF|Precautions with Alcohol}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Brand Names|{{fontcolor|#F8F8FF|Brand Names}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Look-Alike Drug Names|{{fontcolor|#F8F8FF|Look-Alike Drug Names}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm {{fontcolor|#F8F8FF|Drug Shortage Status}}]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price {{fontcolor|#F8F8FF|Price}}]<br />
|-<br />
|}<br />
<div style="width: 80%"><br />
__NOTOC__<br />
{{CMG}}<br />
<br />
{{SB}} Cilostazol®, Pletal®<br />
<br />
==Disclaimer==<br />
<br />
'''''WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature. The information provided is not a medical advice or treatment. WikiDoc does not promote any medication or off-label use of drugs. Please read our full disclaimer [[wikidoc:General_disclaimer|{{fontcolor|#FF0000|here}}]].'''''<br />
<br />
==<span style="color:#FF0000; background:#000000;">Black Box Warning</span>==<br />
<br />
FDA Package Insert for {{PAGENAME}} contains no information regarding ''Black Box Warning''.<br />
<br />
{| style="border: 3px solid #696969;"<br />
| style="background: #000000; border: 0px; padding: 20px 20px; width: 800px;" |<br />
<center><br />
<font color="#F8F8FF" style="font-weight: bold;">CONTRAINDICATION</font><br />
</center><br />
<br />
<center><br />
<font color="#F8F8FF" size="1" style="font-style: italic;">See full prescribing information for complete boxed warning.</font><br />
</center><br />
<br />
<font color="#F8F8FF" style="font-weight: bold;"><br />
''{{fontcolor|#FF0000|Condition Name:}}'' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
</font><br />
|}<br />
<br />
==Overview==<br />
<br />
{{PAGENAME}} is a_Phosphodiesterase 3 Inhibitor drug that is FDA approved for the treatment of intermittent claudication. There is a Black Box Warning for this drug as shown <span style="background:#000000;">'''[[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|here}}]]'''</span>. Common adverse reactions include headache, dizziness, palpitation, diarrhea, rhinitis and pharyngitis.<br />
<br />
==Adult Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Adult)===<br />
<br />
=====Intermittent claudication=====<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
===Off-Label Use and Dosage (Adult)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Secondary prevention of stroke and TIA=====<br />
<br />
* Developed by: American College of Chest Physicians<br />
<br />
* Class of Recommendation: (Class II) (Link)<br />
<br />
* Strength of Evidence: (Category C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* '''100 mg PO q12h'''<ref name="Lansberg-2012">{{Cite journal | last1 = Lansberg | first1 = MG. | last2 = O'Donnell | first2 = MJ. | last3 = Khatri | first3 = P. | last4 = Lang | first4 = ES. | last5 = Nguyen-Huynh | first5 = MN. | last6 = Schwartz | first6 = NE. | last7 = Sonnenberg | first7 = FA. | last8 = Schulman | first8 = S. | last9 = Vandvik | first9 = PO. | title = Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. | journal = Chest | volume = 141 | issue = 2 Suppl | pages = e601S-36S | month = Feb | year = 2012 | doi = 10.1378/chest.11-2302 | PMID = 22315273 }}</ref><br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* There is limited information about ''Off-Label Non–Guideline-Supported Use'' of {{PAGENAME}} in adult patients.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Pediatric Indications and Dosage==<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
==Contraindications==<br />
* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
<br />
==Warnings==<br />
<br />
=====Hematologic Adverse Reactions=====<br />
Rare cases have been reported of [[thrombocytopenia ]]or [[leukopenia ]]progressing to [[agranulocytosis ]]when cilostazol was not immediately discontinued. The agranulocytosis, however, was reversible on discontinuation of cilostazol.<br />
<br />
=====Use with Clopidogrel=====<br />
There is limited information with respect to the efficacy or safety of the concurrent use of cilostazol and [[clopidogrel]], a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Although it cannot be determined whether there was an additive effect on bleeding times during concomitant administration with cilostazol and [[clopidogrel]], caution is advised for checking bleeding times during co-administration.<br />
<br />
==Adverse Reactions==<br />
<br />
===Clinical Trials Experience===<br />
Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol and 134 days for patients on placebo.<br />
<br />
The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with PLETAL 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included [[palpitation ]]and [[diarrhea]], both 1.1% for cilostazol (all doses) versus 0.1% for placebo.<br />
<br />
======Body as a Whole======<br />
*Common:<br />
:*Abdominal pain<br />
:*Back pain<br />
:*Headache <br />
:*Infection<br />
<br />
*Less common:<br />
[[Chills]], face [[edema]], [[fever]], [[generalized edema]], [[malaise]], [[neck rigidity]], [[pelvic pain]], [[retroperitoneal haemorrhage]].<br />
<br />
======Central Nervous System======<br />
<br />
*Common:<br />
:*Dizziness<br />
:*Vertigo<br />
<br />
*Less common:<br />
[[Anxiety]], [[insomnia]], [[neuralgia]].<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
*Common:<br />
:*Abnormal stool<br />
:*Diarrhea<br />
:*Dyspepsia<br />
:*Flatulence<br />
:*Nausea<br />
<br />
*Less common:<br />
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Metabolic & Nutritional======<br />
*Common:<br />
:*Peripheral edema<br />
<br />
*Less common:<br />
Increased [[creatinine]], [[gout]], [[hyperlipemia]], [[hyperuricemia]].<br />
<br />
======Musculoskeletal======<br />
<br />
*Common:<br />
:*Myalgia<br />
<br />
*Less common:<br />
[[Arthralgia]], bone pain, [[bursitis]].<br />
<br />
======Miscellaneous======<br />
Less common adverse reactions:<br />
<br />
*'''Endocrine:''' [[Diabetes mellitus]].<br />
<br />
*'''Hemic and Lymphatic:''' [[Anemia]], [[ecchymosis]],[[ iron deficiency anemia]], [[polycythemia]], [[purpura]].<br />
<br />
*'''Skin and Appendages:''' Dry skin, [[furunculosis]], skin hypertrophy, [[urticaria]].<br />
<br />
*'''Special Senses:''' [[Amblyopia]], [[blindness]], [[conjunctivitis]], [[diplopia]], ear pain, eye haemorrhage, [[retinal haemorrhage]], [[tinnitus]].<br />
<br />
*'''Urogenital:''' [[Albuminuria]], [[cystitis]], [[urinary frequency]], vaginal haemorrhage, vaginitis.<br />
<br />
===Postmarketing Experience===<br />
<br />
The following events have been reported spontaneously from worldwide post-marketing experience since the launch of PLETAL in the US.<br />
<br />
======Blood and lymphatic system disorders:======<br />
[[Agranulocytosis]],[[ aplastic anemia]], [[granulocytopenia]], [[pancytopenia]], [[thrombocytopenia]], [[leukopenia]], <br />
[[bleeding tendency]]<br />
<br />
======Cardiac disorders:======<br />
<br />
[[Torsades de pointes]], [[QT prolongation|QTc prolongation]] (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. [[complete atrioventricular block]], c[[ardiac failure ]]and [[bradyarrythmia]], when treated with cilostazol. Cilostazol was used "off label" due to its positive [[chronotropic]] action)<br />
<br />
======Gastrointestinal disorders:======<br />
<br />
*Gastrointestinal haemorrhage<br />
<br />
======General disorders and administration site conditions:======<br />
<br />
*Pain<br />
*[[chest pain]] <br />
*[[hot flushes]]<br />
<br />
======Hepatobiliary disorders:======<br />
<br />
*Hepatic dysfunction/abnormal liver function tests <br />
*[[jaundice]]<br />
<br />
======Injury, poisoning and procedural complications:======<br />
<br />
*Extradural [[haematoma ]] <br />
*Subdural haematoma<br />
<br />
=====Investigations:=====<br />
<br />
*[[Blood glucose]] increased, blood [[uric acid]] increased, [[platelet count]] decreased, [[white blood cell count]] decreased, increase in [[BUN]] (blood urea increased), blood pressure increase<br />
<br />
======Nervous system disorders:======<br />
<br />
*[[Intracranial haemorrhage]] <br />
*[[cerebral haemorrhage]] <br />
*[[cerebrovascular accident]]<br />
<br />
======Respiratory, thoracic and mediastinal disorders:======<br />
<br />
*Pulmonary haemorrhage<br />
*[[ interstitial pneumonia]]<br />
<br />
'''Skin and subcutaneous tissue disorders:'''<br />
<br />
*Haemorrhage subcutaneous, [[pruritus]], skin eruptions including [[Stevens-Johnson syndrome]], skin drug eruption ([[dermatitis medicamentosa]])<br />
<br />
======Vascular disorders:======<br />
<br />
*Subacute [[thrombosis ]](these cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting)<br />
<br />
==Drug Interactions==<br />
<br />
=====Aspirin=====<br />
<br />
*Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of ADP-induced ex vivo platelet aggregation by 22% to 37% when compared to either aspirin or cilostazol alone. Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to cilostazol alone and by 48% compared to aspirin alone. However, short-term co-administration of aspirin with cilostazol had no clinically significant impact on PT, aPTT or bleeding time compared to aspirin alone. <br />
<br />
*Effects of long-term co-administration in the general population are unknown. In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was co-administered with cilostazol to 201 patients. The most frequent doses and mean durations of aspirin therapy were 75 mg to 81 mg daily for 137 days (107 patients) and 325 mg daily for 54 days (85 patients). There was no apparent increase in incidence of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.<br />
<br />
=====Warfarin=====<br />
<br />
The cytochrome P-450 isoenzymes involved in the metabolism of R-warfarin are CYP3A4, CYP1A2 and CYP2C19 and in the metabolism of S-warfarin, CYP2C9. Cilostazol did not inhibit either the metabolism or the pharmacologic effects (PT, aPTT, bleeding time or platelet aggregation) of R- and S-warfarin after a single 25-mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and cilostazol on the pharmacokinetics and pharmacodynamics of both drugs is unknown.<br />
<br />
=====Clopidogrel=====<br />
<br />
Multiple doses of clopidogrel do not significantly increase steady state plasma concentrations of cilostazol.<br />
<br />
=====Inhibitors of CYP3A4=====<br />
<br />
======Strong Inhibitors of CYP3A4======<br />
<br />
A priming dose of [[ketoconazole ]]400 mg (a strong inhibitor of CYP3A4), was given one day prior to co-administration of single doses of [[ketoconazole ]]400 mg and cilostazol 100 mg. This regimen increased cilostazol Cmax by 94% and AUC by 117%. Other strong inhibitors of CYP3A4, such as [[itraconazole]], [[fluconazole]], [[miconazole]], [[fluvoxamine]], [[fluoxetine]], [[nefazodone ]]and [[sertraline]], would be expected to have a similar effect <br />
<br />
======Moderate Inhibitors of CYP3A4======<br />
<br />
*[[Erythromycin ]]and Other [[Macrolide ]]Antibiotics: [[Erythromycin ]]is a moderately strong inhibitor of CYP3A4. Co-administration of erythromycin 500 mg q 8h with a single dose of cilostazol 100 mg increased cilostazol Cmax by 47% and AUC by 73%. Inhibition of cilostazol metabolism by erythromycin increased the AUC of 4´-trans-hydroxy-cilostazol by 141%. Other macrolide antibiotics (e.g., [[clarithromycin]]), but not all (e.g., [[azithromycin]]), would be expected to have a similar effect.<br />
<br />
*Diltiazem: [[Diltiazem]] 180 mg decreased the clearance of cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC increased ~40%.<br />
<br />
*Grapefruit Juice: [[Grapefruit juice]] increased the Cmax of cilostazol by ~50% , but had no effect on AUC.<br />
=====Inhibitors of CYP2C19=====<br />
<br />
[[Omeprazole]]: Co-administration of omeprazole did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%, probably the result of omeprazole’s potent inhibition of CYP2C19 <br />
<br />
=====Quinidine =====<br />
<br />
Concomitant administration of [[quinidine ]]with a single dose of cilostazol 100 mg did not alter cilostazol pharmacokinetics.<br />
<br />
=====Lovastatin=====<br />
<br />
The concomitant administration of [[lovastatin ]]with cilostazol decreases cilostazol Css, max and AUCT by 15%. There is also a decrease, although nonsignificant, in cilostazol metabolite concentrations. Co-administration of cilostazol with lovastatin increases lovastatin and β–hydroxy lovastatin AUC approximately 70%. This is most likely clinically insignificant.<br />
<br />
==Use in Specific Populations==<br />
<br />
====Pregnancy====<br />
<br />
* '''[[Pregnancy category#United States|Pregnancy Category (FDA)]]: C'''<br />
<br />
* '''[[Pregnancy category#Australia|Pregnancy Category (AUS)]]: {{PAGENAME}} is not included in Australian Drug Evaluation Committee (ADEC) Pregnancy Categories.'''<br />
<br />
In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
<br />
====Labor and Delivery====<br />
<br />
FDA package insert doesn't contain any information regarding "'''Labor and Delivery'''"<br />
<br />
====Nursing Mothers====<br />
<br />
Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
<br />
====Pediatric Use====<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
====Geriatric Use====<br />
Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
====Gender====<br />
<br />
The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range<br />
<br />
====Race====<br />
<br />
(Description)<br />
<br />
====Renal Impairment====<br />
<br />
Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
<br />
====Hepatic Impairment====<br />
<br />
Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
<br />
====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the exposure in humans at the MRHD.<br />
<br />
====Immunocompromised Patients====<br />
<br />
(Description)<br />
<br />
====Miscellaneous====<br />
<br />
=====Smokers=====<br />
Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
<br />
==Administration and Monitoring==<br />
<br />
====Administration====<br />
<br />
Oral<br />
<br />
====Monitoring====<br />
FDA package insert does't contain any information regarding "'''Monitoring'''"<br />
<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability).<br />
<br />
==IV Compatibility==<br />
<br />
FDA package insert doesn't contain any information regarding '''IV Compatibility'''<br />
<br />
==Overdosage==<br />
<br />
===Acute Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
<br />
====Management====<br />
<br />
FDA package insert doesn't contain any information regarding "'''Management '''"<br />
<br />
==Pharmacology==<br />
<br />
{{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
<br />
===Mechanism of Action===<br />
<br />
The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
<br />
===Structure===<br />
<br />
*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
<br />
<br />
===Pharmacodynamics===<br />
<br />
(Description)<br />
<br />
===Pharmacokinetics===<br />
<br />
Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
<br />
====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4‑dehydro‑cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4‑dehydro‑cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
<br />
===Nonclinical Toxicology===<br />
<br />
==Clinical Studies==<br />
<br />
*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
<br />
{|<br />
| [[image:Cilo2.png|400px|thumb]]<br />
|}<br />
<br />
<br />
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
<br />
==How Supplied==<br />
<br />
'''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
<br />
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0223-60 bottles of 60 and 0185-0223-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
==Images==<br />
<br />
===Drug Images===<br />
<br />
{|<br />
| [[File:Cilostazol50mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 50 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;123 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
{|<br />
| [[File:Cilostazol100mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 100 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;223 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
===Package and Label Display Panel===<br />
<br />
Sandoz Inc.<br />
Princeton, NJ 08540<br />
OS8128<br />
Rev. 02/13<br />
MF0223REV02/13<br />
Cilostazol 100mg Tablet<br />
<br />
{|<br />
| [[image:Cilostazollabel.jpg|400px|thumb]]<br />
|}<br />
<br />
{|<br />
| [[image:Cilostazollabel1.png|400px|thumb]]<br />
|}<br />
<br />
==Patient Information==<br />
<br />
===Patient Information from FDA===<br />
(sil-OS-tah-zol)<br />
<br />
Please read this leaflet before you start taking cilostazol tablets and each time you renew it in case anything has changed. This leaflet does not replace careful discussions with your doctor. You and your doctor should discuss cilostazol when you start taking it and at regular check-ups. You should follow your doctor’s advice about when to have check-ups.<br />
What is cilostazol for?<br />
Cilostazol may improve the symptoms of patients with a medical condition called intermittent claudication.<br />
What is intermittent claudication?<br />
Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. It occurs because narrowing or blockage of the arteries decreases blood flow to the legs. The decreased blood flow does not supply enough oxygen to the leg muscles during walking, resulting in these painful leg cramps.<br />
<br />
'''What treatments are available for intermittent claudication?'''<br />
<br />
The three main treatments available for intermittent claudication are:<br />
*Exercise. Your doctor may advise an exercise program.<br />
*Medication. Your doctor may prescribe a medication such as cilostazol. (See Who should not take cilostazol tablets?)<br />
*Surgery. Your doctor may recommend a surgical procedure to bypass the blocked segment of the artery. Another procedure is called a percutaneous transluminal angioplasty. In this procedure, a catheter (a flexible tube) is inserted into the artery to reduce the blockage and improve blood flow.<br />
<br />
'''How does cilostazol work?'''<br />
<br />
*The exact way that many drugs work is not well understood. Although how cilostazol works is not completely clear, its main effects are to dilate (widen) the arteries supplying blood to the legs and to decrease the ability of platelets in the blood to stick together. Platelets are particles that circulate in the blood and play a role in clotting.<br />
*Cilostazol may reduce the leg pain that patients with intermittent claudication experience, allowing them to walk farther before their leg pain occurs.<br />
*Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks. If you have not noticed any benefit from cilostazol tablets after 12 weeks you and your doctor may wish to discuss other forms of treatment.<br />
*Sometimes blood vessel disease of the legs causes pain at rest or breakdown of skin in the leg. Cilostazol has not been shown to work in patients with these problems.<br />
<br />
'''Who should not take cilostazol tablets?'''<br />
<br />
*Patients who have congestive heart failure (CHF) must not take cilostazol tablets. The most common symptoms of CHF are shortness of breath and swelling of the legs. However, other conditions may also cause these symptoms. It is important that you discuss with your doctor whether you have CHF.<br />
*Over 1,300 patients took cilostazol in studies that lasted for 3 to 6 months. The mortality rate in these patients was similar to placebo (less than 1%). These studies were too small to be sure there is not some increased risk of dying with longer use or in patients sicker than those in the studies.<br />
<br />
'''How should cilostazol tablets be taken?'''<br />
<br />
*Follow your doctor’s advice about how to take cilostazol tablets.<br />
*You should take cilostazol tablets twice a day, at least one half-hour before or two hours after breakfast and dinner. Take cilostazol tablets at about the same times each day.<br />
*Do not share cilostazol tablets with anyone else. It was prescribed only for you.<br />
*Keep cilostazol tablets and all drugs out of the reach of children.<br />
<br />
'''Can cilostazol tablets be taken with other drugs?'''<br />
<br />
Certain drugs and foods can increase the amount of cilostazol in the blood. Because of this, your doctor may adjust your dose of cilostazol or even stop it if you are taking or are going to take one of the following medications.<br />
Drugs Interacting with Cilostazol<br />
Generic Name (Brand Names)Type of Drug<br />
[[erythromycin]] (such as E.E.S.®, Erythrocin®) Antibiotic<br />
[[ketoconazole]] (Nizoral®), [[itraconazole]] (Sporanox®) Antifungal<br />
[[diltiazem]] (Cardizem®) Antihypertensive<br />
[[omeprazole]] (Prilosec®) Gastric acid reducer<br />
This list does not include every drug that may interact with cilostazol tablets. Therefore, you should tell your doctor about all medications that you are taking, including vitamins, herbal supplements and over-the-counter drugs you can buy without a prescription. You should also check with your doctor before taking a new medication after you have begun cilostazol tablets.<br />
<br />
'''What are the possible side effects of cilostazol tablets?'''<br />
<br />
Cilostazol tablets may cause side effects including headache, diarrhea, abnormal stools, increased heart rate and palpitations.<br />
You should discuss possible side effects with your doctor before taking cilostazol tablets and any time you think you are having a side effect.<br />
This provides only a summary of information about cilostazol tablets. If you have any questions about cilostazol tablets, talk to your doctor.<br />
'''Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.'''<br />
<br />
===Patient Information from NLM===<br />
<br />
For patient information about Cilostazol from NLM, click [[Cilostazol (patient information)|here]].<br />
<br />
==Precautions with Alcohol==<br />
<br />
Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
<br />
==Brand Names==<br />
<br />
Cilostazol®, Platel®.<br />
<br />
==Look-Alike Drug Names==<br />
<br />
* (Paired Confused Name 1a) — (Paired Confused Name 1b)<br />
* (Paired Confused Name 2a) — (Paired Confused Name 2b)<br />
* (Paired Confused Name 3a) — (Paired Confused Name 3b)<br />
<br />
==[http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm Drug Shortage Status]==<br />
<br />
==[http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price Price]==<br />
<br />
==References==<br />
<br />
{{reflist}}<br />
<br />
</div></div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=Cilostazol&diff=961877Cilostazol2014-04-02T17:53:37Z<p>Abdurahman Khalil: /* Aspirin */</p>
<hr />
<div>{|class="infobox" style="position: fixed; top: 180px; right: 20px; margin: 0 0 0 0; border: 0; float: right; width: 15%; background: #104E8B; border-radius: 10px 10px 10px 10px;" cellpadding="0" cellspacing="0";<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #104E8B;" | [[{{PAGENAME}}|{{fontcolor|#F8F8FF|{{PAGENAME}}®}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #000000; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|Black Box Warning}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adult Indications and Dosage|{{fontcolor|#F8F8FF|Adult Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pediatric Indications and Dosage|{{fontcolor|#F8F8FF|Pediatric Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Contraindications|{{fontcolor|#F8F8FF|Contraindications}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Warnings|{{fontcolor|#F8F8FF|Warnings}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adverse Reactions|{{fontcolor|#F8F8FF|Adverse Reactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Drug Interactions|{{fontcolor|#F8F8FF|Drug Interactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Use in Specific Populations|{{fontcolor|#F8F8FF|Use in Specific Populations}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Administration and Monitoring|{{fontcolor|#F8F8FF|Administration and Monitoring}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#IV Compatibility|{{fontcolor|#F8F8FF|IV Compatibility}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Overdosage|{{fontcolor|#F8F8FF|Overdosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pharmacology|{{fontcolor|#F8F8FF|Pharmacology}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Clinical Studies|{{fontcolor|#F8F8FF|Clinical Studies}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#How Supplied|{{fontcolor|#F8F8FF|How Supplied}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Images|{{fontcolor|#F8F8FF|Images}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Patient Information|{{fontcolor|#F8F8FF|Patient information}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Precautions with Alcohol|{{fontcolor|#F8F8FF|Precautions with Alcohol}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Brand Names|{{fontcolor|#F8F8FF|Brand Names}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Look-Alike Drug Names|{{fontcolor|#F8F8FF|Look-Alike Drug Names}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm {{fontcolor|#F8F8FF|Drug Shortage Status}}]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price {{fontcolor|#F8F8FF|Price}}]<br />
|-<br />
|}<br />
<div style="width: 80%"><br />
__NOTOC__<br />
{{CMG}}<br />
<br />
{{SB}} Cilostazol®, Pletal®<br />
<br />
==Disclaimer==<br />
<br />
'''''WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature. The information provided is not a medical advice or treatment. WikiDoc does not promote any medication or off-label use of drugs. Please read our full disclaimer [[wikidoc:General_disclaimer|{{fontcolor|#FF0000|here}}]].'''''<br />
<br />
==<span style="color:#FF0000; background:#000000;">Black Box Warning</span>==<br />
<br />
FDA Package Insert for {{PAGENAME}} contains no information regarding ''Black Box Warning''.<br />
<br />
{| style="border: 3px solid #696969;"<br />
| style="background: #000000; border: 0px; padding: 20px 20px; width: 800px;" |<br />
<center><br />
<font color="#F8F8FF" style="font-weight: bold;">CONTRAINDICATION</font><br />
</center><br />
<br />
<center><br />
<font color="#F8F8FF" size="1" style="font-style: italic;">See full prescribing information for complete boxed warning.</font><br />
</center><br />
<br />
<font color="#F8F8FF" style="font-weight: bold;"><br />
''{{fontcolor|#FF0000|Condition Name:}}'' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
</font><br />
|}<br />
<br />
==Overview==<br />
<br />
{{PAGENAME}} is a_Phosphodiesterase 3 Inhibitor drug that is FDA approved for the treatment of intermittent claudication. There is a Black Box Warning for this drug as shown <span style="background:#000000;">'''[[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|here}}]]'''</span>. Common adverse reactions include headache, dizziness, palpitation, diarrhea, rhinitis and pharyngitis.<br />
<br />
==Adult Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Adult)===<br />
<br />
=====Intermittent claudication=====<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
===Off-Label Use and Dosage (Adult)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* There is limited information about ''Off-Label Non–Guideline-Supported Use'' of {{PAGENAME}} in adult patients.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Pediatric Indications and Dosage==<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
==Contraindications==<br />
* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
<br />
==Warnings==<br />
<br />
=====Hematologic Adverse Reactions=====<br />
Rare cases have been reported of [[thrombocytopenia ]]or [[leukopenia ]]progressing to [[agranulocytosis ]]when cilostazol was not immediately discontinued. The agranulocytosis, however, was reversible on discontinuation of cilostazol.<br />
<br />
=====Use with Clopidogrel=====<br />
There is limited information with respect to the efficacy or safety of the concurrent use of cilostazol and [[clopidogrel]], a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Although it cannot be determined whether there was an additive effect on bleeding times during concomitant administration with cilostazol and [[clopidogrel]], caution is advised for checking bleeding times during co-administration.<br />
<br />
==Adverse Reactions==<br />
<br />
===Clinical Trials Experience===<br />
Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol and 134 days for patients on placebo.<br />
<br />
The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with PLETAL 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included [[palpitation ]]and [[diarrhea]], both 1.1% for cilostazol (all doses) versus 0.1% for placebo.<br />
<br />
======Body as a Whole======<br />
*Common:<br />
:*Abdominal pain<br />
:*Back pain<br />
:*Headache <br />
:*Infection<br />
<br />
*Less common:<br />
[[Chills]], face [[edema]], [[fever]], [[generalized edema]], [[malaise]], [[neck rigidity]], [[pelvic pain]], [[retroperitoneal haemorrhage]].<br />
<br />
======Central Nervous System======<br />
<br />
*Common:<br />
:*Dizziness<br />
:*Vertigo<br />
<br />
*Less common:<br />
[[Anxiety]], [[insomnia]], [[neuralgia]].<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
*Common:<br />
:*Abnormal stool<br />
:*Diarrhea<br />
:*Dyspepsia<br />
:*Flatulence<br />
:*Nausea<br />
<br />
*Less common:<br />
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Metabolic & Nutritional======<br />
*Common:<br />
:*Peripheral edema<br />
<br />
*Less common:<br />
Increased [[creatinine]], [[gout]], [[hyperlipemia]], [[hyperuricemia]].<br />
<br />
======Musculoskeletal======<br />
<br />
*Common:<br />
:*Myalgia<br />
<br />
*Less common:<br />
[[Arthralgia]], bone pain, [[bursitis]].<br />
<br />
======Miscellaneous======<br />
Less common adverse reactions:<br />
<br />
*'''Endocrine:''' [[Diabetes mellitus]].<br />
<br />
*'''Hemic and Lymphatic:''' [[Anemia]], [[ecchymosis]],[[ iron deficiency anemia]], [[polycythemia]], [[purpura]].<br />
<br />
*'''Skin and Appendages:''' Dry skin, [[furunculosis]], skin hypertrophy, [[urticaria]].<br />
<br />
*'''Special Senses:''' [[Amblyopia]], [[blindness]], [[conjunctivitis]], [[diplopia]], ear pain, eye haemorrhage, [[retinal haemorrhage]], [[tinnitus]].<br />
<br />
*'''Urogenital:''' [[Albuminuria]], [[cystitis]], [[urinary frequency]], vaginal haemorrhage, vaginitis.<br />
<br />
===Postmarketing Experience===<br />
<br />
The following events have been reported spontaneously from worldwide post-marketing experience since the launch of PLETAL in the US.<br />
<br />
======Blood and lymphatic system disorders:======<br />
[[Agranulocytosis]],[[ aplastic anemia]], [[granulocytopenia]], [[pancytopenia]], [[thrombocytopenia]], [[leukopenia]], <br />
[[bleeding tendency]]<br />
<br />
======Cardiac disorders:======<br />
<br />
[[Torsades de pointes]], [[QT prolongation|QTc prolongation]] (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. [[complete atrioventricular block]], c[[ardiac failure ]]and [[bradyarrythmia]], when treated with cilostazol. Cilostazol was used "off label" due to its positive [[chronotropic]] action)<br />
<br />
======Gastrointestinal disorders:======<br />
<br />
*Gastrointestinal haemorrhage<br />
<br />
======General disorders and administration site conditions:======<br />
<br />
*Pain<br />
*[[chest pain]] <br />
*[[hot flushes]]<br />
<br />
======Hepatobiliary disorders:======<br />
<br />
*Hepatic dysfunction/abnormal liver function tests <br />
*[[jaundice]]<br />
<br />
======Injury, poisoning and procedural complications:======<br />
<br />
*Extradural [[haematoma ]] <br />
*Subdural haematoma<br />
<br />
=====Investigations:=====<br />
<br />
*[[Blood glucose]] increased, blood [[uric acid]] increased, [[platelet count]] decreased, [[white blood cell count]] decreased, increase in [[BUN]] (blood urea increased), blood pressure increase<br />
<br />
======Nervous system disorders:======<br />
<br />
*[[Intracranial haemorrhage]] <br />
*[[cerebral haemorrhage]] <br />
*[[cerebrovascular accident]]<br />
<br />
======Respiratory, thoracic and mediastinal disorders:======<br />
<br />
*Pulmonary haemorrhage<br />
*[[ interstitial pneumonia]]<br />
<br />
'''Skin and subcutaneous tissue disorders:'''<br />
<br />
*Haemorrhage subcutaneous, [[pruritus]], skin eruptions including [[Stevens-Johnson syndrome]], skin drug eruption ([[dermatitis medicamentosa]])<br />
<br />
======Vascular disorders:======<br />
<br />
*Subacute [[thrombosis ]](these cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting)<br />
<br />
==Drug Interactions==<br />
<br />
=====Aspirin=====<br />
<br />
*Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of ADP-induced ex vivo platelet aggregation by 22% to 37% when compared to either aspirin or cilostazol alone. Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to cilostazol alone and by 48% compared to aspirin alone. However, short-term co-administration of aspirin with cilostazol had no clinically significant impact on PT, aPTT or bleeding time compared to aspirin alone. <br />
<br />
*Effects of long-term co-administration in the general population are unknown. In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was co-administered with cilostazol to 201 patients. The most frequent doses and mean durations of aspirin therapy were 75 mg to 81 mg daily for 137 days (107 patients) and 325 mg daily for 54 days (85 patients). There was no apparent increase in incidence of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.<br />
<br />
=====Warfarin=====<br />
<br />
The cytochrome P-450 isoenzymes involved in the metabolism of R-warfarin are CYP3A4, CYP1A2 and CYP2C19 and in the metabolism of S-warfarin, CYP2C9. Cilostazol did not inhibit either the metabolism or the pharmacologic effects (PT, aPTT, bleeding time or platelet aggregation) of R- and S-warfarin after a single 25-mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and cilostazol on the pharmacokinetics and pharmacodynamics of both drugs is unknown.<br />
<br />
=====Clopidogrel=====<br />
<br />
Multiple doses of clopidogrel do not significantly increase steady state plasma concentrations of cilostazol.<br />
<br />
=====Inhibitors of CYP3A4=====<br />
<br />
======Strong Inhibitors of CYP3A4======<br />
<br />
A priming dose of [[ketoconazole ]]400 mg (a strong inhibitor of CYP3A4), was given one day prior to co-administration of single doses of [[ketoconazole ]]400 mg and cilostazol 100 mg. This regimen increased cilostazol Cmax by 94% and AUC by 117%. Other strong inhibitors of CYP3A4, such as [[itraconazole]], [[fluconazole]], [[miconazole]], [[fluvoxamine]], [[fluoxetine]], [[nefazodone ]]and [[sertraline]], would be expected to have a similar effect <br />
<br />
======Moderate Inhibitors of CYP3A4======<br />
<br />
*[[Erythromycin ]]and Other [[Macrolide ]]Antibiotics: [[Erythromycin ]]is a moderately strong inhibitor of CYP3A4. Co-administration of erythromycin 500 mg q 8h with a single dose of cilostazol 100 mg increased cilostazol Cmax by 47% and AUC by 73%. Inhibition of cilostazol metabolism by erythromycin increased the AUC of 4´-trans-hydroxy-cilostazol by 141%. Other macrolide antibiotics (e.g., [[clarithromycin]]), but not all (e.g., [[azithromycin]]), would be expected to have a similar effect.<br />
<br />
*Diltiazem: [[Diltiazem]] 180 mg decreased the clearance of cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC increased ~40%.<br />
<br />
*Grapefruit Juice: [[Grapefruit juice]] increased the Cmax of cilostazol by ~50% , but had no effect on AUC.<br />
=====Inhibitors of CYP2C19=====<br />
<br />
[[Omeprazole]]: Co-administration of omeprazole did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%, probably the result of omeprazole’s potent inhibition of CYP2C19 <br />
<br />
=====Quinidine =====<br />
<br />
Concomitant administration of [[quinidine ]]with a single dose of cilostazol 100 mg did not alter cilostazol pharmacokinetics.<br />
<br />
=====Lovastatin=====<br />
<br />
The concomitant administration of [[lovastatin ]]with cilostazol decreases cilostazol Css, max and AUCT by 15%. There is also a decrease, although nonsignificant, in cilostazol metabolite concentrations. Co-administration of cilostazol with lovastatin increases lovastatin and β–hydroxy lovastatin AUC approximately 70%. This is most likely clinically insignificant.<br />
<br />
==Use in Specific Populations==<br />
<br />
====Pregnancy====<br />
<br />
* '''[[Pregnancy category#United States|Pregnancy Category (FDA)]]: C'''<br />
<br />
* '''[[Pregnancy category#Australia|Pregnancy Category (AUS)]]: {{PAGENAME}} is not included in Australian Drug Evaluation Committee (ADEC) Pregnancy Categories.'''<br />
<br />
In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
<br />
====Labor and Delivery====<br />
<br />
FDA package insert doesn't contain any information regarding "'''Labor and Delivery'''"<br />
<br />
====Nursing Mothers====<br />
<br />
Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
<br />
====Pediatric Use====<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
====Geriatric Use====<br />
Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
====Gender====<br />
<br />
The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range<br />
<br />
====Race====<br />
<br />
(Description)<br />
<br />
====Renal Impairment====<br />
<br />
Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
<br />
====Hepatic Impairment====<br />
<br />
Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
<br />
====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the exposure in humans at the MRHD.<br />
<br />
====Immunocompromised Patients====<br />
<br />
(Description)<br />
<br />
====Miscellaneous====<br />
<br />
=====Smokers=====<br />
Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
<br />
==Administration and Monitoring==<br />
<br />
====Administration====<br />
<br />
Oral<br />
<br />
====Monitoring====<br />
FDA package insert does't contain any information regarding "'''Monitoring'''"<br />
<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability).<br />
<br />
==IV Compatibility==<br />
<br />
FDA package insert doesn't contain any information regarding '''IV Compatibility'''<br />
<br />
==Overdosage==<br />
<br />
===Acute Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
<br />
====Management====<br />
<br />
FDA package insert doesn't contain any information regarding "'''Management '''"<br />
<br />
==Pharmacology==<br />
<br />
{{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
<br />
===Mechanism of Action===<br />
<br />
The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
<br />
===Structure===<br />
<br />
*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
<br />
<br />
===Pharmacodynamics===<br />
<br />
(Description)<br />
<br />
===Pharmacokinetics===<br />
<br />
Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
<br />
====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4‑dehydro‑cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4‑dehydro‑cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
<br />
===Nonclinical Toxicology===<br />
<br />
==Clinical Studies==<br />
<br />
*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
<br />
{|<br />
| [[image:Cilo2.png|400px|thumb]]<br />
|}<br />
<br />
<br />
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
<br />
==How Supplied==<br />
<br />
'''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
<br />
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0223-60 bottles of 60 and 0185-0223-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
==Images==<br />
<br />
===Drug Images===<br />
<br />
{|<br />
| [[File:Cilostazol50mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 50 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;123 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
{|<br />
| [[File:Cilostazol100mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 100 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;223 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
===Package and Label Display Panel===<br />
<br />
Sandoz Inc.<br />
Princeton, NJ 08540<br />
OS8128<br />
Rev. 02/13<br />
MF0223REV02/13<br />
Cilostazol 100mg Tablet<br />
<br />
{|<br />
| [[image:Cilostazollabel.jpg|400px|thumb]]<br />
|}<br />
<br />
{|<br />
| [[image:Cilostazollabel1.png|400px|thumb]]<br />
|}<br />
<br />
==Patient Information==<br />
<br />
===Patient Information from FDA===<br />
(sil-OS-tah-zol)<br />
<br />
Please read this leaflet before you start taking cilostazol tablets and each time you renew it in case anything has changed. This leaflet does not replace careful discussions with your doctor. You and your doctor should discuss cilostazol when you start taking it and at regular check-ups. You should follow your doctor’s advice about when to have check-ups.<br />
What is cilostazol for?<br />
Cilostazol may improve the symptoms of patients with a medical condition called intermittent claudication.<br />
What is intermittent claudication?<br />
Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. It occurs because narrowing or blockage of the arteries decreases blood flow to the legs. The decreased blood flow does not supply enough oxygen to the leg muscles during walking, resulting in these painful leg cramps.<br />
<br />
'''What treatments are available for intermittent claudication?'''<br />
<br />
The three main treatments available for intermittent claudication are:<br />
*Exercise. Your doctor may advise an exercise program.<br />
*Medication. Your doctor may prescribe a medication such as cilostazol. (See Who should not take cilostazol tablets?)<br />
*Surgery. Your doctor may recommend a surgical procedure to bypass the blocked segment of the artery. Another procedure is called a percutaneous transluminal angioplasty. In this procedure, a catheter (a flexible tube) is inserted into the artery to reduce the blockage and improve blood flow.<br />
<br />
'''How does cilostazol work?'''<br />
<br />
*The exact way that many drugs work is not well understood. Although how cilostazol works is not completely clear, its main effects are to dilate (widen) the arteries supplying blood to the legs and to decrease the ability of platelets in the blood to stick together. Platelets are particles that circulate in the blood and play a role in clotting.<br />
*Cilostazol may reduce the leg pain that patients with intermittent claudication experience, allowing them to walk farther before their leg pain occurs.<br />
*Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks. If you have not noticed any benefit from cilostazol tablets after 12 weeks you and your doctor may wish to discuss other forms of treatment.<br />
*Sometimes blood vessel disease of the legs causes pain at rest or breakdown of skin in the leg. Cilostazol has not been shown to work in patients with these problems.<br />
<br />
'''Who should not take cilostazol tablets?'''<br />
<br />
*Patients who have congestive heart failure (CHF) must not take cilostazol tablets. The most common symptoms of CHF are shortness of breath and swelling of the legs. However, other conditions may also cause these symptoms. It is important that you discuss with your doctor whether you have CHF.<br />
*Over 1,300 patients took cilostazol in studies that lasted for 3 to 6 months. The mortality rate in these patients was similar to placebo (less than 1%). These studies were too small to be sure there is not some increased risk of dying with longer use or in patients sicker than those in the studies.<br />
<br />
'''How should cilostazol tablets be taken?'''<br />
<br />
*Follow your doctor’s advice about how to take cilostazol tablets.<br />
*You should take cilostazol tablets twice a day, at least one half-hour before or two hours after breakfast and dinner. Take cilostazol tablets at about the same times each day.<br />
*Do not share cilostazol tablets with anyone else. It was prescribed only for you.<br />
*Keep cilostazol tablets and all drugs out of the reach of children.<br />
<br />
'''Can cilostazol tablets be taken with other drugs?'''<br />
<br />
Certain drugs and foods can increase the amount of cilostazol in the blood. Because of this, your doctor may adjust your dose of cilostazol or even stop it if you are taking or are going to take one of the following medications.<br />
Drugs Interacting with Cilostazol<br />
Generic Name (Brand Names)Type of Drug<br />
[[erythromycin]] (such as E.E.S.®, Erythrocin®) Antibiotic<br />
[[ketoconazole]] (Nizoral®), [[itraconazole]] (Sporanox®) Antifungal<br />
[[diltiazem]] (Cardizem®) Antihypertensive<br />
[[omeprazole]] (Prilosec®) Gastric acid reducer<br />
This list does not include every drug that may interact with cilostazol tablets. Therefore, you should tell your doctor about all medications that you are taking, including vitamins, herbal supplements and over-the-counter drugs you can buy without a prescription. You should also check with your doctor before taking a new medication after you have begun cilostazol tablets.<br />
<br />
'''What are the possible side effects of cilostazol tablets?'''<br />
<br />
Cilostazol tablets may cause side effects including headache, diarrhea, abnormal stools, increased heart rate and palpitations.<br />
You should discuss possible side effects with your doctor before taking cilostazol tablets and any time you think you are having a side effect.<br />
This provides only a summary of information about cilostazol tablets. If you have any questions about cilostazol tablets, talk to your doctor.<br />
'''Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.'''<br />
<br />
===Patient Information from NLM===<br />
<br />
For patient information about Cilostazol from NLM, click [[Cilostazol (patient information)|here]].<br />
<br />
==Precautions with Alcohol==<br />
<br />
Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
<br />
==Brand Names==<br />
<br />
Cilostazol®, Platel®.<br />
<br />
==Look-Alike Drug Names==<br />
<br />
* (Paired Confused Name 1a) — (Paired Confused Name 1b)<br />
* (Paired Confused Name 2a) — (Paired Confused Name 2b)<br />
* (Paired Confused Name 3a) — (Paired Confused Name 3b)<br />
<br />
==[http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm Drug Shortage Status]==<br />
<br />
==[http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price Price]==<br />
<br />
==References==<br />
<br />
{{reflist}}<br />
<br />
</div></div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=Cilostazol&diff=961875Cilostazol2014-04-02T17:52:57Z<p>Abdurahman Khalil: /* Chronic Overdose */</p>
<hr />
<div>{|class="infobox" style="position: fixed; top: 180px; right: 20px; margin: 0 0 0 0; border: 0; float: right; width: 15%; background: #104E8B; border-radius: 10px 10px 10px 10px;" cellpadding="0" cellspacing="0";<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #104E8B;" | [[{{PAGENAME}}|{{fontcolor|#F8F8FF|{{PAGENAME}}®}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #000000; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|Black Box Warning}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adult Indications and Dosage|{{fontcolor|#F8F8FF|Adult Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pediatric Indications and Dosage|{{fontcolor|#F8F8FF|Pediatric Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Contraindications|{{fontcolor|#F8F8FF|Contraindications}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Warnings|{{fontcolor|#F8F8FF|Warnings}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adverse Reactions|{{fontcolor|#F8F8FF|Adverse Reactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Drug Interactions|{{fontcolor|#F8F8FF|Drug Interactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Use in Specific Populations|{{fontcolor|#F8F8FF|Use in Specific Populations}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Administration and Monitoring|{{fontcolor|#F8F8FF|Administration and Monitoring}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#IV Compatibility|{{fontcolor|#F8F8FF|IV Compatibility}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Overdosage|{{fontcolor|#F8F8FF|Overdosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pharmacology|{{fontcolor|#F8F8FF|Pharmacology}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Clinical Studies|{{fontcolor|#F8F8FF|Clinical Studies}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#How Supplied|{{fontcolor|#F8F8FF|How Supplied}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Images|{{fontcolor|#F8F8FF|Images}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Patient Information|{{fontcolor|#F8F8FF|Patient information}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Precautions with Alcohol|{{fontcolor|#F8F8FF|Precautions with Alcohol}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Brand Names|{{fontcolor|#F8F8FF|Brand Names}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Look-Alike Drug Names|{{fontcolor|#F8F8FF|Look-Alike Drug Names}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm {{fontcolor|#F8F8FF|Drug Shortage Status}}]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price {{fontcolor|#F8F8FF|Price}}]<br />
|-<br />
|}<br />
<div style="width: 80%"><br />
__NOTOC__<br />
{{CMG}}<br />
<br />
{{SB}} Cilostazol®, Pletal®<br />
<br />
==Disclaimer==<br />
<br />
'''''WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature. The information provided is not a medical advice or treatment. WikiDoc does not promote any medication or off-label use of drugs. Please read our full disclaimer [[wikidoc:General_disclaimer|{{fontcolor|#FF0000|here}}]].'''''<br />
<br />
==<span style="color:#FF0000; background:#000000;">Black Box Warning</span>==<br />
<br />
FDA Package Insert for {{PAGENAME}} contains no information regarding ''Black Box Warning''.<br />
<br />
{| style="border: 3px solid #696969;"<br />
| style="background: #000000; border: 0px; padding: 20px 20px; width: 800px;" |<br />
<center><br />
<font color="#F8F8FF" style="font-weight: bold;">CONTRAINDICATION</font><br />
</center><br />
<br />
<center><br />
<font color="#F8F8FF" size="1" style="font-style: italic;">See full prescribing information for complete boxed warning.</font><br />
</center><br />
<br />
<font color="#F8F8FF" style="font-weight: bold;"><br />
''{{fontcolor|#FF0000|Condition Name:}}'' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
</font><br />
|}<br />
<br />
==Overview==<br />
<br />
{{PAGENAME}} is a_Phosphodiesterase 3 Inhibitor drug that is FDA approved for the treatment of intermittent claudication. There is a Black Box Warning for this drug as shown <span style="background:#000000;">'''[[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|here}}]]'''</span>. Common adverse reactions include headache, dizziness, palpitation, diarrhea, rhinitis and pharyngitis.<br />
<br />
==Adult Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Adult)===<br />
<br />
=====Intermittent claudication=====<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
===Off-Label Use and Dosage (Adult)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* There is limited information about ''Off-Label Non–Guideline-Supported Use'' of {{PAGENAME}} in adult patients.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Pediatric Indications and Dosage==<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
==Contraindications==<br />
* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
<br />
==Warnings==<br />
<br />
=====Hematologic Adverse Reactions=====<br />
Rare cases have been reported of [[thrombocytopenia ]]or [[leukopenia ]]progressing to [[agranulocytosis ]]when cilostazol was not immediately discontinued. The agranulocytosis, however, was reversible on discontinuation of cilostazol.<br />
<br />
=====Use with Clopidogrel=====<br />
There is limited information with respect to the efficacy or safety of the concurrent use of cilostazol and [[clopidogrel]], a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Although it cannot be determined whether there was an additive effect on bleeding times during concomitant administration with cilostazol and [[clopidogrel]], caution is advised for checking bleeding times during co-administration.<br />
<br />
==Adverse Reactions==<br />
<br />
===Clinical Trials Experience===<br />
Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol and 134 days for patients on placebo.<br />
<br />
The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with PLETAL 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included [[palpitation ]]and [[diarrhea]], both 1.1% for cilostazol (all doses) versus 0.1% for placebo.<br />
<br />
======Body as a Whole======<br />
*Common:<br />
:*Abdominal pain<br />
:*Back pain<br />
:*Headache <br />
:*Infection<br />
<br />
*Less common:<br />
[[Chills]], face [[edema]], [[fever]], [[generalized edema]], [[malaise]], [[neck rigidity]], [[pelvic pain]], [[retroperitoneal haemorrhage]].<br />
<br />
======Central Nervous System======<br />
<br />
*Common:<br />
:*Dizziness<br />
:*Vertigo<br />
<br />
*Less common:<br />
[[Anxiety]], [[insomnia]], [[neuralgia]].<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
*Common:<br />
:*Abnormal stool<br />
:*Diarrhea<br />
:*Dyspepsia<br />
:*Flatulence<br />
:*Nausea<br />
<br />
*Less common:<br />
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Metabolic & Nutritional======<br />
*Common:<br />
:*Peripheral edema<br />
<br />
*Less common:<br />
Increased [[creatinine]], [[gout]], [[hyperlipemia]], [[hyperuricemia]].<br />
<br />
======Musculoskeletal======<br />
<br />
*Common:<br />
:*Myalgia<br />
<br />
*Less common:<br />
[[Arthralgia]], bone pain, [[bursitis]].<br />
<br />
======Miscellaneous======<br />
Less common adverse reactions:<br />
<br />
*'''Endocrine:''' [[Diabetes mellitus]].<br />
<br />
*'''Hemic and Lymphatic:''' [[Anemia]], [[ecchymosis]],[[ iron deficiency anemia]], [[polycythemia]], [[purpura]].<br />
<br />
*'''Skin and Appendages:''' Dry skin, [[furunculosis]], skin hypertrophy, [[urticaria]].<br />
<br />
*'''Special Senses:''' [[Amblyopia]], [[blindness]], [[conjunctivitis]], [[diplopia]], ear pain, eye haemorrhage, [[retinal haemorrhage]], [[tinnitus]].<br />
<br />
*'''Urogenital:''' [[Albuminuria]], [[cystitis]], [[urinary frequency]], vaginal haemorrhage, vaginitis.<br />
<br />
===Postmarketing Experience===<br />
<br />
The following events have been reported spontaneously from worldwide post-marketing experience since the launch of PLETAL in the US.<br />
<br />
======Blood and lymphatic system disorders:======<br />
[[Agranulocytosis]],[[ aplastic anemia]], [[granulocytopenia]], [[pancytopenia]], [[thrombocytopenia]], [[leukopenia]], <br />
[[bleeding tendency]]<br />
<br />
======Cardiac disorders:======<br />
<br />
[[Torsades de pointes]], [[QT prolongation|QTc prolongation]] (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. [[complete atrioventricular block]], c[[ardiac failure ]]and [[bradyarrythmia]], when treated with cilostazol. Cilostazol was used "off label" due to its positive [[chronotropic]] action)<br />
<br />
======Gastrointestinal disorders:======<br />
<br />
*Gastrointestinal haemorrhage<br />
<br />
======General disorders and administration site conditions:======<br />
<br />
*Pain<br />
*[[chest pain]] <br />
*[[hot flushes]]<br />
<br />
======Hepatobiliary disorders:======<br />
<br />
*Hepatic dysfunction/abnormal liver function tests <br />
*[[jaundice]]<br />
<br />
======Injury, poisoning and procedural complications:======<br />
<br />
*Extradural [[haematoma ]] <br />
*Subdural haematoma<br />
<br />
=====Investigations:=====<br />
<br />
*[[Blood glucose]] increased, blood [[uric acid]] increased, [[platelet count]] decreased, [[white blood cell count]] decreased, increase in [[BUN]] (blood urea increased), blood pressure increase<br />
<br />
======Nervous system disorders:======<br />
<br />
*[[Intracranial haemorrhage]] <br />
*[[cerebral haemorrhage]] <br />
*[[cerebrovascular accident]]<br />
<br />
======Respiratory, thoracic and mediastinal disorders:======<br />
<br />
*Pulmonary haemorrhage<br />
*[[ interstitial pneumonia]]<br />
<br />
'''Skin and subcutaneous tissue disorders:'''<br />
<br />
*Haemorrhage subcutaneous, [[pruritus]], skin eruptions including [[Stevens-Johnson syndrome]], skin drug eruption ([[dermatitis medicamentosa]])<br />
<br />
======Vascular disorders:======<br />
<br />
*Subacute [[thrombosis ]](these cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting)<br />
<br />
==Drug Interactions==<br />
<br />
=====Aspirin=====<br />
<br />
*Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of ADP-induced ex vivo platelet aggregation by 22% to 37% when compared to either aspirin or cilostazol alone. Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to cilostazol alone and by 48% compared to aspirin alone. However, short-term co-administration of aspirin with cilostazol had no clinically significant impact on PT, aPTT or bleeding time compared to aspirin alone. <br />
*Effects of long-term co-administration in the general population are unknown. In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was co-administered with cilostazol to 201 patients. The most frequent doses and mean durations of aspirin therapy were 75 mg to 81 mg daily for 137 days (107 patients) and 325 mg daily for 54 days (85 patients). There was no apparent increase in incidence of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.<br />
(Description)<br />
<br />
=====Warfarin=====<br />
<br />
The cytochrome P-450 isoenzymes involved in the metabolism of R-warfarin are CYP3A4, CYP1A2 and CYP2C19 and in the metabolism of S-warfarin, CYP2C9. Cilostazol did not inhibit either the metabolism or the pharmacologic effects (PT, aPTT, bleeding time or platelet aggregation) of R- and S-warfarin after a single 25-mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and cilostazol on the pharmacokinetics and pharmacodynamics of both drugs is unknown.<br />
<br />
=====Clopidogrel=====<br />
<br />
Multiple doses of clopidogrel do not significantly increase steady state plasma concentrations of cilostazol.<br />
<br />
=====Inhibitors of CYP3A4=====<br />
<br />
======Strong Inhibitors of CYP3A4======<br />
<br />
A priming dose of [[ketoconazole ]]400 mg (a strong inhibitor of CYP3A4), was given one day prior to co-administration of single doses of [[ketoconazole ]]400 mg and cilostazol 100 mg. This regimen increased cilostazol Cmax by 94% and AUC by 117%. Other strong inhibitors of CYP3A4, such as [[itraconazole]], [[fluconazole]], [[miconazole]], [[fluvoxamine]], [[fluoxetine]], [[nefazodone ]]and [[sertraline]], would be expected to have a similar effect <br />
<br />
======Moderate Inhibitors of CYP3A4======<br />
<br />
*[[Erythromycin ]]and Other [[Macrolide ]]Antibiotics: [[Erythromycin ]]is a moderately strong inhibitor of CYP3A4. Co-administration of erythromycin 500 mg q 8h with a single dose of cilostazol 100 mg increased cilostazol Cmax by 47% and AUC by 73%. Inhibition of cilostazol metabolism by erythromycin increased the AUC of 4´-trans-hydroxy-cilostazol by 141%. Other macrolide antibiotics (e.g., [[clarithromycin]]), but not all (e.g., [[azithromycin]]), would be expected to have a similar effect.<br />
<br />
*Diltiazem: [[Diltiazem]] 180 mg decreased the clearance of cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC increased ~40%.<br />
<br />
*Grapefruit Juice: [[Grapefruit juice]] increased the Cmax of cilostazol by ~50% , but had no effect on AUC.<br />
=====Inhibitors of CYP2C19=====<br />
<br />
[[Omeprazole]]: Co-administration of omeprazole did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%, probably the result of omeprazole’s potent inhibition of CYP2C19 <br />
<br />
=====Quinidine =====<br />
<br />
Concomitant administration of [[quinidine ]]with a single dose of cilostazol 100 mg did not alter cilostazol pharmacokinetics.<br />
<br />
=====Lovastatin=====<br />
<br />
The concomitant administration of [[lovastatin ]]with cilostazol decreases cilostazol Css, max and AUCT by 15%. There is also a decrease, although nonsignificant, in cilostazol metabolite concentrations. Co-administration of cilostazol with lovastatin increases lovastatin and β–hydroxy lovastatin AUC approximately 70%. This is most likely clinically insignificant.<br />
<br />
==Use in Specific Populations==<br />
<br />
====Pregnancy====<br />
<br />
* '''[[Pregnancy category#United States|Pregnancy Category (FDA)]]: C'''<br />
<br />
* '''[[Pregnancy category#Australia|Pregnancy Category (AUS)]]: {{PAGENAME}} is not included in Australian Drug Evaluation Committee (ADEC) Pregnancy Categories.'''<br />
<br />
In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
<br />
====Labor and Delivery====<br />
<br />
FDA package insert doesn't contain any information regarding "'''Labor and Delivery'''"<br />
<br />
====Nursing Mothers====<br />
<br />
Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
<br />
====Pediatric Use====<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
====Geriatric Use====<br />
Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
====Gender====<br />
<br />
The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range<br />
<br />
====Race====<br />
<br />
(Description)<br />
<br />
====Renal Impairment====<br />
<br />
Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
<br />
====Hepatic Impairment====<br />
<br />
Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
<br />
====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the exposure in humans at the MRHD.<br />
<br />
====Immunocompromised Patients====<br />
<br />
(Description)<br />
<br />
====Miscellaneous====<br />
<br />
=====Smokers=====<br />
Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
<br />
==Administration and Monitoring==<br />
<br />
====Administration====<br />
<br />
Oral<br />
<br />
====Monitoring====<br />
FDA package insert does't contain any information regarding "'''Monitoring'''"<br />
<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability).<br />
<br />
==IV Compatibility==<br />
<br />
FDA package insert doesn't contain any information regarding '''IV Compatibility'''<br />
<br />
==Overdosage==<br />
<br />
===Acute Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
<br />
====Management====<br />
<br />
FDA package insert doesn't contain any information regarding "'''Management '''"<br />
<br />
==Pharmacology==<br />
<br />
{{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
<br />
===Mechanism of Action===<br />
<br />
The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
<br />
===Structure===<br />
<br />
*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
<br />
<br />
===Pharmacodynamics===<br />
<br />
(Description)<br />
<br />
===Pharmacokinetics===<br />
<br />
Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
<br />
====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4‑dehydro‑cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4‑dehydro‑cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
<br />
===Nonclinical Toxicology===<br />
<br />
==Clinical Studies==<br />
<br />
*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
<br />
{|<br />
| [[image:Cilo2.png|400px|thumb]]<br />
|}<br />
<br />
<br />
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
<br />
==How Supplied==<br />
<br />
'''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
<br />
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0223-60 bottles of 60 and 0185-0223-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
==Images==<br />
<br />
===Drug Images===<br />
<br />
{|<br />
| [[File:Cilostazol50mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 50 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;123 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
{|<br />
| [[File:Cilostazol100mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 100 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;223 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
===Package and Label Display Panel===<br />
<br />
Sandoz Inc.<br />
Princeton, NJ 08540<br />
OS8128<br />
Rev. 02/13<br />
MF0223REV02/13<br />
Cilostazol 100mg Tablet<br />
<br />
{|<br />
| [[image:Cilostazollabel.jpg|400px|thumb]]<br />
|}<br />
<br />
{|<br />
| [[image:Cilostazollabel1.png|400px|thumb]]<br />
|}<br />
<br />
==Patient Information==<br />
<br />
===Patient Information from FDA===<br />
(sil-OS-tah-zol)<br />
<br />
Please read this leaflet before you start taking cilostazol tablets and each time you renew it in case anything has changed. This leaflet does not replace careful discussions with your doctor. You and your doctor should discuss cilostazol when you start taking it and at regular check-ups. You should follow your doctor’s advice about when to have check-ups.<br />
What is cilostazol for?<br />
Cilostazol may improve the symptoms of patients with a medical condition called intermittent claudication.<br />
What is intermittent claudication?<br />
Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. It occurs because narrowing or blockage of the arteries decreases blood flow to the legs. The decreased blood flow does not supply enough oxygen to the leg muscles during walking, resulting in these painful leg cramps.<br />
<br />
'''What treatments are available for intermittent claudication?'''<br />
<br />
The three main treatments available for intermittent claudication are:<br />
*Exercise. Your doctor may advise an exercise program.<br />
*Medication. Your doctor may prescribe a medication such as cilostazol. (See Who should not take cilostazol tablets?)<br />
*Surgery. Your doctor may recommend a surgical procedure to bypass the blocked segment of the artery. Another procedure is called a percutaneous transluminal angioplasty. In this procedure, a catheter (a flexible tube) is inserted into the artery to reduce the blockage and improve blood flow.<br />
<br />
'''How does cilostazol work?'''<br />
<br />
*The exact way that many drugs work is not well understood. Although how cilostazol works is not completely clear, its main effects are to dilate (widen) the arteries supplying blood to the legs and to decrease the ability of platelets in the blood to stick together. Platelets are particles that circulate in the blood and play a role in clotting.<br />
*Cilostazol may reduce the leg pain that patients with intermittent claudication experience, allowing them to walk farther before their leg pain occurs.<br />
*Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks. If you have not noticed any benefit from cilostazol tablets after 12 weeks you and your doctor may wish to discuss other forms of treatment.<br />
*Sometimes blood vessel disease of the legs causes pain at rest or breakdown of skin in the leg. Cilostazol has not been shown to work in patients with these problems.<br />
<br />
'''Who should not take cilostazol tablets?'''<br />
<br />
*Patients who have congestive heart failure (CHF) must not take cilostazol tablets. The most common symptoms of CHF are shortness of breath and swelling of the legs. However, other conditions may also cause these symptoms. It is important that you discuss with your doctor whether you have CHF.<br />
*Over 1,300 patients took cilostazol in studies that lasted for 3 to 6 months. The mortality rate in these patients was similar to placebo (less than 1%). These studies were too small to be sure there is not some increased risk of dying with longer use or in patients sicker than those in the studies.<br />
<br />
'''How should cilostazol tablets be taken?'''<br />
<br />
*Follow your doctor’s advice about how to take cilostazol tablets.<br />
*You should take cilostazol tablets twice a day, at least one half-hour before or two hours after breakfast and dinner. Take cilostazol tablets at about the same times each day.<br />
*Do not share cilostazol tablets with anyone else. It was prescribed only for you.<br />
*Keep cilostazol tablets and all drugs out of the reach of children.<br />
<br />
'''Can cilostazol tablets be taken with other drugs?'''<br />
<br />
Certain drugs and foods can increase the amount of cilostazol in the blood. Because of this, your doctor may adjust your dose of cilostazol or even stop it if you are taking or are going to take one of the following medications.<br />
Drugs Interacting with Cilostazol<br />
Generic Name (Brand Names)Type of Drug<br />
[[erythromycin]] (such as E.E.S.®, Erythrocin®) Antibiotic<br />
[[ketoconazole]] (Nizoral®), [[itraconazole]] (Sporanox®) Antifungal<br />
[[diltiazem]] (Cardizem®) Antihypertensive<br />
[[omeprazole]] (Prilosec®) Gastric acid reducer<br />
This list does not include every drug that may interact with cilostazol tablets. Therefore, you should tell your doctor about all medications that you are taking, including vitamins, herbal supplements and over-the-counter drugs you can buy without a prescription. You should also check with your doctor before taking a new medication after you have begun cilostazol tablets.<br />
<br />
'''What are the possible side effects of cilostazol tablets?'''<br />
<br />
Cilostazol tablets may cause side effects including headache, diarrhea, abnormal stools, increased heart rate and palpitations.<br />
You should discuss possible side effects with your doctor before taking cilostazol tablets and any time you think you are having a side effect.<br />
This provides only a summary of information about cilostazol tablets. If you have any questions about cilostazol tablets, talk to your doctor.<br />
'''Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.'''<br />
<br />
===Patient Information from NLM===<br />
<br />
For patient information about Cilostazol from NLM, click [[Cilostazol (patient information)|here]].<br />
<br />
==Precautions with Alcohol==<br />
<br />
Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
<br />
==Brand Names==<br />
<br />
Cilostazol®, Platel®.<br />
<br />
==Look-Alike Drug Names==<br />
<br />
* (Paired Confused Name 1a) — (Paired Confused Name 1b)<br />
* (Paired Confused Name 2a) — (Paired Confused Name 2b)<br />
* (Paired Confused Name 3a) — (Paired Confused Name 3b)<br />
<br />
==[http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm Drug Shortage Status]==<br />
<br />
==[http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price Price]==<br />
<br />
==References==<br />
<br />
{{reflist}}<br />
<br />
</div></div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=Cilostazol&diff=961871Cilostazol2014-04-02T17:48:02Z<p>Abdurahman Khalil: /* Management */</p>
<hr />
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! style="font-size: 80%; padding: 0 5px; background: #104E8B;" | [[{{PAGENAME}}|{{fontcolor|#F8F8FF|{{PAGENAME}}®}}]]<br />
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adult Indications and Dosage|{{fontcolor|#F8F8FF|Adult Indications and Dosage}}]]<br />
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pediatric Indications and Dosage|{{fontcolor|#F8F8FF|Pediatric Indications and Dosage}}]]<br />
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Contraindications|{{fontcolor|#F8F8FF|Contraindications}}]]<br />
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adverse Reactions|{{fontcolor|#F8F8FF|Adverse Reactions}}]]<br />
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Administration and Monitoring|{{fontcolor|#F8F8FF|Administration and Monitoring}}]]<br />
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__NOTOC__<br />
{{CMG}}<br />
<br />
{{SB}} Cilostazol®, Pletal®<br />
<br />
==Disclaimer==<br />
<br />
'''''WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature. The information provided is not a medical advice or treatment. WikiDoc does not promote any medication or off-label use of drugs. Please read our full disclaimer [[wikidoc:General_disclaimer|{{fontcolor|#FF0000|here}}]].'''''<br />
<br />
==<span style="color:#FF0000; background:#000000;">Black Box Warning</span>==<br />
<br />
FDA Package Insert for {{PAGENAME}} contains no information regarding ''Black Box Warning''.<br />
<br />
{| style="border: 3px solid #696969;"<br />
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<center><br />
<font color="#F8F8FF" style="font-weight: bold;">CONTRAINDICATION</font><br />
</center><br />
<br />
<center><br />
<font color="#F8F8FF" size="1" style="font-style: italic;">See full prescribing information for complete boxed warning.</font><br />
</center><br />
<br />
<font color="#F8F8FF" style="font-weight: bold;"><br />
''{{fontcolor|#FF0000|Condition Name:}}'' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
</font><br />
|}<br />
<br />
==Overview==<br />
<br />
{{PAGENAME}} is a_Phosphodiesterase 3 Inhibitor drug that is FDA approved for the treatment of intermittent claudication. There is a Black Box Warning for this drug as shown <span style="background:#000000;">'''[[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|here}}]]'''</span>. Common adverse reactions include headache, dizziness, palpitation, diarrhea, rhinitis and pharyngitis.<br />
<br />
==Adult Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Adult)===<br />
<br />
=====Intermittent claudication=====<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
===Off-Label Use and Dosage (Adult)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* There is limited information about ''Off-Label Non–Guideline-Supported Use'' of {{PAGENAME}} in adult patients.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Pediatric Indications and Dosage==<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
==Contraindications==<br />
* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
<br />
==Warnings==<br />
<br />
=====Hematologic Adverse Reactions=====<br />
Rare cases have been reported of [[thrombocytopenia ]]or [[leukopenia ]]progressing to [[agranulocytosis ]]when cilostazol was not immediately discontinued. The agranulocytosis, however, was reversible on discontinuation of cilostazol.<br />
<br />
=====Use with Clopidogrel=====<br />
There is limited information with respect to the efficacy or safety of the concurrent use of cilostazol and [[clopidogrel]], a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Although it cannot be determined whether there was an additive effect on bleeding times during concomitant administration with cilostazol and [[clopidogrel]], caution is advised for checking bleeding times during co-administration.<br />
<br />
==Adverse Reactions==<br />
<br />
===Clinical Trials Experience===<br />
Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol and 134 days for patients on placebo.<br />
<br />
The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with PLETAL 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included [[palpitation ]]and [[diarrhea]], both 1.1% for cilostazol (all doses) versus 0.1% for placebo.<br />
<br />
======Body as a Whole======<br />
*Common:<br />
:*Abdominal pain<br />
:*Back pain<br />
:*Headache <br />
:*Infection<br />
<br />
*Less common:<br />
[[Chills]], face [[edema]], [[fever]], [[generalized edema]], [[malaise]], [[neck rigidity]], [[pelvic pain]], [[retroperitoneal haemorrhage]].<br />
<br />
======Central Nervous System======<br />
<br />
*Common:<br />
:*Dizziness<br />
:*Vertigo<br />
<br />
*Less common:<br />
[[Anxiety]], [[insomnia]], [[neuralgia]].<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
*Common:<br />
:*Abnormal stool<br />
:*Diarrhea<br />
:*Dyspepsia<br />
:*Flatulence<br />
:*Nausea<br />
<br />
*Less common:<br />
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Metabolic & Nutritional======<br />
*Common:<br />
:*Peripheral edema<br />
<br />
*Less common:<br />
Increased [[creatinine]], [[gout]], [[hyperlipemia]], [[hyperuricemia]].<br />
<br />
======Musculoskeletal======<br />
<br />
*Common:<br />
:*Myalgia<br />
<br />
*Less common:<br />
[[Arthralgia]], bone pain, [[bursitis]].<br />
<br />
======Miscellaneous======<br />
Less common adverse reactions:<br />
<br />
*'''Endocrine:''' [[Diabetes mellitus]].<br />
<br />
*'''Hemic and Lymphatic:''' [[Anemia]], [[ecchymosis]],[[ iron deficiency anemia]], [[polycythemia]], [[purpura]].<br />
<br />
*'''Skin and Appendages:''' Dry skin, [[furunculosis]], skin hypertrophy, [[urticaria]].<br />
<br />
*'''Special Senses:''' [[Amblyopia]], [[blindness]], [[conjunctivitis]], [[diplopia]], ear pain, eye haemorrhage, [[retinal haemorrhage]], [[tinnitus]].<br />
<br />
*'''Urogenital:''' [[Albuminuria]], [[cystitis]], [[urinary frequency]], vaginal haemorrhage, vaginitis.<br />
<br />
===Postmarketing Experience===<br />
<br />
The following events have been reported spontaneously from worldwide post-marketing experience since the launch of PLETAL in the US.<br />
<br />
======Blood and lymphatic system disorders:======<br />
[[Agranulocytosis]],[[ aplastic anemia]], [[granulocytopenia]], [[pancytopenia]], [[thrombocytopenia]], [[leukopenia]], <br />
[[bleeding tendency]]<br />
<br />
======Cardiac disorders:======<br />
<br />
[[Torsades de pointes]], [[QT prolongation|QTc prolongation]] (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. [[complete atrioventricular block]], c[[ardiac failure ]]and [[bradyarrythmia]], when treated with cilostazol. Cilostazol was used "off label" due to its positive [[chronotropic]] action)<br />
<br />
======Gastrointestinal disorders:======<br />
<br />
*Gastrointestinal haemorrhage<br />
<br />
======General disorders and administration site conditions:======<br />
<br />
*Pain<br />
*[[chest pain]] <br />
*[[hot flushes]]<br />
<br />
======Hepatobiliary disorders:======<br />
<br />
*Hepatic dysfunction/abnormal liver function tests <br />
*[[jaundice]]<br />
<br />
======Injury, poisoning and procedural complications:======<br />
<br />
*Extradural [[haematoma ]] <br />
*Subdural haematoma<br />
<br />
=====Investigations:=====<br />
<br />
*[[Blood glucose]] increased, blood [[uric acid]] increased, [[platelet count]] decreased, [[white blood cell count]] decreased, increase in [[BUN]] (blood urea increased), blood pressure increase<br />
<br />
======Nervous system disorders:======<br />
<br />
*[[Intracranial haemorrhage]] <br />
*[[cerebral haemorrhage]] <br />
*[[cerebrovascular accident]]<br />
<br />
======Respiratory, thoracic and mediastinal disorders:======<br />
<br />
*Pulmonary haemorrhage<br />
*[[ interstitial pneumonia]]<br />
<br />
'''Skin and subcutaneous tissue disorders:'''<br />
<br />
*Haemorrhage subcutaneous, [[pruritus]], skin eruptions including [[Stevens-Johnson syndrome]], skin drug eruption ([[dermatitis medicamentosa]])<br />
<br />
======Vascular disorders:======<br />
<br />
*Subacute [[thrombosis ]](these cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting)<br />
<br />
==Drug Interactions==<br />
<br />
=====Aspirin=====<br />
<br />
*Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of ADP-induced ex vivo platelet aggregation by 22% to 37% when compared to either aspirin or cilostazol alone. Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to cilostazol alone and by 48% compared to aspirin alone. However, short-term co-administration of aspirin with cilostazol had no clinically significant impact on PT, aPTT or bleeding time compared to aspirin alone. <br />
*Effects of long-term co-administration in the general population are unknown. In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was co-administered with cilostazol to 201 patients. The most frequent doses and mean durations of aspirin therapy were 75 mg to 81 mg daily for 137 days (107 patients) and 325 mg daily for 54 days (85 patients). There was no apparent increase in incidence of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.<br />
(Description)<br />
<br />
=====Warfarin=====<br />
<br />
The cytochrome P-450 isoenzymes involved in the metabolism of R-warfarin are CYP3A4, CYP1A2 and CYP2C19 and in the metabolism of S-warfarin, CYP2C9. Cilostazol did not inhibit either the metabolism or the pharmacologic effects (PT, aPTT, bleeding time or platelet aggregation) of R- and S-warfarin after a single 25-mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and cilostazol on the pharmacokinetics and pharmacodynamics of both drugs is unknown.<br />
<br />
=====Clopidogrel=====<br />
<br />
Multiple doses of clopidogrel do not significantly increase steady state plasma concentrations of cilostazol.<br />
<br />
=====Inhibitors of CYP3A4=====<br />
<br />
======Strong Inhibitors of CYP3A4======<br />
<br />
A priming dose of [[ketoconazole ]]400 mg (a strong inhibitor of CYP3A4), was given one day prior to co-administration of single doses of [[ketoconazole ]]400 mg and cilostazol 100 mg. This regimen increased cilostazol Cmax by 94% and AUC by 117%. Other strong inhibitors of CYP3A4, such as [[itraconazole]], [[fluconazole]], [[miconazole]], [[fluvoxamine]], [[fluoxetine]], [[nefazodone ]]and [[sertraline]], would be expected to have a similar effect <br />
<br />
======Moderate Inhibitors of CYP3A4======<br />
<br />
*[[Erythromycin ]]and Other [[Macrolide ]]Antibiotics: [[Erythromycin ]]is a moderately strong inhibitor of CYP3A4. Co-administration of erythromycin 500 mg q 8h with a single dose of cilostazol 100 mg increased cilostazol Cmax by 47% and AUC by 73%. Inhibition of cilostazol metabolism by erythromycin increased the AUC of 4´-trans-hydroxy-cilostazol by 141%. Other macrolide antibiotics (e.g., [[clarithromycin]]), but not all (e.g., [[azithromycin]]), would be expected to have a similar effect.<br />
<br />
*Diltiazem: [[Diltiazem]] 180 mg decreased the clearance of cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC increased ~40%.<br />
<br />
*Grapefruit Juice: [[Grapefruit juice]] increased the Cmax of cilostazol by ~50% , but had no effect on AUC.<br />
=====Inhibitors of CYP2C19=====<br />
<br />
[[Omeprazole]]: Co-administration of omeprazole did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%, probably the result of omeprazole’s potent inhibition of CYP2C19 <br />
<br />
=====Quinidine =====<br />
<br />
Concomitant administration of [[quinidine ]]with a single dose of cilostazol 100 mg did not alter cilostazol pharmacokinetics.<br />
<br />
=====Lovastatin=====<br />
<br />
The concomitant administration of [[lovastatin ]]with cilostazol decreases cilostazol Css, max and AUCT by 15%. There is also a decrease, although nonsignificant, in cilostazol metabolite concentrations. Co-administration of cilostazol with lovastatin increases lovastatin and β–hydroxy lovastatin AUC approximately 70%. This is most likely clinically insignificant.<br />
<br />
==Use in Specific Populations==<br />
<br />
====Pregnancy====<br />
<br />
* '''[[Pregnancy category#United States|Pregnancy Category (FDA)]]: C'''<br />
<br />
* '''[[Pregnancy category#Australia|Pregnancy Category (AUS)]]: {{PAGENAME}} is not included in Australian Drug Evaluation Committee (ADEC) Pregnancy Categories.'''<br />
<br />
In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
<br />
====Labor and Delivery====<br />
<br />
FDA package insert doesn't contain any information regarding "'''Labor and Delivery'''"<br />
<br />
====Nursing Mothers====<br />
<br />
Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
<br />
====Pediatric Use====<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
====Geriatric Use====<br />
Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
====Gender====<br />
<br />
The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range<br />
<br />
====Race====<br />
<br />
(Description)<br />
<br />
====Renal Impairment====<br />
<br />
Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
<br />
====Hepatic Impairment====<br />
<br />
Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
<br />
====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the exposure in humans at the MRHD.<br />
<br />
====Immunocompromised Patients====<br />
<br />
(Description)<br />
<br />
====Miscellaneous====<br />
<br />
=====Smokers=====<br />
Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
<br />
==Administration and Monitoring==<br />
<br />
====Administration====<br />
<br />
Oral<br />
<br />
====Monitoring====<br />
FDA package insert does't contain any information regarding "'''Monitoring'''"<br />
<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability).<br />
<br />
==IV Compatibility==<br />
<br />
FDA package insert doesn't contain any information regarding '''IV Compatibility'''<br />
<br />
==Overdosage==<br />
<br />
===Acute Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
<br />
====Management====<br />
<br />
FDA package insert doesn't contain any information regarding "'''Management '''"<br />
<br />
===Chronic Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
(Description)<br />
<br />
====Management====<br />
<br />
(Description)<br />
<br />
==Pharmacology==<br />
<br />
{{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
<br />
===Mechanism of Action===<br />
<br />
The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
<br />
===Structure===<br />
<br />
*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
<br />
<br />
===Pharmacodynamics===<br />
<br />
(Description)<br />
<br />
===Pharmacokinetics===<br />
<br />
Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
<br />
====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4‑dehydro‑cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4‑dehydro‑cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
<br />
===Nonclinical Toxicology===<br />
<br />
==Clinical Studies==<br />
<br />
*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
<br />
{|<br />
| [[image:Cilo2.png|400px|thumb]]<br />
|}<br />
<br />
<br />
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
<br />
==How Supplied==<br />
<br />
'''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
<br />
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0223-60 bottles of 60 and 0185-0223-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
==Images==<br />
<br />
===Drug Images===<br />
<br />
{|<br />
| [[File:Cilostazol50mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 50 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;123 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
{|<br />
| [[File:Cilostazol100mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 100 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;223 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
===Package and Label Display Panel===<br />
<br />
Sandoz Inc.<br />
Princeton, NJ 08540<br />
OS8128<br />
Rev. 02/13<br />
MF0223REV02/13<br />
Cilostazol 100mg Tablet<br />
<br />
{|<br />
| [[image:Cilostazollabel.jpg|400px|thumb]]<br />
|}<br />
<br />
{|<br />
| [[image:Cilostazollabel1.png|400px|thumb]]<br />
|}<br />
<br />
==Patient Information==<br />
<br />
===Patient Information from FDA===<br />
(sil-OS-tah-zol)<br />
<br />
Please read this leaflet before you start taking cilostazol tablets and each time you renew it in case anything has changed. This leaflet does not replace careful discussions with your doctor. You and your doctor should discuss cilostazol when you start taking it and at regular check-ups. You should follow your doctor’s advice about when to have check-ups.<br />
What is cilostazol for?<br />
Cilostazol may improve the symptoms of patients with a medical condition called intermittent claudication.<br />
What is intermittent claudication?<br />
Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. It occurs because narrowing or blockage of the arteries decreases blood flow to the legs. The decreased blood flow does not supply enough oxygen to the leg muscles during walking, resulting in these painful leg cramps.<br />
<br />
'''What treatments are available for intermittent claudication?'''<br />
<br />
The three main treatments available for intermittent claudication are:<br />
*Exercise. Your doctor may advise an exercise program.<br />
*Medication. Your doctor may prescribe a medication such as cilostazol. (See Who should not take cilostazol tablets?)<br />
*Surgery. Your doctor may recommend a surgical procedure to bypass the blocked segment of the artery. Another procedure is called a percutaneous transluminal angioplasty. In this procedure, a catheter (a flexible tube) is inserted into the artery to reduce the blockage and improve blood flow.<br />
<br />
'''How does cilostazol work?'''<br />
<br />
*The exact way that many drugs work is not well understood. Although how cilostazol works is not completely clear, its main effects are to dilate (widen) the arteries supplying blood to the legs and to decrease the ability of platelets in the blood to stick together. Platelets are particles that circulate in the blood and play a role in clotting.<br />
*Cilostazol may reduce the leg pain that patients with intermittent claudication experience, allowing them to walk farther before their leg pain occurs.<br />
*Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks. If you have not noticed any benefit from cilostazol tablets after 12 weeks you and your doctor may wish to discuss other forms of treatment.<br />
*Sometimes blood vessel disease of the legs causes pain at rest or breakdown of skin in the leg. Cilostazol has not been shown to work in patients with these problems.<br />
<br />
'''Who should not take cilostazol tablets?'''<br />
<br />
*Patients who have congestive heart failure (CHF) must not take cilostazol tablets. The most common symptoms of CHF are shortness of breath and swelling of the legs. However, other conditions may also cause these symptoms. It is important that you discuss with your doctor whether you have CHF.<br />
*Over 1,300 patients took cilostazol in studies that lasted for 3 to 6 months. The mortality rate in these patients was similar to placebo (less than 1%). These studies were too small to be sure there is not some increased risk of dying with longer use or in patients sicker than those in the studies.<br />
<br />
'''How should cilostazol tablets be taken?'''<br />
<br />
*Follow your doctor’s advice about how to take cilostazol tablets.<br />
*You should take cilostazol tablets twice a day, at least one half-hour before or two hours after breakfast and dinner. Take cilostazol tablets at about the same times each day.<br />
*Do not share cilostazol tablets with anyone else. It was prescribed only for you.<br />
*Keep cilostazol tablets and all drugs out of the reach of children.<br />
<br />
'''Can cilostazol tablets be taken with other drugs?'''<br />
<br />
Certain drugs and foods can increase the amount of cilostazol in the blood. Because of this, your doctor may adjust your dose of cilostazol or even stop it if you are taking or are going to take one of the following medications.<br />
Drugs Interacting with Cilostazol<br />
Generic Name (Brand Names)Type of Drug<br />
[[erythromycin]] (such as E.E.S.®, Erythrocin®) Antibiotic<br />
[[ketoconazole]] (Nizoral®), [[itraconazole]] (Sporanox®) Antifungal<br />
[[diltiazem]] (Cardizem®) Antihypertensive<br />
[[omeprazole]] (Prilosec®) Gastric acid reducer<br />
This list does not include every drug that may interact with cilostazol tablets. Therefore, you should tell your doctor about all medications that you are taking, including vitamins, herbal supplements and over-the-counter drugs you can buy without a prescription. You should also check with your doctor before taking a new medication after you have begun cilostazol tablets.<br />
<br />
'''What are the possible side effects of cilostazol tablets?'''<br />
<br />
Cilostazol tablets may cause side effects including headache, diarrhea, abnormal stools, increased heart rate and palpitations.<br />
You should discuss possible side effects with your doctor before taking cilostazol tablets and any time you think you are having a side effect.<br />
This provides only a summary of information about cilostazol tablets. If you have any questions about cilostazol tablets, talk to your doctor.<br />
'''Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.'''<br />
<br />
===Patient Information from NLM===<br />
<br />
For patient information about Cilostazol from NLM, click [[Cilostazol (patient information)|here]].<br />
<br />
==Precautions with Alcohol==<br />
<br />
Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
<br />
==Brand Names==<br />
<br />
Cilostazol®, Platel®.<br />
<br />
==Look-Alike Drug Names==<br />
<br />
* (Paired Confused Name 1a) — (Paired Confused Name 1b)<br />
* (Paired Confused Name 2a) — (Paired Confused Name 2b)<br />
* (Paired Confused Name 3a) — (Paired Confused Name 3b)<br />
<br />
==[http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm Drug Shortage Status]==<br />
<br />
==[http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price Price]==<br />
<br />
==References==<br />
<br />
{{reflist}}<br />
<br />
</div></div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=Cilostazol&diff=961870Cilostazol2014-04-02T17:46:43Z<p>Abdurahman Khalil: /* Monitoring */</p>
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! style="font-size: 80%; padding: 0 5px; background: #000000; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|Black Box Warning}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adult Indications and Dosage|{{fontcolor|#F8F8FF|Adult Indications and Dosage}}]]<br />
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|-<br />
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|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Warnings|{{fontcolor|#F8F8FF|Warnings}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adverse Reactions|{{fontcolor|#F8F8FF|Adverse Reactions}}]]<br />
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Use in Specific Populations|{{fontcolor|#F8F8FF|Use in Specific Populations}}]]<br />
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Administration and Monitoring|{{fontcolor|#F8F8FF|Administration and Monitoring}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#IV Compatibility|{{fontcolor|#F8F8FF|IV Compatibility}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Overdosage|{{fontcolor|#F8F8FF|Overdosage}}]]<br />
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Clinical Studies|{{fontcolor|#F8F8FF|Clinical Studies}}]]<br />
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#How Supplied|{{fontcolor|#F8F8FF|How Supplied}}]]<br />
|-<br />
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|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Patient Information|{{fontcolor|#F8F8FF|Patient information}}]]<br />
|-<br />
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<div style="width: 80%"><br />
__NOTOC__<br />
{{CMG}}<br />
<br />
{{SB}} Cilostazol®, Pletal®<br />
<br />
==Disclaimer==<br />
<br />
'''''WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature. The information provided is not a medical advice or treatment. WikiDoc does not promote any medication or off-label use of drugs. Please read our full disclaimer [[wikidoc:General_disclaimer|{{fontcolor|#FF0000|here}}]].'''''<br />
<br />
==<span style="color:#FF0000; background:#000000;">Black Box Warning</span>==<br />
<br />
FDA Package Insert for {{PAGENAME}} contains no information regarding ''Black Box Warning''.<br />
<br />
{| style="border: 3px solid #696969;"<br />
| style="background: #000000; border: 0px; padding: 20px 20px; width: 800px;" |<br />
<center><br />
<font color="#F8F8FF" style="font-weight: bold;">CONTRAINDICATION</font><br />
</center><br />
<br />
<center><br />
<font color="#F8F8FF" size="1" style="font-style: italic;">See full prescribing information for complete boxed warning.</font><br />
</center><br />
<br />
<font color="#F8F8FF" style="font-weight: bold;"><br />
''{{fontcolor|#FF0000|Condition Name:}}'' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
</font><br />
|}<br />
<br />
==Overview==<br />
<br />
{{PAGENAME}} is a_Phosphodiesterase 3 Inhibitor drug that is FDA approved for the treatment of intermittent claudication. There is a Black Box Warning for this drug as shown <span style="background:#000000;">'''[[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|here}}]]'''</span>. Common adverse reactions include headache, dizziness, palpitation, diarrhea, rhinitis and pharyngitis.<br />
<br />
==Adult Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Adult)===<br />
<br />
=====Intermittent claudication=====<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
===Off-Label Use and Dosage (Adult)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* There is limited information about ''Off-Label Non–Guideline-Supported Use'' of {{PAGENAME}} in adult patients.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Pediatric Indications and Dosage==<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
==Contraindications==<br />
* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
<br />
==Warnings==<br />
<br />
=====Hematologic Adverse Reactions=====<br />
Rare cases have been reported of [[thrombocytopenia ]]or [[leukopenia ]]progressing to [[agranulocytosis ]]when cilostazol was not immediately discontinued. The agranulocytosis, however, was reversible on discontinuation of cilostazol.<br />
<br />
=====Use with Clopidogrel=====<br />
There is limited information with respect to the efficacy or safety of the concurrent use of cilostazol and [[clopidogrel]], a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Although it cannot be determined whether there was an additive effect on bleeding times during concomitant administration with cilostazol and [[clopidogrel]], caution is advised for checking bleeding times during co-administration.<br />
<br />
==Adverse Reactions==<br />
<br />
===Clinical Trials Experience===<br />
Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol and 134 days for patients on placebo.<br />
<br />
The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with PLETAL 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included [[palpitation ]]and [[diarrhea]], both 1.1% for cilostazol (all doses) versus 0.1% for placebo.<br />
<br />
======Body as a Whole======<br />
*Common:<br />
:*Abdominal pain<br />
:*Back pain<br />
:*Headache <br />
:*Infection<br />
<br />
*Less common:<br />
[[Chills]], face [[edema]], [[fever]], [[generalized edema]], [[malaise]], [[neck rigidity]], [[pelvic pain]], [[retroperitoneal haemorrhage]].<br />
<br />
======Central Nervous System======<br />
<br />
*Common:<br />
:*Dizziness<br />
:*Vertigo<br />
<br />
*Less common:<br />
[[Anxiety]], [[insomnia]], [[neuralgia]].<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
*Common:<br />
:*Abnormal stool<br />
:*Diarrhea<br />
:*Dyspepsia<br />
:*Flatulence<br />
:*Nausea<br />
<br />
*Less common:<br />
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Metabolic & Nutritional======<br />
*Common:<br />
:*Peripheral edema<br />
<br />
*Less common:<br />
Increased [[creatinine]], [[gout]], [[hyperlipemia]], [[hyperuricemia]].<br />
<br />
======Musculoskeletal======<br />
<br />
*Common:<br />
:*Myalgia<br />
<br />
*Less common:<br />
[[Arthralgia]], bone pain, [[bursitis]].<br />
<br />
======Miscellaneous======<br />
Less common adverse reactions:<br />
<br />
*'''Endocrine:''' [[Diabetes mellitus]].<br />
<br />
*'''Hemic and Lymphatic:''' [[Anemia]], [[ecchymosis]],[[ iron deficiency anemia]], [[polycythemia]], [[purpura]].<br />
<br />
*'''Skin and Appendages:''' Dry skin, [[furunculosis]], skin hypertrophy, [[urticaria]].<br />
<br />
*'''Special Senses:''' [[Amblyopia]], [[blindness]], [[conjunctivitis]], [[diplopia]], ear pain, eye haemorrhage, [[retinal haemorrhage]], [[tinnitus]].<br />
<br />
*'''Urogenital:''' [[Albuminuria]], [[cystitis]], [[urinary frequency]], vaginal haemorrhage, vaginitis.<br />
<br />
===Postmarketing Experience===<br />
<br />
The following events have been reported spontaneously from worldwide post-marketing experience since the launch of PLETAL in the US.<br />
<br />
======Blood and lymphatic system disorders:======<br />
[[Agranulocytosis]],[[ aplastic anemia]], [[granulocytopenia]], [[pancytopenia]], [[thrombocytopenia]], [[leukopenia]], <br />
[[bleeding tendency]]<br />
<br />
======Cardiac disorders:======<br />
<br />
[[Torsades de pointes]], [[QT prolongation|QTc prolongation]] (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. [[complete atrioventricular block]], c[[ardiac failure ]]and [[bradyarrythmia]], when treated with cilostazol. Cilostazol was used "off label" due to its positive [[chronotropic]] action)<br />
<br />
======Gastrointestinal disorders:======<br />
<br />
*Gastrointestinal haemorrhage<br />
<br />
======General disorders and administration site conditions:======<br />
<br />
*Pain<br />
*[[chest pain]] <br />
*[[hot flushes]]<br />
<br />
======Hepatobiliary disorders:======<br />
<br />
*Hepatic dysfunction/abnormal liver function tests <br />
*[[jaundice]]<br />
<br />
======Injury, poisoning and procedural complications:======<br />
<br />
*Extradural [[haematoma ]] <br />
*Subdural haematoma<br />
<br />
=====Investigations:=====<br />
<br />
*[[Blood glucose]] increased, blood [[uric acid]] increased, [[platelet count]] decreased, [[white blood cell count]] decreased, increase in [[BUN]] (blood urea increased), blood pressure increase<br />
<br />
======Nervous system disorders:======<br />
<br />
*[[Intracranial haemorrhage]] <br />
*[[cerebral haemorrhage]] <br />
*[[cerebrovascular accident]]<br />
<br />
======Respiratory, thoracic and mediastinal disorders:======<br />
<br />
*Pulmonary haemorrhage<br />
*[[ interstitial pneumonia]]<br />
<br />
'''Skin and subcutaneous tissue disorders:'''<br />
<br />
*Haemorrhage subcutaneous, [[pruritus]], skin eruptions including [[Stevens-Johnson syndrome]], skin drug eruption ([[dermatitis medicamentosa]])<br />
<br />
======Vascular disorders:======<br />
<br />
*Subacute [[thrombosis ]](these cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting)<br />
<br />
==Drug Interactions==<br />
<br />
=====Aspirin=====<br />
<br />
*Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of ADP-induced ex vivo platelet aggregation by 22% to 37% when compared to either aspirin or cilostazol alone. Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to cilostazol alone and by 48% compared to aspirin alone. However, short-term co-administration of aspirin with cilostazol had no clinically significant impact on PT, aPTT or bleeding time compared to aspirin alone. <br />
*Effects of long-term co-administration in the general population are unknown. In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was co-administered with cilostazol to 201 patients. The most frequent doses and mean durations of aspirin therapy were 75 mg to 81 mg daily for 137 days (107 patients) and 325 mg daily for 54 days (85 patients). There was no apparent increase in incidence of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.<br />
(Description)<br />
<br />
=====Warfarin=====<br />
<br />
The cytochrome P-450 isoenzymes involved in the metabolism of R-warfarin are CYP3A4, CYP1A2 and CYP2C19 and in the metabolism of S-warfarin, CYP2C9. Cilostazol did not inhibit either the metabolism or the pharmacologic effects (PT, aPTT, bleeding time or platelet aggregation) of R- and S-warfarin after a single 25-mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and cilostazol on the pharmacokinetics and pharmacodynamics of both drugs is unknown.<br />
<br />
=====Clopidogrel=====<br />
<br />
Multiple doses of clopidogrel do not significantly increase steady state plasma concentrations of cilostazol.<br />
<br />
=====Inhibitors of CYP3A4=====<br />
<br />
======Strong Inhibitors of CYP3A4======<br />
<br />
A priming dose of [[ketoconazole ]]400 mg (a strong inhibitor of CYP3A4), was given one day prior to co-administration of single doses of [[ketoconazole ]]400 mg and cilostazol 100 mg. This regimen increased cilostazol Cmax by 94% and AUC by 117%. Other strong inhibitors of CYP3A4, such as [[itraconazole]], [[fluconazole]], [[miconazole]], [[fluvoxamine]], [[fluoxetine]], [[nefazodone ]]and [[sertraline]], would be expected to have a similar effect <br />
<br />
======Moderate Inhibitors of CYP3A4======<br />
<br />
*[[Erythromycin ]]and Other [[Macrolide ]]Antibiotics: [[Erythromycin ]]is a moderately strong inhibitor of CYP3A4. Co-administration of erythromycin 500 mg q 8h with a single dose of cilostazol 100 mg increased cilostazol Cmax by 47% and AUC by 73%. Inhibition of cilostazol metabolism by erythromycin increased the AUC of 4´-trans-hydroxy-cilostazol by 141%. Other macrolide antibiotics (e.g., [[clarithromycin]]), but not all (e.g., [[azithromycin]]), would be expected to have a similar effect.<br />
<br />
*Diltiazem: [[Diltiazem]] 180 mg decreased the clearance of cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC increased ~40%.<br />
<br />
*Grapefruit Juice: [[Grapefruit juice]] increased the Cmax of cilostazol by ~50% , but had no effect on AUC.<br />
=====Inhibitors of CYP2C19=====<br />
<br />
[[Omeprazole]]: Co-administration of omeprazole did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%, probably the result of omeprazole’s potent inhibition of CYP2C19 <br />
<br />
=====Quinidine =====<br />
<br />
Concomitant administration of [[quinidine ]]with a single dose of cilostazol 100 mg did not alter cilostazol pharmacokinetics.<br />
<br />
=====Lovastatin=====<br />
<br />
The concomitant administration of [[lovastatin ]]with cilostazol decreases cilostazol Css, max and AUCT by 15%. There is also a decrease, although nonsignificant, in cilostazol metabolite concentrations. Co-administration of cilostazol with lovastatin increases lovastatin and β–hydroxy lovastatin AUC approximately 70%. This is most likely clinically insignificant.<br />
<br />
==Use in Specific Populations==<br />
<br />
====Pregnancy====<br />
<br />
* '''[[Pregnancy category#United States|Pregnancy Category (FDA)]]: C'''<br />
<br />
* '''[[Pregnancy category#Australia|Pregnancy Category (AUS)]]: {{PAGENAME}} is not included in Australian Drug Evaluation Committee (ADEC) Pregnancy Categories.'''<br />
<br />
In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
<br />
====Labor and Delivery====<br />
<br />
FDA package insert doesn't contain any information regarding "'''Labor and Delivery'''"<br />
<br />
====Nursing Mothers====<br />
<br />
Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
<br />
====Pediatric Use====<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
====Geriatric Use====<br />
Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
====Gender====<br />
<br />
The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range<br />
<br />
====Race====<br />
<br />
(Description)<br />
<br />
====Renal Impairment====<br />
<br />
Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
<br />
====Hepatic Impairment====<br />
<br />
Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
<br />
====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the exposure in humans at the MRHD.<br />
<br />
====Immunocompromised Patients====<br />
<br />
(Description)<br />
<br />
====Miscellaneous====<br />
<br />
=====Smokers=====<br />
Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
<br />
==Administration and Monitoring==<br />
<br />
====Administration====<br />
<br />
Oral<br />
<br />
====Monitoring====<br />
FDA package insert does't contain any information regarding "'''Monitoring'''"<br />
<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability).<br />
<br />
==IV Compatibility==<br />
<br />
FDA package insert doesn't contain any information regarding '''IV Compatibility'''<br />
<br />
==Overdosage==<br />
<br />
===Acute Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
<br />
====Management====<br />
<br />
(Description)<br />
<br />
===Chronic Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
(Description)<br />
<br />
====Management====<br />
<br />
(Description)<br />
<br />
==Pharmacology==<br />
<br />
{{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
<br />
===Mechanism of Action===<br />
<br />
The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
<br />
===Structure===<br />
<br />
*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
<br />
<br />
===Pharmacodynamics===<br />
<br />
(Description)<br />
<br />
===Pharmacokinetics===<br />
<br />
Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
<br />
====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4‑dehydro‑cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4‑dehydro‑cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
<br />
===Nonclinical Toxicology===<br />
<br />
==Clinical Studies==<br />
<br />
*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
<br />
{|<br />
| [[image:Cilo2.png|400px|thumb]]<br />
|}<br />
<br />
<br />
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
<br />
==How Supplied==<br />
<br />
'''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
<br />
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0223-60 bottles of 60 and 0185-0223-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
==Images==<br />
<br />
===Drug Images===<br />
<br />
{|<br />
| [[File:Cilostazol50mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 50 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;123 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
{|<br />
| [[File:Cilostazol100mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 100 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;223 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
===Package and Label Display Panel===<br />
<br />
Sandoz Inc.<br />
Princeton, NJ 08540<br />
OS8128<br />
Rev. 02/13<br />
MF0223REV02/13<br />
Cilostazol 100mg Tablet<br />
<br />
{|<br />
| [[image:Cilostazollabel.jpg|400px|thumb]]<br />
|}<br />
<br />
{|<br />
| [[image:Cilostazollabel1.png|400px|thumb]]<br />
|}<br />
<br />
==Patient Information==<br />
<br />
===Patient Information from FDA===<br />
(sil-OS-tah-zol)<br />
<br />
Please read this leaflet before you start taking cilostazol tablets and each time you renew it in case anything has changed. This leaflet does not replace careful discussions with your doctor. You and your doctor should discuss cilostazol when you start taking it and at regular check-ups. You should follow your doctor’s advice about when to have check-ups.<br />
What is cilostazol for?<br />
Cilostazol may improve the symptoms of patients with a medical condition called intermittent claudication.<br />
What is intermittent claudication?<br />
Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. It occurs because narrowing or blockage of the arteries decreases blood flow to the legs. The decreased blood flow does not supply enough oxygen to the leg muscles during walking, resulting in these painful leg cramps.<br />
<br />
'''What treatments are available for intermittent claudication?'''<br />
<br />
The three main treatments available for intermittent claudication are:<br />
*Exercise. Your doctor may advise an exercise program.<br />
*Medication. Your doctor may prescribe a medication such as cilostazol. (See Who should not take cilostazol tablets?)<br />
*Surgery. Your doctor may recommend a surgical procedure to bypass the blocked segment of the artery. Another procedure is called a percutaneous transluminal angioplasty. In this procedure, a catheter (a flexible tube) is inserted into the artery to reduce the blockage and improve blood flow.<br />
<br />
'''How does cilostazol work?'''<br />
<br />
*The exact way that many drugs work is not well understood. Although how cilostazol works is not completely clear, its main effects are to dilate (widen) the arteries supplying blood to the legs and to decrease the ability of platelets in the blood to stick together. Platelets are particles that circulate in the blood and play a role in clotting.<br />
*Cilostazol may reduce the leg pain that patients with intermittent claudication experience, allowing them to walk farther before their leg pain occurs.<br />
*Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks. If you have not noticed any benefit from cilostazol tablets after 12 weeks you and your doctor may wish to discuss other forms of treatment.<br />
*Sometimes blood vessel disease of the legs causes pain at rest or breakdown of skin in the leg. Cilostazol has not been shown to work in patients with these problems.<br />
<br />
'''Who should not take cilostazol tablets?'''<br />
<br />
*Patients who have congestive heart failure (CHF) must not take cilostazol tablets. The most common symptoms of CHF are shortness of breath and swelling of the legs. However, other conditions may also cause these symptoms. It is important that you discuss with your doctor whether you have CHF.<br />
*Over 1,300 patients took cilostazol in studies that lasted for 3 to 6 months. The mortality rate in these patients was similar to placebo (less than 1%). These studies were too small to be sure there is not some increased risk of dying with longer use or in patients sicker than those in the studies.<br />
<br />
'''How should cilostazol tablets be taken?'''<br />
<br />
*Follow your doctor’s advice about how to take cilostazol tablets.<br />
*You should take cilostazol tablets twice a day, at least one half-hour before or two hours after breakfast and dinner. Take cilostazol tablets at about the same times each day.<br />
*Do not share cilostazol tablets with anyone else. It was prescribed only for you.<br />
*Keep cilostazol tablets and all drugs out of the reach of children.<br />
<br />
'''Can cilostazol tablets be taken with other drugs?'''<br />
<br />
Certain drugs and foods can increase the amount of cilostazol in the blood. Because of this, your doctor may adjust your dose of cilostazol or even stop it if you are taking or are going to take one of the following medications.<br />
Drugs Interacting with Cilostazol<br />
Generic Name (Brand Names)Type of Drug<br />
[[erythromycin]] (such as E.E.S.®, Erythrocin®) Antibiotic<br />
[[ketoconazole]] (Nizoral®), [[itraconazole]] (Sporanox®) Antifungal<br />
[[diltiazem]] (Cardizem®) Antihypertensive<br />
[[omeprazole]] (Prilosec®) Gastric acid reducer<br />
This list does not include every drug that may interact with cilostazol tablets. Therefore, you should tell your doctor about all medications that you are taking, including vitamins, herbal supplements and over-the-counter drugs you can buy without a prescription. You should also check with your doctor before taking a new medication after you have begun cilostazol tablets.<br />
<br />
'''What are the possible side effects of cilostazol tablets?'''<br />
<br />
Cilostazol tablets may cause side effects including headache, diarrhea, abnormal stools, increased heart rate and palpitations.<br />
You should discuss possible side effects with your doctor before taking cilostazol tablets and any time you think you are having a side effect.<br />
This provides only a summary of information about cilostazol tablets. If you have any questions about cilostazol tablets, talk to your doctor.<br />
'''Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.'''<br />
<br />
===Patient Information from NLM===<br />
<br />
For patient information about Cilostazol from NLM, click [[Cilostazol (patient information)|here]].<br />
<br />
==Precautions with Alcohol==<br />
<br />
Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
<br />
==Brand Names==<br />
<br />
Cilostazol®, Platel®.<br />
<br />
==Look-Alike Drug Names==<br />
<br />
* (Paired Confused Name 1a) — (Paired Confused Name 1b)<br />
* (Paired Confused Name 2a) — (Paired Confused Name 2b)<br />
* (Paired Confused Name 3a) — (Paired Confused Name 3b)<br />
<br />
==[http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm Drug Shortage Status]==<br />
<br />
==[http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price Price]==<br />
<br />
==References==<br />
<br />
{{reflist}}<br />
<br />
</div></div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=Cilostazol&diff=961869Cilostazol2014-04-02T17:44:38Z<p>Abdurahman Khalil: /* Labor and Delivery */</p>
<hr />
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|-<br />
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|-<br />
! style="font-size: 80%; padding: 0 5px; background: #000000; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|Black Box Warning}}]]<br />
|-<br />
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pediatric Indications and Dosage|{{fontcolor|#F8F8FF|Pediatric Indications and Dosage}}]]<br />
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Warnings|{{fontcolor|#F8F8FF|Warnings}}]]<br />
|-<br />
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|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Drug Interactions|{{fontcolor|#F8F8FF|Drug Interactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Use in Specific Populations|{{fontcolor|#F8F8FF|Use in Specific Populations}}]]<br />
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Administration and Monitoring|{{fontcolor|#F8F8FF|Administration and Monitoring}}]]<br />
|-<br />
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|-<br />
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|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Clinical Studies|{{fontcolor|#F8F8FF|Clinical Studies}}]]<br />
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#How Supplied|{{fontcolor|#F8F8FF|How Supplied}}]]<br />
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|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Brand Names|{{fontcolor|#F8F8FF|Brand Names}}]]<br />
|-<br />
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|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm {{fontcolor|#F8F8FF|Drug Shortage Status}}]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price {{fontcolor|#F8F8FF|Price}}]<br />
|-<br />
|}<br />
<div style="width: 80%"><br />
__NOTOC__<br />
{{CMG}}<br />
<br />
{{SB}} Cilostazol®, Pletal®<br />
<br />
==Disclaimer==<br />
<br />
'''''WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature. The information provided is not a medical advice or treatment. WikiDoc does not promote any medication or off-label use of drugs. Please read our full disclaimer [[wikidoc:General_disclaimer|{{fontcolor|#FF0000|here}}]].'''''<br />
<br />
==<span style="color:#FF0000; background:#000000;">Black Box Warning</span>==<br />
<br />
FDA Package Insert for {{PAGENAME}} contains no information regarding ''Black Box Warning''.<br />
<br />
{| style="border: 3px solid #696969;"<br />
| style="background: #000000; border: 0px; padding: 20px 20px; width: 800px;" |<br />
<center><br />
<font color="#F8F8FF" style="font-weight: bold;">CONTRAINDICATION</font><br />
</center><br />
<br />
<center><br />
<font color="#F8F8FF" size="1" style="font-style: italic;">See full prescribing information for complete boxed warning.</font><br />
</center><br />
<br />
<font color="#F8F8FF" style="font-weight: bold;"><br />
''{{fontcolor|#FF0000|Condition Name:}}'' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
</font><br />
|}<br />
<br />
==Overview==<br />
<br />
{{PAGENAME}} is a_Phosphodiesterase 3 Inhibitor drug that is FDA approved for the treatment of intermittent claudication. There is a Black Box Warning for this drug as shown <span style="background:#000000;">'''[[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|here}}]]'''</span>. Common adverse reactions include headache, dizziness, palpitation, diarrhea, rhinitis and pharyngitis.<br />
<br />
==Adult Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Adult)===<br />
<br />
=====Intermittent claudication=====<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
===Off-Label Use and Dosage (Adult)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* There is limited information about ''Off-Label Non–Guideline-Supported Use'' of {{PAGENAME}} in adult patients.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Pediatric Indications and Dosage==<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
==Contraindications==<br />
* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
<br />
==Warnings==<br />
<br />
=====Hematologic Adverse Reactions=====<br />
Rare cases have been reported of [[thrombocytopenia ]]or [[leukopenia ]]progressing to [[agranulocytosis ]]when cilostazol was not immediately discontinued. The agranulocytosis, however, was reversible on discontinuation of cilostazol.<br />
<br />
=====Use with Clopidogrel=====<br />
There is limited information with respect to the efficacy or safety of the concurrent use of cilostazol and [[clopidogrel]], a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Although it cannot be determined whether there was an additive effect on bleeding times during concomitant administration with cilostazol and [[clopidogrel]], caution is advised for checking bleeding times during co-administration.<br />
<br />
==Adverse Reactions==<br />
<br />
===Clinical Trials Experience===<br />
Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol and 134 days for patients on placebo.<br />
<br />
The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with PLETAL 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included [[palpitation ]]and [[diarrhea]], both 1.1% for cilostazol (all doses) versus 0.1% for placebo.<br />
<br />
======Body as a Whole======<br />
*Common:<br />
:*Abdominal pain<br />
:*Back pain<br />
:*Headache <br />
:*Infection<br />
<br />
*Less common:<br />
[[Chills]], face [[edema]], [[fever]], [[generalized edema]], [[malaise]], [[neck rigidity]], [[pelvic pain]], [[retroperitoneal haemorrhage]].<br />
<br />
======Central Nervous System======<br />
<br />
*Common:<br />
:*Dizziness<br />
:*Vertigo<br />
<br />
*Less common:<br />
[[Anxiety]], [[insomnia]], [[neuralgia]].<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
*Common:<br />
:*Abnormal stool<br />
:*Diarrhea<br />
:*Dyspepsia<br />
:*Flatulence<br />
:*Nausea<br />
<br />
*Less common:<br />
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Metabolic & Nutritional======<br />
*Common:<br />
:*Peripheral edema<br />
<br />
*Less common:<br />
Increased [[creatinine]], [[gout]], [[hyperlipemia]], [[hyperuricemia]].<br />
<br />
======Musculoskeletal======<br />
<br />
*Common:<br />
:*Myalgia<br />
<br />
*Less common:<br />
[[Arthralgia]], bone pain, [[bursitis]].<br />
<br />
======Miscellaneous======<br />
Less common adverse reactions:<br />
<br />
*'''Endocrine:''' [[Diabetes mellitus]].<br />
<br />
*'''Hemic and Lymphatic:''' [[Anemia]], [[ecchymosis]],[[ iron deficiency anemia]], [[polycythemia]], [[purpura]].<br />
<br />
*'''Skin and Appendages:''' Dry skin, [[furunculosis]], skin hypertrophy, [[urticaria]].<br />
<br />
*'''Special Senses:''' [[Amblyopia]], [[blindness]], [[conjunctivitis]], [[diplopia]], ear pain, eye haemorrhage, [[retinal haemorrhage]], [[tinnitus]].<br />
<br />
*'''Urogenital:''' [[Albuminuria]], [[cystitis]], [[urinary frequency]], vaginal haemorrhage, vaginitis.<br />
<br />
===Postmarketing Experience===<br />
<br />
The following events have been reported spontaneously from worldwide post-marketing experience since the launch of PLETAL in the US.<br />
<br />
======Blood and lymphatic system disorders:======<br />
[[Agranulocytosis]],[[ aplastic anemia]], [[granulocytopenia]], [[pancytopenia]], [[thrombocytopenia]], [[leukopenia]], <br />
[[bleeding tendency]]<br />
<br />
======Cardiac disorders:======<br />
<br />
[[Torsades de pointes]], [[QT prolongation|QTc prolongation]] (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. [[complete atrioventricular block]], c[[ardiac failure ]]and [[bradyarrythmia]], when treated with cilostazol. Cilostazol was used "off label" due to its positive [[chronotropic]] action)<br />
<br />
======Gastrointestinal disorders:======<br />
<br />
*Gastrointestinal haemorrhage<br />
<br />
======General disorders and administration site conditions:======<br />
<br />
*Pain<br />
*[[chest pain]] <br />
*[[hot flushes]]<br />
<br />
======Hepatobiliary disorders:======<br />
<br />
*Hepatic dysfunction/abnormal liver function tests <br />
*[[jaundice]]<br />
<br />
======Injury, poisoning and procedural complications:======<br />
<br />
*Extradural [[haematoma ]] <br />
*Subdural haematoma<br />
<br />
=====Investigations:=====<br />
<br />
*[[Blood glucose]] increased, blood [[uric acid]] increased, [[platelet count]] decreased, [[white blood cell count]] decreased, increase in [[BUN]] (blood urea increased), blood pressure increase<br />
<br />
======Nervous system disorders:======<br />
<br />
*[[Intracranial haemorrhage]] <br />
*[[cerebral haemorrhage]] <br />
*[[cerebrovascular accident]]<br />
<br />
======Respiratory, thoracic and mediastinal disorders:======<br />
<br />
*Pulmonary haemorrhage<br />
*[[ interstitial pneumonia]]<br />
<br />
'''Skin and subcutaneous tissue disorders:'''<br />
<br />
*Haemorrhage subcutaneous, [[pruritus]], skin eruptions including [[Stevens-Johnson syndrome]], skin drug eruption ([[dermatitis medicamentosa]])<br />
<br />
======Vascular disorders:======<br />
<br />
*Subacute [[thrombosis ]](these cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting)<br />
<br />
==Drug Interactions==<br />
<br />
=====Aspirin=====<br />
<br />
*Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of ADP-induced ex vivo platelet aggregation by 22% to 37% when compared to either aspirin or cilostazol alone. Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to cilostazol alone and by 48% compared to aspirin alone. However, short-term co-administration of aspirin with cilostazol had no clinically significant impact on PT, aPTT or bleeding time compared to aspirin alone. <br />
*Effects of long-term co-administration in the general population are unknown. In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was co-administered with cilostazol to 201 patients. The most frequent doses and mean durations of aspirin therapy were 75 mg to 81 mg daily for 137 days (107 patients) and 325 mg daily for 54 days (85 patients). There was no apparent increase in incidence of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.<br />
(Description)<br />
<br />
=====Warfarin=====<br />
<br />
The cytochrome P-450 isoenzymes involved in the metabolism of R-warfarin are CYP3A4, CYP1A2 and CYP2C19 and in the metabolism of S-warfarin, CYP2C9. Cilostazol did not inhibit either the metabolism or the pharmacologic effects (PT, aPTT, bleeding time or platelet aggregation) of R- and S-warfarin after a single 25-mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and cilostazol on the pharmacokinetics and pharmacodynamics of both drugs is unknown.<br />
<br />
=====Clopidogrel=====<br />
<br />
Multiple doses of clopidogrel do not significantly increase steady state plasma concentrations of cilostazol.<br />
<br />
=====Inhibitors of CYP3A4=====<br />
<br />
======Strong Inhibitors of CYP3A4======<br />
<br />
A priming dose of [[ketoconazole ]]400 mg (a strong inhibitor of CYP3A4), was given one day prior to co-administration of single doses of [[ketoconazole ]]400 mg and cilostazol 100 mg. This regimen increased cilostazol Cmax by 94% and AUC by 117%. Other strong inhibitors of CYP3A4, such as [[itraconazole]], [[fluconazole]], [[miconazole]], [[fluvoxamine]], [[fluoxetine]], [[nefazodone ]]and [[sertraline]], would be expected to have a similar effect <br />
<br />
======Moderate Inhibitors of CYP3A4======<br />
<br />
*[[Erythromycin ]]and Other [[Macrolide ]]Antibiotics: [[Erythromycin ]]is a moderately strong inhibitor of CYP3A4. Co-administration of erythromycin 500 mg q 8h with a single dose of cilostazol 100 mg increased cilostazol Cmax by 47% and AUC by 73%. Inhibition of cilostazol metabolism by erythromycin increased the AUC of 4´-trans-hydroxy-cilostazol by 141%. Other macrolide antibiotics (e.g., [[clarithromycin]]), but not all (e.g., [[azithromycin]]), would be expected to have a similar effect.<br />
<br />
*Diltiazem: [[Diltiazem]] 180 mg decreased the clearance of cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC increased ~40%.<br />
<br />
*Grapefruit Juice: [[Grapefruit juice]] increased the Cmax of cilostazol by ~50% , but had no effect on AUC.<br />
=====Inhibitors of CYP2C19=====<br />
<br />
[[Omeprazole]]: Co-administration of omeprazole did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%, probably the result of omeprazole’s potent inhibition of CYP2C19 <br />
<br />
=====Quinidine =====<br />
<br />
Concomitant administration of [[quinidine ]]with a single dose of cilostazol 100 mg did not alter cilostazol pharmacokinetics.<br />
<br />
=====Lovastatin=====<br />
<br />
The concomitant administration of [[lovastatin ]]with cilostazol decreases cilostazol Css, max and AUCT by 15%. There is also a decrease, although nonsignificant, in cilostazol metabolite concentrations. Co-administration of cilostazol with lovastatin increases lovastatin and β–hydroxy lovastatin AUC approximately 70%. This is most likely clinically insignificant.<br />
<br />
==Use in Specific Populations==<br />
<br />
====Pregnancy====<br />
<br />
* '''[[Pregnancy category#United States|Pregnancy Category (FDA)]]: C'''<br />
<br />
* '''[[Pregnancy category#Australia|Pregnancy Category (AUS)]]: {{PAGENAME}} is not included in Australian Drug Evaluation Committee (ADEC) Pregnancy Categories.'''<br />
<br />
In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
<br />
====Labor and Delivery====<br />
<br />
FDA package insert doesn't contain any information regarding "'''Labor and Delivery'''"<br />
<br />
====Nursing Mothers====<br />
<br />
Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
<br />
====Pediatric Use====<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
====Geriatric Use====<br />
Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
====Gender====<br />
<br />
The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range<br />
<br />
====Race====<br />
<br />
(Description)<br />
<br />
====Renal Impairment====<br />
<br />
Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
<br />
====Hepatic Impairment====<br />
<br />
Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
<br />
====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the exposure in humans at the MRHD.<br />
<br />
====Immunocompromised Patients====<br />
<br />
(Description)<br />
<br />
====Miscellaneous====<br />
<br />
=====Smokers=====<br />
Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
<br />
==Administration and Monitoring==<br />
<br />
====Administration====<br />
<br />
Oral<br />
<br />
====Monitoring====<br />
<br />
<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability).<br />
<br />
==IV Compatibility==<br />
<br />
FDA package insert doesn't contain any information regarding '''IV Compatibility'''<br />
<br />
==Overdosage==<br />
<br />
===Acute Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
<br />
====Management====<br />
<br />
(Description)<br />
<br />
===Chronic Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
(Description)<br />
<br />
====Management====<br />
<br />
(Description)<br />
<br />
==Pharmacology==<br />
<br />
{{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
<br />
===Mechanism of Action===<br />
<br />
The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
<br />
===Structure===<br />
<br />
*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
<br />
<br />
===Pharmacodynamics===<br />
<br />
(Description)<br />
<br />
===Pharmacokinetics===<br />
<br />
Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
<br />
====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4‑dehydro‑cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4‑dehydro‑cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
<br />
===Nonclinical Toxicology===<br />
<br />
==Clinical Studies==<br />
<br />
*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
<br />
{|<br />
| [[image:Cilo2.png|400px|thumb]]<br />
|}<br />
<br />
<br />
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
<br />
==How Supplied==<br />
<br />
'''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
<br />
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0223-60 bottles of 60 and 0185-0223-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
==Images==<br />
<br />
===Drug Images===<br />
<br />
{|<br />
| [[File:Cilostazol50mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 50 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;123 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
{|<br />
| [[File:Cilostazol100mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 100 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;223 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
===Package and Label Display Panel===<br />
<br />
Sandoz Inc.<br />
Princeton, NJ 08540<br />
OS8128<br />
Rev. 02/13<br />
MF0223REV02/13<br />
Cilostazol 100mg Tablet<br />
<br />
{|<br />
| [[image:Cilostazollabel.jpg|400px|thumb]]<br />
|}<br />
<br />
{|<br />
| [[image:Cilostazollabel1.png|400px|thumb]]<br />
|}<br />
<br />
==Patient Information==<br />
<br />
===Patient Information from FDA===<br />
(sil-OS-tah-zol)<br />
<br />
Please read this leaflet before you start taking cilostazol tablets and each time you renew it in case anything has changed. This leaflet does not replace careful discussions with your doctor. You and your doctor should discuss cilostazol when you start taking it and at regular check-ups. You should follow your doctor’s advice about when to have check-ups.<br />
What is cilostazol for?<br />
Cilostazol may improve the symptoms of patients with a medical condition called intermittent claudication.<br />
What is intermittent claudication?<br />
Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. It occurs because narrowing or blockage of the arteries decreases blood flow to the legs. The decreased blood flow does not supply enough oxygen to the leg muscles during walking, resulting in these painful leg cramps.<br />
<br />
'''What treatments are available for intermittent claudication?'''<br />
<br />
The three main treatments available for intermittent claudication are:<br />
*Exercise. Your doctor may advise an exercise program.<br />
*Medication. Your doctor may prescribe a medication such as cilostazol. (See Who should not take cilostazol tablets?)<br />
*Surgery. Your doctor may recommend a surgical procedure to bypass the blocked segment of the artery. Another procedure is called a percutaneous transluminal angioplasty. In this procedure, a catheter (a flexible tube) is inserted into the artery to reduce the blockage and improve blood flow.<br />
<br />
'''How does cilostazol work?'''<br />
<br />
*The exact way that many drugs work is not well understood. Although how cilostazol works is not completely clear, its main effects are to dilate (widen) the arteries supplying blood to the legs and to decrease the ability of platelets in the blood to stick together. Platelets are particles that circulate in the blood and play a role in clotting.<br />
*Cilostazol may reduce the leg pain that patients with intermittent claudication experience, allowing them to walk farther before their leg pain occurs.<br />
*Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks. If you have not noticed any benefit from cilostazol tablets after 12 weeks you and your doctor may wish to discuss other forms of treatment.<br />
*Sometimes blood vessel disease of the legs causes pain at rest or breakdown of skin in the leg. Cilostazol has not been shown to work in patients with these problems.<br />
<br />
'''Who should not take cilostazol tablets?'''<br />
<br />
*Patients who have congestive heart failure (CHF) must not take cilostazol tablets. The most common symptoms of CHF are shortness of breath and swelling of the legs. However, other conditions may also cause these symptoms. It is important that you discuss with your doctor whether you have CHF.<br />
*Over 1,300 patients took cilostazol in studies that lasted for 3 to 6 months. The mortality rate in these patients was similar to placebo (less than 1%). These studies were too small to be sure there is not some increased risk of dying with longer use or in patients sicker than those in the studies.<br />
<br />
'''How should cilostazol tablets be taken?'''<br />
<br />
*Follow your doctor’s advice about how to take cilostazol tablets.<br />
*You should take cilostazol tablets twice a day, at least one half-hour before or two hours after breakfast and dinner. Take cilostazol tablets at about the same times each day.<br />
*Do not share cilostazol tablets with anyone else. It was prescribed only for you.<br />
*Keep cilostazol tablets and all drugs out of the reach of children.<br />
<br />
'''Can cilostazol tablets be taken with other drugs?'''<br />
<br />
Certain drugs and foods can increase the amount of cilostazol in the blood. Because of this, your doctor may adjust your dose of cilostazol or even stop it if you are taking or are going to take one of the following medications.<br />
Drugs Interacting with Cilostazol<br />
Generic Name (Brand Names)Type of Drug<br />
[[erythromycin]] (such as E.E.S.®, Erythrocin®) Antibiotic<br />
[[ketoconazole]] (Nizoral®), [[itraconazole]] (Sporanox®) Antifungal<br />
[[diltiazem]] (Cardizem®) Antihypertensive<br />
[[omeprazole]] (Prilosec®) Gastric acid reducer<br />
This list does not include every drug that may interact with cilostazol tablets. Therefore, you should tell your doctor about all medications that you are taking, including vitamins, herbal supplements and over-the-counter drugs you can buy without a prescription. You should also check with your doctor before taking a new medication after you have begun cilostazol tablets.<br />
<br />
'''What are the possible side effects of cilostazol tablets?'''<br />
<br />
Cilostazol tablets may cause side effects including headache, diarrhea, abnormal stools, increased heart rate and palpitations.<br />
You should discuss possible side effects with your doctor before taking cilostazol tablets and any time you think you are having a side effect.<br />
This provides only a summary of information about cilostazol tablets. If you have any questions about cilostazol tablets, talk to your doctor.<br />
'''Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.'''<br />
<br />
===Patient Information from NLM===<br />
<br />
For patient information about Cilostazol from NLM, click [[Cilostazol (patient information)|here]].<br />
<br />
==Precautions with Alcohol==<br />
<br />
Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
<br />
==Brand Names==<br />
<br />
Cilostazol®, Platel®.<br />
<br />
==Look-Alike Drug Names==<br />
<br />
* (Paired Confused Name 1a) — (Paired Confused Name 1b)<br />
* (Paired Confused Name 2a) — (Paired Confused Name 2b)<br />
* (Paired Confused Name 3a) — (Paired Confused Name 3b)<br />
<br />
==[http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm Drug Shortage Status]==<br />
<br />
==[http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price Price]==<br />
<br />
==References==<br />
<br />
{{reflist}}<br />
<br />
</div></div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=Cilostazol&diff=961868Cilostazol2014-04-02T17:38:55Z<p>Abdurahman Khalil: /* Adverse Reactions */</p>
<hr />
<div>{|class="infobox" style="position: fixed; top: 180px; right: 20px; margin: 0 0 0 0; border: 0; float: right; width: 15%; background: #104E8B; border-radius: 10px 10px 10px 10px;" cellpadding="0" cellspacing="0";<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #104E8B;" | [[{{PAGENAME}}|{{fontcolor|#F8F8FF|{{PAGENAME}}®}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #000000; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|Black Box Warning}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adult Indications and Dosage|{{fontcolor|#F8F8FF|Adult Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pediatric Indications and Dosage|{{fontcolor|#F8F8FF|Pediatric Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Contraindications|{{fontcolor|#F8F8FF|Contraindications}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Warnings|{{fontcolor|#F8F8FF|Warnings}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adverse Reactions|{{fontcolor|#F8F8FF|Adverse Reactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Drug Interactions|{{fontcolor|#F8F8FF|Drug Interactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Use in Specific Populations|{{fontcolor|#F8F8FF|Use in Specific Populations}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Administration and Monitoring|{{fontcolor|#F8F8FF|Administration and Monitoring}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#IV Compatibility|{{fontcolor|#F8F8FF|IV Compatibility}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Overdosage|{{fontcolor|#F8F8FF|Overdosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pharmacology|{{fontcolor|#F8F8FF|Pharmacology}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Clinical Studies|{{fontcolor|#F8F8FF|Clinical Studies}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#How Supplied|{{fontcolor|#F8F8FF|How Supplied}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Images|{{fontcolor|#F8F8FF|Images}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Patient Information|{{fontcolor|#F8F8FF|Patient information}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Precautions with Alcohol|{{fontcolor|#F8F8FF|Precautions with Alcohol}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Brand Names|{{fontcolor|#F8F8FF|Brand Names}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Look-Alike Drug Names|{{fontcolor|#F8F8FF|Look-Alike Drug Names}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm {{fontcolor|#F8F8FF|Drug Shortage Status}}]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price {{fontcolor|#F8F8FF|Price}}]<br />
|-<br />
|}<br />
<div style="width: 80%"><br />
__NOTOC__<br />
{{CMG}}<br />
<br />
{{SB}} Cilostazol®, Pletal®<br />
<br />
==Disclaimer==<br />
<br />
'''''WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature. The information provided is not a medical advice or treatment. WikiDoc does not promote any medication or off-label use of drugs. Please read our full disclaimer [[wikidoc:General_disclaimer|{{fontcolor|#FF0000|here}}]].'''''<br />
<br />
==<span style="color:#FF0000; background:#000000;">Black Box Warning</span>==<br />
<br />
FDA Package Insert for {{PAGENAME}} contains no information regarding ''Black Box Warning''.<br />
<br />
{| style="border: 3px solid #696969;"<br />
| style="background: #000000; border: 0px; padding: 20px 20px; width: 800px;" |<br />
<center><br />
<font color="#F8F8FF" style="font-weight: bold;">CONTRAINDICATION</font><br />
</center><br />
<br />
<center><br />
<font color="#F8F8FF" size="1" style="font-style: italic;">See full prescribing information for complete boxed warning.</font><br />
</center><br />
<br />
<font color="#F8F8FF" style="font-weight: bold;"><br />
''{{fontcolor|#FF0000|Condition Name:}}'' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
</font><br />
|}<br />
<br />
==Overview==<br />
<br />
{{PAGENAME}} is a_Phosphodiesterase 3 Inhibitor drug that is FDA approved for the treatment of intermittent claudication. There is a Black Box Warning for this drug as shown <span style="background:#000000;">'''[[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|here}}]]'''</span>. Common adverse reactions include headache, dizziness, palpitation, diarrhea, rhinitis and pharyngitis.<br />
<br />
==Adult Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Adult)===<br />
<br />
=====Intermittent claudication=====<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
===Off-Label Use and Dosage (Adult)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* There is limited information about ''Off-Label Non–Guideline-Supported Use'' of {{PAGENAME}} in adult patients.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Pediatric Indications and Dosage==<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
==Contraindications==<br />
* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
<br />
==Warnings==<br />
<br />
=====Hematologic Adverse Reactions=====<br />
Rare cases have been reported of [[thrombocytopenia ]]or [[leukopenia ]]progressing to [[agranulocytosis ]]when cilostazol was not immediately discontinued. The agranulocytosis, however, was reversible on discontinuation of cilostazol.<br />
<br />
=====Use with Clopidogrel=====<br />
There is limited information with respect to the efficacy or safety of the concurrent use of cilostazol and [[clopidogrel]], a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Although it cannot be determined whether there was an additive effect on bleeding times during concomitant administration with cilostazol and [[clopidogrel]], caution is advised for checking bleeding times during co-administration.<br />
<br />
==Adverse Reactions==<br />
<br />
===Clinical Trials Experience===<br />
Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol and 134 days for patients on placebo.<br />
<br />
The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with PLETAL 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included [[palpitation ]]and [[diarrhea]], both 1.1% for cilostazol (all doses) versus 0.1% for placebo.<br />
<br />
======Body as a Whole======<br />
*Common:<br />
:*Abdominal pain<br />
:*Back pain<br />
:*Headache <br />
:*Infection<br />
<br />
*Less common:<br />
[[Chills]], face [[edema]], [[fever]], [[generalized edema]], [[malaise]], [[neck rigidity]], [[pelvic pain]], [[retroperitoneal haemorrhage]].<br />
<br />
======Central Nervous System======<br />
<br />
*Common:<br />
:*Dizziness<br />
:*Vertigo<br />
<br />
*Less common:<br />
[[Anxiety]], [[insomnia]], [[neuralgia]].<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
*Common:<br />
:*Abnormal stool<br />
:*Diarrhea<br />
:*Dyspepsia<br />
:*Flatulence<br />
:*Nausea<br />
<br />
*Less common:<br />
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Metabolic & Nutritional======<br />
*Common:<br />
:*Peripheral edema<br />
<br />
*Less common:<br />
Increased [[creatinine]], [[gout]], [[hyperlipemia]], [[hyperuricemia]].<br />
<br />
======Musculoskeletal======<br />
<br />
*Common:<br />
:*Myalgia<br />
<br />
*Less common:<br />
[[Arthralgia]], bone pain, [[bursitis]].<br />
<br />
======Miscellaneous======<br />
Less common adverse reactions:<br />
<br />
*'''Endocrine:''' [[Diabetes mellitus]].<br />
<br />
*'''Hemic and Lymphatic:''' [[Anemia]], [[ecchymosis]],[[ iron deficiency anemia]], [[polycythemia]], [[purpura]].<br />
<br />
*'''Skin and Appendages:''' Dry skin, [[furunculosis]], skin hypertrophy, [[urticaria]].<br />
<br />
*'''Special Senses:''' [[Amblyopia]], [[blindness]], [[conjunctivitis]], [[diplopia]], ear pain, eye haemorrhage, [[retinal haemorrhage]], [[tinnitus]].<br />
<br />
*'''Urogenital:''' [[Albuminuria]], [[cystitis]], [[urinary frequency]], vaginal haemorrhage, vaginitis.<br />
<br />
===Postmarketing Experience===<br />
<br />
The following events have been reported spontaneously from worldwide post-marketing experience since the launch of PLETAL in the US.<br />
<br />
======Blood and lymphatic system disorders:======<br />
[[Agranulocytosis]],[[ aplastic anemia]], [[granulocytopenia]], [[pancytopenia]], [[thrombocytopenia]], [[leukopenia]], <br />
[[bleeding tendency]]<br />
<br />
======Cardiac disorders:======<br />
<br />
[[Torsades de pointes]], [[QT prolongation|QTc prolongation]] (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. [[complete atrioventricular block]], c[[ardiac failure ]]and [[bradyarrythmia]], when treated with cilostazol. Cilostazol was used "off label" due to its positive [[chronotropic]] action)<br />
<br />
======Gastrointestinal disorders:======<br />
<br />
*Gastrointestinal haemorrhage<br />
<br />
======General disorders and administration site conditions:======<br />
<br />
*Pain<br />
*[[chest pain]] <br />
*[[hot flushes]]<br />
<br />
======Hepatobiliary disorders:======<br />
<br />
*Hepatic dysfunction/abnormal liver function tests <br />
*[[jaundice]]<br />
<br />
======Injury, poisoning and procedural complications:======<br />
<br />
*Extradural [[haematoma ]] <br />
*Subdural haematoma<br />
<br />
=====Investigations:=====<br />
<br />
*[[Blood glucose]] increased, blood [[uric acid]] increased, [[platelet count]] decreased, [[white blood cell count]] decreased, increase in [[BUN]] (blood urea increased), blood pressure increase<br />
<br />
======Nervous system disorders:======<br />
<br />
*[[Intracranial haemorrhage]] <br />
*[[cerebral haemorrhage]] <br />
*[[cerebrovascular accident]]<br />
<br />
======Respiratory, thoracic and mediastinal disorders:======<br />
<br />
*Pulmonary haemorrhage<br />
*[[ interstitial pneumonia]]<br />
<br />
'''Skin and subcutaneous tissue disorders:'''<br />
<br />
*Haemorrhage subcutaneous, [[pruritus]], skin eruptions including [[Stevens-Johnson syndrome]], skin drug eruption ([[dermatitis medicamentosa]])<br />
<br />
======Vascular disorders:======<br />
<br />
*Subacute [[thrombosis ]](these cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting)<br />
<br />
==Drug Interactions==<br />
<br />
=====Aspirin=====<br />
<br />
*Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of ADP-induced ex vivo platelet aggregation by 22% to 37% when compared to either aspirin or cilostazol alone. Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to cilostazol alone and by 48% compared to aspirin alone. However, short-term co-administration of aspirin with cilostazol had no clinically significant impact on PT, aPTT or bleeding time compared to aspirin alone. <br />
*Effects of long-term co-administration in the general population are unknown. In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was co-administered with cilostazol to 201 patients. The most frequent doses and mean durations of aspirin therapy were 75 mg to 81 mg daily for 137 days (107 patients) and 325 mg daily for 54 days (85 patients). There was no apparent increase in incidence of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.<br />
(Description)<br />
<br />
=====Warfarin=====<br />
<br />
The cytochrome P-450 isoenzymes involved in the metabolism of R-warfarin are CYP3A4, CYP1A2 and CYP2C19 and in the metabolism of S-warfarin, CYP2C9. Cilostazol did not inhibit either the metabolism or the pharmacologic effects (PT, aPTT, bleeding time or platelet aggregation) of R- and S-warfarin after a single 25-mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and cilostazol on the pharmacokinetics and pharmacodynamics of both drugs is unknown.<br />
<br />
=====Clopidogrel=====<br />
<br />
Multiple doses of clopidogrel do not significantly increase steady state plasma concentrations of cilostazol.<br />
<br />
=====Inhibitors of CYP3A4=====<br />
<br />
======Strong Inhibitors of CYP3A4======<br />
<br />
A priming dose of [[ketoconazole ]]400 mg (a strong inhibitor of CYP3A4), was given one day prior to co-administration of single doses of [[ketoconazole ]]400 mg and cilostazol 100 mg. This regimen increased cilostazol Cmax by 94% and AUC by 117%. Other strong inhibitors of CYP3A4, such as [[itraconazole]], [[fluconazole]], [[miconazole]], [[fluvoxamine]], [[fluoxetine]], [[nefazodone ]]and [[sertraline]], would be expected to have a similar effect <br />
<br />
======Moderate Inhibitors of CYP3A4======<br />
<br />
*[[Erythromycin ]]and Other [[Macrolide ]]Antibiotics: [[Erythromycin ]]is a moderately strong inhibitor of CYP3A4. Co-administration of erythromycin 500 mg q 8h with a single dose of cilostazol 100 mg increased cilostazol Cmax by 47% and AUC by 73%. Inhibition of cilostazol metabolism by erythromycin increased the AUC of 4´-trans-hydroxy-cilostazol by 141%. Other macrolide antibiotics (e.g., [[clarithromycin]]), but not all (e.g., [[azithromycin]]), would be expected to have a similar effect.<br />
<br />
*Diltiazem: [[Diltiazem]] 180 mg decreased the clearance of cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC increased ~40%.<br />
<br />
*Grapefruit Juice: [[Grapefruit juice]] increased the Cmax of cilostazol by ~50% , but had no effect on AUC.<br />
=====Inhibitors of CYP2C19=====<br />
<br />
[[Omeprazole]]: Co-administration of omeprazole did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%, probably the result of omeprazole’s potent inhibition of CYP2C19 <br />
<br />
=====Quinidine =====<br />
<br />
Concomitant administration of [[quinidine ]]with a single dose of cilostazol 100 mg did not alter cilostazol pharmacokinetics.<br />
<br />
=====Lovastatin=====<br />
<br />
The concomitant administration of [[lovastatin ]]with cilostazol decreases cilostazol Css, max and AUCT by 15%. There is also a decrease, although nonsignificant, in cilostazol metabolite concentrations. Co-administration of cilostazol with lovastatin increases lovastatin and β–hydroxy lovastatin AUC approximately 70%. This is most likely clinically insignificant.<br />
<br />
==Use in Specific Populations==<br />
<br />
====Pregnancy====<br />
<br />
* '''[[Pregnancy category#United States|Pregnancy Category (FDA)]]: C'''<br />
<br />
* '''[[Pregnancy category#Australia|Pregnancy Category (AUS)]]: {{PAGENAME}} is not included in Australian Drug Evaluation Committee (ADEC) Pregnancy Categories.'''<br />
<br />
In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
<br />
====Labor and Delivery====<br />
<br />
(Description)<br />
<br />
====Nursing Mothers====<br />
<br />
Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
<br />
====Pediatric Use====<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
====Geriatric Use====<br />
Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
====Gender====<br />
<br />
The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range<br />
<br />
====Race====<br />
<br />
(Description)<br />
<br />
====Renal Impairment====<br />
<br />
Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
<br />
====Hepatic Impairment====<br />
<br />
Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
<br />
====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the exposure in humans at the MRHD.<br />
<br />
====Immunocompromised Patients====<br />
<br />
(Description)<br />
<br />
====Miscellaneous====<br />
<br />
=====Smokers=====<br />
Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
<br />
==Administration and Monitoring==<br />
<br />
====Administration====<br />
<br />
Oral<br />
<br />
====Monitoring====<br />
<br />
<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability).<br />
<br />
==IV Compatibility==<br />
<br />
FDA package insert doesn't contain any information regarding '''IV Compatibility'''<br />
<br />
==Overdosage==<br />
<br />
===Acute Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
<br />
====Management====<br />
<br />
(Description)<br />
<br />
===Chronic Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
(Description)<br />
<br />
====Management====<br />
<br />
(Description)<br />
<br />
==Pharmacology==<br />
<br />
{{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
<br />
===Mechanism of Action===<br />
<br />
The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
<br />
===Structure===<br />
<br />
*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
<br />
<br />
===Pharmacodynamics===<br />
<br />
(Description)<br />
<br />
===Pharmacokinetics===<br />
<br />
Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
<br />
====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4‑dehydro‑cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4‑dehydro‑cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
<br />
===Nonclinical Toxicology===<br />
<br />
==Clinical Studies==<br />
<br />
*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
<br />
{|<br />
| [[image:Cilo2.png|400px|thumb]]<br />
|}<br />
<br />
<br />
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
<br />
==How Supplied==<br />
<br />
'''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
<br />
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0223-60 bottles of 60 and 0185-0223-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
==Images==<br />
<br />
===Drug Images===<br />
<br />
{|<br />
| [[File:Cilostazol50mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 50 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;123 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
{|<br />
| [[File:Cilostazol100mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 100 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;223 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
===Package and Label Display Panel===<br />
<br />
Sandoz Inc.<br />
Princeton, NJ 08540<br />
OS8128<br />
Rev. 02/13<br />
MF0223REV02/13<br />
Cilostazol 100mg Tablet<br />
<br />
{|<br />
| [[image:Cilostazollabel.jpg|400px|thumb]]<br />
|}<br />
<br />
{|<br />
| [[image:Cilostazollabel1.png|400px|thumb]]<br />
|}<br />
<br />
==Patient Information==<br />
<br />
===Patient Information from FDA===<br />
(sil-OS-tah-zol)<br />
<br />
Please read this leaflet before you start taking cilostazol tablets and each time you renew it in case anything has changed. This leaflet does not replace careful discussions with your doctor. You and your doctor should discuss cilostazol when you start taking it and at regular check-ups. You should follow your doctor’s advice about when to have check-ups.<br />
What is cilostazol for?<br />
Cilostazol may improve the symptoms of patients with a medical condition called intermittent claudication.<br />
What is intermittent claudication?<br />
Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. It occurs because narrowing or blockage of the arteries decreases blood flow to the legs. The decreased blood flow does not supply enough oxygen to the leg muscles during walking, resulting in these painful leg cramps.<br />
<br />
'''What treatments are available for intermittent claudication?'''<br />
<br />
The three main treatments available for intermittent claudication are:<br />
*Exercise. Your doctor may advise an exercise program.<br />
*Medication. Your doctor may prescribe a medication such as cilostazol. (See Who should not take cilostazol tablets?)<br />
*Surgery. Your doctor may recommend a surgical procedure to bypass the blocked segment of the artery. Another procedure is called a percutaneous transluminal angioplasty. In this procedure, a catheter (a flexible tube) is inserted into the artery to reduce the blockage and improve blood flow.<br />
<br />
'''How does cilostazol work?'''<br />
<br />
*The exact way that many drugs work is not well understood. Although how cilostazol works is not completely clear, its main effects are to dilate (widen) the arteries supplying blood to the legs and to decrease the ability of platelets in the blood to stick together. Platelets are particles that circulate in the blood and play a role in clotting.<br />
*Cilostazol may reduce the leg pain that patients with intermittent claudication experience, allowing them to walk farther before their leg pain occurs.<br />
*Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks. If you have not noticed any benefit from cilostazol tablets after 12 weeks you and your doctor may wish to discuss other forms of treatment.<br />
*Sometimes blood vessel disease of the legs causes pain at rest or breakdown of skin in the leg. Cilostazol has not been shown to work in patients with these problems.<br />
<br />
'''Who should not take cilostazol tablets?'''<br />
<br />
*Patients who have congestive heart failure (CHF) must not take cilostazol tablets. The most common symptoms of CHF are shortness of breath and swelling of the legs. However, other conditions may also cause these symptoms. It is important that you discuss with your doctor whether you have CHF.<br />
*Over 1,300 patients took cilostazol in studies that lasted for 3 to 6 months. The mortality rate in these patients was similar to placebo (less than 1%). These studies were too small to be sure there is not some increased risk of dying with longer use or in patients sicker than those in the studies.<br />
<br />
'''How should cilostazol tablets be taken?'''<br />
<br />
*Follow your doctor’s advice about how to take cilostazol tablets.<br />
*You should take cilostazol tablets twice a day, at least one half-hour before or two hours after breakfast and dinner. Take cilostazol tablets at about the same times each day.<br />
*Do not share cilostazol tablets with anyone else. It was prescribed only for you.<br />
*Keep cilostazol tablets and all drugs out of the reach of children.<br />
<br />
'''Can cilostazol tablets be taken with other drugs?'''<br />
<br />
Certain drugs and foods can increase the amount of cilostazol in the blood. Because of this, your doctor may adjust your dose of cilostazol or even stop it if you are taking or are going to take one of the following medications.<br />
Drugs Interacting with Cilostazol<br />
Generic Name (Brand Names)Type of Drug<br />
[[erythromycin]] (such as E.E.S.®, Erythrocin®) Antibiotic<br />
[[ketoconazole]] (Nizoral®), [[itraconazole]] (Sporanox®) Antifungal<br />
[[diltiazem]] (Cardizem®) Antihypertensive<br />
[[omeprazole]] (Prilosec®) Gastric acid reducer<br />
This list does not include every drug that may interact with cilostazol tablets. Therefore, you should tell your doctor about all medications that you are taking, including vitamins, herbal supplements and over-the-counter drugs you can buy without a prescription. You should also check with your doctor before taking a new medication after you have begun cilostazol tablets.<br />
<br />
'''What are the possible side effects of cilostazol tablets?'''<br />
<br />
Cilostazol tablets may cause side effects including headache, diarrhea, abnormal stools, increased heart rate and palpitations.<br />
You should discuss possible side effects with your doctor before taking cilostazol tablets and any time you think you are having a side effect.<br />
This provides only a summary of information about cilostazol tablets. If you have any questions about cilostazol tablets, talk to your doctor.<br />
'''Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.'''<br />
<br />
===Patient Information from NLM===<br />
<br />
For patient information about Cilostazol from NLM, click [[Cilostazol (patient information)|here]].<br />
<br />
==Precautions with Alcohol==<br />
<br />
Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
<br />
==Brand Names==<br />
<br />
Cilostazol®, Platel®.<br />
<br />
==Look-Alike Drug Names==<br />
<br />
* (Paired Confused Name 1a) — (Paired Confused Name 1b)<br />
* (Paired Confused Name 2a) — (Paired Confused Name 2b)<br />
* (Paired Confused Name 3a) — (Paired Confused Name 3b)<br />
<br />
==[http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm Drug Shortage Status]==<br />
<br />
==[http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price Price]==<br />
<br />
==References==<br />
<br />
{{reflist}}<br />
<br />
</div></div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=Cilostazol&diff=961867Cilostazol2014-04-02T17:35:42Z<p>Abdurahman Khalil: /* Warnings */</p>
<hr />
<div>{|class="infobox" style="position: fixed; top: 180px; right: 20px; margin: 0 0 0 0; border: 0; float: right; width: 15%; background: #104E8B; border-radius: 10px 10px 10px 10px;" cellpadding="0" cellspacing="0";<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #104E8B;" | [[{{PAGENAME}}|{{fontcolor|#F8F8FF|{{PAGENAME}}®}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #000000; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|Black Box Warning}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adult Indications and Dosage|{{fontcolor|#F8F8FF|Adult Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pediatric Indications and Dosage|{{fontcolor|#F8F8FF|Pediatric Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Contraindications|{{fontcolor|#F8F8FF|Contraindications}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Warnings|{{fontcolor|#F8F8FF|Warnings}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adverse Reactions|{{fontcolor|#F8F8FF|Adverse Reactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Drug Interactions|{{fontcolor|#F8F8FF|Drug Interactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Use in Specific Populations|{{fontcolor|#F8F8FF|Use in Specific Populations}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Administration and Monitoring|{{fontcolor|#F8F8FF|Administration and Monitoring}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#IV Compatibility|{{fontcolor|#F8F8FF|IV Compatibility}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Overdosage|{{fontcolor|#F8F8FF|Overdosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pharmacology|{{fontcolor|#F8F8FF|Pharmacology}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Clinical Studies|{{fontcolor|#F8F8FF|Clinical Studies}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#How Supplied|{{fontcolor|#F8F8FF|How Supplied}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Images|{{fontcolor|#F8F8FF|Images}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Patient Information|{{fontcolor|#F8F8FF|Patient information}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Precautions with Alcohol|{{fontcolor|#F8F8FF|Precautions with Alcohol}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Brand Names|{{fontcolor|#F8F8FF|Brand Names}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Look-Alike Drug Names|{{fontcolor|#F8F8FF|Look-Alike Drug Names}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm {{fontcolor|#F8F8FF|Drug Shortage Status}}]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price {{fontcolor|#F8F8FF|Price}}]<br />
|-<br />
|}<br />
<div style="width: 80%"><br />
__NOTOC__<br />
{{CMG}}<br />
<br />
{{SB}} Cilostazol®, Pletal®<br />
<br />
==Disclaimer==<br />
<br />
'''''WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature. The information provided is not a medical advice or treatment. WikiDoc does not promote any medication or off-label use of drugs. Please read our full disclaimer [[wikidoc:General_disclaimer|{{fontcolor|#FF0000|here}}]].'''''<br />
<br />
==<span style="color:#FF0000; background:#000000;">Black Box Warning</span>==<br />
<br />
FDA Package Insert for {{PAGENAME}} contains no information regarding ''Black Box Warning''.<br />
<br />
{| style="border: 3px solid #696969;"<br />
| style="background: #000000; border: 0px; padding: 20px 20px; width: 800px;" |<br />
<center><br />
<font color="#F8F8FF" style="font-weight: bold;">CONTRAINDICATION</font><br />
</center><br />
<br />
<center><br />
<font color="#F8F8FF" size="1" style="font-style: italic;">See full prescribing information for complete boxed warning.</font><br />
</center><br />
<br />
<font color="#F8F8FF" style="font-weight: bold;"><br />
''{{fontcolor|#FF0000|Condition Name:}}'' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
</font><br />
|}<br />
<br />
==Overview==<br />
<br />
{{PAGENAME}} is a_Phosphodiesterase 3 Inhibitor drug that is FDA approved for the treatment of intermittent claudication. There is a Black Box Warning for this drug as shown <span style="background:#000000;">'''[[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|here}}]]'''</span>. Common adverse reactions include headache, dizziness, palpitation, diarrhea, rhinitis and pharyngitis.<br />
<br />
==Adult Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Adult)===<br />
<br />
=====Intermittent claudication=====<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
===Off-Label Use and Dosage (Adult)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* There is limited information about ''Off-Label Non–Guideline-Supported Use'' of {{PAGENAME}} in adult patients.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Pediatric Indications and Dosage==<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
==Contraindications==<br />
* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
<br />
==Warnings==<br />
<br />
=====Hematologic Adverse Reactions=====<br />
Rare cases have been reported of [[thrombocytopenia ]]or [[leukopenia ]]progressing to [[agranulocytosis ]]when cilostazol was not immediately discontinued. The agranulocytosis, however, was reversible on discontinuation of cilostazol.<br />
<br />
=====Use with Clopidogrel=====<br />
There is limited information with respect to the efficacy or safety of the concurrent use of cilostazol and [[clopidogrel]], a platelet-aggregation inhibiting drug indicated for use in patients with peripheral arterial disease. Although it cannot be determined whether there was an additive effect on bleeding times during concomitant administration with cilostazol and [[clopidogrel]], caution is advised for checking bleeding times during co-administration.<br />
<br />
==Adverse Reactions==<br />
<br />
===Clinical Trials Experience===<br />
Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol and 134 days for patients on placebo.<br />
<br />
The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with PLETAL 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included [[palpitation ]]and [[diarrhea]], both 1.1% for cilostazol (all doses) versus 0.1% for placebo.<br />
<br />
======Body as a Whole======<br />
*Common:<br />
:*Abdominal pain<br />
:*Back pain<br />
:*Headache <br />
:*Infection<br />
<br />
*Less common:<br />
[[Chills]], face [[edema]], [[fever]], [[generalized edema]], [[malaise]], [[neck rigidity]], [[pelvic pain]], [[retroperitoneal haemorrhage]].<br />
<br />
======Central Nervous System======<br />
<br />
*Common:<br />
:*Dizziness<br />
:*Vertigo<br />
<br />
*Less common:<br />
[[Anxiety]], [[insomnia]], [[neuralgia]].<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
*Common:<br />
:*Abnormal stool<br />
:*Diarrhea<br />
:*Dyspepsia<br />
:*Flatulence<br />
:*Nausea<br />
<br />
*Less common:<br />
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Metabolic & Nutritional======<br />
*Common:<br />
:*Peripheral edema<br />
<br />
*Less common:<br />
Increased [[creatinine]], [[gout]], [[hyperlipemia]], [[hyperuricemia]].<br />
<br />
======Musculoskeletal======<br />
<br />
*Common:<br />
:*Myalgia<br />
<br />
*Less common:<br />
[[Arthralgia]], bone pain, [[bursitis]].<br />
<br />
<br />
<br />
<br />
======Miscellaneous======<br />
Less common adverse reactions:<br />
<br />
*'''Endocrine:''' [[Diabetes mellitus]].<br />
<br />
*'''Hemic and Lymphatic:''' [[Anemia]], [[ecchymosis]],[[ iron deficiency anemia]], [[polycythemia]], [[purpura]].<br />
<br />
*'''Skin and Appendages:''' Dry skin, [[furunculosis]], skin hypertrophy, [[urticaria]].<br />
<br />
*'''Special Senses:''' [[Amblyopia]], [[blindness]], [[conjunctivitis]], [[diplopia]], ear pain, eye haemorrhage, [[retinal haemorrhage]], [[tinnitus]].<br />
<br />
*'''Urogenital:''' [[Albuminuria]], [[cystitis]], [[urinary frequency]], vaginal haemorrhage, vaginitis.<br />
<br />
===Postmarketing Experience===<br />
<br />
The following events have been reported spontaneously from worldwide post-marketing experience since the launch of PLETAL in the US.<br />
<br />
======Blood and lymphatic system disorders:======<br />
[[Agranulocytosis]],[[ aplastic anemia]], [[granulocytopenia]], [[pancytopenia]], [[thrombocytopenia]], [[leukopenia]], <br />
[[bleeding tendency]]<br />
<br />
======Cardiac disorders:======<br />
<br />
[[Torsades de pointes]], [[QT prolongation|QTc prolongation]] (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. [[complete atrioventricular block]], c[[ardiac failure ]]and [[bradyarrythmia]], when treated with cilostazol. Cilostazol was used "off label" due to its positive [[chronotropic]] action)<br />
<br />
======Gastrointestinal disorders:======<br />
<br />
*Gastrointestinal haemorrhage<br />
<br />
======General disorders and administration site conditions:======<br />
<br />
*Pain<br />
*[[chest pain]] <br />
*[[hot flushes]]<br />
<br />
======Hepatobiliary disorders:======<br />
<br />
*Hepatic dysfunction/abnormal liver function tests <br />
*[[jaundice]]<br />
<br />
======Injury, poisoning and procedural complications:======<br />
<br />
*Extradural [[haematoma ]] <br />
*Subdural haematoma<br />
<br />
=====Investigations:=====<br />
<br />
*[[Blood glucose]] increased, blood [[uric acid]] increased, [[platelet count]] decreased, [[white blood cell count]] decreased, increase in [[BUN]] (blood urea increased), blood pressure increase<br />
<br />
======Nervous system disorders:======<br />
<br />
*[[Intracranial haemorrhage]] <br />
*[[cerebral haemorrhage]] <br />
*[[cerebrovascular accident]]<br />
<br />
======Respiratory, thoracic and mediastinal disorders:======<br />
<br />
*Pulmonary haemorrhage<br />
*[[ interstitial pneumonia]]<br />
<br />
'''Skin and subcutaneous tissue disorders:'''<br />
<br />
*Haemorrhage subcutaneous, [[pruritus]], skin eruptions including [[Stevens-Johnson syndrome]], skin drug eruption ([[dermatitis medicamentosa]])<br />
<br />
======Vascular disorders:======<br />
<br />
*Subacute [[thrombosis ]](these cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting)<br />
<br />
==Drug Interactions==<br />
<br />
=====Aspirin=====<br />
<br />
*Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of ADP-induced ex vivo platelet aggregation by 22% to 37% when compared to either aspirin or cilostazol alone. Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to cilostazol alone and by 48% compared to aspirin alone. However, short-term co-administration of aspirin with cilostazol had no clinically significant impact on PT, aPTT or bleeding time compared to aspirin alone. <br />
*Effects of long-term co-administration in the general population are unknown. In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was co-administered with cilostazol to 201 patients. The most frequent doses and mean durations of aspirin therapy were 75 mg to 81 mg daily for 137 days (107 patients) and 325 mg daily for 54 days (85 patients). There was no apparent increase in incidence of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.<br />
(Description)<br />
<br />
=====Warfarin=====<br />
<br />
The cytochrome P-450 isoenzymes involved in the metabolism of R-warfarin are CYP3A4, CYP1A2 and CYP2C19 and in the metabolism of S-warfarin, CYP2C9. Cilostazol did not inhibit either the metabolism or the pharmacologic effects (PT, aPTT, bleeding time or platelet aggregation) of R- and S-warfarin after a single 25-mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and cilostazol on the pharmacokinetics and pharmacodynamics of both drugs is unknown.<br />
<br />
=====Clopidogrel=====<br />
<br />
Multiple doses of clopidogrel do not significantly increase steady state plasma concentrations of cilostazol.<br />
<br />
=====Inhibitors of CYP3A4=====<br />
<br />
======Strong Inhibitors of CYP3A4======<br />
<br />
A priming dose of [[ketoconazole ]]400 mg (a strong inhibitor of CYP3A4), was given one day prior to co-administration of single doses of [[ketoconazole ]]400 mg and cilostazol 100 mg. This regimen increased cilostazol Cmax by 94% and AUC by 117%. Other strong inhibitors of CYP3A4, such as [[itraconazole]], [[fluconazole]], [[miconazole]], [[fluvoxamine]], [[fluoxetine]], [[nefazodone ]]and [[sertraline]], would be expected to have a similar effect <br />
<br />
======Moderate Inhibitors of CYP3A4======<br />
<br />
*[[Erythromycin ]]and Other [[Macrolide ]]Antibiotics: [[Erythromycin ]]is a moderately strong inhibitor of CYP3A4. Co-administration of erythromycin 500 mg q 8h with a single dose of cilostazol 100 mg increased cilostazol Cmax by 47% and AUC by 73%. Inhibition of cilostazol metabolism by erythromycin increased the AUC of 4´-trans-hydroxy-cilostazol by 141%. Other macrolide antibiotics (e.g., [[clarithromycin]]), but not all (e.g., [[azithromycin]]), would be expected to have a similar effect.<br />
<br />
*Diltiazem: [[Diltiazem]] 180 mg decreased the clearance of cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC increased ~40%.<br />
<br />
*Grapefruit Juice: [[Grapefruit juice]] increased the Cmax of cilostazol by ~50% , but had no effect on AUC.<br />
=====Inhibitors of CYP2C19=====<br />
<br />
[[Omeprazole]]: Co-administration of omeprazole did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%, probably the result of omeprazole’s potent inhibition of CYP2C19 <br />
<br />
=====Quinidine =====<br />
<br />
Concomitant administration of [[quinidine ]]with a single dose of cilostazol 100 mg did not alter cilostazol pharmacokinetics.<br />
<br />
=====Lovastatin=====<br />
<br />
The concomitant administration of [[lovastatin ]]with cilostazol decreases cilostazol Css, max and AUCT by 15%. There is also a decrease, although nonsignificant, in cilostazol metabolite concentrations. Co-administration of cilostazol with lovastatin increases lovastatin and β–hydroxy lovastatin AUC approximately 70%. This is most likely clinically insignificant.<br />
<br />
==Use in Specific Populations==<br />
<br />
====Pregnancy====<br />
<br />
* '''[[Pregnancy category#United States|Pregnancy Category (FDA)]]: C'''<br />
<br />
* '''[[Pregnancy category#Australia|Pregnancy Category (AUS)]]: {{PAGENAME}} is not included in Australian Drug Evaluation Committee (ADEC) Pregnancy Categories.'''<br />
<br />
In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
<br />
====Labor and Delivery====<br />
<br />
(Description)<br />
<br />
====Nursing Mothers====<br />
<br />
Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
<br />
====Pediatric Use====<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
====Geriatric Use====<br />
Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
====Gender====<br />
<br />
The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range<br />
<br />
====Race====<br />
<br />
(Description)<br />
<br />
====Renal Impairment====<br />
<br />
Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
<br />
====Hepatic Impairment====<br />
<br />
Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
<br />
====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the exposure in humans at the MRHD.<br />
<br />
====Immunocompromised Patients====<br />
<br />
(Description)<br />
<br />
====Miscellaneous====<br />
<br />
=====Smokers=====<br />
Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
<br />
==Administration and Monitoring==<br />
<br />
====Administration====<br />
<br />
Oral<br />
<br />
====Monitoring====<br />
<br />
<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability).<br />
<br />
==IV Compatibility==<br />
<br />
FDA package insert doesn't contain any information regarding '''IV Compatibility'''<br />
<br />
==Overdosage==<br />
<br />
===Acute Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
<br />
====Management====<br />
<br />
(Description)<br />
<br />
===Chronic Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
(Description)<br />
<br />
====Management====<br />
<br />
(Description)<br />
<br />
==Pharmacology==<br />
<br />
{{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
<br />
===Mechanism of Action===<br />
<br />
The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
<br />
===Structure===<br />
<br />
*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
<br />
<br />
===Pharmacodynamics===<br />
<br />
(Description)<br />
<br />
===Pharmacokinetics===<br />
<br />
Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
<br />
====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4‑dehydro‑cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4‑dehydro‑cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
<br />
===Nonclinical Toxicology===<br />
<br />
==Clinical Studies==<br />
<br />
*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
<br />
{|<br />
| [[image:Cilo2.png|400px|thumb]]<br />
|}<br />
<br />
<br />
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
<br />
==How Supplied==<br />
<br />
'''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
<br />
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0223-60 bottles of 60 and 0185-0223-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
==Images==<br />
<br />
===Drug Images===<br />
<br />
{|<br />
| [[File:Cilostazol50mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 50 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;123 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
{|<br />
| [[File:Cilostazol100mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 100 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;223 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
===Package and Label Display Panel===<br />
<br />
Sandoz Inc.<br />
Princeton, NJ 08540<br />
OS8128<br />
Rev. 02/13<br />
MF0223REV02/13<br />
Cilostazol 100mg Tablet<br />
<br />
{|<br />
| [[image:Cilostazollabel.jpg|400px|thumb]]<br />
|}<br />
<br />
{|<br />
| [[image:Cilostazollabel1.png|400px|thumb]]<br />
|}<br />
<br />
==Patient Information==<br />
<br />
===Patient Information from FDA===<br />
(sil-OS-tah-zol)<br />
<br />
Please read this leaflet before you start taking cilostazol tablets and each time you renew it in case anything has changed. This leaflet does not replace careful discussions with your doctor. You and your doctor should discuss cilostazol when you start taking it and at regular check-ups. You should follow your doctor’s advice about when to have check-ups.<br />
What is cilostazol for?<br />
Cilostazol may improve the symptoms of patients with a medical condition called intermittent claudication.<br />
What is intermittent claudication?<br />
Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. It occurs because narrowing or blockage of the arteries decreases blood flow to the legs. The decreased blood flow does not supply enough oxygen to the leg muscles during walking, resulting in these painful leg cramps.<br />
<br />
'''What treatments are available for intermittent claudication?'''<br />
<br />
The three main treatments available for intermittent claudication are:<br />
*Exercise. Your doctor may advise an exercise program.<br />
*Medication. Your doctor may prescribe a medication such as cilostazol. (See Who should not take cilostazol tablets?)<br />
*Surgery. Your doctor may recommend a surgical procedure to bypass the blocked segment of the artery. Another procedure is called a percutaneous transluminal angioplasty. In this procedure, a catheter (a flexible tube) is inserted into the artery to reduce the blockage and improve blood flow.<br />
<br />
'''How does cilostazol work?'''<br />
<br />
*The exact way that many drugs work is not well understood. Although how cilostazol works is not completely clear, its main effects are to dilate (widen) the arteries supplying blood to the legs and to decrease the ability of platelets in the blood to stick together. Platelets are particles that circulate in the blood and play a role in clotting.<br />
*Cilostazol may reduce the leg pain that patients with intermittent claudication experience, allowing them to walk farther before their leg pain occurs.<br />
*Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks. If you have not noticed any benefit from cilostazol tablets after 12 weeks you and your doctor may wish to discuss other forms of treatment.<br />
*Sometimes blood vessel disease of the legs causes pain at rest or breakdown of skin in the leg. Cilostazol has not been shown to work in patients with these problems.<br />
<br />
'''Who should not take cilostazol tablets?'''<br />
<br />
*Patients who have congestive heart failure (CHF) must not take cilostazol tablets. The most common symptoms of CHF are shortness of breath and swelling of the legs. However, other conditions may also cause these symptoms. It is important that you discuss with your doctor whether you have CHF.<br />
*Over 1,300 patients took cilostazol in studies that lasted for 3 to 6 months. The mortality rate in these patients was similar to placebo (less than 1%). These studies were too small to be sure there is not some increased risk of dying with longer use or in patients sicker than those in the studies.<br />
<br />
'''How should cilostazol tablets be taken?'''<br />
<br />
*Follow your doctor’s advice about how to take cilostazol tablets.<br />
*You should take cilostazol tablets twice a day, at least one half-hour before or two hours after breakfast and dinner. Take cilostazol tablets at about the same times each day.<br />
*Do not share cilostazol tablets with anyone else. It was prescribed only for you.<br />
*Keep cilostazol tablets and all drugs out of the reach of children.<br />
<br />
'''Can cilostazol tablets be taken with other drugs?'''<br />
<br />
Certain drugs and foods can increase the amount of cilostazol in the blood. Because of this, your doctor may adjust your dose of cilostazol or even stop it if you are taking or are going to take one of the following medications.<br />
Drugs Interacting with Cilostazol<br />
Generic Name (Brand Names)Type of Drug<br />
[[erythromycin]] (such as E.E.S.®, Erythrocin®) Antibiotic<br />
[[ketoconazole]] (Nizoral®), [[itraconazole]] (Sporanox®) Antifungal<br />
[[diltiazem]] (Cardizem®) Antihypertensive<br />
[[omeprazole]] (Prilosec®) Gastric acid reducer<br />
This list does not include every drug that may interact with cilostazol tablets. Therefore, you should tell your doctor about all medications that you are taking, including vitamins, herbal supplements and over-the-counter drugs you can buy without a prescription. You should also check with your doctor before taking a new medication after you have begun cilostazol tablets.<br />
<br />
'''What are the possible side effects of cilostazol tablets?'''<br />
<br />
Cilostazol tablets may cause side effects including headache, diarrhea, abnormal stools, increased heart rate and palpitations.<br />
You should discuss possible side effects with your doctor before taking cilostazol tablets and any time you think you are having a side effect.<br />
This provides only a summary of information about cilostazol tablets. If you have any questions about cilostazol tablets, talk to your doctor.<br />
'''Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.'''<br />
<br />
===Patient Information from NLM===<br />
<br />
For patient information about Cilostazol from NLM, click [[Cilostazol (patient information)|here]].<br />
<br />
==Precautions with Alcohol==<br />
<br />
Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
<br />
==Brand Names==<br />
<br />
Cilostazol®, Platel®.<br />
<br />
==Look-Alike Drug Names==<br />
<br />
* (Paired Confused Name 1a) — (Paired Confused Name 1b)<br />
* (Paired Confused Name 2a) — (Paired Confused Name 2b)<br />
* (Paired Confused Name 3a) — (Paired Confused Name 3b)<br />
<br />
==[http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm Drug Shortage Status]==<br />
<br />
==[http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price Price]==<br />
<br />
==References==<br />
<br />
{{reflist}}<br />
<br />
</div></div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=Cilostazol&diff=961808Cilostazol2014-04-02T15:38:05Z<p>Abdurahman Khalil: /* Drug Interactions */</p>
<hr />
<div>{|class="infobox" style="position: fixed; top: 180px; right: 20px; margin: 0 0 0 0; border: 0; float: right; width: 15%; background: #104E8B; border-radius: 10px 10px 10px 10px;" cellpadding="0" cellspacing="0";<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #104E8B;" | [[{{PAGENAME}}|{{fontcolor|#F8F8FF|{{PAGENAME}}®}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #000000; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|Black Box Warning}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adult Indications and Dosage|{{fontcolor|#F8F8FF|Adult Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pediatric Indications and Dosage|{{fontcolor|#F8F8FF|Pediatric Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Contraindications|{{fontcolor|#F8F8FF|Contraindications}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Warnings|{{fontcolor|#F8F8FF|Warnings}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adverse Reactions|{{fontcolor|#F8F8FF|Adverse Reactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Drug Interactions|{{fontcolor|#F8F8FF|Drug Interactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Use in Specific Populations|{{fontcolor|#F8F8FF|Use in Specific Populations}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Administration and Monitoring|{{fontcolor|#F8F8FF|Administration and Monitoring}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#IV Compatibility|{{fontcolor|#F8F8FF|IV Compatibility}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Overdosage|{{fontcolor|#F8F8FF|Overdosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pharmacology|{{fontcolor|#F8F8FF|Pharmacology}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Clinical Studies|{{fontcolor|#F8F8FF|Clinical Studies}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#How Supplied|{{fontcolor|#F8F8FF|How Supplied}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Images|{{fontcolor|#F8F8FF|Images}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Patient Information|{{fontcolor|#F8F8FF|Patient information}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Precautions with Alcohol|{{fontcolor|#F8F8FF|Precautions with Alcohol}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Brand Names|{{fontcolor|#F8F8FF|Brand Names}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Look-Alike Drug Names|{{fontcolor|#F8F8FF|Look-Alike Drug Names}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm {{fontcolor|#F8F8FF|Drug Shortage Status}}]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price {{fontcolor|#F8F8FF|Price}}]<br />
|-<br />
|}<br />
<div style="width: 80%"><br />
__NOTOC__<br />
{{CMG}}<br />
<br />
{{SB}} Cilostazol®, Pletal®<br />
<br />
==Disclaimer==<br />
<br />
'''''WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature. The information provided is not a medical advice or treatment. WikiDoc does not promote any medication or off-label use of drugs. Please read our full disclaimer [[wikidoc:General_disclaimer|{{fontcolor|#FF0000|here}}]].'''''<br />
<br />
==<span style="color:#FF0000; background:#000000;">Black Box Warning</span>==<br />
<br />
FDA Package Insert for {{PAGENAME}} contains no information regarding ''Black Box Warning''.<br />
<br />
{| style="border: 3px solid #696969;"<br />
| style="background: #000000; border: 0px; padding: 20px 20px; width: 800px;" |<br />
<center><br />
<font color="#F8F8FF" style="font-weight: bold;">CONTRAINDICATION</font><br />
</center><br />
<br />
<center><br />
<font color="#F8F8FF" size="1" style="font-style: italic;">See full prescribing information for complete boxed warning.</font><br />
</center><br />
<br />
<font color="#F8F8FF" style="font-weight: bold;"><br />
''{{fontcolor|#FF0000|Condition Name:}}'' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
</font><br />
|}<br />
<br />
==Overview==<br />
<br />
{{PAGENAME}} is a_Phosphodiesterase 3 Inhibitor drug that is FDA approved for the treatment of intermittent claudication. There is a Black Box Warning for this drug as shown <span style="background:#000000;">'''[[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|here}}]]'''</span>. Common adverse reactions include headache, dizziness, palpitation, diarrhea, rhinitis and pharyngitis.<br />
<br />
==Adult Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Adult)===<br />
<br />
=====Intermittent claudication=====<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
===Off-Label Use and Dosage (Adult)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* There is limited information about ''Off-Label Non–Guideline-Supported Use'' of {{PAGENAME}} in adult patients.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Pediatric Indications and Dosage==<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
==Contraindications==<br />
* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
<br />
==Warnings==<br />
<br />
=====Conidition 1=====<br />
<br />
(Description)<br />
<br />
=====Conidition 2=====<br />
<br />
(Description)<br />
<br />
=====Conidition 3=====<br />
<br />
(Description)<br />
<br />
==Adverse Reactions==<br />
<br />
===Clinical Trials Experience===<br />
Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol and 134 days for patients on placebo.<br />
<br />
The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with PLETAL 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included [[palpitation ]]and [[diarrhea]], both 1.1% for cilostazol (all doses) versus 0.1% for placebo.<br />
<br />
======Body as a Whole======<br />
*Common:<br />
:*Abdominal pain<br />
:*Back pain<br />
:*Headache <br />
:*Infection<br />
<br />
*Less common:<br />
[[Chills]], face [[edema]], [[fever]], [[generalized edema]], [[malaise]], [[neck rigidity]], [[pelvic pain]], [[retroperitoneal haemorrhage]].<br />
<br />
======Central Nervous System======<br />
<br />
*Common:<br />
:*Dizziness<br />
:*Vertigo<br />
<br />
*Less common:<br />
[[Anxiety]], [[insomnia]], [[neuralgia]].<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
*Common:<br />
:*Abnormal stool<br />
:*Diarrhea<br />
:*Dyspepsia<br />
:*Flatulence<br />
:*Nausea<br />
<br />
*Less common:<br />
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Metabolic & Nutritional======<br />
*Common:<br />
:*Peripheral edema<br />
<br />
*Less common:<br />
Increased [[creatinine]], [[gout]], [[hyperlipemia]], [[hyperuricemia]].<br />
<br />
======Musculoskeletal======<br />
<br />
*Common:<br />
:*Myalgia<br />
<br />
*Less common:<br />
[[Arthralgia]], bone pain, [[bursitis]].<br />
<br />
<br />
<br />
<br />
======Miscellaneous======<br />
Less common adverse reactions:<br />
<br />
*'''Endocrine:''' [[Diabetes mellitus]].<br />
<br />
*'''Hemic and Lymphatic:''' [[Anemia]], [[ecchymosis]],[[ iron deficiency anemia]], [[polycythemia]], [[purpura]].<br />
<br />
*'''Skin and Appendages:''' Dry skin, [[furunculosis]], skin hypertrophy, [[urticaria]].<br />
<br />
*'''Special Senses:''' [[Amblyopia]], [[blindness]], [[conjunctivitis]], [[diplopia]], ear pain, eye haemorrhage, [[retinal haemorrhage]], [[tinnitus]].<br />
<br />
*'''Urogenital:''' [[Albuminuria]], [[cystitis]], [[urinary frequency]], vaginal haemorrhage, vaginitis.<br />
<br />
===Postmarketing Experience===<br />
<br />
The following events have been reported spontaneously from worldwide post-marketing experience since the launch of PLETAL in the US.<br />
<br />
======Blood and lymphatic system disorders:======<br />
[[Agranulocytosis]],[[ aplastic anemia]], [[granulocytopenia]], [[pancytopenia]], [[thrombocytopenia]], [[leukopenia]], <br />
[[bleeding tendency]]<br />
<br />
======Cardiac disorders:======<br />
<br />
[[Torsades de pointes]], [[QT prolongation|QTc prolongation]] (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. [[complete atrioventricular block]], c[[ardiac failure ]]and [[bradyarrythmia]], when treated with cilostazol. Cilostazol was used "off label" due to its positive [[chronotropic]] action)<br />
<br />
======Gastrointestinal disorders:======<br />
<br />
*Gastrointestinal haemorrhage<br />
<br />
======General disorders and administration site conditions:======<br />
<br />
*Pain<br />
*[[chest pain]] <br />
*[[hot flushes]]<br />
<br />
======Hepatobiliary disorders:======<br />
<br />
*Hepatic dysfunction/abnormal liver function tests <br />
*[[jaundice]]<br />
<br />
======Injury, poisoning and procedural complications:======<br />
<br />
*Extradural [[haematoma ]] <br />
*Subdural haematoma<br />
<br />
=====Investigations:=====<br />
<br />
*[[Blood glucose]] increased, blood [[uric acid]] increased, [[platelet count]] decreased, [[white blood cell count]] decreased, increase in [[BUN]] (blood urea increased), blood pressure increase<br />
<br />
======Nervous system disorders:======<br />
<br />
*[[Intracranial haemorrhage]] <br />
*[[cerebral haemorrhage]] <br />
*[[cerebrovascular accident]]<br />
<br />
======Respiratory, thoracic and mediastinal disorders:======<br />
<br />
*Pulmonary haemorrhage<br />
*[[ interstitial pneumonia]]<br />
<br />
'''Skin and subcutaneous tissue disorders:'''<br />
<br />
*Haemorrhage subcutaneous, [[pruritus]], skin eruptions including [[Stevens-Johnson syndrome]], skin drug eruption ([[dermatitis medicamentosa]])<br />
<br />
======Vascular disorders:======<br />
<br />
*Subacute [[thrombosis ]](these cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting)<br />
<br />
==Drug Interactions==<br />
<br />
=====Aspirin=====<br />
<br />
*Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of ADP-induced ex vivo platelet aggregation by 22% to 37% when compared to either aspirin or cilostazol alone. Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to cilostazol alone and by 48% compared to aspirin alone. However, short-term co-administration of aspirin with cilostazol had no clinically significant impact on PT, aPTT or bleeding time compared to aspirin alone. <br />
*Effects of long-term co-administration in the general population are unknown. In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was co-administered with cilostazol to 201 patients. The most frequent doses and mean durations of aspirin therapy were 75 mg to 81 mg daily for 137 days (107 patients) and 325 mg daily for 54 days (85 patients). There was no apparent increase in incidence of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.<br />
(Description)<br />
<br />
=====Warfarin=====<br />
<br />
The cytochrome P-450 isoenzymes involved in the metabolism of R-warfarin are CYP3A4, CYP1A2 and CYP2C19 and in the metabolism of S-warfarin, CYP2C9. Cilostazol did not inhibit either the metabolism or the pharmacologic effects (PT, aPTT, bleeding time or platelet aggregation) of R- and S-warfarin after a single 25-mg dose of warfarin. The effect of concomitant multiple dosing of warfarin and cilostazol on the pharmacokinetics and pharmacodynamics of both drugs is unknown.<br />
<br />
=====Clopidogrel=====<br />
<br />
Multiple doses of clopidogrel do not significantly increase steady state plasma concentrations of cilostazol.<br />
<br />
=====Inhibitors of CYP3A4=====<br />
<br />
======Strong Inhibitors of CYP3A4======<br />
<br />
A priming dose of [[ketoconazole ]]400 mg (a strong inhibitor of CYP3A4), was given one day prior to co-administration of single doses of [[ketoconazole ]]400 mg and cilostazol 100 mg. This regimen increased cilostazol Cmax by 94% and AUC by 117%. Other strong inhibitors of CYP3A4, such as [[itraconazole]], [[fluconazole]], [[miconazole]], [[fluvoxamine]], [[fluoxetine]], [[nefazodone ]]and [[sertraline]], would be expected to have a similar effect <br />
<br />
======Moderate Inhibitors of CYP3A4======<br />
<br />
*[[Erythromycin ]]and Other [[Macrolide ]]Antibiotics: [[Erythromycin ]]is a moderately strong inhibitor of CYP3A4. Co-administration of erythromycin 500 mg q 8h with a single dose of cilostazol 100 mg increased cilostazol Cmax by 47% and AUC by 73%. Inhibition of cilostazol metabolism by erythromycin increased the AUC of 4´-trans-hydroxy-cilostazol by 141%. Other macrolide antibiotics (e.g., [[clarithromycin]]), but not all (e.g., [[azithromycin]]), would be expected to have a similar effect.<br />
<br />
*Diltiazem: [[Diltiazem]] 180 mg decreased the clearance of cilostazol by ~30%. Cilostazol Cmax increased ~30% and AUC increased ~40%.<br />
<br />
*Grapefruit Juice: [[Grapefruit juice]] increased the Cmax of cilostazol by ~50% , but had no effect on AUC.<br />
=====Inhibitors of CYP2C19=====<br />
<br />
[[Omeprazole]]: Co-administration of omeprazole did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%, probably the result of omeprazole’s potent inhibition of CYP2C19 <br />
<br />
=====Quinidine =====<br />
<br />
Concomitant administration of [[quinidine ]]with a single dose of cilostazol 100 mg did not alter cilostazol pharmacokinetics.<br />
<br />
=====Lovastatin=====<br />
<br />
The concomitant administration of [[lovastatin ]]with cilostazol decreases cilostazol Css, max and AUCT by 15%. There is also a decrease, although nonsignificant, in cilostazol metabolite concentrations. Co-administration of cilostazol with lovastatin increases lovastatin and β–hydroxy lovastatin AUC approximately 70%. This is most likely clinically insignificant.<br />
<br />
==Use in Specific Populations==<br />
<br />
====Pregnancy====<br />
<br />
* '''[[Pregnancy category#United States|Pregnancy Category (FDA)]]: C'''<br />
<br />
* '''[[Pregnancy category#Australia|Pregnancy Category (AUS)]]: {{PAGENAME}} is not included in Australian Drug Evaluation Committee (ADEC) Pregnancy Categories.'''<br />
<br />
In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
<br />
====Labor and Delivery====<br />
<br />
(Description)<br />
<br />
====Nursing Mothers====<br />
<br />
Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
<br />
====Pediatric Use====<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
====Geriatric Use====<br />
Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
====Gender====<br />
<br />
The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range<br />
<br />
====Race====<br />
<br />
(Description)<br />
<br />
====Renal Impairment====<br />
<br />
Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
<br />
====Hepatic Impairment====<br />
<br />
Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
<br />
====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the exposure in humans at the MRHD.<br />
<br />
====Immunocompromised Patients====<br />
<br />
(Description)<br />
<br />
====Miscellaneous====<br />
<br />
=====Smokers=====<br />
Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
<br />
==Administration and Monitoring==<br />
<br />
====Administration====<br />
<br />
Oral<br />
<br />
====Monitoring====<br />
<br />
<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability).<br />
<br />
==IV Compatibility==<br />
<br />
FDA package insert doesn't contain any information regarding '''IV Compatibility'''<br />
<br />
==Overdosage==<br />
<br />
===Acute Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
<br />
====Management====<br />
<br />
(Description)<br />
<br />
===Chronic Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
(Description)<br />
<br />
====Management====<br />
<br />
(Description)<br />
<br />
==Pharmacology==<br />
<br />
{{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
<br />
===Mechanism of Action===<br />
<br />
The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
<br />
===Structure===<br />
<br />
*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
<br />
<br />
===Pharmacodynamics===<br />
<br />
(Description)<br />
<br />
===Pharmacokinetics===<br />
<br />
Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
<br />
====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4‑dehydro‑cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4‑dehydro‑cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
<br />
===Nonclinical Toxicology===<br />
<br />
==Clinical Studies==<br />
<br />
*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
<br />
{|<br />
| [[image:Cilo2.png|400px|thumb]]<br />
|}<br />
<br />
<br />
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
<br />
==How Supplied==<br />
<br />
'''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
<br />
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0223-60 bottles of 60 and 0185-0223-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
==Images==<br />
<br />
===Drug Images===<br />
<br />
{|<br />
| [[File:Cilostazol50mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 50 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;123 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
{|<br />
| [[File:Cilostazol100mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 100 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;223 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
===Package and Label Display Panel===<br />
<br />
Sandoz Inc.<br />
Princeton, NJ 08540<br />
OS8128<br />
Rev. 02/13<br />
MF0223REV02/13<br />
Cilostazol 100mg Tablet<br />
<br />
{|<br />
| [[image:Cilostazollabel.jpg|400px|thumb]]<br />
|}<br />
<br />
{|<br />
| [[image:Cilostazollabel1.png|400px|thumb]]<br />
|}<br />
<br />
==Patient Information==<br />
<br />
===Patient Information from FDA===<br />
(sil-OS-tah-zol)<br />
<br />
Please read this leaflet before you start taking cilostazol tablets and each time you renew it in case anything has changed. This leaflet does not replace careful discussions with your doctor. You and your doctor should discuss cilostazol when you start taking it and at regular check-ups. You should follow your doctor’s advice about when to have check-ups.<br />
What is cilostazol for?<br />
Cilostazol may improve the symptoms of patients with a medical condition called intermittent claudication.<br />
What is intermittent claudication?<br />
Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. It occurs because narrowing or blockage of the arteries decreases blood flow to the legs. The decreased blood flow does not supply enough oxygen to the leg muscles during walking, resulting in these painful leg cramps.<br />
<br />
'''What treatments are available for intermittent claudication?'''<br />
<br />
The three main treatments available for intermittent claudication are:<br />
*Exercise. Your doctor may advise an exercise program.<br />
*Medication. Your doctor may prescribe a medication such as cilostazol. (See Who should not take cilostazol tablets?)<br />
*Surgery. Your doctor may recommend a surgical procedure to bypass the blocked segment of the artery. Another procedure is called a percutaneous transluminal angioplasty. In this procedure, a catheter (a flexible tube) is inserted into the artery to reduce the blockage and improve blood flow.<br />
<br />
'''How does cilostazol work?'''<br />
<br />
*The exact way that many drugs work is not well understood. Although how cilostazol works is not completely clear, its main effects are to dilate (widen) the arteries supplying blood to the legs and to decrease the ability of platelets in the blood to stick together. Platelets are particles that circulate in the blood and play a role in clotting.<br />
*Cilostazol may reduce the leg pain that patients with intermittent claudication experience, allowing them to walk farther before their leg pain occurs.<br />
*Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks. If you have not noticed any benefit from cilostazol tablets after 12 weeks you and your doctor may wish to discuss other forms of treatment.<br />
*Sometimes blood vessel disease of the legs causes pain at rest or breakdown of skin in the leg. Cilostazol has not been shown to work in patients with these problems.<br />
<br />
'''Who should not take cilostazol tablets?'''<br />
<br />
*Patients who have congestive heart failure (CHF) must not take cilostazol tablets. The most common symptoms of CHF are shortness of breath and swelling of the legs. However, other conditions may also cause these symptoms. It is important that you discuss with your doctor whether you have CHF.<br />
*Over 1,300 patients took cilostazol in studies that lasted for 3 to 6 months. The mortality rate in these patients was similar to placebo (less than 1%). These studies were too small to be sure there is not some increased risk of dying with longer use or in patients sicker than those in the studies.<br />
<br />
'''How should cilostazol tablets be taken?'''<br />
<br />
*Follow your doctor’s advice about how to take cilostazol tablets.<br />
*You should take cilostazol tablets twice a day, at least one half-hour before or two hours after breakfast and dinner. Take cilostazol tablets at about the same times each day.<br />
*Do not share cilostazol tablets with anyone else. It was prescribed only for you.<br />
*Keep cilostazol tablets and all drugs out of the reach of children.<br />
<br />
'''Can cilostazol tablets be taken with other drugs?'''<br />
<br />
Certain drugs and foods can increase the amount of cilostazol in the blood. Because of this, your doctor may adjust your dose of cilostazol or even stop it if you are taking or are going to take one of the following medications.<br />
Drugs Interacting with Cilostazol<br />
Generic Name (Brand Names)Type of Drug<br />
[[erythromycin]] (such as E.E.S.®, Erythrocin®) Antibiotic<br />
[[ketoconazole]] (Nizoral®), [[itraconazole]] (Sporanox®) Antifungal<br />
[[diltiazem]] (Cardizem®) Antihypertensive<br />
[[omeprazole]] (Prilosec®) Gastric acid reducer<br />
This list does not include every drug that may interact with cilostazol tablets. Therefore, you should tell your doctor about all medications that you are taking, including vitamins, herbal supplements and over-the-counter drugs you can buy without a prescription. You should also check with your doctor before taking a new medication after you have begun cilostazol tablets.<br />
<br />
'''What are the possible side effects of cilostazol tablets?'''<br />
<br />
Cilostazol tablets may cause side effects including headache, diarrhea, abnormal stools, increased heart rate and palpitations.<br />
You should discuss possible side effects with your doctor before taking cilostazol tablets and any time you think you are having a side effect.<br />
This provides only a summary of information about cilostazol tablets. If you have any questions about cilostazol tablets, talk to your doctor.<br />
'''Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.'''<br />
<br />
===Patient Information from NLM===<br />
<br />
For patient information about Cilostazol from NLM, click [[Cilostazol (patient information)|here]].<br />
<br />
==Precautions with Alcohol==<br />
<br />
Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
<br />
==Brand Names==<br />
<br />
Cilostazol®, Platel®.<br />
<br />
==Look-Alike Drug Names==<br />
<br />
* (Paired Confused Name 1a) — (Paired Confused Name 1b)<br />
* (Paired Confused Name 2a) — (Paired Confused Name 2b)<br />
* (Paired Confused Name 3a) — (Paired Confused Name 3b)<br />
<br />
==[http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm Drug Shortage Status]==<br />
<br />
==[http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price Price]==<br />
<br />
==References==<br />
<br />
{{reflist}}<br />
<br />
</div></div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=Cilostazol&diff=961794Cilostazol2014-04-02T15:24:34Z<p>Abdurahman Khalil: /* Drug 1 */</p>
<hr />
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|-<br />
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|-<br />
! style="font-size: 80%; padding: 0 5px; background: #000000; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|Black Box Warning}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adult Indications and Dosage|{{fontcolor|#F8F8FF|Adult Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pediatric Indications and Dosage|{{fontcolor|#F8F8FF|Pediatric Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Contraindications|{{fontcolor|#F8F8FF|Contraindications}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Warnings|{{fontcolor|#F8F8FF|Warnings}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adverse Reactions|{{fontcolor|#F8F8FF|Adverse Reactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Drug Interactions|{{fontcolor|#F8F8FF|Drug Interactions}}]]<br />
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|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Administration and Monitoring|{{fontcolor|#F8F8FF|Administration and Monitoring}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#IV Compatibility|{{fontcolor|#F8F8FF|IV Compatibility}}]]<br />
|-<br />
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<div style="width: 80%"><br />
__NOTOC__<br />
{{CMG}}<br />
<br />
{{SB}} Cilostazol®, Pletal®<br />
<br />
==Disclaimer==<br />
<br />
'''''WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature. The information provided is not a medical advice or treatment. WikiDoc does not promote any medication or off-label use of drugs. Please read our full disclaimer [[wikidoc:General_disclaimer|{{fontcolor|#FF0000|here}}]].'''''<br />
<br />
==<span style="color:#FF0000; background:#000000;">Black Box Warning</span>==<br />
<br />
FDA Package Insert for {{PAGENAME}} contains no information regarding ''Black Box Warning''.<br />
<br />
{| style="border: 3px solid #696969;"<br />
| style="background: #000000; border: 0px; padding: 20px 20px; width: 800px;" |<br />
<center><br />
<font color="#F8F8FF" style="font-weight: bold;">CONTRAINDICATION</font><br />
</center><br />
<br />
<center><br />
<font color="#F8F8FF" size="1" style="font-style: italic;">See full prescribing information for complete boxed warning.</font><br />
</center><br />
<br />
<font color="#F8F8FF" style="font-weight: bold;"><br />
''{{fontcolor|#FF0000|Condition Name:}}'' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
</font><br />
|}<br />
<br />
==Overview==<br />
<br />
{{PAGENAME}} is a_Phosphodiesterase 3 Inhibitor drug that is FDA approved for the treatment of intermittent claudication. There is a Black Box Warning for this drug as shown <span style="background:#000000;">'''[[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|here}}]]'''</span>. Common adverse reactions include headache, dizziness, palpitation, diarrhea, rhinitis and pharyngitis.<br />
<br />
==Adult Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Adult)===<br />
<br />
=====Intermittent claudication=====<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
===Off-Label Use and Dosage (Adult)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* There is limited information about ''Off-Label Non–Guideline-Supported Use'' of {{PAGENAME}} in adult patients.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Pediatric Indications and Dosage==<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
==Contraindications==<br />
* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
<br />
==Warnings==<br />
<br />
=====Conidition 1=====<br />
<br />
(Description)<br />
<br />
=====Conidition 2=====<br />
<br />
(Description)<br />
<br />
=====Conidition 3=====<br />
<br />
(Description)<br />
<br />
==Adverse Reactions==<br />
<br />
===Clinical Trials Experience===<br />
Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol and 134 days for patients on placebo.<br />
<br />
The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with PLETAL 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included [[palpitation ]]and [[diarrhea]], both 1.1% for cilostazol (all doses) versus 0.1% for placebo.<br />
<br />
======Body as a Whole======<br />
*Common:<br />
:*Abdominal pain<br />
:*Back pain<br />
:*Headache <br />
:*Infection<br />
<br />
*Less common:<br />
[[Chills]], face [[edema]], [[fever]], [[generalized edema]], [[malaise]], [[neck rigidity]], [[pelvic pain]], [[retroperitoneal haemorrhage]].<br />
<br />
======Central Nervous System======<br />
<br />
*Common:<br />
:*Dizziness<br />
:*Vertigo<br />
<br />
*Less common:<br />
[[Anxiety]], [[insomnia]], [[neuralgia]].<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
*Common:<br />
:*Abnormal stool<br />
:*Diarrhea<br />
:*Dyspepsia<br />
:*Flatulence<br />
:*Nausea<br />
<br />
*Less common:<br />
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Metabolic & Nutritional======<br />
*Common:<br />
:*Peripheral edema<br />
<br />
*Less common:<br />
Increased [[creatinine]], [[gout]], [[hyperlipemia]], [[hyperuricemia]].<br />
<br />
======Musculoskeletal======<br />
<br />
*Common:<br />
:*Myalgia<br />
<br />
*Less common:<br />
[[Arthralgia]], bone pain, [[bursitis]].<br />
<br />
<br />
<br />
<br />
======Miscellaneous======<br />
Less common adverse reactions:<br />
<br />
*'''Endocrine:''' [[Diabetes mellitus]].<br />
<br />
*'''Hemic and Lymphatic:''' [[Anemia]], [[ecchymosis]],[[ iron deficiency anemia]], [[polycythemia]], [[purpura]].<br />
<br />
*'''Skin and Appendages:''' Dry skin, [[furunculosis]], skin hypertrophy, [[urticaria]].<br />
<br />
*'''Special Senses:''' [[Amblyopia]], [[blindness]], [[conjunctivitis]], [[diplopia]], ear pain, eye haemorrhage, [[retinal haemorrhage]], [[tinnitus]].<br />
<br />
*'''Urogenital:''' [[Albuminuria]], [[cystitis]], [[urinary frequency]], vaginal haemorrhage, vaginitis.<br />
<br />
===Postmarketing Experience===<br />
<br />
The following events have been reported spontaneously from worldwide post-marketing experience since the launch of PLETAL in the US.<br />
<br />
======Blood and lymphatic system disorders:======<br />
[[Agranulocytosis]],[[ aplastic anemia]], [[granulocytopenia]], [[pancytopenia]], [[thrombocytopenia]], [[leukopenia]], <br />
[[bleeding tendency]]<br />
<br />
======Cardiac disorders:======<br />
<br />
[[Torsades de pointes]], [[QT prolongation|QTc prolongation]] (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. [[complete atrioventricular block]], c[[ardiac failure ]]and [[bradyarrythmia]], when treated with cilostazol. Cilostazol was used "off label" due to its positive [[chronotropic]] action)<br />
<br />
======Gastrointestinal disorders:======<br />
<br />
*Gastrointestinal haemorrhage<br />
<br />
======General disorders and administration site conditions:======<br />
<br />
*Pain<br />
*[[chest pain]] <br />
*[[hot flushes]]<br />
<br />
======Hepatobiliary disorders:======<br />
<br />
*Hepatic dysfunction/abnormal liver function tests <br />
*[[jaundice]]<br />
<br />
======Injury, poisoning and procedural complications:======<br />
<br />
*Extradural [[haematoma ]] <br />
*Subdural haematoma<br />
<br />
=====Investigations:=====<br />
<br />
*[[Blood glucose]] increased, blood [[uric acid]] increased, [[platelet count]] decreased, [[white blood cell count]] decreased, increase in [[BUN]] (blood urea increased), blood pressure increase<br />
<br />
======Nervous system disorders:======<br />
<br />
*[[Intracranial haemorrhage]] <br />
*[[cerebral haemorrhage]] <br />
*[[cerebrovascular accident]]<br />
<br />
======Respiratory, thoracic and mediastinal disorders:======<br />
<br />
*Pulmonary haemorrhage<br />
*[[ interstitial pneumonia]]<br />
<br />
'''Skin and subcutaneous tissue disorders:'''<br />
<br />
*Haemorrhage subcutaneous, [[pruritus]], skin eruptions including [[Stevens-Johnson syndrome]], skin drug eruption ([[dermatitis medicamentosa]])<br />
<br />
======Vascular disorders:======<br />
<br />
*Subacute [[thrombosis ]](these cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting)<br />
<br />
==Drug Interactions==<br />
<br />
* Drug 1<br />
* Drug 2<br />
* Drug 3<br />
* Drug 4<br />
* Drug 5<br />
<br />
=====Aspirin=====<br />
<br />
*Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of ADP-induced ex vivo platelet aggregation by 22% to 37% when compared to either aspirin or cilostazol alone. Short-term (<4 days) co-administration of aspirin with cilostazol increased the inhibition of arachidonic acid-induced ex vivo platelet aggregation by 20% compared to cilostazol alone and by 48% compared to aspirin alone. However, short-term co-administration of aspirin with cilostazol had no clinically significant impact on PT, aPTT or bleeding time compared to aspirin alone. <br />
*Effects of long-term co-administration in the general population are unknown. In eight randomized, placebo-controlled, double-blind clinical trials, aspirin was co-administered with cilostazol to 201 patients. The most frequent doses and mean durations of aspirin therapy were 75 mg to 81 mg daily for 137 days (107 patients) and 325 mg daily for 54 days (85 patients). There was no apparent increase in incidence of hemorrhagic adverse effects in patients taking cilostazol and aspirin compared to patients taking placebo and equivalent doses of aspirin.<br />
(Description)<br />
<br />
=====Drug 2=====<br />
<br />
(Description)<br />
<br />
=====Drug 3=====<br />
<br />
(Description)<br />
<br />
=====Drug 4=====<br />
<br />
(Description)<br />
<br />
=====Drug 5=====<br />
<br />
(Description)<br />
<br />
==Use in Specific Populations==<br />
<br />
====Pregnancy====<br />
<br />
* '''[[Pregnancy category#United States|Pregnancy Category (FDA)]]: C'''<br />
<br />
* '''[[Pregnancy category#Australia|Pregnancy Category (AUS)]]: {{PAGENAME}} is not included in Australian Drug Evaluation Committee (ADEC) Pregnancy Categories.'''<br />
<br />
In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
<br />
====Labor and Delivery====<br />
<br />
(Description)<br />
<br />
====Nursing Mothers====<br />
<br />
Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
<br />
====Pediatric Use====<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
====Geriatric Use====<br />
Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
====Gender====<br />
<br />
The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range<br />
<br />
====Race====<br />
<br />
(Description)<br />
<br />
====Renal Impairment====<br />
<br />
Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
<br />
====Hepatic Impairment====<br />
<br />
Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
<br />
====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the exposure in humans at the MRHD.<br />
<br />
====Immunocompromised Patients====<br />
<br />
(Description)<br />
<br />
====Miscellaneous====<br />
<br />
=====Smokers=====<br />
Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
<br />
==Administration and Monitoring==<br />
<br />
====Administration====<br />
<br />
Oral<br />
<br />
====Monitoring====<br />
<br />
<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability).<br />
<br />
==IV Compatibility==<br />
<br />
FDA package insert doesn't contain any information regarding '''IV Compatibility'''<br />
<br />
==Overdosage==<br />
<br />
===Acute Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
<br />
====Management====<br />
<br />
(Description)<br />
<br />
===Chronic Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
(Description)<br />
<br />
====Management====<br />
<br />
(Description)<br />
<br />
==Pharmacology==<br />
<br />
{{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
<br />
===Mechanism of Action===<br />
<br />
The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
<br />
===Structure===<br />
<br />
*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
<br />
<br />
===Pharmacodynamics===<br />
<br />
(Description)<br />
<br />
===Pharmacokinetics===<br />
<br />
Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
<br />
====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4‑dehydro‑cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4‑dehydro‑cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
<br />
===Nonclinical Toxicology===<br />
<br />
==Clinical Studies==<br />
<br />
*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
<br />
{|<br />
| [[image:Cilo2.png|400px|thumb]]<br />
|}<br />
<br />
<br />
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
<br />
==How Supplied==<br />
<br />
'''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
<br />
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0223-60 bottles of 60 and 0185-0223-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
==Images==<br />
<br />
===Drug Images===<br />
<br />
{|<br />
| [[File:Cilostazol50mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 50 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;123 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
{|<br />
| [[File:Cilostazol100mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 100 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;223 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
===Package and Label Display Panel===<br />
<br />
Sandoz Inc.<br />
Princeton, NJ 08540<br />
OS8128<br />
Rev. 02/13<br />
MF0223REV02/13<br />
Cilostazol 100mg Tablet<br />
<br />
{|<br />
| [[image:Cilostazollabel.jpg|400px|thumb]]<br />
|}<br />
<br />
{|<br />
| [[image:Cilostazollabel1.png|400px|thumb]]<br />
|}<br />
<br />
==Patient Information==<br />
<br />
===Patient Information from FDA===<br />
(sil-OS-tah-zol)<br />
<br />
Please read this leaflet before you start taking cilostazol tablets and each time you renew it in case anything has changed. This leaflet does not replace careful discussions with your doctor. You and your doctor should discuss cilostazol when you start taking it and at regular check-ups. You should follow your doctor’s advice about when to have check-ups.<br />
What is cilostazol for?<br />
Cilostazol may improve the symptoms of patients with a medical condition called intermittent claudication.<br />
What is intermittent claudication?<br />
Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. It occurs because narrowing or blockage of the arteries decreases blood flow to the legs. The decreased blood flow does not supply enough oxygen to the leg muscles during walking, resulting in these painful leg cramps.<br />
<br />
'''What treatments are available for intermittent claudication?'''<br />
<br />
The three main treatments available for intermittent claudication are:<br />
*Exercise. Your doctor may advise an exercise program.<br />
*Medication. Your doctor may prescribe a medication such as cilostazol. (See Who should not take cilostazol tablets?)<br />
*Surgery. Your doctor may recommend a surgical procedure to bypass the blocked segment of the artery. Another procedure is called a percutaneous transluminal angioplasty. In this procedure, a catheter (a flexible tube) is inserted into the artery to reduce the blockage and improve blood flow.<br />
<br />
'''How does cilostazol work?'''<br />
<br />
*The exact way that many drugs work is not well understood. Although how cilostazol works is not completely clear, its main effects are to dilate (widen) the arteries supplying blood to the legs and to decrease the ability of platelets in the blood to stick together. Platelets are particles that circulate in the blood and play a role in clotting.<br />
*Cilostazol may reduce the leg pain that patients with intermittent claudication experience, allowing them to walk farther before their leg pain occurs.<br />
*Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks. If you have not noticed any benefit from cilostazol tablets after 12 weeks you and your doctor may wish to discuss other forms of treatment.<br />
*Sometimes blood vessel disease of the legs causes pain at rest or breakdown of skin in the leg. Cilostazol has not been shown to work in patients with these problems.<br />
<br />
'''Who should not take cilostazol tablets?'''<br />
<br />
*Patients who have congestive heart failure (CHF) must not take cilostazol tablets. The most common symptoms of CHF are shortness of breath and swelling of the legs. However, other conditions may also cause these symptoms. It is important that you discuss with your doctor whether you have CHF.<br />
*Over 1,300 patients took cilostazol in studies that lasted for 3 to 6 months. The mortality rate in these patients was similar to placebo (less than 1%). These studies were too small to be sure there is not some increased risk of dying with longer use or in patients sicker than those in the studies.<br />
<br />
'''How should cilostazol tablets be taken?'''<br />
<br />
*Follow your doctor’s advice about how to take cilostazol tablets.<br />
*You should take cilostazol tablets twice a day, at least one half-hour before or two hours after breakfast and dinner. Take cilostazol tablets at about the same times each day.<br />
*Do not share cilostazol tablets with anyone else. It was prescribed only for you.<br />
*Keep cilostazol tablets and all drugs out of the reach of children.<br />
<br />
'''Can cilostazol tablets be taken with other drugs?'''<br />
<br />
Certain drugs and foods can increase the amount of cilostazol in the blood. Because of this, your doctor may adjust your dose of cilostazol or even stop it if you are taking or are going to take one of the following medications.<br />
Drugs Interacting with Cilostazol<br />
Generic Name (Brand Names)Type of Drug<br />
[[erythromycin]] (such as E.E.S.®, Erythrocin®) Antibiotic<br />
[[ketoconazole]] (Nizoral®), [[itraconazole]] (Sporanox®) Antifungal<br />
[[diltiazem]] (Cardizem®) Antihypertensive<br />
[[omeprazole]] (Prilosec®) Gastric acid reducer<br />
This list does not include every drug that may interact with cilostazol tablets. Therefore, you should tell your doctor about all medications that you are taking, including vitamins, herbal supplements and over-the-counter drugs you can buy without a prescription. You should also check with your doctor before taking a new medication after you have begun cilostazol tablets.<br />
<br />
'''What are the possible side effects of cilostazol tablets?'''<br />
<br />
Cilostazol tablets may cause side effects including headache, diarrhea, abnormal stools, increased heart rate and palpitations.<br />
You should discuss possible side effects with your doctor before taking cilostazol tablets and any time you think you are having a side effect.<br />
This provides only a summary of information about cilostazol tablets. If you have any questions about cilostazol tablets, talk to your doctor.<br />
'''Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.'''<br />
<br />
===Patient Information from NLM===<br />
<br />
For patient information about Cilostazol from NLM, click [[Cilostazol (patient information)|here]].<br />
<br />
==Precautions with Alcohol==<br />
<br />
Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
<br />
==Brand Names==<br />
<br />
Cilostazol®, Platel®.<br />
<br />
==Look-Alike Drug Names==<br />
<br />
* (Paired Confused Name 1a) — (Paired Confused Name 1b)<br />
* (Paired Confused Name 2a) — (Paired Confused Name 2b)<br />
* (Paired Confused Name 3a) — (Paired Confused Name 3b)<br />
<br />
==[http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm Drug Shortage Status]==<br />
<br />
==[http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price Price]==<br />
<br />
==References==<br />
<br />
{{reflist}}<br />
<br />
</div></div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=Cilostazol&diff=961776Cilostazol2014-04-02T15:08:11Z<p>Abdurahman Khalil: /* Pediatric Indications and Dosage */</p>
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! style="font-size: 80%; padding: 0 5px; background: #104E8B;" | [[{{PAGENAME}}|{{fontcolor|#F8F8FF|{{PAGENAME}}®}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #000000; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|Black Box Warning}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adult Indications and Dosage|{{fontcolor|#F8F8FF|Adult Indications and Dosage}}]]<br />
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pediatric Indications and Dosage|{{fontcolor|#F8F8FF|Pediatric Indications and Dosage}}]]<br />
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Warnings|{{fontcolor|#F8F8FF|Warnings}}]]<br />
|-<br />
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|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Drug Interactions|{{fontcolor|#F8F8FF|Drug Interactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Use in Specific Populations|{{fontcolor|#F8F8FF|Use in Specific Populations}}]]<br />
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Administration and Monitoring|{{fontcolor|#F8F8FF|Administration and Monitoring}}]]<br />
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#IV Compatibility|{{fontcolor|#F8F8FF|IV Compatibility}}]]<br />
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|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Clinical Studies|{{fontcolor|#F8F8FF|Clinical Studies}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#How Supplied|{{fontcolor|#F8F8FF|How Supplied}}]]<br />
|-<br />
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|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Precautions with Alcohol|{{fontcolor|#F8F8FF|Precautions with Alcohol}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Brand Names|{{fontcolor|#F8F8FF|Brand Names}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Look-Alike Drug Names|{{fontcolor|#F8F8FF|Look-Alike Drug Names}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm {{fontcolor|#F8F8FF|Drug Shortage Status}}]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price {{fontcolor|#F8F8FF|Price}}]<br />
|-<br />
|}<br />
<div style="width: 80%"><br />
__NOTOC__<br />
{{CMG}}<br />
<br />
{{SB}} Cilostazol®, Pletal®<br />
<br />
==Disclaimer==<br />
<br />
'''''WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature. The information provided is not a medical advice or treatment. WikiDoc does not promote any medication or off-label use of drugs. Please read our full disclaimer [[wikidoc:General_disclaimer|{{fontcolor|#FF0000|here}}]].'''''<br />
<br />
==<span style="color:#FF0000; background:#000000;">Black Box Warning</span>==<br />
<br />
FDA Package Insert for {{PAGENAME}} contains no information regarding ''Black Box Warning''.<br />
<br />
{| style="border: 3px solid #696969;"<br />
| style="background: #000000; border: 0px; padding: 20px 20px; width: 800px;" |<br />
<center><br />
<font color="#F8F8FF" style="font-weight: bold;">CONTRAINDICATION</font><br />
</center><br />
<br />
<center><br />
<font color="#F8F8FF" size="1" style="font-style: italic;">See full prescribing information for complete boxed warning.</font><br />
</center><br />
<br />
<font color="#F8F8FF" style="font-weight: bold;"><br />
''{{fontcolor|#FF0000|Condition Name:}}'' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
</font><br />
|}<br />
<br />
==Overview==<br />
<br />
{{PAGENAME}} is a_Phosphodiesterase 3 Inhibitor drug that is FDA approved for the treatment of intermittent claudication. There is a Black Box Warning for this drug as shown <span style="background:#000000;">'''[[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|here}}]]'''</span>. Common adverse reactions include headache, dizziness, palpitation, diarrhea, rhinitis and pharyngitis.<br />
<br />
==Adult Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Adult)===<br />
<br />
=====Intermittent claudication=====<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
===Off-Label Use and Dosage (Adult)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* There is limited information about ''Off-Label Non–Guideline-Supported Use'' of {{PAGENAME}} in adult patients.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Pediatric Indications and Dosage==<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
==Contraindications==<br />
* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
<br />
==Warnings==<br />
<br />
=====Conidition 1=====<br />
<br />
(Description)<br />
<br />
=====Conidition 2=====<br />
<br />
(Description)<br />
<br />
=====Conidition 3=====<br />
<br />
(Description)<br />
<br />
==Adverse Reactions==<br />
<br />
===Clinical Trials Experience===<br />
Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol and 134 days for patients on placebo.<br />
<br />
The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with PLETAL 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included [[palpitation ]]and [[diarrhea]], both 1.1% for cilostazol (all doses) versus 0.1% for placebo.<br />
<br />
======Body as a Whole======<br />
*Common:<br />
:*Abdominal pain<br />
:*Back pain<br />
:*Headache <br />
:*Infection<br />
<br />
*Less common:<br />
[[Chills]], face [[edema]], [[fever]], [[generalized edema]], [[malaise]], [[neck rigidity]], [[pelvic pain]], [[retroperitoneal haemorrhage]].<br />
<br />
======Central Nervous System======<br />
<br />
*Common:<br />
:*Dizziness<br />
:*Vertigo<br />
<br />
*Less common:<br />
[[Anxiety]], [[insomnia]], [[neuralgia]].<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
*Common:<br />
:*Abnormal stool<br />
:*Diarrhea<br />
:*Dyspepsia<br />
:*Flatulence<br />
:*Nausea<br />
<br />
*Less common:<br />
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Metabolic & Nutritional======<br />
*Common:<br />
:*Peripheral edema<br />
<br />
*Less common:<br />
Increased [[creatinine]], [[gout]], [[hyperlipemia]], [[hyperuricemia]].<br />
<br />
======Musculoskeletal======<br />
<br />
*Common:<br />
:*Myalgia<br />
<br />
*Less common:<br />
[[Arthralgia]], bone pain, [[bursitis]].<br />
<br />
<br />
<br />
<br />
======Miscellaneous======<br />
Less common adverse reactions:<br />
<br />
*'''Endocrine:''' [[Diabetes mellitus]].<br />
<br />
*'''Hemic and Lymphatic:''' [[Anemia]], [[ecchymosis]],[[ iron deficiency anemia]], [[polycythemia]], [[purpura]].<br />
<br />
*'''Skin and Appendages:''' Dry skin, [[furunculosis]], skin hypertrophy, [[urticaria]].<br />
<br />
*'''Special Senses:''' [[Amblyopia]], [[blindness]], [[conjunctivitis]], [[diplopia]], ear pain, eye haemorrhage, [[retinal haemorrhage]], [[tinnitus]].<br />
<br />
*'''Urogenital:''' [[Albuminuria]], [[cystitis]], [[urinary frequency]], vaginal haemorrhage, vaginitis.<br />
<br />
===Postmarketing Experience===<br />
<br />
The following events have been reported spontaneously from worldwide post-marketing experience since the launch of PLETAL in the US.<br />
<br />
======Blood and lymphatic system disorders:======<br />
[[Agranulocytosis]],[[ aplastic anemia]], [[granulocytopenia]], [[pancytopenia]], [[thrombocytopenia]], [[leukopenia]], <br />
[[bleeding tendency]]<br />
<br />
======Cardiac disorders:======<br />
<br />
[[Torsades de pointes]], [[QT prolongation|QTc prolongation]] (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. [[complete atrioventricular block]], c[[ardiac failure ]]and [[bradyarrythmia]], when treated with cilostazol. Cilostazol was used "off label" due to its positive [[chronotropic]] action)<br />
<br />
======Gastrointestinal disorders:======<br />
<br />
*Gastrointestinal haemorrhage<br />
<br />
======General disorders and administration site conditions:======<br />
<br />
*Pain<br />
*[[chest pain]] <br />
*[[hot flushes]]<br />
<br />
======Hepatobiliary disorders:======<br />
<br />
*Hepatic dysfunction/abnormal liver function tests <br />
*[[jaundice]]<br />
<br />
======Injury, poisoning and procedural complications:======<br />
<br />
*Extradural [[haematoma ]] <br />
*Subdural haematoma<br />
<br />
=====Investigations:=====<br />
<br />
*[[Blood glucose]] increased, blood [[uric acid]] increased, [[platelet count]] decreased, [[white blood cell count]] decreased, increase in [[BUN]] (blood urea increased), blood pressure increase<br />
<br />
======Nervous system disorders:======<br />
<br />
*[[Intracranial haemorrhage]] <br />
*[[cerebral haemorrhage]] <br />
*[[cerebrovascular accident]]<br />
<br />
======Respiratory, thoracic and mediastinal disorders:======<br />
<br />
*Pulmonary haemorrhage<br />
*[[ interstitial pneumonia]]<br />
<br />
'''Skin and subcutaneous tissue disorders:'''<br />
<br />
*Haemorrhage subcutaneous, [[pruritus]], skin eruptions including [[Stevens-Johnson syndrome]], skin drug eruption ([[dermatitis medicamentosa]])<br />
<br />
======Vascular disorders:======<br />
<br />
*Subacute [[thrombosis ]](these cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting)<br />
<br />
==Drug Interactions==<br />
<br />
* Drug 1<br />
* Drug 2<br />
* Drug 3<br />
* Drug 4<br />
* Drug 5<br />
<br />
=====Drug 1=====<br />
<br />
(Description)<br />
<br />
=====Drug 2=====<br />
<br />
(Description)<br />
<br />
=====Drug 3=====<br />
<br />
(Description)<br />
<br />
=====Drug 4=====<br />
<br />
(Description)<br />
<br />
=====Drug 5=====<br />
<br />
(Description)<br />
<br />
==Use in Specific Populations==<br />
<br />
====Pregnancy====<br />
<br />
* '''[[Pregnancy category#United States|Pregnancy Category (FDA)]]: C'''<br />
<br />
* '''[[Pregnancy category#Australia|Pregnancy Category (AUS)]]: {{PAGENAME}} is not included in Australian Drug Evaluation Committee (ADEC) Pregnancy Categories.'''<br />
<br />
In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
<br />
====Labor and Delivery====<br />
<br />
(Description)<br />
<br />
====Nursing Mothers====<br />
<br />
Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
<br />
====Pediatric Use====<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
====Geriatric Use====<br />
Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
====Gender====<br />
<br />
The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range<br />
<br />
====Race====<br />
<br />
(Description)<br />
<br />
====Renal Impairment====<br />
<br />
Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
<br />
====Hepatic Impairment====<br />
<br />
Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
<br />
====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the exposure in humans at the MRHD.<br />
<br />
====Immunocompromised Patients====<br />
<br />
(Description)<br />
<br />
====Miscellaneous====<br />
<br />
=====Smokers=====<br />
Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
<br />
==Administration and Monitoring==<br />
<br />
====Administration====<br />
<br />
Oral<br />
<br />
====Monitoring====<br />
<br />
<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability).<br />
<br />
==IV Compatibility==<br />
<br />
FDA package insert doesn't contain any information regarding '''IV Compatibility'''<br />
<br />
==Overdosage==<br />
<br />
===Acute Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
<br />
====Management====<br />
<br />
(Description)<br />
<br />
===Chronic Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
(Description)<br />
<br />
====Management====<br />
<br />
(Description)<br />
<br />
==Pharmacology==<br />
<br />
{{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
<br />
===Mechanism of Action===<br />
<br />
The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
<br />
===Structure===<br />
<br />
*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
<br />
<br />
===Pharmacodynamics===<br />
<br />
(Description)<br />
<br />
===Pharmacokinetics===<br />
<br />
Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
<br />
====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4‑dehydro‑cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4‑dehydro‑cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
<br />
===Nonclinical Toxicology===<br />
<br />
==Clinical Studies==<br />
<br />
*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
<br />
{|<br />
| [[image:Cilo2.png|400px|thumb]]<br />
|}<br />
<br />
<br />
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
<br />
==How Supplied==<br />
<br />
'''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
<br />
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0223-60 bottles of 60 and 0185-0223-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
==Images==<br />
<br />
===Drug Images===<br />
<br />
{|<br />
| [[File:Cilostazol50mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 50 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;123 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
{|<br />
| [[File:Cilostazol100mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 100 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;223 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
===Package and Label Display Panel===<br />
<br />
Sandoz Inc.<br />
Princeton, NJ 08540<br />
OS8128<br />
Rev. 02/13<br />
MF0223REV02/13<br />
Cilostazol 100mg Tablet<br />
<br />
{|<br />
| [[image:Cilostazollabel.jpg|400px|thumb]]<br />
|}<br />
<br />
{|<br />
| [[image:Cilostazollabel1.png|400px|thumb]]<br />
|}<br />
<br />
==Patient Information==<br />
<br />
===Patient Information from FDA===<br />
(sil-OS-tah-zol)<br />
<br />
Please read this leaflet before you start taking cilostazol tablets and each time you renew it in case anything has changed. This leaflet does not replace careful discussions with your doctor. You and your doctor should discuss cilostazol when you start taking it and at regular check-ups. You should follow your doctor’s advice about when to have check-ups.<br />
What is cilostazol for?<br />
Cilostazol may improve the symptoms of patients with a medical condition called intermittent claudication.<br />
What is intermittent claudication?<br />
Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. It occurs because narrowing or blockage of the arteries decreases blood flow to the legs. The decreased blood flow does not supply enough oxygen to the leg muscles during walking, resulting in these painful leg cramps.<br />
<br />
'''What treatments are available for intermittent claudication?'''<br />
<br />
The three main treatments available for intermittent claudication are:<br />
*Exercise. Your doctor may advise an exercise program.<br />
*Medication. Your doctor may prescribe a medication such as cilostazol. (See Who should not take cilostazol tablets?)<br />
*Surgery. Your doctor may recommend a surgical procedure to bypass the blocked segment of the artery. Another procedure is called a percutaneous transluminal angioplasty. In this procedure, a catheter (a flexible tube) is inserted into the artery to reduce the blockage and improve blood flow.<br />
<br />
'''How does cilostazol work?'''<br />
<br />
*The exact way that many drugs work is not well understood. Although how cilostazol works is not completely clear, its main effects are to dilate (widen) the arteries supplying blood to the legs and to decrease the ability of platelets in the blood to stick together. Platelets are particles that circulate in the blood and play a role in clotting.<br />
*Cilostazol may reduce the leg pain that patients with intermittent claudication experience, allowing them to walk farther before their leg pain occurs.<br />
*Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks. If you have not noticed any benefit from cilostazol tablets after 12 weeks you and your doctor may wish to discuss other forms of treatment.<br />
*Sometimes blood vessel disease of the legs causes pain at rest or breakdown of skin in the leg. Cilostazol has not been shown to work in patients with these problems.<br />
<br />
'''Who should not take cilostazol tablets?'''<br />
<br />
*Patients who have congestive heart failure (CHF) must not take cilostazol tablets. The most common symptoms of CHF are shortness of breath and swelling of the legs. However, other conditions may also cause these symptoms. It is important that you discuss with your doctor whether you have CHF.<br />
*Over 1,300 patients took cilostazol in studies that lasted for 3 to 6 months. The mortality rate in these patients was similar to placebo (less than 1%). These studies were too small to be sure there is not some increased risk of dying with longer use or in patients sicker than those in the studies.<br />
<br />
'''How should cilostazol tablets be taken?'''<br />
<br />
*Follow your doctor’s advice about how to take cilostazol tablets.<br />
*You should take cilostazol tablets twice a day, at least one half-hour before or two hours after breakfast and dinner. Take cilostazol tablets at about the same times each day.<br />
*Do not share cilostazol tablets with anyone else. It was prescribed only for you.<br />
*Keep cilostazol tablets and all drugs out of the reach of children.<br />
<br />
'''Can cilostazol tablets be taken with other drugs?'''<br />
<br />
Certain drugs and foods can increase the amount of cilostazol in the blood. Because of this, your doctor may adjust your dose of cilostazol or even stop it if you are taking or are going to take one of the following medications.<br />
Drugs Interacting with Cilostazol<br />
Generic Name (Brand Names)Type of Drug<br />
[[erythromycin]] (such as E.E.S.®, Erythrocin®) Antibiotic<br />
[[ketoconazole]] (Nizoral®), [[itraconazole]] (Sporanox®) Antifungal<br />
[[diltiazem]] (Cardizem®) Antihypertensive<br />
[[omeprazole]] (Prilosec®) Gastric acid reducer<br />
This list does not include every drug that may interact with cilostazol tablets. Therefore, you should tell your doctor about all medications that you are taking, including vitamins, herbal supplements and over-the-counter drugs you can buy without a prescription. You should also check with your doctor before taking a new medication after you have begun cilostazol tablets.<br />
<br />
'''What are the possible side effects of cilostazol tablets?'''<br />
<br />
Cilostazol tablets may cause side effects including headache, diarrhea, abnormal stools, increased heart rate and palpitations.<br />
You should discuss possible side effects with your doctor before taking cilostazol tablets and any time you think you are having a side effect.<br />
This provides only a summary of information about cilostazol tablets. If you have any questions about cilostazol tablets, talk to your doctor.<br />
'''Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.'''<br />
<br />
===Patient Information from NLM===<br />
<br />
For patient information about Cilostazol from NLM, click [[Cilostazol (patient information)|here]].<br />
<br />
==Precautions with Alcohol==<br />
<br />
Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
<br />
==Brand Names==<br />
<br />
Cilostazol®, Platel®.<br />
<br />
==Look-Alike Drug Names==<br />
<br />
* (Paired Confused Name 1a) — (Paired Confused Name 1b)<br />
* (Paired Confused Name 2a) — (Paired Confused Name 2b)<br />
* (Paired Confused Name 3a) — (Paired Confused Name 3b)<br />
<br />
==[http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm Drug Shortage Status]==<br />
<br />
==[http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price Price]==<br />
<br />
==References==<br />
<br />
{{reflist}}<br />
<br />
</div></div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=Cilostazol&diff=961764Cilostazol2014-04-02T14:50:02Z<p>Abdurahman Khalil: /* Package and Label Display Panel */</p>
<hr />
<div>{|class="infobox" style="position: fixed; top: 180px; right: 20px; margin: 0 0 0 0; border: 0; float: right; width: 15%; background: #104E8B; border-radius: 10px 10px 10px 10px;" cellpadding="0" cellspacing="0";<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #104E8B;" | [[{{PAGENAME}}|{{fontcolor|#F8F8FF|{{PAGENAME}}®}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #000000; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|Black Box Warning}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adult Indications and Dosage|{{fontcolor|#F8F8FF|Adult Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pediatric Indications and Dosage|{{fontcolor|#F8F8FF|Pediatric Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Contraindications|{{fontcolor|#F8F8FF|Contraindications}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Warnings|{{fontcolor|#F8F8FF|Warnings}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adverse Reactions|{{fontcolor|#F8F8FF|Adverse Reactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Drug Interactions|{{fontcolor|#F8F8FF|Drug Interactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Use in Specific Populations|{{fontcolor|#F8F8FF|Use in Specific Populations}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Administration and Monitoring|{{fontcolor|#F8F8FF|Administration and Monitoring}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#IV Compatibility|{{fontcolor|#F8F8FF|IV Compatibility}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Overdosage|{{fontcolor|#F8F8FF|Overdosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pharmacology|{{fontcolor|#F8F8FF|Pharmacology}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Clinical Studies|{{fontcolor|#F8F8FF|Clinical Studies}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#How Supplied|{{fontcolor|#F8F8FF|How Supplied}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Images|{{fontcolor|#F8F8FF|Images}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Patient Information|{{fontcolor|#F8F8FF|Patient information}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Precautions with Alcohol|{{fontcolor|#F8F8FF|Precautions with Alcohol}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Brand Names|{{fontcolor|#F8F8FF|Brand Names}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Look-Alike Drug Names|{{fontcolor|#F8F8FF|Look-Alike Drug Names}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm {{fontcolor|#F8F8FF|Drug Shortage Status}}]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price {{fontcolor|#F8F8FF|Price}}]<br />
|-<br />
|}<br />
<div style="width: 80%"><br />
__NOTOC__<br />
{{CMG}}<br />
<br />
{{SB}} Cilostazol®, Pletal®<br />
<br />
==Disclaimer==<br />
<br />
'''''WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature. The information provided is not a medical advice or treatment. WikiDoc does not promote any medication or off-label use of drugs. Please read our full disclaimer [[wikidoc:General_disclaimer|{{fontcolor|#FF0000|here}}]].'''''<br />
<br />
==<span style="color:#FF0000; background:#000000;">Black Box Warning</span>==<br />
<br />
FDA Package Insert for {{PAGENAME}} contains no information regarding ''Black Box Warning''.<br />
<br />
{| style="border: 3px solid #696969;"<br />
| style="background: #000000; border: 0px; padding: 20px 20px; width: 800px;" |<br />
<center><br />
<font color="#F8F8FF" style="font-weight: bold;">CONTRAINDICATION</font><br />
</center><br />
<br />
<center><br />
<font color="#F8F8FF" size="1" style="font-style: italic;">See full prescribing information for complete boxed warning.</font><br />
</center><br />
<br />
<font color="#F8F8FF" style="font-weight: bold;"><br />
''{{fontcolor|#FF0000|Condition Name:}}'' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
</font><br />
|}<br />
<br />
==Overview==<br />
<br />
{{PAGENAME}} is a_Phosphodiesterase 3 Inhibitor drug that is FDA approved for the treatment of intermittent claudication. There is a Black Box Warning for this drug as shown <span style="background:#000000;">'''[[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|here}}]]'''</span>. Common adverse reactions include headache, dizziness, palpitation, diarrhea, rhinitis and pharyngitis.<br />
<br />
==Adult Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Adult)===<br />
<br />
=====Intermittent claudication=====<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
===Off-Label Use and Dosage (Adult)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* There is limited information about ''Off-Label Non–Guideline-Supported Use'' of {{PAGENAME}} in adult patients.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Pediatric Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Pediatric)===<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
===Off-Label Use and Dosage (Pediatric)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Contraindications==<br />
* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
<br />
==Warnings==<br />
<br />
=====Conidition 1=====<br />
<br />
(Description)<br />
<br />
=====Conidition 2=====<br />
<br />
(Description)<br />
<br />
=====Conidition 3=====<br />
<br />
(Description)<br />
<br />
==Adverse Reactions==<br />
<br />
===Clinical Trials Experience===<br />
Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol and 134 days for patients on placebo.<br />
<br />
The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with PLETAL 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included [[palpitation ]]and [[diarrhea]], both 1.1% for cilostazol (all doses) versus 0.1% for placebo.<br />
<br />
======Body as a Whole======<br />
*Common:<br />
:*Abdominal pain<br />
:*Back pain<br />
:*Headache <br />
:*Infection<br />
<br />
*Less common:<br />
[[Chills]], face [[edema]], [[fever]], [[generalized edema]], [[malaise]], [[neck rigidity]], [[pelvic pain]], [[retroperitoneal haemorrhage]].<br />
<br />
======Central Nervous System======<br />
<br />
*Common:<br />
:*Dizziness<br />
:*Vertigo<br />
<br />
*Less common:<br />
[[Anxiety]], [[insomnia]], [[neuralgia]].<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
*Common:<br />
:*Abnormal stool<br />
:*Diarrhea<br />
:*Dyspepsia<br />
:*Flatulence<br />
:*Nausea<br />
<br />
*Less common:<br />
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Metabolic & Nutritional======<br />
*Common:<br />
:*Peripheral edema<br />
<br />
*Less common:<br />
Increased [[creatinine]], [[gout]], [[hyperlipemia]], [[hyperuricemia]].<br />
<br />
======Musculoskeletal======<br />
<br />
*Common:<br />
:*Myalgia<br />
<br />
*Less common:<br />
[[Arthralgia]], bone pain, [[bursitis]].<br />
<br />
<br />
<br />
<br />
======Miscellaneous======<br />
Less common adverse reactions:<br />
<br />
*'''Endocrine:''' [[Diabetes mellitus]].<br />
<br />
*'''Hemic and Lymphatic:''' [[Anemia]], [[ecchymosis]],[[ iron deficiency anemia]], [[polycythemia]], [[purpura]].<br />
<br />
*'''Skin and Appendages:''' Dry skin, [[furunculosis]], skin hypertrophy, [[urticaria]].<br />
<br />
*'''Special Senses:''' [[Amblyopia]], [[blindness]], [[conjunctivitis]], [[diplopia]], ear pain, eye haemorrhage, [[retinal haemorrhage]], [[tinnitus]].<br />
<br />
*'''Urogenital:''' [[Albuminuria]], [[cystitis]], [[urinary frequency]], vaginal haemorrhage, vaginitis.<br />
<br />
===Postmarketing Experience===<br />
<br />
The following events have been reported spontaneously from worldwide post-marketing experience since the launch of PLETAL in the US.<br />
<br />
======Blood and lymphatic system disorders:======<br />
[[Agranulocytosis]],[[ aplastic anemia]], [[granulocytopenia]], [[pancytopenia]], [[thrombocytopenia]], [[leukopenia]], <br />
[[bleeding tendency]]<br />
<br />
======Cardiac disorders:======<br />
<br />
[[Torsades de pointes]], [[QT prolongation|QTc prolongation]] (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. [[complete atrioventricular block]], c[[ardiac failure ]]and [[bradyarrythmia]], when treated with cilostazol. Cilostazol was used "off label" due to its positive [[chronotropic]] action)<br />
<br />
======Gastrointestinal disorders:======<br />
<br />
*Gastrointestinal haemorrhage<br />
<br />
======General disorders and administration site conditions:======<br />
<br />
*Pain<br />
*[[chest pain]] <br />
*[[hot flushes]]<br />
<br />
======Hepatobiliary disorders:======<br />
<br />
*Hepatic dysfunction/abnormal liver function tests <br />
*[[jaundice]]<br />
<br />
======Injury, poisoning and procedural complications:======<br />
<br />
*Extradural [[haematoma ]] <br />
*Subdural haematoma<br />
<br />
=====Investigations:=====<br />
<br />
*[[Blood glucose]] increased, blood [[uric acid]] increased, [[platelet count]] decreased, [[white blood cell count]] decreased, increase in [[BUN]] (blood urea increased), blood pressure increase<br />
<br />
======Nervous system disorders:======<br />
<br />
*[[Intracranial haemorrhage]] <br />
*[[cerebral haemorrhage]] <br />
*[[cerebrovascular accident]]<br />
<br />
======Respiratory, thoracic and mediastinal disorders:======<br />
<br />
*Pulmonary haemorrhage<br />
*[[ interstitial pneumonia]]<br />
<br />
'''Skin and subcutaneous tissue disorders:'''<br />
<br />
*Haemorrhage subcutaneous, [[pruritus]], skin eruptions including [[Stevens-Johnson syndrome]], skin drug eruption ([[dermatitis medicamentosa]])<br />
<br />
======Vascular disorders:======<br />
<br />
*Subacute [[thrombosis ]](these cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting)<br />
<br />
==Drug Interactions==<br />
<br />
* Drug 1<br />
* Drug 2<br />
* Drug 3<br />
* Drug 4<br />
* Drug 5<br />
<br />
=====Drug 1=====<br />
<br />
(Description)<br />
<br />
=====Drug 2=====<br />
<br />
(Description)<br />
<br />
=====Drug 3=====<br />
<br />
(Description)<br />
<br />
=====Drug 4=====<br />
<br />
(Description)<br />
<br />
=====Drug 5=====<br />
<br />
(Description)<br />
<br />
==Use in Specific Populations==<br />
<br />
====Pregnancy====<br />
<br />
* '''[[Pregnancy category#United States|Pregnancy Category (FDA)]]: C'''<br />
<br />
* '''[[Pregnancy category#Australia|Pregnancy Category (AUS)]]: {{PAGENAME}} is not included in Australian Drug Evaluation Committee (ADEC) Pregnancy Categories.'''<br />
<br />
In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
<br />
====Labor and Delivery====<br />
<br />
(Description)<br />
<br />
====Nursing Mothers====<br />
<br />
Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
<br />
====Pediatric Use====<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
====Geriatric Use====<br />
Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
====Gender====<br />
<br />
The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range<br />
<br />
====Race====<br />
<br />
(Description)<br />
<br />
====Renal Impairment====<br />
<br />
Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
<br />
====Hepatic Impairment====<br />
<br />
Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
<br />
====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the exposure in humans at the MRHD.<br />
<br />
====Immunocompromised Patients====<br />
<br />
(Description)<br />
<br />
====Miscellaneous====<br />
<br />
=====Smokers=====<br />
Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
<br />
==Administration and Monitoring==<br />
<br />
====Administration====<br />
<br />
Oral<br />
<br />
====Monitoring====<br />
<br />
<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability).<br />
<br />
==IV Compatibility==<br />
<br />
FDA package insert doesn't contain any information regarding '''IV Compatibility'''<br />
<br />
==Overdosage==<br />
<br />
===Acute Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
<br />
====Management====<br />
<br />
(Description)<br />
<br />
===Chronic Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
(Description)<br />
<br />
====Management====<br />
<br />
(Description)<br />
<br />
==Pharmacology==<br />
<br />
{{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
<br />
===Mechanism of Action===<br />
<br />
The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
<br />
===Structure===<br />
<br />
*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
<br />
<br />
===Pharmacodynamics===<br />
<br />
(Description)<br />
<br />
===Pharmacokinetics===<br />
<br />
Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
<br />
====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4‑dehydro‑cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4‑dehydro‑cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
<br />
===Nonclinical Toxicology===<br />
<br />
==Clinical Studies==<br />
<br />
*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
<br />
{|<br />
| [[image:Cilo2.png|400px|thumb]]<br />
|}<br />
<br />
<br />
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
<br />
==How Supplied==<br />
<br />
'''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
<br />
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0223-60 bottles of 60 and 0185-0223-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
==Images==<br />
<br />
===Drug Images===<br />
<br />
{|<br />
| [[File:Cilostazol50mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 50 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;123 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
{|<br />
| [[File:Cilostazol100mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 100 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;223 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
===Package and Label Display Panel===<br />
<br />
Sandoz Inc.<br />
Princeton, NJ 08540<br />
OS8128<br />
Rev. 02/13<br />
MF0223REV02/13<br />
Cilostazol 100mg Tablet<br />
<br />
{|<br />
| [[image:Cilostazollabel.jpg|400px|thumb]]<br />
|}<br />
<br />
{|<br />
| [[image:Cilostazollabel1.png|400px|thumb]]<br />
|}<br />
<br />
==Patient Information==<br />
<br />
===Patient Information from FDA===<br />
(sil-OS-tah-zol)<br />
<br />
Please read this leaflet before you start taking cilostazol tablets and each time you renew it in case anything has changed. This leaflet does not replace careful discussions with your doctor. You and your doctor should discuss cilostazol when you start taking it and at regular check-ups. You should follow your doctor’s advice about when to have check-ups.<br />
What is cilostazol for?<br />
Cilostazol may improve the symptoms of patients with a medical condition called intermittent claudication.<br />
What is intermittent claudication?<br />
Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. It occurs because narrowing or blockage of the arteries decreases blood flow to the legs. The decreased blood flow does not supply enough oxygen to the leg muscles during walking, resulting in these painful leg cramps.<br />
<br />
'''What treatments are available for intermittent claudication?'''<br />
<br />
The three main treatments available for intermittent claudication are:<br />
*Exercise. Your doctor may advise an exercise program.<br />
*Medication. Your doctor may prescribe a medication such as cilostazol. (See Who should not take cilostazol tablets?)<br />
*Surgery. Your doctor may recommend a surgical procedure to bypass the blocked segment of the artery. Another procedure is called a percutaneous transluminal angioplasty. In this procedure, a catheter (a flexible tube) is inserted into the artery to reduce the blockage and improve blood flow.<br />
<br />
'''How does cilostazol work?'''<br />
<br />
*The exact way that many drugs work is not well understood. Although how cilostazol works is not completely clear, its main effects are to dilate (widen) the arteries supplying blood to the legs and to decrease the ability of platelets in the blood to stick together. Platelets are particles that circulate in the blood and play a role in clotting.<br />
*Cilostazol may reduce the leg pain that patients with intermittent claudication experience, allowing them to walk farther before their leg pain occurs.<br />
*Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks. If you have not noticed any benefit from cilostazol tablets after 12 weeks you and your doctor may wish to discuss other forms of treatment.<br />
*Sometimes blood vessel disease of the legs causes pain at rest or breakdown of skin in the leg. Cilostazol has not been shown to work in patients with these problems.<br />
<br />
'''Who should not take cilostazol tablets?'''<br />
<br />
*Patients who have congestive heart failure (CHF) must not take cilostazol tablets. The most common symptoms of CHF are shortness of breath and swelling of the legs. However, other conditions may also cause these symptoms. It is important that you discuss with your doctor whether you have CHF.<br />
*Over 1,300 patients took cilostazol in studies that lasted for 3 to 6 months. The mortality rate in these patients was similar to placebo (less than 1%). These studies were too small to be sure there is not some increased risk of dying with longer use or in patients sicker than those in the studies.<br />
<br />
'''How should cilostazol tablets be taken?'''<br />
<br />
*Follow your doctor’s advice about how to take cilostazol tablets.<br />
*You should take cilostazol tablets twice a day, at least one half-hour before or two hours after breakfast and dinner. Take cilostazol tablets at about the same times each day.<br />
*Do not share cilostazol tablets with anyone else. It was prescribed only for you.<br />
*Keep cilostazol tablets and all drugs out of the reach of children.<br />
<br />
'''Can cilostazol tablets be taken with other drugs?'''<br />
<br />
Certain drugs and foods can increase the amount of cilostazol in the blood. Because of this, your doctor may adjust your dose of cilostazol or even stop it if you are taking or are going to take one of the following medications.<br />
Drugs Interacting with Cilostazol<br />
Generic Name (Brand Names)Type of Drug<br />
[[erythromycin]] (such as E.E.S.®, Erythrocin®) Antibiotic<br />
[[ketoconazole]] (Nizoral®), [[itraconazole]] (Sporanox®) Antifungal<br />
[[diltiazem]] (Cardizem®) Antihypertensive<br />
[[omeprazole]] (Prilosec®) Gastric acid reducer<br />
This list does not include every drug that may interact with cilostazol tablets. Therefore, you should tell your doctor about all medications that you are taking, including vitamins, herbal supplements and over-the-counter drugs you can buy without a prescription. You should also check with your doctor before taking a new medication after you have begun cilostazol tablets.<br />
<br />
'''What are the possible side effects of cilostazol tablets?'''<br />
<br />
Cilostazol tablets may cause side effects including headache, diarrhea, abnormal stools, increased heart rate and palpitations.<br />
You should discuss possible side effects with your doctor before taking cilostazol tablets and any time you think you are having a side effect.<br />
This provides only a summary of information about cilostazol tablets. If you have any questions about cilostazol tablets, talk to your doctor.<br />
'''Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.'''<br />
<br />
===Patient Information from NLM===<br />
<br />
For patient information about Cilostazol from NLM, click [[Cilostazol (patient information)|here]].<br />
<br />
==Precautions with Alcohol==<br />
<br />
Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
<br />
==Brand Names==<br />
<br />
Cilostazol®, Platel®.<br />
<br />
==Look-Alike Drug Names==<br />
<br />
* (Paired Confused Name 1a) — (Paired Confused Name 1b)<br />
* (Paired Confused Name 2a) — (Paired Confused Name 2b)<br />
* (Paired Confused Name 3a) — (Paired Confused Name 3b)<br />
<br />
==[http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm Drug Shortage Status]==<br />
<br />
==[http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price Price]==<br />
<br />
==References==<br />
<br />
{{reflist}}<br />
<br />
</div></div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=File:Cilostazollabel1.png&diff=961763File:Cilostazollabel1.png2014-04-02T14:49:26Z<p>Abdurahman Khalil: </p>
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<div></div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=File:Cilostazollabel.jpg&diff=961758File:Cilostazollabel.jpg2014-04-02T14:45:00Z<p>Abdurahman Khalil: </p>
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<div></div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=Cilostazol&diff=961755Cilostazol2014-04-02T14:42:18Z<p>Abdurahman Khalil: /* Package and Label Display Panel */</p>
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<div>{|class="infobox" style="position: fixed; top: 180px; right: 20px; margin: 0 0 0 0; border: 0; float: right; width: 15%; background: #104E8B; border-radius: 10px 10px 10px 10px;" cellpadding="0" cellspacing="0";<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #104E8B;" | [[{{PAGENAME}}|{{fontcolor|#F8F8FF|{{PAGENAME}}®}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #000000; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|Black Box Warning}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adult Indications and Dosage|{{fontcolor|#F8F8FF|Adult Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pediatric Indications and Dosage|{{fontcolor|#F8F8FF|Pediatric Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Contraindications|{{fontcolor|#F8F8FF|Contraindications}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Warnings|{{fontcolor|#F8F8FF|Warnings}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adverse Reactions|{{fontcolor|#F8F8FF|Adverse Reactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Drug Interactions|{{fontcolor|#F8F8FF|Drug Interactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Use in Specific Populations|{{fontcolor|#F8F8FF|Use in Specific Populations}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Administration and Monitoring|{{fontcolor|#F8F8FF|Administration and Monitoring}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#IV Compatibility|{{fontcolor|#F8F8FF|IV Compatibility}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Overdosage|{{fontcolor|#F8F8FF|Overdosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pharmacology|{{fontcolor|#F8F8FF|Pharmacology}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Clinical Studies|{{fontcolor|#F8F8FF|Clinical Studies}}]]<br />
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#How Supplied|{{fontcolor|#F8F8FF|How Supplied}}]]<br />
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Images|{{fontcolor|#F8F8FF|Images}}]]<br />
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Brand Names|{{fontcolor|#F8F8FF|Brand Names}}]]<br />
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Look-Alike Drug Names|{{fontcolor|#F8F8FF|Look-Alike Drug Names}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm {{fontcolor|#F8F8FF|Drug Shortage Status}}]<br />
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price {{fontcolor|#F8F8FF|Price}}]<br />
|-<br />
|}<br />
<div style="width: 80%"><br />
__NOTOC__<br />
{{CMG}}<br />
<br />
{{SB}} Cilostazol®, Pletal®<br />
<br />
==Disclaimer==<br />
<br />
'''''WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature. The information provided is not a medical advice or treatment. WikiDoc does not promote any medication or off-label use of drugs. Please read our full disclaimer [[wikidoc:General_disclaimer|{{fontcolor|#FF0000|here}}]].'''''<br />
<br />
==<span style="color:#FF0000; background:#000000;">Black Box Warning</span>==<br />
<br />
FDA Package Insert for {{PAGENAME}} contains no information regarding ''Black Box Warning''.<br />
<br />
{| style="border: 3px solid #696969;"<br />
| style="background: #000000; border: 0px; padding: 20px 20px; width: 800px;" |<br />
<center><br />
<font color="#F8F8FF" style="font-weight: bold;">CONTRAINDICATION</font><br />
</center><br />
<br />
<center><br />
<font color="#F8F8FF" size="1" style="font-style: italic;">See full prescribing information for complete boxed warning.</font><br />
</center><br />
<br />
<font color="#F8F8FF" style="font-weight: bold;"><br />
''{{fontcolor|#FF0000|Condition Name:}}'' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
</font><br />
|}<br />
<br />
==Overview==<br />
<br />
{{PAGENAME}} is a_Phosphodiesterase 3 Inhibitor drug that is FDA approved for the treatment of intermittent claudication. There is a Black Box Warning for this drug as shown <span style="background:#000000;">'''[[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|here}}]]'''</span>. Common adverse reactions include headache, dizziness, palpitation, diarrhea, rhinitis and pharyngitis.<br />
<br />
==Adult Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Adult)===<br />
<br />
=====Intermittent claudication=====<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
===Off-Label Use and Dosage (Adult)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* There is limited information about ''Off-Label Non–Guideline-Supported Use'' of {{PAGENAME}} in adult patients.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Pediatric Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Pediatric)===<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
===Off-Label Use and Dosage (Pediatric)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Contraindications==<br />
* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
<br />
==Warnings==<br />
<br />
=====Conidition 1=====<br />
<br />
(Description)<br />
<br />
=====Conidition 2=====<br />
<br />
(Description)<br />
<br />
=====Conidition 3=====<br />
<br />
(Description)<br />
<br />
==Adverse Reactions==<br />
<br />
===Clinical Trials Experience===<br />
Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol and 134 days for patients on placebo.<br />
<br />
The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with PLETAL 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included [[palpitation ]]and [[diarrhea]], both 1.1% for cilostazol (all doses) versus 0.1% for placebo.<br />
<br />
======Body as a Whole======<br />
*Common:<br />
:*Abdominal pain<br />
:*Back pain<br />
:*Headache <br />
:*Infection<br />
<br />
*Less common:<br />
[[Chills]], face [[edema]], [[fever]], [[generalized edema]], [[malaise]], [[neck rigidity]], [[pelvic pain]], [[retroperitoneal haemorrhage]].<br />
<br />
======Central Nervous System======<br />
<br />
*Common:<br />
:*Dizziness<br />
:*Vertigo<br />
<br />
*Less common:<br />
[[Anxiety]], [[insomnia]], [[neuralgia]].<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
*Common:<br />
:*Abnormal stool<br />
:*Diarrhea<br />
:*Dyspepsia<br />
:*Flatulence<br />
:*Nausea<br />
<br />
*Less common:<br />
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Metabolic & Nutritional======<br />
*Common:<br />
:*Peripheral edema<br />
<br />
*Less common:<br />
Increased [[creatinine]], [[gout]], [[hyperlipemia]], [[hyperuricemia]].<br />
<br />
======Musculoskeletal======<br />
<br />
*Common:<br />
:*Myalgia<br />
<br />
*Less common:<br />
[[Arthralgia]], bone pain, [[bursitis]].<br />
<br />
<br />
<br />
<br />
======Miscellaneous======<br />
Less common adverse reactions:<br />
<br />
*'''Endocrine:''' [[Diabetes mellitus]].<br />
<br />
*'''Hemic and Lymphatic:''' [[Anemia]], [[ecchymosis]],[[ iron deficiency anemia]], [[polycythemia]], [[purpura]].<br />
<br />
*'''Skin and Appendages:''' Dry skin, [[furunculosis]], skin hypertrophy, [[urticaria]].<br />
<br />
*'''Special Senses:''' [[Amblyopia]], [[blindness]], [[conjunctivitis]], [[diplopia]], ear pain, eye haemorrhage, [[retinal haemorrhage]], [[tinnitus]].<br />
<br />
*'''Urogenital:''' [[Albuminuria]], [[cystitis]], [[urinary frequency]], vaginal haemorrhage, vaginitis.<br />
<br />
===Postmarketing Experience===<br />
<br />
The following events have been reported spontaneously from worldwide post-marketing experience since the launch of PLETAL in the US.<br />
<br />
======Blood and lymphatic system disorders:======<br />
[[Agranulocytosis]],[[ aplastic anemia]], [[granulocytopenia]], [[pancytopenia]], [[thrombocytopenia]], [[leukopenia]], <br />
[[bleeding tendency]]<br />
<br />
======Cardiac disorders:======<br />
<br />
[[Torsades de pointes]], [[QT prolongation|QTc prolongation]] (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. [[complete atrioventricular block]], c[[ardiac failure ]]and [[bradyarrythmia]], when treated with cilostazol. Cilostazol was used "off label" due to its positive [[chronotropic]] action)<br />
<br />
======Gastrointestinal disorders:======<br />
<br />
*Gastrointestinal haemorrhage<br />
<br />
======General disorders and administration site conditions:======<br />
<br />
*Pain<br />
*[[chest pain]] <br />
*[[hot flushes]]<br />
<br />
======Hepatobiliary disorders:======<br />
<br />
*Hepatic dysfunction/abnormal liver function tests <br />
*[[jaundice]]<br />
<br />
======Injury, poisoning and procedural complications:======<br />
<br />
*Extradural [[haematoma ]] <br />
*Subdural haematoma<br />
<br />
=====Investigations:=====<br />
<br />
*[[Blood glucose]] increased, blood [[uric acid]] increased, [[platelet count]] decreased, [[white blood cell count]] decreased, increase in [[BUN]] (blood urea increased), blood pressure increase<br />
<br />
======Nervous system disorders:======<br />
<br />
*[[Intracranial haemorrhage]] <br />
*[[cerebral haemorrhage]] <br />
*[[cerebrovascular accident]]<br />
<br />
======Respiratory, thoracic and mediastinal disorders:======<br />
<br />
*Pulmonary haemorrhage<br />
*[[ interstitial pneumonia]]<br />
<br />
'''Skin and subcutaneous tissue disorders:'''<br />
<br />
*Haemorrhage subcutaneous, [[pruritus]], skin eruptions including [[Stevens-Johnson syndrome]], skin drug eruption ([[dermatitis medicamentosa]])<br />
<br />
======Vascular disorders:======<br />
<br />
*Subacute [[thrombosis ]](these cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting)<br />
<br />
==Drug Interactions==<br />
<br />
* Drug 1<br />
* Drug 2<br />
* Drug 3<br />
* Drug 4<br />
* Drug 5<br />
<br />
=====Drug 1=====<br />
<br />
(Description)<br />
<br />
=====Drug 2=====<br />
<br />
(Description)<br />
<br />
=====Drug 3=====<br />
<br />
(Description)<br />
<br />
=====Drug 4=====<br />
<br />
(Description)<br />
<br />
=====Drug 5=====<br />
<br />
(Description)<br />
<br />
==Use in Specific Populations==<br />
<br />
====Pregnancy====<br />
<br />
* '''[[Pregnancy category#United States|Pregnancy Category (FDA)]]: C'''<br />
<br />
* '''[[Pregnancy category#Australia|Pregnancy Category (AUS)]]: {{PAGENAME}} is not included in Australian Drug Evaluation Committee (ADEC) Pregnancy Categories.'''<br />
<br />
In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
<br />
====Labor and Delivery====<br />
<br />
(Description)<br />
<br />
====Nursing Mothers====<br />
<br />
Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
<br />
====Pediatric Use====<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
====Geriatric Use====<br />
Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
====Gender====<br />
<br />
The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range<br />
<br />
====Race====<br />
<br />
(Description)<br />
<br />
====Renal Impairment====<br />
<br />
Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
<br />
====Hepatic Impairment====<br />
<br />
Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
<br />
====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the exposure in humans at the MRHD.<br />
<br />
====Immunocompromised Patients====<br />
<br />
(Description)<br />
<br />
====Miscellaneous====<br />
<br />
=====Smokers=====<br />
Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
<br />
==Administration and Monitoring==<br />
<br />
====Administration====<br />
<br />
Oral<br />
<br />
====Monitoring====<br />
<br />
<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability).<br />
<br />
==IV Compatibility==<br />
<br />
FDA package insert doesn't contain any information regarding '''IV Compatibility'''<br />
<br />
==Overdosage==<br />
<br />
===Acute Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
<br />
====Management====<br />
<br />
(Description)<br />
<br />
===Chronic Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
(Description)<br />
<br />
====Management====<br />
<br />
(Description)<br />
<br />
==Pharmacology==<br />
<br />
{{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
<br />
===Mechanism of Action===<br />
<br />
The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
<br />
===Structure===<br />
<br />
*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
<br />
<br />
===Pharmacodynamics===<br />
<br />
(Description)<br />
<br />
===Pharmacokinetics===<br />
<br />
Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
<br />
====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4‑dehydro‑cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4‑dehydro‑cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
<br />
===Nonclinical Toxicology===<br />
<br />
==Clinical Studies==<br />
<br />
*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
<br />
{|<br />
| [[image:Cilo2.png|400px|thumb]]<br />
|}<br />
<br />
<br />
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
<br />
==How Supplied==<br />
<br />
'''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
<br />
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0223-60 bottles of 60 and 0185-0223-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
==Images==<br />
<br />
===Drug Images===<br />
<br />
{|<br />
| [[File:Cilostazol50mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 50 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;123 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
{|<br />
| [[File:Cilostazol100mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 100 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;223 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
===Package and Label Display Panel===<br />
<br />
Sandoz Inc.<br />
Princeton, NJ 08540<br />
OS8128<br />
Rev. 02/13<br />
MF0223REV02/13<br />
Cilostazol 100mg Tablet<br />
<br />
{|<br />
| [[image:Cilostazollabel.jpg|400px|thumb]]<br />
|}<br />
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{|<br />
| [[image:Cilostazollabel1.jpg|400px|thumb]]<br />
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==Patient Information==<br />
<br />
===Patient Information from FDA===<br />
(sil-OS-tah-zol)<br />
<br />
Please read this leaflet before you start taking cilostazol tablets and each time you renew it in case anything has changed. This leaflet does not replace careful discussions with your doctor. You and your doctor should discuss cilostazol when you start taking it and at regular check-ups. You should follow your doctor’s advice about when to have check-ups.<br />
What is cilostazol for?<br />
Cilostazol may improve the symptoms of patients with a medical condition called intermittent claudication.<br />
What is intermittent claudication?<br />
Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. It occurs because narrowing or blockage of the arteries decreases blood flow to the legs. The decreased blood flow does not supply enough oxygen to the leg muscles during walking, resulting in these painful leg cramps.<br />
<br />
'''What treatments are available for intermittent claudication?'''<br />
<br />
The three main treatments available for intermittent claudication are:<br />
*Exercise. Your doctor may advise an exercise program.<br />
*Medication. Your doctor may prescribe a medication such as cilostazol. (See Who should not take cilostazol tablets?)<br />
*Surgery. Your doctor may recommend a surgical procedure to bypass the blocked segment of the artery. Another procedure is called a percutaneous transluminal angioplasty. In this procedure, a catheter (a flexible tube) is inserted into the artery to reduce the blockage and improve blood flow.<br />
<br />
'''How does cilostazol work?'''<br />
<br />
*The exact way that many drugs work is not well understood. Although how cilostazol works is not completely clear, its main effects are to dilate (widen) the arteries supplying blood to the legs and to decrease the ability of platelets in the blood to stick together. Platelets are particles that circulate in the blood and play a role in clotting.<br />
*Cilostazol may reduce the leg pain that patients with intermittent claudication experience, allowing them to walk farther before their leg pain occurs.<br />
*Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks. If you have not noticed any benefit from cilostazol tablets after 12 weeks you and your doctor may wish to discuss other forms of treatment.<br />
*Sometimes blood vessel disease of the legs causes pain at rest or breakdown of skin in the leg. Cilostazol has not been shown to work in patients with these problems.<br />
<br />
'''Who should not take cilostazol tablets?'''<br />
<br />
*Patients who have congestive heart failure (CHF) must not take cilostazol tablets. The most common symptoms of CHF are shortness of breath and swelling of the legs. However, other conditions may also cause these symptoms. It is important that you discuss with your doctor whether you have CHF.<br />
*Over 1,300 patients took cilostazol in studies that lasted for 3 to 6 months. The mortality rate in these patients was similar to placebo (less than 1%). These studies were too small to be sure there is not some increased risk of dying with longer use or in patients sicker than those in the studies.<br />
<br />
'''How should cilostazol tablets be taken?'''<br />
<br />
*Follow your doctor’s advice about how to take cilostazol tablets.<br />
*You should take cilostazol tablets twice a day, at least one half-hour before or two hours after breakfast and dinner. Take cilostazol tablets at about the same times each day.<br />
*Do not share cilostazol tablets with anyone else. It was prescribed only for you.<br />
*Keep cilostazol tablets and all drugs out of the reach of children.<br />
<br />
'''Can cilostazol tablets be taken with other drugs?'''<br />
<br />
Certain drugs and foods can increase the amount of cilostazol in the blood. Because of this, your doctor may adjust your dose of cilostazol or even stop it if you are taking or are going to take one of the following medications.<br />
Drugs Interacting with Cilostazol<br />
Generic Name (Brand Names)Type of Drug<br />
[[erythromycin]] (such as E.E.S.®, Erythrocin®) Antibiotic<br />
[[ketoconazole]] (Nizoral®), [[itraconazole]] (Sporanox®) Antifungal<br />
[[diltiazem]] (Cardizem®) Antihypertensive<br />
[[omeprazole]] (Prilosec®) Gastric acid reducer<br />
This list does not include every drug that may interact with cilostazol tablets. Therefore, you should tell your doctor about all medications that you are taking, including vitamins, herbal supplements and over-the-counter drugs you can buy without a prescription. You should also check with your doctor before taking a new medication after you have begun cilostazol tablets.<br />
<br />
'''What are the possible side effects of cilostazol tablets?'''<br />
<br />
Cilostazol tablets may cause side effects including headache, diarrhea, abnormal stools, increased heart rate and palpitations.<br />
You should discuss possible side effects with your doctor before taking cilostazol tablets and any time you think you are having a side effect.<br />
This provides only a summary of information about cilostazol tablets. If you have any questions about cilostazol tablets, talk to your doctor.<br />
'''Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.'''<br />
<br />
===Patient Information from NLM===<br />
<br />
For patient information about Cilostazol from NLM, click [[Cilostazol (patient information)|here]].<br />
<br />
==Precautions with Alcohol==<br />
<br />
Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
<br />
==Brand Names==<br />
<br />
Cilostazol®, Platel®.<br />
<br />
==Look-Alike Drug Names==<br />
<br />
* (Paired Confused Name 1a) — (Paired Confused Name 1b)<br />
* (Paired Confused Name 2a) — (Paired Confused Name 2b)<br />
* (Paired Confused Name 3a) — (Paired Confused Name 3b)<br />
<br />
==[http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm Drug Shortage Status]==<br />
<br />
==[http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price Price]==<br />
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==References==<br />
<br />
{{reflist}}<br />
<br />
</div></div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=File:Cilostazol100mg.jpg&diff=961743File:Cilostazol100mg.jpg2014-04-02T14:33:25Z<p>Abdurahman Khalil: </p>
<hr />
<div></div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=File:Cilostazol50mg.jpg&diff=961742File:Cilostazol50mg.jpg2014-04-02T14:33:09Z<p>Abdurahman Khalil: </p>
<hr />
<div></div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=Cilostazol&diff=961738Cilostazol2014-04-02T14:31:40Z<p>Abdurahman Khalil: /* Drug Images */</p>
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Brand Names|{{fontcolor|#F8F8FF|Brand Names}}]]<br />
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<div style="width: 80%"><br />
__NOTOC__<br />
{{CMG}}<br />
<br />
{{SB}} Cilostazol®, Pletal®<br />
<br />
==Disclaimer==<br />
<br />
'''''WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature. The information provided is not a medical advice or treatment. WikiDoc does not promote any medication or off-label use of drugs. Please read our full disclaimer [[wikidoc:General_disclaimer|{{fontcolor|#FF0000|here}}]].'''''<br />
<br />
==<span style="color:#FF0000; background:#000000;">Black Box Warning</span>==<br />
<br />
FDA Package Insert for {{PAGENAME}} contains no information regarding ''Black Box Warning''.<br />
<br />
{| style="border: 3px solid #696969;"<br />
| style="background: #000000; border: 0px; padding: 20px 20px; width: 800px;" |<br />
<center><br />
<font color="#F8F8FF" style="font-weight: bold;">CONTRAINDICATION</font><br />
</center><br />
<br />
<center><br />
<font color="#F8F8FF" size="1" style="font-style: italic;">See full prescribing information for complete boxed warning.</font><br />
</center><br />
<br />
<font color="#F8F8FF" style="font-weight: bold;"><br />
''{{fontcolor|#FF0000|Condition Name:}}'' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
</font><br />
|}<br />
<br />
==Overview==<br />
<br />
{{PAGENAME}} is a_Phosphodiesterase 3 Inhibitor drug that is FDA approved for the treatment of intermittent claudication. There is a Black Box Warning for this drug as shown <span style="background:#000000;">'''[[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|here}}]]'''</span>. Common adverse reactions include headache, dizziness, palpitation, diarrhea, rhinitis and pharyngitis.<br />
<br />
==Adult Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Adult)===<br />
<br />
=====Intermittent claudication=====<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
===Off-Label Use and Dosage (Adult)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* There is limited information about ''Off-Label Non–Guideline-Supported Use'' of {{PAGENAME}} in adult patients.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Pediatric Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Pediatric)===<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
===Off-Label Use and Dosage (Pediatric)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Contraindications==<br />
* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
<br />
==Warnings==<br />
<br />
=====Conidition 1=====<br />
<br />
(Description)<br />
<br />
=====Conidition 2=====<br />
<br />
(Description)<br />
<br />
=====Conidition 3=====<br />
<br />
(Description)<br />
<br />
==Adverse Reactions==<br />
<br />
===Clinical Trials Experience===<br />
Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol and 134 days for patients on placebo.<br />
<br />
The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with PLETAL 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included [[palpitation ]]and [[diarrhea]], both 1.1% for cilostazol (all doses) versus 0.1% for placebo.<br />
<br />
======Body as a Whole======<br />
*Common:<br />
:*Abdominal pain<br />
:*Back pain<br />
:*Headache <br />
:*Infection<br />
<br />
*Less common:<br />
[[Chills]], face [[edema]], [[fever]], [[generalized edema]], [[malaise]], [[neck rigidity]], [[pelvic pain]], [[retroperitoneal haemorrhage]].<br />
<br />
======Central Nervous System======<br />
<br />
*Common:<br />
:*Dizziness<br />
:*Vertigo<br />
<br />
*Less common:<br />
[[Anxiety]], [[insomnia]], [[neuralgia]].<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
*Common:<br />
:*Abnormal stool<br />
:*Diarrhea<br />
:*Dyspepsia<br />
:*Flatulence<br />
:*Nausea<br />
<br />
*Less common:<br />
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Metabolic & Nutritional======<br />
*Common:<br />
:*Peripheral edema<br />
<br />
*Less common:<br />
Increased [[creatinine]], [[gout]], [[hyperlipemia]], [[hyperuricemia]].<br />
<br />
======Musculoskeletal======<br />
<br />
*Common:<br />
:*Myalgia<br />
<br />
*Less common:<br />
[[Arthralgia]], bone pain, [[bursitis]].<br />
<br />
<br />
<br />
<br />
======Miscellaneous======<br />
Less common adverse reactions:<br />
<br />
*'''Endocrine:''' [[Diabetes mellitus]].<br />
<br />
*'''Hemic and Lymphatic:''' [[Anemia]], [[ecchymosis]],[[ iron deficiency anemia]], [[polycythemia]], [[purpura]].<br />
<br />
*'''Skin and Appendages:''' Dry skin, [[furunculosis]], skin hypertrophy, [[urticaria]].<br />
<br />
*'''Special Senses:''' [[Amblyopia]], [[blindness]], [[conjunctivitis]], [[diplopia]], ear pain, eye haemorrhage, [[retinal haemorrhage]], [[tinnitus]].<br />
<br />
*'''Urogenital:''' [[Albuminuria]], [[cystitis]], [[urinary frequency]], vaginal haemorrhage, vaginitis.<br />
<br />
===Postmarketing Experience===<br />
<br />
The following events have been reported spontaneously from worldwide post-marketing experience since the launch of PLETAL in the US.<br />
<br />
======Blood and lymphatic system disorders:======<br />
[[Agranulocytosis]],[[ aplastic anemia]], [[granulocytopenia]], [[pancytopenia]], [[thrombocytopenia]], [[leukopenia]], <br />
[[bleeding tendency]]<br />
<br />
======Cardiac disorders:======<br />
<br />
[[Torsades de pointes]], [[QT prolongation|QTc prolongation]] (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. [[complete atrioventricular block]], c[[ardiac failure ]]and [[bradyarrythmia]], when treated with cilostazol. Cilostazol was used "off label" due to its positive [[chronotropic]] action)<br />
<br />
======Gastrointestinal disorders:======<br />
<br />
*Gastrointestinal haemorrhage<br />
<br />
======General disorders and administration site conditions:======<br />
<br />
*Pain<br />
*[[chest pain]] <br />
*[[hot flushes]]<br />
<br />
======Hepatobiliary disorders:======<br />
<br />
*Hepatic dysfunction/abnormal liver function tests <br />
*[[jaundice]]<br />
<br />
======Injury, poisoning and procedural complications:======<br />
<br />
*Extradural [[haematoma ]] <br />
*Subdural haematoma<br />
<br />
=====Investigations:=====<br />
<br />
*[[Blood glucose]] increased, blood [[uric acid]] increased, [[platelet count]] decreased, [[white blood cell count]] decreased, increase in [[BUN]] (blood urea increased), blood pressure increase<br />
<br />
======Nervous system disorders:======<br />
<br />
*[[Intracranial haemorrhage]] <br />
*[[cerebral haemorrhage]] <br />
*[[cerebrovascular accident]]<br />
<br />
======Respiratory, thoracic and mediastinal disorders:======<br />
<br />
*Pulmonary haemorrhage<br />
*[[ interstitial pneumonia]]<br />
<br />
'''Skin and subcutaneous tissue disorders:'''<br />
<br />
*Haemorrhage subcutaneous, [[pruritus]], skin eruptions including [[Stevens-Johnson syndrome]], skin drug eruption ([[dermatitis medicamentosa]])<br />
<br />
======Vascular disorders:======<br />
<br />
*Subacute [[thrombosis ]](these cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting)<br />
<br />
==Drug Interactions==<br />
<br />
* Drug 1<br />
* Drug 2<br />
* Drug 3<br />
* Drug 4<br />
* Drug 5<br />
<br />
=====Drug 1=====<br />
<br />
(Description)<br />
<br />
=====Drug 2=====<br />
<br />
(Description)<br />
<br />
=====Drug 3=====<br />
<br />
(Description)<br />
<br />
=====Drug 4=====<br />
<br />
(Description)<br />
<br />
=====Drug 5=====<br />
<br />
(Description)<br />
<br />
==Use in Specific Populations==<br />
<br />
====Pregnancy====<br />
<br />
* '''[[Pregnancy category#United States|Pregnancy Category (FDA)]]: C'''<br />
<br />
* '''[[Pregnancy category#Australia|Pregnancy Category (AUS)]]: {{PAGENAME}} is not included in Australian Drug Evaluation Committee (ADEC) Pregnancy Categories.'''<br />
<br />
In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
<br />
====Labor and Delivery====<br />
<br />
(Description)<br />
<br />
====Nursing Mothers====<br />
<br />
Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
<br />
====Pediatric Use====<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
====Geriatric Use====<br />
Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
====Gender====<br />
<br />
The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range<br />
<br />
====Race====<br />
<br />
(Description)<br />
<br />
====Renal Impairment====<br />
<br />
Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
<br />
====Hepatic Impairment====<br />
<br />
Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
<br />
====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the exposure in humans at the MRHD.<br />
<br />
====Immunocompromised Patients====<br />
<br />
(Description)<br />
<br />
====Miscellaneous====<br />
<br />
=====Smokers=====<br />
Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
<br />
==Administration and Monitoring==<br />
<br />
====Administration====<br />
<br />
Oral<br />
<br />
====Monitoring====<br />
<br />
<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability).<br />
<br />
==IV Compatibility==<br />
<br />
FDA package insert doesn't contain any information regarding '''IV Compatibility'''<br />
<br />
==Overdosage==<br />
<br />
===Acute Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
<br />
====Management====<br />
<br />
(Description)<br />
<br />
===Chronic Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
(Description)<br />
<br />
====Management====<br />
<br />
(Description)<br />
<br />
==Pharmacology==<br />
<br />
{{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
<br />
===Mechanism of Action===<br />
<br />
The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
<br />
===Structure===<br />
<br />
*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
<br />
<br />
===Pharmacodynamics===<br />
<br />
(Description)<br />
<br />
===Pharmacokinetics===<br />
<br />
Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
<br />
====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4‑dehydro‑cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4‑dehydro‑cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
<br />
===Nonclinical Toxicology===<br />
<br />
==Clinical Studies==<br />
<br />
*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
<br />
{|<br />
| [[image:Cilo2.png|400px|thumb]]<br />
|}<br />
<br />
<br />
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
<br />
==How Supplied==<br />
<br />
'''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
<br />
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0223-60 bottles of 60 and 0185-0223-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
==Images==<br />
<br />
===Drug Images===<br />
<br />
{|<br />
| [[File:Cilostazol50mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 50 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;123 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
{|<br />
| [[File:Cilostazol100mg.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': Cilostazol 100 MG Oral Tablet <BR><br />
'''Ingredient(s)''': carboxymethylcellulose calcium / magnesium stearate / cellulose, microcrystalline <BR><br />
'''Imprint''': E;223 <BR><br />
'''Color(s)''': White<BR><br />
'''Shape''': Round <BR><br />
'''Size (mm)''': 9 mm <BR><br />
'''Score''': 1 <BR><br />
'''Drug Label Author''': Bryant Ranch Prepack ]]</p><br />
|}<br />
<br />
===Package and Label Display Panel===<br />
<br />
(Package Images)<br />
<br />
(Display Panel Images)<br />
<br />
==Patient Information==<br />
<br />
===Patient Information from FDA===<br />
(sil-OS-tah-zol)<br />
<br />
Please read this leaflet before you start taking cilostazol tablets and each time you renew it in case anything has changed. This leaflet does not replace careful discussions with your doctor. You and your doctor should discuss cilostazol when you start taking it and at regular check-ups. You should follow your doctor’s advice about when to have check-ups.<br />
What is cilostazol for?<br />
Cilostazol may improve the symptoms of patients with a medical condition called intermittent claudication.<br />
What is intermittent claudication?<br />
Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. It occurs because narrowing or blockage of the arteries decreases blood flow to the legs. The decreased blood flow does not supply enough oxygen to the leg muscles during walking, resulting in these painful leg cramps.<br />
<br />
'''What treatments are available for intermittent claudication?'''<br />
<br />
The three main treatments available for intermittent claudication are:<br />
*Exercise. Your doctor may advise an exercise program.<br />
*Medication. Your doctor may prescribe a medication such as cilostazol. (See Who should not take cilostazol tablets?)<br />
*Surgery. Your doctor may recommend a surgical procedure to bypass the blocked segment of the artery. Another procedure is called a percutaneous transluminal angioplasty. In this procedure, a catheter (a flexible tube) is inserted into the artery to reduce the blockage and improve blood flow.<br />
<br />
'''How does cilostazol work?'''<br />
<br />
*The exact way that many drugs work is not well understood. Although how cilostazol works is not completely clear, its main effects are to dilate (widen) the arteries supplying blood to the legs and to decrease the ability of platelets in the blood to stick together. Platelets are particles that circulate in the blood and play a role in clotting.<br />
*Cilostazol may reduce the leg pain that patients with intermittent claudication experience, allowing them to walk farther before their leg pain occurs.<br />
*Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks. If you have not noticed any benefit from cilostazol tablets after 12 weeks you and your doctor may wish to discuss other forms of treatment.<br />
*Sometimes blood vessel disease of the legs causes pain at rest or breakdown of skin in the leg. Cilostazol has not been shown to work in patients with these problems.<br />
<br />
'''Who should not take cilostazol tablets?'''<br />
<br />
*Patients who have congestive heart failure (CHF) must not take cilostazol tablets. The most common symptoms of CHF are shortness of breath and swelling of the legs. However, other conditions may also cause these symptoms. It is important that you discuss with your doctor whether you have CHF.<br />
*Over 1,300 patients took cilostazol in studies that lasted for 3 to 6 months. The mortality rate in these patients was similar to placebo (less than 1%). These studies were too small to be sure there is not some increased risk of dying with longer use or in patients sicker than those in the studies.<br />
<br />
'''How should cilostazol tablets be taken?'''<br />
<br />
*Follow your doctor’s advice about how to take cilostazol tablets.<br />
*You should take cilostazol tablets twice a day, at least one half-hour before or two hours after breakfast and dinner. Take cilostazol tablets at about the same times each day.<br />
*Do not share cilostazol tablets with anyone else. It was prescribed only for you.<br />
*Keep cilostazol tablets and all drugs out of the reach of children.<br />
<br />
'''Can cilostazol tablets be taken with other drugs?'''<br />
<br />
Certain drugs and foods can increase the amount of cilostazol in the blood. Because of this, your doctor may adjust your dose of cilostazol or even stop it if you are taking or are going to take one of the following medications.<br />
Drugs Interacting with Cilostazol<br />
Generic Name (Brand Names)Type of Drug<br />
[[erythromycin]] (such as E.E.S.®, Erythrocin®) Antibiotic<br />
[[ketoconazole]] (Nizoral®), [[itraconazole]] (Sporanox®) Antifungal<br />
[[diltiazem]] (Cardizem®) Antihypertensive<br />
[[omeprazole]] (Prilosec®) Gastric acid reducer<br />
This list does not include every drug that may interact with cilostazol tablets. Therefore, you should tell your doctor about all medications that you are taking, including vitamins, herbal supplements and over-the-counter drugs you can buy without a prescription. You should also check with your doctor before taking a new medication after you have begun cilostazol tablets.<br />
<br />
'''What are the possible side effects of cilostazol tablets?'''<br />
<br />
Cilostazol tablets may cause side effects including headache, diarrhea, abnormal stools, increased heart rate and palpitations.<br />
You should discuss possible side effects with your doctor before taking cilostazol tablets and any time you think you are having a side effect.<br />
This provides only a summary of information about cilostazol tablets. If you have any questions about cilostazol tablets, talk to your doctor.<br />
'''Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.'''<br />
<br />
===Patient Information from NLM===<br />
<br />
For patient information about Cilostazol from NLM, click [[Cilostazol (patient information)|here]].<br />
<br />
==Precautions with Alcohol==<br />
<br />
Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
<br />
==Brand Names==<br />
<br />
Cilostazol®, Platel®.<br />
<br />
==Look-Alike Drug Names==<br />
<br />
* (Paired Confused Name 1a) — (Paired Confused Name 1b)<br />
* (Paired Confused Name 2a) — (Paired Confused Name 2b)<br />
* (Paired Confused Name 3a) — (Paired Confused Name 3b)<br />
<br />
==[http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm Drug Shortage Status]==<br />
<br />
==[http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price Price]==<br />
<br />
==References==<br />
<br />
{{reflist}}<br />
<br />
</div></div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=Cilostazol&diff=961723Cilostazol2014-04-02T11:24:28Z<p>Abdurahman Khalil: /* IV Compatibility */</p>
<hr />
<div>{|class="infobox" style="position: fixed; top: 180px; right: 20px; margin: 0 0 0 0; border: 0; float: right; width: 15%; background: #104E8B; border-radius: 10px 10px 10px 10px;" cellpadding="0" cellspacing="0";<br />
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|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adverse Reactions|{{fontcolor|#F8F8FF|Adverse Reactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Drug Interactions|{{fontcolor|#F8F8FF|Drug Interactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Use in Specific Populations|{{fontcolor|#F8F8FF|Use in Specific Populations}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Administration and Monitoring|{{fontcolor|#F8F8FF|Administration and Monitoring}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#IV Compatibility|{{fontcolor|#F8F8FF|IV Compatibility}}]]<br />
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#How Supplied|{{fontcolor|#F8F8FF|How Supplied}}]]<br />
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|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Brand Names|{{fontcolor|#F8F8FF|Brand Names}}]]<br />
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|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm {{fontcolor|#F8F8FF|Drug Shortage Status}}]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price {{fontcolor|#F8F8FF|Price}}]<br />
|-<br />
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<div style="width: 80%"><br />
__NOTOC__<br />
{{CMG}}<br />
<br />
{{SB}} Cilostazol®, Pletal®<br />
<br />
==Disclaimer==<br />
<br />
'''''WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature. The information provided is not a medical advice or treatment. WikiDoc does not promote any medication or off-label use of drugs. Please read our full disclaimer [[wikidoc:General_disclaimer|{{fontcolor|#FF0000|here}}]].'''''<br />
<br />
==<span style="color:#FF0000; background:#000000;">Black Box Warning</span>==<br />
<br />
FDA Package Insert for {{PAGENAME}} contains no information regarding ''Black Box Warning''.<br />
<br />
{| style="border: 3px solid #696969;"<br />
| style="background: #000000; border: 0px; padding: 20px 20px; width: 800px;" |<br />
<center><br />
<font color="#F8F8FF" style="font-weight: bold;">CONTRAINDICATION</font><br />
</center><br />
<br />
<center><br />
<font color="#F8F8FF" size="1" style="font-style: italic;">See full prescribing information for complete boxed warning.</font><br />
</center><br />
<br />
<font color="#F8F8FF" style="font-weight: bold;"><br />
''{{fontcolor|#FF0000|Condition Name:}}'' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
</font><br />
|}<br />
<br />
==Overview==<br />
<br />
{{PAGENAME}} is a_Phosphodiesterase 3 Inhibitor drug that is FDA approved for the treatment of intermittent claudication. There is a Black Box Warning for this drug as shown <span style="background:#000000;">'''[[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|here}}]]'''</span>. Common adverse reactions include headache, dizziness, palpitation, diarrhea, rhinitis and pharyngitis.<br />
<br />
==Adult Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Adult)===<br />
<br />
=====Intermittent claudication=====<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
===Off-Label Use and Dosage (Adult)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* There is limited information about ''Off-Label Non–Guideline-Supported Use'' of {{PAGENAME}} in adult patients.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
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=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Pediatric Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Pediatric)===<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
===Off-Label Use and Dosage (Pediatric)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
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=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Contraindications==<br />
* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
<br />
==Warnings==<br />
<br />
=====Conidition 1=====<br />
<br />
(Description)<br />
<br />
=====Conidition 2=====<br />
<br />
(Description)<br />
<br />
=====Conidition 3=====<br />
<br />
(Description)<br />
<br />
==Adverse Reactions==<br />
<br />
===Clinical Trials Experience===<br />
Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol and 134 days for patients on placebo.<br />
<br />
The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with PLETAL 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included [[palpitation ]]and [[diarrhea]], both 1.1% for cilostazol (all doses) versus 0.1% for placebo.<br />
<br />
======Body as a Whole======<br />
*Common:<br />
:*Abdominal pain<br />
:*Back pain<br />
:*Headache <br />
:*Infection<br />
<br />
*Less common:<br />
[[Chills]], face [[edema]], [[fever]], [[generalized edema]], [[malaise]], [[neck rigidity]], [[pelvic pain]], [[retroperitoneal haemorrhage]].<br />
<br />
======Central Nervous System======<br />
<br />
*Common:<br />
:*Dizziness<br />
:*Vertigo<br />
<br />
*Less common:<br />
[[Anxiety]], [[insomnia]], [[neuralgia]].<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
*Common:<br />
:*Abnormal stool<br />
:*Diarrhea<br />
:*Dyspepsia<br />
:*Flatulence<br />
:*Nausea<br />
<br />
*Less common:<br />
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Metabolic & Nutritional======<br />
*Common:<br />
:*Peripheral edema<br />
<br />
*Less common:<br />
Increased [[creatinine]], [[gout]], [[hyperlipemia]], [[hyperuricemia]].<br />
<br />
======Musculoskeletal======<br />
<br />
*Common:<br />
:*Myalgia<br />
<br />
*Less common:<br />
[[Arthralgia]], bone pain, [[bursitis]].<br />
<br />
<br />
<br />
<br />
======Miscellaneous======<br />
Less common adverse reactions:<br />
<br />
*'''Endocrine:''' [[Diabetes mellitus]].<br />
<br />
*'''Hemic and Lymphatic:''' [[Anemia]], [[ecchymosis]],[[ iron deficiency anemia]], [[polycythemia]], [[purpura]].<br />
<br />
*'''Skin and Appendages:''' Dry skin, [[furunculosis]], skin hypertrophy, [[urticaria]].<br />
<br />
*'''Special Senses:''' [[Amblyopia]], [[blindness]], [[conjunctivitis]], [[diplopia]], ear pain, eye haemorrhage, [[retinal haemorrhage]], [[tinnitus]].<br />
<br />
*'''Urogenital:''' [[Albuminuria]], [[cystitis]], [[urinary frequency]], vaginal haemorrhage, vaginitis.<br />
<br />
===Postmarketing Experience===<br />
<br />
The following events have been reported spontaneously from worldwide post-marketing experience since the launch of PLETAL in the US.<br />
<br />
======Blood and lymphatic system disorders:======<br />
[[Agranulocytosis]],[[ aplastic anemia]], [[granulocytopenia]], [[pancytopenia]], [[thrombocytopenia]], [[leukopenia]], <br />
[[bleeding tendency]]<br />
<br />
======Cardiac disorders:======<br />
<br />
[[Torsades de pointes]], [[QT prolongation|QTc prolongation]] (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. [[complete atrioventricular block]], c[[ardiac failure ]]and [[bradyarrythmia]], when treated with cilostazol. Cilostazol was used "off label" due to its positive [[chronotropic]] action)<br />
<br />
======Gastrointestinal disorders:======<br />
<br />
*Gastrointestinal haemorrhage<br />
<br />
======General disorders and administration site conditions:======<br />
<br />
*Pain<br />
*[[chest pain]] <br />
*[[hot flushes]]<br />
<br />
======Hepatobiliary disorders:======<br />
<br />
*Hepatic dysfunction/abnormal liver function tests <br />
*[[jaundice]]<br />
<br />
======Injury, poisoning and procedural complications:======<br />
<br />
*Extradural [[haematoma ]] <br />
*Subdural haematoma<br />
<br />
=====Investigations:=====<br />
<br />
*[[Blood glucose]] increased, blood [[uric acid]] increased, [[platelet count]] decreased, [[white blood cell count]] decreased, increase in [[BUN]] (blood urea increased), blood pressure increase<br />
<br />
======Nervous system disorders:======<br />
<br />
*[[Intracranial haemorrhage]] <br />
*[[cerebral haemorrhage]] <br />
*[[cerebrovascular accident]]<br />
<br />
======Respiratory, thoracic and mediastinal disorders:======<br />
<br />
*Pulmonary haemorrhage<br />
*[[ interstitial pneumonia]]<br />
<br />
'''Skin and subcutaneous tissue disorders:'''<br />
<br />
*Haemorrhage subcutaneous, [[pruritus]], skin eruptions including [[Stevens-Johnson syndrome]], skin drug eruption ([[dermatitis medicamentosa]])<br />
<br />
======Vascular disorders:======<br />
<br />
*Subacute [[thrombosis ]](these cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting)<br />
<br />
==Drug Interactions==<br />
<br />
* Drug 1<br />
* Drug 2<br />
* Drug 3<br />
* Drug 4<br />
* Drug 5<br />
<br />
=====Drug 1=====<br />
<br />
(Description)<br />
<br />
=====Drug 2=====<br />
<br />
(Description)<br />
<br />
=====Drug 3=====<br />
<br />
(Description)<br />
<br />
=====Drug 4=====<br />
<br />
(Description)<br />
<br />
=====Drug 5=====<br />
<br />
(Description)<br />
<br />
==Use in Specific Populations==<br />
<br />
====Pregnancy====<br />
<br />
* '''[[Pregnancy category#United States|Pregnancy Category (FDA)]]: C'''<br />
<br />
* '''[[Pregnancy category#Australia|Pregnancy Category (AUS)]]: {{PAGENAME}} is not included in Australian Drug Evaluation Committee (ADEC) Pregnancy Categories.'''<br />
<br />
In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
<br />
====Labor and Delivery====<br />
<br />
(Description)<br />
<br />
====Nursing Mothers====<br />
<br />
Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
<br />
====Pediatric Use====<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
====Geriatric Use====<br />
Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
====Gender====<br />
<br />
The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range<br />
<br />
====Race====<br />
<br />
(Description)<br />
<br />
====Renal Impairment====<br />
<br />
Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
<br />
====Hepatic Impairment====<br />
<br />
Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
<br />
====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the exposure in humans at the MRHD.<br />
<br />
====Immunocompromised Patients====<br />
<br />
(Description)<br />
<br />
====Miscellaneous====<br />
<br />
=====Smokers=====<br />
Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
<br />
==Administration and Monitoring==<br />
<br />
====Administration====<br />
<br />
Oral<br />
<br />
====Monitoring====<br />
<br />
<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability).<br />
<br />
==IV Compatibility==<br />
<br />
FDA package insert doesn't contain any information regarding '''IV Compatibility'''<br />
<br />
==Overdosage==<br />
<br />
===Acute Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
<br />
====Management====<br />
<br />
(Description)<br />
<br />
===Chronic Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
(Description)<br />
<br />
====Management====<br />
<br />
(Description)<br />
<br />
==Pharmacology==<br />
<br />
{{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
<br />
===Mechanism of Action===<br />
<br />
The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
<br />
===Structure===<br />
<br />
*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
<br />
<br />
===Pharmacodynamics===<br />
<br />
(Description)<br />
<br />
===Pharmacokinetics===<br />
<br />
Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
<br />
====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4‑dehydro‑cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4‑dehydro‑cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
<br />
===Nonclinical Toxicology===<br />
<br />
==Clinical Studies==<br />
<br />
*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
<br />
{|<br />
| [[image:Cilo2.png|400px|thumb]]<br />
|}<br />
<br />
<br />
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
<br />
==How Supplied==<br />
<br />
'''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
<br />
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0223-60 bottles of 60 and 0185-0223-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
==Images==<br />
<br />
===Drug Images===<br />
<br />
{|<br />
| [[File:PILLIMAGE.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': <BR><br />
'''Ingredient(s)''': <BR><br />
'''Imprint''': <BR><br />
'''Color(s)''': <BR><br />
'''Shape''': <BR><br />
'''Size (mm)''': <BR><br />
'''Score''': <BR><br />
'''Drug Label Author''': ]]</p><br />
|}<br />
<br />
===Package and Label Display Panel===<br />
<br />
(Package Images)<br />
<br />
(Display Panel Images)<br />
<br />
==Patient Information==<br />
<br />
===Patient Information from FDA===<br />
(sil-OS-tah-zol)<br />
<br />
Please read this leaflet before you start taking cilostazol tablets and each time you renew it in case anything has changed. This leaflet does not replace careful discussions with your doctor. You and your doctor should discuss cilostazol when you start taking it and at regular check-ups. You should follow your doctor’s advice about when to have check-ups.<br />
What is cilostazol for?<br />
Cilostazol may improve the symptoms of patients with a medical condition called intermittent claudication.<br />
What is intermittent claudication?<br />
Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. It occurs because narrowing or blockage of the arteries decreases blood flow to the legs. The decreased blood flow does not supply enough oxygen to the leg muscles during walking, resulting in these painful leg cramps.<br />
<br />
'''What treatments are available for intermittent claudication?'''<br />
<br />
The three main treatments available for intermittent claudication are:<br />
*Exercise. Your doctor may advise an exercise program.<br />
*Medication. Your doctor may prescribe a medication such as cilostazol. (See Who should not take cilostazol tablets?)<br />
*Surgery. Your doctor may recommend a surgical procedure to bypass the blocked segment of the artery. Another procedure is called a percutaneous transluminal angioplasty. In this procedure, a catheter (a flexible tube) is inserted into the artery to reduce the blockage and improve blood flow.<br />
<br />
'''How does cilostazol work?'''<br />
<br />
*The exact way that many drugs work is not well understood. Although how cilostazol works is not completely clear, its main effects are to dilate (widen) the arteries supplying blood to the legs and to decrease the ability of platelets in the blood to stick together. Platelets are particles that circulate in the blood and play a role in clotting.<br />
*Cilostazol may reduce the leg pain that patients with intermittent claudication experience, allowing them to walk farther before their leg pain occurs.<br />
*Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks. If you have not noticed any benefit from cilostazol tablets after 12 weeks you and your doctor may wish to discuss other forms of treatment.<br />
*Sometimes blood vessel disease of the legs causes pain at rest or breakdown of skin in the leg. Cilostazol has not been shown to work in patients with these problems.<br />
<br />
'''Who should not take cilostazol tablets?'''<br />
<br />
*Patients who have congestive heart failure (CHF) must not take cilostazol tablets. The most common symptoms of CHF are shortness of breath and swelling of the legs. However, other conditions may also cause these symptoms. It is important that you discuss with your doctor whether you have CHF.<br />
*Over 1,300 patients took cilostazol in studies that lasted for 3 to 6 months. The mortality rate in these patients was similar to placebo (less than 1%). These studies were too small to be sure there is not some increased risk of dying with longer use or in patients sicker than those in the studies.<br />
<br />
'''How should cilostazol tablets be taken?'''<br />
<br />
*Follow your doctor’s advice about how to take cilostazol tablets.<br />
*You should take cilostazol tablets twice a day, at least one half-hour before or two hours after breakfast and dinner. Take cilostazol tablets at about the same times each day.<br />
*Do not share cilostazol tablets with anyone else. It was prescribed only for you.<br />
*Keep cilostazol tablets and all drugs out of the reach of children.<br />
<br />
'''Can cilostazol tablets be taken with other drugs?'''<br />
<br />
Certain drugs and foods can increase the amount of cilostazol in the blood. Because of this, your doctor may adjust your dose of cilostazol or even stop it if you are taking or are going to take one of the following medications.<br />
Drugs Interacting with Cilostazol<br />
Generic Name (Brand Names)Type of Drug<br />
[[erythromycin]] (such as E.E.S.®, Erythrocin®) Antibiotic<br />
[[ketoconazole]] (Nizoral®), [[itraconazole]] (Sporanox®) Antifungal<br />
[[diltiazem]] (Cardizem®) Antihypertensive<br />
[[omeprazole]] (Prilosec®) Gastric acid reducer<br />
This list does not include every drug that may interact with cilostazol tablets. Therefore, you should tell your doctor about all medications that you are taking, including vitamins, herbal supplements and over-the-counter drugs you can buy without a prescription. You should also check with your doctor before taking a new medication after you have begun cilostazol tablets.<br />
<br />
'''What are the possible side effects of cilostazol tablets?'''<br />
<br />
Cilostazol tablets may cause side effects including headache, diarrhea, abnormal stools, increased heart rate and palpitations.<br />
You should discuss possible side effects with your doctor before taking cilostazol tablets and any time you think you are having a side effect.<br />
This provides only a summary of information about cilostazol tablets. If you have any questions about cilostazol tablets, talk to your doctor.<br />
'''Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.'''<br />
<br />
===Patient Information from NLM===<br />
<br />
For patient information about Cilostazol from NLM, click [[Cilostazol (patient information)|here]].<br />
<br />
==Precautions with Alcohol==<br />
<br />
Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
<br />
==Brand Names==<br />
<br />
Cilostazol®, Platel®.<br />
<br />
==Look-Alike Drug Names==<br />
<br />
* (Paired Confused Name 1a) — (Paired Confused Name 1b)<br />
* (Paired Confused Name 2a) — (Paired Confused Name 2b)<br />
* (Paired Confused Name 3a) — (Paired Confused Name 3b)<br />
<br />
==[http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm Drug Shortage Status]==<br />
<br />
==[http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price Price]==<br />
<br />
==References==<br />
<br />
{{reflist}}<br />
<br />
</div></div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=Cilostazol&diff=961722Cilostazol2014-04-02T11:22:41Z<p>Abdurahman Khalil: /* Postmarketing Experience */</p>
<hr />
<div>{|class="infobox" style="position: fixed; top: 180px; right: 20px; margin: 0 0 0 0; border: 0; float: right; width: 15%; background: #104E8B; border-radius: 10px 10px 10px 10px;" cellpadding="0" cellspacing="0";<br />
|-<br />
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|-<br />
! style="font-size: 80%; padding: 0 5px; background: #000000; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|Black Box Warning}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adult Indications and Dosage|{{fontcolor|#F8F8FF|Adult Indications and Dosage}}]]<br />
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pediatric Indications and Dosage|{{fontcolor|#F8F8FF|Pediatric Indications and Dosage}}]]<br />
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Contraindications|{{fontcolor|#F8F8FF|Contraindications}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Warnings|{{fontcolor|#F8F8FF|Warnings}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adverse Reactions|{{fontcolor|#F8F8FF|Adverse Reactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Drug Interactions|{{fontcolor|#F8F8FF|Drug Interactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Use in Specific Populations|{{fontcolor|#F8F8FF|Use in Specific Populations}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Administration and Monitoring|{{fontcolor|#F8F8FF|Administration and Monitoring}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#IV Compatibility|{{fontcolor|#F8F8FF|IV Compatibility}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Overdosage|{{fontcolor|#F8F8FF|Overdosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pharmacology|{{fontcolor|#F8F8FF|Pharmacology}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Clinical Studies|{{fontcolor|#F8F8FF|Clinical Studies}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#How Supplied|{{fontcolor|#F8F8FF|How Supplied}}]]<br />
|-<br />
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|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Precautions with Alcohol|{{fontcolor|#F8F8FF|Precautions with Alcohol}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Brand Names|{{fontcolor|#F8F8FF|Brand Names}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Look-Alike Drug Names|{{fontcolor|#F8F8FF|Look-Alike Drug Names}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm {{fontcolor|#F8F8FF|Drug Shortage Status}}]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price {{fontcolor|#F8F8FF|Price}}]<br />
|-<br />
|}<br />
<div style="width: 80%"><br />
__NOTOC__<br />
{{CMG}}<br />
<br />
{{SB}} Cilostazol®, Pletal®<br />
<br />
==Disclaimer==<br />
<br />
'''''WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature. The information provided is not a medical advice or treatment. WikiDoc does not promote any medication or off-label use of drugs. Please read our full disclaimer [[wikidoc:General_disclaimer|{{fontcolor|#FF0000|here}}]].'''''<br />
<br />
==<span style="color:#FF0000; background:#000000;">Black Box Warning</span>==<br />
<br />
FDA Package Insert for {{PAGENAME}} contains no information regarding ''Black Box Warning''.<br />
<br />
{| style="border: 3px solid #696969;"<br />
| style="background: #000000; border: 0px; padding: 20px 20px; width: 800px;" |<br />
<center><br />
<font color="#F8F8FF" style="font-weight: bold;">CONTRAINDICATION</font><br />
</center><br />
<br />
<center><br />
<font color="#F8F8FF" size="1" style="font-style: italic;">See full prescribing information for complete boxed warning.</font><br />
</center><br />
<br />
<font color="#F8F8FF" style="font-weight: bold;"><br />
''{{fontcolor|#FF0000|Condition Name:}}'' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
</font><br />
|}<br />
<br />
==Overview==<br />
<br />
{{PAGENAME}} is a_Phosphodiesterase 3 Inhibitor drug that is FDA approved for the treatment of intermittent claudication. There is a Black Box Warning for this drug as shown <span style="background:#000000;">'''[[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|here}}]]'''</span>. Common adverse reactions include headache, dizziness, palpitation, diarrhea, rhinitis and pharyngitis.<br />
<br />
==Adult Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Adult)===<br />
<br />
=====Intermittent claudication=====<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
===Off-Label Use and Dosage (Adult)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* There is limited information about ''Off-Label Non–Guideline-Supported Use'' of {{PAGENAME}} in adult patients.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Pediatric Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Pediatric)===<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
===Off-Label Use and Dosage (Pediatric)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Contraindications==<br />
* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
<br />
==Warnings==<br />
<br />
=====Conidition 1=====<br />
<br />
(Description)<br />
<br />
=====Conidition 2=====<br />
<br />
(Description)<br />
<br />
=====Conidition 3=====<br />
<br />
(Description)<br />
<br />
==Adverse Reactions==<br />
<br />
===Clinical Trials Experience===<br />
Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol and 134 days for patients on placebo.<br />
<br />
The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with PLETAL 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included [[palpitation ]]and [[diarrhea]], both 1.1% for cilostazol (all doses) versus 0.1% for placebo.<br />
<br />
======Body as a Whole======<br />
*Common:<br />
:*Abdominal pain<br />
:*Back pain<br />
:*Headache <br />
:*Infection<br />
<br />
*Less common:<br />
[[Chills]], face [[edema]], [[fever]], [[generalized edema]], [[malaise]], [[neck rigidity]], [[pelvic pain]], [[retroperitoneal haemorrhage]].<br />
<br />
======Central Nervous System======<br />
<br />
*Common:<br />
:*Dizziness<br />
:*Vertigo<br />
<br />
*Less common:<br />
[[Anxiety]], [[insomnia]], [[neuralgia]].<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
*Common:<br />
:*Abnormal stool<br />
:*Diarrhea<br />
:*Dyspepsia<br />
:*Flatulence<br />
:*Nausea<br />
<br />
*Less common:<br />
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Metabolic & Nutritional======<br />
*Common:<br />
:*Peripheral edema<br />
<br />
*Less common:<br />
Increased [[creatinine]], [[gout]], [[hyperlipemia]], [[hyperuricemia]].<br />
<br />
======Musculoskeletal======<br />
<br />
*Common:<br />
:*Myalgia<br />
<br />
*Less common:<br />
[[Arthralgia]], bone pain, [[bursitis]].<br />
<br />
<br />
<br />
<br />
======Miscellaneous======<br />
Less common adverse reactions:<br />
<br />
*'''Endocrine:''' [[Diabetes mellitus]].<br />
<br />
*'''Hemic and Lymphatic:''' [[Anemia]], [[ecchymosis]],[[ iron deficiency anemia]], [[polycythemia]], [[purpura]].<br />
<br />
*'''Skin and Appendages:''' Dry skin, [[furunculosis]], skin hypertrophy, [[urticaria]].<br />
<br />
*'''Special Senses:''' [[Amblyopia]], [[blindness]], [[conjunctivitis]], [[diplopia]], ear pain, eye haemorrhage, [[retinal haemorrhage]], [[tinnitus]].<br />
<br />
*'''Urogenital:''' [[Albuminuria]], [[cystitis]], [[urinary frequency]], vaginal haemorrhage, vaginitis.<br />
<br />
===Postmarketing Experience===<br />
<br />
The following events have been reported spontaneously from worldwide post-marketing experience since the launch of PLETAL in the US.<br />
<br />
======Blood and lymphatic system disorders:======<br />
[[Agranulocytosis]],[[ aplastic anemia]], [[granulocytopenia]], [[pancytopenia]], [[thrombocytopenia]], [[leukopenia]], <br />
[[bleeding tendency]]<br />
<br />
======Cardiac disorders:======<br />
<br />
[[Torsades de pointes]], [[QT prolongation|QTc prolongation]] (torsades de pointes and QTc prolongation occurred in patients with cardiac disorders, e.g. [[complete atrioventricular block]], c[[ardiac failure ]]and [[bradyarrythmia]], when treated with cilostazol. Cilostazol was used "off label" due to its positive [[chronotropic]] action)<br />
<br />
======Gastrointestinal disorders:======<br />
<br />
*Gastrointestinal haemorrhage<br />
<br />
======General disorders and administration site conditions:======<br />
<br />
*Pain<br />
*[[chest pain]] <br />
*[[hot flushes]]<br />
<br />
======Hepatobiliary disorders:======<br />
<br />
*Hepatic dysfunction/abnormal liver function tests <br />
*[[jaundice]]<br />
<br />
======Injury, poisoning and procedural complications:======<br />
<br />
*Extradural [[haematoma ]] <br />
*Subdural haematoma<br />
<br />
=====Investigations:=====<br />
<br />
*[[Blood glucose]] increased, blood [[uric acid]] increased, [[platelet count]] decreased, [[white blood cell count]] decreased, increase in [[BUN]] (blood urea increased), blood pressure increase<br />
<br />
======Nervous system disorders:======<br />
<br />
*[[Intracranial haemorrhage]] <br />
*[[cerebral haemorrhage]] <br />
*[[cerebrovascular accident]]<br />
<br />
======Respiratory, thoracic and mediastinal disorders:======<br />
<br />
*Pulmonary haemorrhage<br />
*[[ interstitial pneumonia]]<br />
<br />
'''Skin and subcutaneous tissue disorders:'''<br />
<br />
*Haemorrhage subcutaneous, [[pruritus]], skin eruptions including [[Stevens-Johnson syndrome]], skin drug eruption ([[dermatitis medicamentosa]])<br />
<br />
======Vascular disorders:======<br />
<br />
*Subacute [[thrombosis ]](these cases of subacute thrombosis occurred in patients treated with aspirin and "off label" use of cilostazol for prevention of thrombotic complication after coronary stenting)<br />
<br />
==Drug Interactions==<br />
<br />
* Drug 1<br />
* Drug 2<br />
* Drug 3<br />
* Drug 4<br />
* Drug 5<br />
<br />
=====Drug 1=====<br />
<br />
(Description)<br />
<br />
=====Drug 2=====<br />
<br />
(Description)<br />
<br />
=====Drug 3=====<br />
<br />
(Description)<br />
<br />
=====Drug 4=====<br />
<br />
(Description)<br />
<br />
=====Drug 5=====<br />
<br />
(Description)<br />
<br />
==Use in Specific Populations==<br />
<br />
====Pregnancy====<br />
<br />
* '''[[Pregnancy category#United States|Pregnancy Category (FDA)]]: C'''<br />
<br />
* '''[[Pregnancy category#Australia|Pregnancy Category (AUS)]]: {{PAGENAME}} is not included in Australian Drug Evaluation Committee (ADEC) Pregnancy Categories.'''<br />
<br />
In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
<br />
====Labor and Delivery====<br />
<br />
(Description)<br />
<br />
====Nursing Mothers====<br />
<br />
Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
<br />
====Pediatric Use====<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
====Geriatric Use====<br />
Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
====Gender====<br />
<br />
The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range<br />
<br />
====Race====<br />
<br />
(Description)<br />
<br />
====Renal Impairment====<br />
<br />
Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
<br />
====Hepatic Impairment====<br />
<br />
Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
<br />
====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the exposure in humans at the MRHD.<br />
<br />
====Immunocompromised Patients====<br />
<br />
(Description)<br />
<br />
====Miscellaneous====<br />
<br />
=====Smokers=====<br />
Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
<br />
==Administration and Monitoring==<br />
<br />
====Administration====<br />
<br />
Oral<br />
<br />
====Monitoring====<br />
<br />
<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability).<br />
<br />
==IV Compatibility==<br />
<br />
===Solution===<br />
<br />
====Compatible====<br />
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* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
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====Not Tested====<br />
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* Solution 2<br />
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====Incompatible====<br />
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* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
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===Y-Site===<br />
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====Compatible====<br />
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* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
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====Not Tested====<br />
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* Solution 2<br />
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====Variable====<br />
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* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
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====Incompatible====<br />
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* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
===Admixture===<br />
<br />
====Compatible====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Not Tested====<br />
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* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
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====Variable====<br />
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* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
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====Incompatible====<br />
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* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
===Syringe===<br />
<br />
====Compatible====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Not Tested====<br />
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* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
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====Variable====<br />
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* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
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====Incompatible====<br />
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* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
===TPN/TNA===<br />
<br />
====Compatible====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Not Tested====<br />
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* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
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====Variable====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Incompatible====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
==Overdosage==<br />
<br />
===Acute Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
<br />
====Management====<br />
<br />
(Description)<br />
<br />
===Chronic Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
(Description)<br />
<br />
====Management====<br />
<br />
(Description)<br />
<br />
==Pharmacology==<br />
<br />
{{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
<br />
===Mechanism of Action===<br />
<br />
The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
<br />
===Structure===<br />
<br />
*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
<br />
<br />
===Pharmacodynamics===<br />
<br />
(Description)<br />
<br />
===Pharmacokinetics===<br />
<br />
Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
<br />
====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4‑dehydro‑cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4‑dehydro‑cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
<br />
===Nonclinical Toxicology===<br />
<br />
==Clinical Studies==<br />
<br />
*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
<br />
{|<br />
| [[image:Cilo2.png|400px|thumb]]<br />
|}<br />
<br />
<br />
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
<br />
==How Supplied==<br />
<br />
'''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
<br />
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0223-60 bottles of 60 and 0185-0223-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
==Images==<br />
<br />
===Drug Images===<br />
<br />
{|<br />
| [[File:PILLIMAGE.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': <BR><br />
'''Ingredient(s)''': <BR><br />
'''Imprint''': <BR><br />
'''Color(s)''': <BR><br />
'''Shape''': <BR><br />
'''Size (mm)''': <BR><br />
'''Score''': <BR><br />
'''Drug Label Author''': ]]</p><br />
|}<br />
<br />
===Package and Label Display Panel===<br />
<br />
(Package Images)<br />
<br />
(Display Panel Images)<br />
<br />
==Patient Information==<br />
<br />
===Patient Information from FDA===<br />
(sil-OS-tah-zol)<br />
<br />
Please read this leaflet before you start taking cilostazol tablets and each time you renew it in case anything has changed. This leaflet does not replace careful discussions with your doctor. You and your doctor should discuss cilostazol when you start taking it and at regular check-ups. You should follow your doctor’s advice about when to have check-ups.<br />
What is cilostazol for?<br />
Cilostazol may improve the symptoms of patients with a medical condition called intermittent claudication.<br />
What is intermittent claudication?<br />
Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. It occurs because narrowing or blockage of the arteries decreases blood flow to the legs. The decreased blood flow does not supply enough oxygen to the leg muscles during walking, resulting in these painful leg cramps.<br />
<br />
'''What treatments are available for intermittent claudication?'''<br />
<br />
The three main treatments available for intermittent claudication are:<br />
*Exercise. Your doctor may advise an exercise program.<br />
*Medication. Your doctor may prescribe a medication such as cilostazol. (See Who should not take cilostazol tablets?)<br />
*Surgery. Your doctor may recommend a surgical procedure to bypass the blocked segment of the artery. Another procedure is called a percutaneous transluminal angioplasty. In this procedure, a catheter (a flexible tube) is inserted into the artery to reduce the blockage and improve blood flow.<br />
<br />
'''How does cilostazol work?'''<br />
<br />
*The exact way that many drugs work is not well understood. Although how cilostazol works is not completely clear, its main effects are to dilate (widen) the arteries supplying blood to the legs and to decrease the ability of platelets in the blood to stick together. Platelets are particles that circulate in the blood and play a role in clotting.<br />
*Cilostazol may reduce the leg pain that patients with intermittent claudication experience, allowing them to walk farther before their leg pain occurs.<br />
*Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks. If you have not noticed any benefit from cilostazol tablets after 12 weeks you and your doctor may wish to discuss other forms of treatment.<br />
*Sometimes blood vessel disease of the legs causes pain at rest or breakdown of skin in the leg. Cilostazol has not been shown to work in patients with these problems.<br />
<br />
'''Who should not take cilostazol tablets?'''<br />
<br />
*Patients who have congestive heart failure (CHF) must not take cilostazol tablets. The most common symptoms of CHF are shortness of breath and swelling of the legs. However, other conditions may also cause these symptoms. It is important that you discuss with your doctor whether you have CHF.<br />
*Over 1,300 patients took cilostazol in studies that lasted for 3 to 6 months. The mortality rate in these patients was similar to placebo (less than 1%). These studies were too small to be sure there is not some increased risk of dying with longer use or in patients sicker than those in the studies.<br />
<br />
'''How should cilostazol tablets be taken?'''<br />
<br />
*Follow your doctor’s advice about how to take cilostazol tablets.<br />
*You should take cilostazol tablets twice a day, at least one half-hour before or two hours after breakfast and dinner. Take cilostazol tablets at about the same times each day.<br />
*Do not share cilostazol tablets with anyone else. It was prescribed only for you.<br />
*Keep cilostazol tablets and all drugs out of the reach of children.<br />
<br />
'''Can cilostazol tablets be taken with other drugs?'''<br />
<br />
Certain drugs and foods can increase the amount of cilostazol in the blood. Because of this, your doctor may adjust your dose of cilostazol or even stop it if you are taking or are going to take one of the following medications.<br />
Drugs Interacting with Cilostazol<br />
Generic Name (Brand Names)Type of Drug<br />
[[erythromycin]] (such as E.E.S.®, Erythrocin®) Antibiotic<br />
[[ketoconazole]] (Nizoral®), [[itraconazole]] (Sporanox®) Antifungal<br />
[[diltiazem]] (Cardizem®) Antihypertensive<br />
[[omeprazole]] (Prilosec®) Gastric acid reducer<br />
This list does not include every drug that may interact with cilostazol tablets. Therefore, you should tell your doctor about all medications that you are taking, including vitamins, herbal supplements and over-the-counter drugs you can buy without a prescription. You should also check with your doctor before taking a new medication after you have begun cilostazol tablets.<br />
<br />
'''What are the possible side effects of cilostazol tablets?'''<br />
<br />
Cilostazol tablets may cause side effects including headache, diarrhea, abnormal stools, increased heart rate and palpitations.<br />
You should discuss possible side effects with your doctor before taking cilostazol tablets and any time you think you are having a side effect.<br />
This provides only a summary of information about cilostazol tablets. If you have any questions about cilostazol tablets, talk to your doctor.<br />
'''Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.'''<br />
<br />
===Patient Information from NLM===<br />
<br />
For patient information about Cilostazol from NLM, click [[Cilostazol (patient information)|here]].<br />
<br />
==Precautions with Alcohol==<br />
<br />
Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
<br />
==Brand Names==<br />
<br />
Cilostazol®, Platel®.<br />
<br />
==Look-Alike Drug Names==<br />
<br />
* (Paired Confused Name 1a) — (Paired Confused Name 1b)<br />
* (Paired Confused Name 2a) — (Paired Confused Name 2b)<br />
* (Paired Confused Name 3a) — (Paired Confused Name 3b)<br />
<br />
==[http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm Drug Shortage Status]==<br />
<br />
==[http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price Price]==<br />
<br />
==References==<br />
<br />
{{reflist}}<br />
<br />
</div></div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=Cilostazol&diff=961721Cilostazol2014-04-02T11:16:29Z<p>Abdurahman Khalil: /* Clinical Trials Experience */</p>
<hr />
<div>{|class="infobox" style="position: fixed; top: 180px; right: 20px; margin: 0 0 0 0; border: 0; float: right; width: 15%; background: #104E8B; border-radius: 10px 10px 10px 10px;" cellpadding="0" cellspacing="0";<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #104E8B;" | [[{{PAGENAME}}|{{fontcolor|#F8F8FF|{{PAGENAME}}®}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #000000; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|Black Box Warning}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adult Indications and Dosage|{{fontcolor|#F8F8FF|Adult Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pediatric Indications and Dosage|{{fontcolor|#F8F8FF|Pediatric Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Contraindications|{{fontcolor|#F8F8FF|Contraindications}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Warnings|{{fontcolor|#F8F8FF|Warnings}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adverse Reactions|{{fontcolor|#F8F8FF|Adverse Reactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Drug Interactions|{{fontcolor|#F8F8FF|Drug Interactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Use in Specific Populations|{{fontcolor|#F8F8FF|Use in Specific Populations}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Administration and Monitoring|{{fontcolor|#F8F8FF|Administration and Monitoring}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#IV Compatibility|{{fontcolor|#F8F8FF|IV Compatibility}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Overdosage|{{fontcolor|#F8F8FF|Overdosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pharmacology|{{fontcolor|#F8F8FF|Pharmacology}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Clinical Studies|{{fontcolor|#F8F8FF|Clinical Studies}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#How Supplied|{{fontcolor|#F8F8FF|How Supplied}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Images|{{fontcolor|#F8F8FF|Images}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Patient Information|{{fontcolor|#F8F8FF|Patient information}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Precautions with Alcohol|{{fontcolor|#F8F8FF|Precautions with Alcohol}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Brand Names|{{fontcolor|#F8F8FF|Brand Names}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Look-Alike Drug Names|{{fontcolor|#F8F8FF|Look-Alike Drug Names}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm {{fontcolor|#F8F8FF|Drug Shortage Status}}]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price {{fontcolor|#F8F8FF|Price}}]<br />
|-<br />
|}<br />
<div style="width: 80%"><br />
__NOTOC__<br />
{{CMG}}<br />
<br />
{{SB}} Cilostazol®, Pletal®<br />
<br />
==Disclaimer==<br />
<br />
'''''WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature. The information provided is not a medical advice or treatment. WikiDoc does not promote any medication or off-label use of drugs. Please read our full disclaimer [[wikidoc:General_disclaimer|{{fontcolor|#FF0000|here}}]].'''''<br />
<br />
==<span style="color:#FF0000; background:#000000;">Black Box Warning</span>==<br />
<br />
FDA Package Insert for {{PAGENAME}} contains no information regarding ''Black Box Warning''.<br />
<br />
{| style="border: 3px solid #696969;"<br />
| style="background: #000000; border: 0px; padding: 20px 20px; width: 800px;" |<br />
<center><br />
<font color="#F8F8FF" style="font-weight: bold;">CONTRAINDICATION</font><br />
</center><br />
<br />
<center><br />
<font color="#F8F8FF" size="1" style="font-style: italic;">See full prescribing information for complete boxed warning.</font><br />
</center><br />
<br />
<font color="#F8F8FF" style="font-weight: bold;"><br />
''{{fontcolor|#FF0000|Condition Name:}}'' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
</font><br />
|}<br />
<br />
==Overview==<br />
<br />
{{PAGENAME}} is a_Phosphodiesterase 3 Inhibitor drug that is FDA approved for the treatment of intermittent claudication. There is a Black Box Warning for this drug as shown <span style="background:#000000;">'''[[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|here}}]]'''</span>. Common adverse reactions include headache, dizziness, palpitation, diarrhea, rhinitis and pharyngitis.<br />
<br />
==Adult Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Adult)===<br />
<br />
=====Intermittent claudication=====<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
===Off-Label Use and Dosage (Adult)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* There is limited information about ''Off-Label Non–Guideline-Supported Use'' of {{PAGENAME}} in adult patients.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Pediatric Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Pediatric)===<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
===Off-Label Use and Dosage (Pediatric)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Contraindications==<br />
* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
<br />
==Warnings==<br />
<br />
=====Conidition 1=====<br />
<br />
(Description)<br />
<br />
=====Conidition 2=====<br />
<br />
(Description)<br />
<br />
=====Conidition 3=====<br />
<br />
(Description)<br />
<br />
==Adverse Reactions==<br />
<br />
===Clinical Trials Experience===<br />
Adverse events were assessed in eight placebo-controlled clinical trials involving 2274 patients exposed to either 50 or 100 mg b.i.d. cilostazol (n=1301) or placebo (n=973), with a median treatment duration of 127 days for patients on cilostazol and 134 days for patients on placebo.<br />
<br />
The only adverse event resulting in discontinuation of therapy in ≥3% of patients treated with cilostazol 50 or 100 mg b.i.d. was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients treated with PLETAL 50 mg b.i.d., 100 mg b.i.d, or placebo, respectively. Other frequent causes of discontinuation included [[palpitation ]]and [[diarrhea]], both 1.1% for cilostazol (all doses) versus 0.1% for placebo.<br />
<br />
======Body as a Whole======<br />
*Common:<br />
:*Abdominal pain<br />
:*Back pain<br />
:*Headache <br />
:*Infection<br />
<br />
*Less common:<br />
[[Chills]], face [[edema]], [[fever]], [[generalized edema]], [[malaise]], [[neck rigidity]], [[pelvic pain]], [[retroperitoneal haemorrhage]].<br />
<br />
======Central Nervous System======<br />
<br />
*Common:<br />
:*Dizziness<br />
:*Vertigo<br />
<br />
*Less common:<br />
[[Anxiety]], [[insomnia]], [[neuralgia]].<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
*Common:<br />
:*Abnormal stool<br />
:*Diarrhea<br />
:*Dyspepsia<br />
:*Flatulence<br />
:*Nausea<br />
<br />
*Less common:<br />
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Metabolic & Nutritional======<br />
*Common:<br />
:*Peripheral edema<br />
<br />
*Less common:<br />
Increased [[creatinine]], [[gout]], [[hyperlipemia]], [[hyperuricemia]].<br />
<br />
======Musculoskeletal======<br />
<br />
*Common:<br />
:*Myalgia<br />
<br />
*Less common:<br />
[[Arthralgia]], bone pain, [[bursitis]].<br />
<br />
<br />
<br />
<br />
======Miscellaneous======<br />
Less common adverse reactions:<br />
<br />
*'''Endocrine:''' [[Diabetes mellitus]].<br />
<br />
*'''Hemic and Lymphatic:''' [[Anemia]], [[ecchymosis]],[[ iron deficiency anemia]], [[polycythemia]], [[purpura]].<br />
<br />
*'''Skin and Appendages:''' Dry skin, [[furunculosis]], skin hypertrophy, [[urticaria]].<br />
<br />
*'''Special Senses:''' [[Amblyopia]], [[blindness]], [[conjunctivitis]], [[diplopia]], ear pain, eye haemorrhage, [[retinal haemorrhage]], [[tinnitus]].<br />
<br />
*'''Urogenital:''' [[Albuminuria]], [[cystitis]], [[urinary frequency]], vaginal haemorrhage, vaginitis.<br />
<br />
===Postmarketing Experience===<br />
<br />
(Description)<br />
<br />
==Drug Interactions==<br />
<br />
* Drug 1<br />
* Drug 2<br />
* Drug 3<br />
* Drug 4<br />
* Drug 5<br />
<br />
=====Drug 1=====<br />
<br />
(Description)<br />
<br />
=====Drug 2=====<br />
<br />
(Description)<br />
<br />
=====Drug 3=====<br />
<br />
(Description)<br />
<br />
=====Drug 4=====<br />
<br />
(Description)<br />
<br />
=====Drug 5=====<br />
<br />
(Description)<br />
<br />
==Use in Specific Populations==<br />
<br />
====Pregnancy====<br />
<br />
* '''[[Pregnancy category#United States|Pregnancy Category (FDA)]]: C'''<br />
<br />
* '''[[Pregnancy category#Australia|Pregnancy Category (AUS)]]: {{PAGENAME}} is not included in Australian Drug Evaluation Committee (ADEC) Pregnancy Categories.'''<br />
<br />
In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
<br />
====Labor and Delivery====<br />
<br />
(Description)<br />
<br />
====Nursing Mothers====<br />
<br />
Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
<br />
====Pediatric Use====<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
====Geriatric Use====<br />
Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
====Gender====<br />
<br />
The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range<br />
<br />
====Race====<br />
<br />
(Description)<br />
<br />
====Renal Impairment====<br />
<br />
Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
<br />
====Hepatic Impairment====<br />
<br />
Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
<br />
====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the exposure in humans at the MRHD.<br />
<br />
====Immunocompromised Patients====<br />
<br />
(Description)<br />
<br />
====Miscellaneous====<br />
<br />
=====Smokers=====<br />
Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
<br />
==Administration and Monitoring==<br />
<br />
====Administration====<br />
<br />
Oral<br />
<br />
====Monitoring====<br />
<br />
<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability).<br />
<br />
==IV Compatibility==<br />
<br />
===Solution===<br />
<br />
====Compatible====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Not Tested====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Variable====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Incompatible====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
===Y-Site===<br />
<br />
====Compatible====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Not Tested====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Variable====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Incompatible====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
===Admixture===<br />
<br />
====Compatible====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Not Tested====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Variable====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Incompatible====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
===Syringe===<br />
<br />
====Compatible====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Not Tested====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Variable====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Incompatible====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
===TPN/TNA===<br />
<br />
====Compatible====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Not Tested====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Variable====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Incompatible====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
==Overdosage==<br />
<br />
===Acute Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
<br />
====Management====<br />
<br />
(Description)<br />
<br />
===Chronic Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
(Description)<br />
<br />
====Management====<br />
<br />
(Description)<br />
<br />
==Pharmacology==<br />
<br />
{{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
<br />
===Mechanism of Action===<br />
<br />
The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
<br />
===Structure===<br />
<br />
*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
<br />
<br />
===Pharmacodynamics===<br />
<br />
(Description)<br />
<br />
===Pharmacokinetics===<br />
<br />
Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
<br />
====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4‑dehydro‑cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4‑dehydro‑cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
<br />
===Nonclinical Toxicology===<br />
<br />
==Clinical Studies==<br />
<br />
*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
<br />
{|<br />
| [[image:Cilo2.png|400px|thumb]]<br />
|}<br />
<br />
<br />
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
<br />
==How Supplied==<br />
<br />
'''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
<br />
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0223-60 bottles of 60 and 0185-0223-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
==Images==<br />
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===Drug Images===<br />
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{|<br />
| [[File:PILLIMAGE.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': <BR><br />
'''Ingredient(s)''': <BR><br />
'''Imprint''': <BR><br />
'''Color(s)''': <BR><br />
'''Shape''': <BR><br />
'''Size (mm)''': <BR><br />
'''Score''': <BR><br />
'''Drug Label Author''': ]]</p><br />
|}<br />
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===Package and Label Display Panel===<br />
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(Package Images)<br />
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(Display Panel Images)<br />
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==Patient Information==<br />
<br />
===Patient Information from FDA===<br />
(sil-OS-tah-zol)<br />
<br />
Please read this leaflet before you start taking cilostazol tablets and each time you renew it in case anything has changed. This leaflet does not replace careful discussions with your doctor. You and your doctor should discuss cilostazol when you start taking it and at regular check-ups. You should follow your doctor’s advice about when to have check-ups.<br />
What is cilostazol for?<br />
Cilostazol may improve the symptoms of patients with a medical condition called intermittent claudication.<br />
What is intermittent claudication?<br />
Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. It occurs because narrowing or blockage of the arteries decreases blood flow to the legs. The decreased blood flow does not supply enough oxygen to the leg muscles during walking, resulting in these painful leg cramps.<br />
<br />
'''What treatments are available for intermittent claudication?'''<br />
<br />
The three main treatments available for intermittent claudication are:<br />
*Exercise. Your doctor may advise an exercise program.<br />
*Medication. Your doctor may prescribe a medication such as cilostazol. (See Who should not take cilostazol tablets?)<br />
*Surgery. Your doctor may recommend a surgical procedure to bypass the blocked segment of the artery. Another procedure is called a percutaneous transluminal angioplasty. In this procedure, a catheter (a flexible tube) is inserted into the artery to reduce the blockage and improve blood flow.<br />
<br />
'''How does cilostazol work?'''<br />
<br />
*The exact way that many drugs work is not well understood. Although how cilostazol works is not completely clear, its main effects are to dilate (widen) the arteries supplying blood to the legs and to decrease the ability of platelets in the blood to stick together. Platelets are particles that circulate in the blood and play a role in clotting.<br />
*Cilostazol may reduce the leg pain that patients with intermittent claudication experience, allowing them to walk farther before their leg pain occurs.<br />
*Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks. If you have not noticed any benefit from cilostazol tablets after 12 weeks you and your doctor may wish to discuss other forms of treatment.<br />
*Sometimes blood vessel disease of the legs causes pain at rest or breakdown of skin in the leg. Cilostazol has not been shown to work in patients with these problems.<br />
<br />
'''Who should not take cilostazol tablets?'''<br />
<br />
*Patients who have congestive heart failure (CHF) must not take cilostazol tablets. The most common symptoms of CHF are shortness of breath and swelling of the legs. However, other conditions may also cause these symptoms. It is important that you discuss with your doctor whether you have CHF.<br />
*Over 1,300 patients took cilostazol in studies that lasted for 3 to 6 months. The mortality rate in these patients was similar to placebo (less than 1%). These studies were too small to be sure there is not some increased risk of dying with longer use or in patients sicker than those in the studies.<br />
<br />
'''How should cilostazol tablets be taken?'''<br />
<br />
*Follow your doctor’s advice about how to take cilostazol tablets.<br />
*You should take cilostazol tablets twice a day, at least one half-hour before or two hours after breakfast and dinner. Take cilostazol tablets at about the same times each day.<br />
*Do not share cilostazol tablets with anyone else. It was prescribed only for you.<br />
*Keep cilostazol tablets and all drugs out of the reach of children.<br />
<br />
'''Can cilostazol tablets be taken with other drugs?'''<br />
<br />
Certain drugs and foods can increase the amount of cilostazol in the blood. Because of this, your doctor may adjust your dose of cilostazol or even stop it if you are taking or are going to take one of the following medications.<br />
Drugs Interacting with Cilostazol<br />
Generic Name (Brand Names)Type of Drug<br />
[[erythromycin]] (such as E.E.S.®, Erythrocin®) Antibiotic<br />
[[ketoconazole]] (Nizoral®), [[itraconazole]] (Sporanox®) Antifungal<br />
[[diltiazem]] (Cardizem®) Antihypertensive<br />
[[omeprazole]] (Prilosec®) Gastric acid reducer<br />
This list does not include every drug that may interact with cilostazol tablets. Therefore, you should tell your doctor about all medications that you are taking, including vitamins, herbal supplements and over-the-counter drugs you can buy without a prescription. You should also check with your doctor before taking a new medication after you have begun cilostazol tablets.<br />
<br />
'''What are the possible side effects of cilostazol tablets?'''<br />
<br />
Cilostazol tablets may cause side effects including headache, diarrhea, abnormal stools, increased heart rate and palpitations.<br />
You should discuss possible side effects with your doctor before taking cilostazol tablets and any time you think you are having a side effect.<br />
This provides only a summary of information about cilostazol tablets. If you have any questions about cilostazol tablets, talk to your doctor.<br />
'''Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.'''<br />
<br />
===Patient Information from NLM===<br />
<br />
For patient information about Cilostazol from NLM, click [[Cilostazol (patient information)|here]].<br />
<br />
==Precautions with Alcohol==<br />
<br />
Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
<br />
==Brand Names==<br />
<br />
Cilostazol®, Platel®.<br />
<br />
==Look-Alike Drug Names==<br />
<br />
* (Paired Confused Name 1a) — (Paired Confused Name 1b)<br />
* (Paired Confused Name 2a) — (Paired Confused Name 2b)<br />
* (Paired Confused Name 3a) — (Paired Confused Name 3b)<br />
<br />
==[http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm Drug Shortage Status]==<br />
<br />
==[http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price Price]==<br />
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==References==<br />
<br />
{{reflist}}<br />
<br />
</div></div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=Cilostazol&diff=961718Cilostazol2014-04-02T11:04:00Z<p>Abdurahman Khalil: /* Central Nervous System */</p>
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! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pediatric Indications and Dosage|{{fontcolor|#F8F8FF|Pediatric Indications and Dosage}}]]<br />
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|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm {{fontcolor|#F8F8FF|Drug Shortage Status}}]<br />
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__NOTOC__<br />
{{CMG}}<br />
<br />
{{SB}} Cilostazol®, Pletal®<br />
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==Disclaimer==<br />
<br />
'''''WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature. The information provided is not a medical advice or treatment. WikiDoc does not promote any medication or off-label use of drugs. Please read our full disclaimer [[wikidoc:General_disclaimer|{{fontcolor|#FF0000|here}}]].'''''<br />
<br />
==<span style="color:#FF0000; background:#000000;">Black Box Warning</span>==<br />
<br />
FDA Package Insert for {{PAGENAME}} contains no information regarding ''Black Box Warning''.<br />
<br />
{| style="border: 3px solid #696969;"<br />
| style="background: #000000; border: 0px; padding: 20px 20px; width: 800px;" |<br />
<center><br />
<font color="#F8F8FF" style="font-weight: bold;">CONTRAINDICATION</font><br />
</center><br />
<br />
<center><br />
<font color="#F8F8FF" size="1" style="font-style: italic;">See full prescribing information for complete boxed warning.</font><br />
</center><br />
<br />
<font color="#F8F8FF" style="font-weight: bold;"><br />
''{{fontcolor|#FF0000|Condition Name:}}'' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
</font><br />
|}<br />
<br />
==Overview==<br />
<br />
{{PAGENAME}} is a_Phosphodiesterase 3 Inhibitor drug that is FDA approved for the treatment of intermittent claudication. There is a Black Box Warning for this drug as shown <span style="background:#000000;">'''[[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|here}}]]'''</span>. Common adverse reactions include headache, dizziness, palpitation, diarrhea, rhinitis and pharyngitis.<br />
<br />
==Adult Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Adult)===<br />
<br />
=====Intermittent claudication=====<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
===Off-Label Use and Dosage (Adult)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* There is limited information about ''Off-Label Non–Guideline-Supported Use'' of {{PAGENAME}} in adult patients.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Pediatric Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Pediatric)===<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
===Off-Label Use and Dosage (Pediatric)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Contraindications==<br />
* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
<br />
==Warnings==<br />
<br />
=====Conidition 1=====<br />
<br />
(Description)<br />
<br />
=====Conidition 2=====<br />
<br />
(Description)<br />
<br />
=====Conidition 3=====<br />
<br />
(Description)<br />
<br />
==Adverse Reactions==<br />
<br />
===Clinical Trials Experience===<br />
<br />
=====Condition 1=====<br />
<br />
======Central Nervous System======<br />
<br />
*Common:<br />
:*Dizziness<br />
:*Vertigo<br />
<br />
*Less common:<br />
[[Anxiety]], [[insomnia]], [[neuralgia]].<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
*Common:<br />
:*Abnormal stool<br />
:*Diarrhea<br />
:*Dyspepsia<br />
:*Flatulence<br />
:*Nausea<br />
<br />
*Less common:<br />
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Miscellaneous======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
=====Condition 2=====<br />
<br />
======Central Nervous System======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Cardiovascular======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Respiratory======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Gastrointestinal======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Miscellaneous======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
===Postmarketing Experience===<br />
<br />
(Description)<br />
<br />
==Drug Interactions==<br />
<br />
* Drug 1<br />
* Drug 2<br />
* Drug 3<br />
* Drug 4<br />
* Drug 5<br />
<br />
=====Drug 1=====<br />
<br />
(Description)<br />
<br />
=====Drug 2=====<br />
<br />
(Description)<br />
<br />
=====Drug 3=====<br />
<br />
(Description)<br />
<br />
=====Drug 4=====<br />
<br />
(Description)<br />
<br />
=====Drug 5=====<br />
<br />
(Description)<br />
<br />
==Use in Specific Populations==<br />
<br />
====Pregnancy====<br />
<br />
* '''[[Pregnancy category#United States|Pregnancy Category (FDA)]]: C'''<br />
<br />
* '''[[Pregnancy category#Australia|Pregnancy Category (AUS)]]: {{PAGENAME}} is not included in Australian Drug Evaluation Committee (ADEC) Pregnancy Categories.'''<br />
<br />
In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
<br />
====Labor and Delivery====<br />
<br />
(Description)<br />
<br />
====Nursing Mothers====<br />
<br />
Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
<br />
====Pediatric Use====<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
====Geriatric Use====<br />
Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
====Gender====<br />
<br />
The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range<br />
<br />
====Race====<br />
<br />
(Description)<br />
<br />
====Renal Impairment====<br />
<br />
Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
<br />
====Hepatic Impairment====<br />
<br />
Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
<br />
====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the exposure in humans at the MRHD.<br />
<br />
====Immunocompromised Patients====<br />
<br />
(Description)<br />
<br />
====Miscellaneous====<br />
<br />
=====Smokers=====<br />
Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
<br />
==Administration and Monitoring==<br />
<br />
====Administration====<br />
<br />
Oral<br />
<br />
====Monitoring====<br />
<br />
<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability).<br />
<br />
==IV Compatibility==<br />
<br />
===Solution===<br />
<br />
====Compatible====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Not Tested====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Variable====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Incompatible====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
===Y-Site===<br />
<br />
====Compatible====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Not Tested====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Variable====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Incompatible====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
===Admixture===<br />
<br />
====Compatible====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Not Tested====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Variable====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Incompatible====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
===Syringe===<br />
<br />
====Compatible====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Not Tested====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Variable====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Incompatible====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
===TPN/TNA===<br />
<br />
====Compatible====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Not Tested====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Variable====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Incompatible====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
==Overdosage==<br />
<br />
===Acute Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
<br />
====Management====<br />
<br />
(Description)<br />
<br />
===Chronic Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
(Description)<br />
<br />
====Management====<br />
<br />
(Description)<br />
<br />
==Pharmacology==<br />
<br />
{{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
<br />
===Mechanism of Action===<br />
<br />
The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
<br />
===Structure===<br />
<br />
*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
<br />
<br />
===Pharmacodynamics===<br />
<br />
(Description)<br />
<br />
===Pharmacokinetics===<br />
<br />
Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
<br />
====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4‑dehydro‑cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4‑dehydro‑cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
<br />
===Nonclinical Toxicology===<br />
<br />
==Clinical Studies==<br />
<br />
*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
<br />
{|<br />
| [[image:Cilo2.png|400px|thumb]]<br />
|}<br />
<br />
<br />
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
<br />
==How Supplied==<br />
<br />
'''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
<br />
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0223-60 bottles of 60 and 0185-0223-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
==Images==<br />
<br />
===Drug Images===<br />
<br />
{|<br />
| [[File:PILLIMAGE.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': <BR><br />
'''Ingredient(s)''': <BR><br />
'''Imprint''': <BR><br />
'''Color(s)''': <BR><br />
'''Shape''': <BR><br />
'''Size (mm)''': <BR><br />
'''Score''': <BR><br />
'''Drug Label Author''': ]]</p><br />
|}<br />
<br />
===Package and Label Display Panel===<br />
<br />
(Package Images)<br />
<br />
(Display Panel Images)<br />
<br />
==Patient Information==<br />
<br />
===Patient Information from FDA===<br />
(sil-OS-tah-zol)<br />
<br />
Please read this leaflet before you start taking cilostazol tablets and each time you renew it in case anything has changed. This leaflet does not replace careful discussions with your doctor. You and your doctor should discuss cilostazol when you start taking it and at regular check-ups. You should follow your doctor’s advice about when to have check-ups.<br />
What is cilostazol for?<br />
Cilostazol may improve the symptoms of patients with a medical condition called intermittent claudication.<br />
What is intermittent claudication?<br />
Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. It occurs because narrowing or blockage of the arteries decreases blood flow to the legs. The decreased blood flow does not supply enough oxygen to the leg muscles during walking, resulting in these painful leg cramps.<br />
<br />
'''What treatments are available for intermittent claudication?'''<br />
<br />
The three main treatments available for intermittent claudication are:<br />
*Exercise. Your doctor may advise an exercise program.<br />
*Medication. Your doctor may prescribe a medication such as cilostazol. (See Who should not take cilostazol tablets?)<br />
*Surgery. Your doctor may recommend a surgical procedure to bypass the blocked segment of the artery. Another procedure is called a percutaneous transluminal angioplasty. In this procedure, a catheter (a flexible tube) is inserted into the artery to reduce the blockage and improve blood flow.<br />
<br />
'''How does cilostazol work?'''<br />
<br />
*The exact way that many drugs work is not well understood. Although how cilostazol works is not completely clear, its main effects are to dilate (widen) the arteries supplying blood to the legs and to decrease the ability of platelets in the blood to stick together. Platelets are particles that circulate in the blood and play a role in clotting.<br />
*Cilostazol may reduce the leg pain that patients with intermittent claudication experience, allowing them to walk farther before their leg pain occurs.<br />
*Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks. If you have not noticed any benefit from cilostazol tablets after 12 weeks you and your doctor may wish to discuss other forms of treatment.<br />
*Sometimes blood vessel disease of the legs causes pain at rest or breakdown of skin in the leg. Cilostazol has not been shown to work in patients with these problems.<br />
<br />
'''Who should not take cilostazol tablets?'''<br />
<br />
*Patients who have congestive heart failure (CHF) must not take cilostazol tablets. The most common symptoms of CHF are shortness of breath and swelling of the legs. However, other conditions may also cause these symptoms. It is important that you discuss with your doctor whether you have CHF.<br />
*Over 1,300 patients took cilostazol in studies that lasted for 3 to 6 months. The mortality rate in these patients was similar to placebo (less than 1%). These studies were too small to be sure there is not some increased risk of dying with longer use or in patients sicker than those in the studies.<br />
<br />
'''How should cilostazol tablets be taken?'''<br />
<br />
*Follow your doctor’s advice about how to take cilostazol tablets.<br />
*You should take cilostazol tablets twice a day, at least one half-hour before or two hours after breakfast and dinner. Take cilostazol tablets at about the same times each day.<br />
*Do not share cilostazol tablets with anyone else. It was prescribed only for you.<br />
*Keep cilostazol tablets and all drugs out of the reach of children.<br />
<br />
'''Can cilostazol tablets be taken with other drugs?'''<br />
<br />
Certain drugs and foods can increase the amount of cilostazol in the blood. Because of this, your doctor may adjust your dose of cilostazol or even stop it if you are taking or are going to take one of the following medications.<br />
Drugs Interacting with Cilostazol<br />
Generic Name (Brand Names)Type of Drug<br />
[[erythromycin]] (such as E.E.S.®, Erythrocin®) Antibiotic<br />
[[ketoconazole]] (Nizoral®), [[itraconazole]] (Sporanox®) Antifungal<br />
[[diltiazem]] (Cardizem®) Antihypertensive<br />
[[omeprazole]] (Prilosec®) Gastric acid reducer<br />
This list does not include every drug that may interact with cilostazol tablets. Therefore, you should tell your doctor about all medications that you are taking, including vitamins, herbal supplements and over-the-counter drugs you can buy without a prescription. You should also check with your doctor before taking a new medication after you have begun cilostazol tablets.<br />
<br />
'''What are the possible side effects of cilostazol tablets?'''<br />
<br />
Cilostazol tablets may cause side effects including headache, diarrhea, abnormal stools, increased heart rate and palpitations.<br />
You should discuss possible side effects with your doctor before taking cilostazol tablets and any time you think you are having a side effect.<br />
This provides only a summary of information about cilostazol tablets. If you have any questions about cilostazol tablets, talk to your doctor.<br />
'''Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.'''<br />
<br />
===Patient Information from NLM===<br />
<br />
For patient information about Cilostazol from NLM, click [[Cilostazol (patient information)|here]].<br />
<br />
==Precautions with Alcohol==<br />
<br />
Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
<br />
==Brand Names==<br />
<br />
Cilostazol®, Platel®.<br />
<br />
==Look-Alike Drug Names==<br />
<br />
* (Paired Confused Name 1a) — (Paired Confused Name 1b)<br />
* (Paired Confused Name 2a) — (Paired Confused Name 2b)<br />
* (Paired Confused Name 3a) — (Paired Confused Name 3b)<br />
<br />
==[http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm Drug Shortage Status]==<br />
<br />
==[http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price Price]==<br />
<br />
==References==<br />
<br />
{{reflist}}<br />
<br />
</div></div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=Cilostazol&diff=961717Cilostazol2014-04-02T11:02:37Z<p>Abdurahman Khalil: /* Gastrointestinal */</p>
<hr />
<div>{|class="infobox" style="position: fixed; top: 180px; right: 20px; margin: 0 0 0 0; border: 0; float: right; width: 15%; background: #104E8B; border-radius: 10px 10px 10px 10px;" cellpadding="0" cellspacing="0";<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #104E8B;" | [[{{PAGENAME}}|{{fontcolor|#F8F8FF|{{PAGENAME}}®}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #000000; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|Black Box Warning}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adult Indications and Dosage|{{fontcolor|#F8F8FF|Adult Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pediatric Indications and Dosage|{{fontcolor|#F8F8FF|Pediatric Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Contraindications|{{fontcolor|#F8F8FF|Contraindications}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Warnings|{{fontcolor|#F8F8FF|Warnings}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adverse Reactions|{{fontcolor|#F8F8FF|Adverse Reactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Drug Interactions|{{fontcolor|#F8F8FF|Drug Interactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Use in Specific Populations|{{fontcolor|#F8F8FF|Use in Specific Populations}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Administration and Monitoring|{{fontcolor|#F8F8FF|Administration and Monitoring}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#IV Compatibility|{{fontcolor|#F8F8FF|IV Compatibility}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Overdosage|{{fontcolor|#F8F8FF|Overdosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pharmacology|{{fontcolor|#F8F8FF|Pharmacology}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Clinical Studies|{{fontcolor|#F8F8FF|Clinical Studies}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#How Supplied|{{fontcolor|#F8F8FF|How Supplied}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Images|{{fontcolor|#F8F8FF|Images}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Patient Information|{{fontcolor|#F8F8FF|Patient information}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Precautions with Alcohol|{{fontcolor|#F8F8FF|Precautions with Alcohol}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Brand Names|{{fontcolor|#F8F8FF|Brand Names}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Look-Alike Drug Names|{{fontcolor|#F8F8FF|Look-Alike Drug Names}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm {{fontcolor|#F8F8FF|Drug Shortage Status}}]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price {{fontcolor|#F8F8FF|Price}}]<br />
|-<br />
|}<br />
<div style="width: 80%"><br />
__NOTOC__<br />
{{CMG}}<br />
<br />
{{SB}} Cilostazol®, Pletal®<br />
<br />
==Disclaimer==<br />
<br />
'''''WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature. The information provided is not a medical advice or treatment. WikiDoc does not promote any medication or off-label use of drugs. Please read our full disclaimer [[wikidoc:General_disclaimer|{{fontcolor|#FF0000|here}}]].'''''<br />
<br />
==<span style="color:#FF0000; background:#000000;">Black Box Warning</span>==<br />
<br />
FDA Package Insert for {{PAGENAME}} contains no information regarding ''Black Box Warning''.<br />
<br />
{| style="border: 3px solid #696969;"<br />
| style="background: #000000; border: 0px; padding: 20px 20px; width: 800px;" |<br />
<center><br />
<font color="#F8F8FF" style="font-weight: bold;">CONTRAINDICATION</font><br />
</center><br />
<br />
<center><br />
<font color="#F8F8FF" size="1" style="font-style: italic;">See full prescribing information for complete boxed warning.</font><br />
</center><br />
<br />
<font color="#F8F8FF" style="font-weight: bold;"><br />
''{{fontcolor|#FF0000|Condition Name:}}'' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
</font><br />
|}<br />
<br />
==Overview==<br />
<br />
{{PAGENAME}} is a_Phosphodiesterase 3 Inhibitor drug that is FDA approved for the treatment of intermittent claudication. There is a Black Box Warning for this drug as shown <span style="background:#000000;">'''[[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|here}}]]'''</span>. Common adverse reactions include headache, dizziness, palpitation, diarrhea, rhinitis and pharyngitis.<br />
<br />
==Adult Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Adult)===<br />
<br />
=====Intermittent claudication=====<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
===Off-Label Use and Dosage (Adult)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* There is limited information about ''Off-Label Non–Guideline-Supported Use'' of {{PAGENAME}} in adult patients.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Pediatric Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Pediatric)===<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
===Off-Label Use and Dosage (Pediatric)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Contraindications==<br />
* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
<br />
==Warnings==<br />
<br />
=====Conidition 1=====<br />
<br />
(Description)<br />
<br />
=====Conidition 2=====<br />
<br />
(Description)<br />
<br />
=====Conidition 3=====<br />
<br />
(Description)<br />
<br />
==Adverse Reactions==<br />
<br />
===Clinical Trials Experience===<br />
<br />
=====Condition 1=====<br />
<br />
======Central Nervous System======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
*Common:<br />
:*Abnormal stool<br />
:*Diarrhea<br />
:*Dyspepsia<br />
:*Flatulence<br />
:*Nausea<br />
<br />
*Less common:<br />
[[Anorexia]], [[cholelithiasis]],[[ colitis]], [[duodenal ulcer]], [[duodenitis]], esophageal haemorrhage, [[esophagitis]], increased [[GGT]], [[gastritis]], [[gastroenteritis]], gum haemorrhage, [[hematemesis]], [[melena]],[[ peptic ulcer]], periodontal abscess, rectal haemorrhage, [[stomach ulcer]], tongue edema.<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Miscellaneous======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
=====Condition 2=====<br />
<br />
======Central Nervous System======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Cardiovascular======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Respiratory======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Gastrointestinal======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Miscellaneous======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
===Postmarketing Experience===<br />
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(Description)<br />
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==Drug Interactions==<br />
<br />
* Drug 1<br />
* Drug 2<br />
* Drug 3<br />
* Drug 4<br />
* Drug 5<br />
<br />
=====Drug 1=====<br />
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(Description)<br />
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=====Drug 2=====<br />
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(Description)<br />
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=====Drug 3=====<br />
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(Description)<br />
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=====Drug 4=====<br />
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(Description)<br />
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=====Drug 5=====<br />
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(Description)<br />
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==Use in Specific Populations==<br />
<br />
====Pregnancy====<br />
<br />
* '''[[Pregnancy category#United States|Pregnancy Category (FDA)]]: C'''<br />
<br />
* '''[[Pregnancy category#Australia|Pregnancy Category (AUS)]]: {{PAGENAME}} is not included in Australian Drug Evaluation Committee (ADEC) Pregnancy Categories.'''<br />
<br />
In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
<br />
====Labor and Delivery====<br />
<br />
(Description)<br />
<br />
====Nursing Mothers====<br />
<br />
Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
<br />
====Pediatric Use====<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
====Geriatric Use====<br />
Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
====Gender====<br />
<br />
The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range<br />
<br />
====Race====<br />
<br />
(Description)<br />
<br />
====Renal Impairment====<br />
<br />
Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
<br />
====Hepatic Impairment====<br />
<br />
Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
<br />
====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the exposure in humans at the MRHD.<br />
<br />
====Immunocompromised Patients====<br />
<br />
(Description)<br />
<br />
====Miscellaneous====<br />
<br />
=====Smokers=====<br />
Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
<br />
==Administration and Monitoring==<br />
<br />
====Administration====<br />
<br />
Oral<br />
<br />
====Monitoring====<br />
<br />
<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability).<br />
<br />
==IV Compatibility==<br />
<br />
===Solution===<br />
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====Compatible====<br />
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* Solution 1<br />
* Solution 2<br />
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====Not Tested====<br />
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====Incompatible====<br />
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* Solution 2<br />
* Solution 3<br />
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===Y-Site===<br />
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* Solution 1<br />
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====Not Tested====<br />
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* Solution 2<br />
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====Incompatible====<br />
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* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
===Admixture===<br />
<br />
====Compatible====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
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====Not Tested====<br />
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* Solution 2<br />
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====Incompatible====<br />
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* Solution 2<br />
* Solution 3<br />
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===Syringe===<br />
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====Compatible====<br />
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* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
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====Not Tested====<br />
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* Solution 2<br />
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* Solution 2<br />
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====Incompatible====<br />
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* Solution 3<br />
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===TPN/TNA===<br />
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====Compatible====<br />
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* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
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====Not Tested====<br />
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* Solution 2<br />
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* Solution 2<br />
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====Incompatible====<br />
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* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
==Overdosage==<br />
<br />
===Acute Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
<br />
====Management====<br />
<br />
(Description)<br />
<br />
===Chronic Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
(Description)<br />
<br />
====Management====<br />
<br />
(Description)<br />
<br />
==Pharmacology==<br />
<br />
{{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
<br />
===Mechanism of Action===<br />
<br />
The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
<br />
===Structure===<br />
<br />
*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
<br />
<br />
===Pharmacodynamics===<br />
<br />
(Description)<br />
<br />
===Pharmacokinetics===<br />
<br />
Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
<br />
====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4‑dehydro‑cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4‑dehydro‑cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
<br />
===Nonclinical Toxicology===<br />
<br />
==Clinical Studies==<br />
<br />
*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
<br />
{|<br />
| [[image:Cilo2.png|400px|thumb]]<br />
|}<br />
<br />
<br />
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
<br />
==How Supplied==<br />
<br />
'''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
<br />
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0223-60 bottles of 60 and 0185-0223-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
==Images==<br />
<br />
===Drug Images===<br />
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{|<br />
| [[File:PILLIMAGE.jpg|thumb|300px|<p style="text-align: left;"><br />
'''Drug Name''': <BR><br />
'''Ingredient(s)''': <BR><br />
'''Imprint''': <BR><br />
'''Color(s)''': <BR><br />
'''Shape''': <BR><br />
'''Size (mm)''': <BR><br />
'''Score''': <BR><br />
'''Drug Label Author''': ]]</p><br />
|}<br />
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===Package and Label Display Panel===<br />
<br />
(Package Images)<br />
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(Display Panel Images)<br />
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==Patient Information==<br />
<br />
===Patient Information from FDA===<br />
(sil-OS-tah-zol)<br />
<br />
Please read this leaflet before you start taking cilostazol tablets and each time you renew it in case anything has changed. This leaflet does not replace careful discussions with your doctor. You and your doctor should discuss cilostazol when you start taking it and at regular check-ups. You should follow your doctor’s advice about when to have check-ups.<br />
What is cilostazol for?<br />
Cilostazol may improve the symptoms of patients with a medical condition called intermittent claudication.<br />
What is intermittent claudication?<br />
Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. It occurs because narrowing or blockage of the arteries decreases blood flow to the legs. The decreased blood flow does not supply enough oxygen to the leg muscles during walking, resulting in these painful leg cramps.<br />
<br />
'''What treatments are available for intermittent claudication?'''<br />
<br />
The three main treatments available for intermittent claudication are:<br />
*Exercise. Your doctor may advise an exercise program.<br />
*Medication. Your doctor may prescribe a medication such as cilostazol. (See Who should not take cilostazol tablets?)<br />
*Surgery. Your doctor may recommend a surgical procedure to bypass the blocked segment of the artery. Another procedure is called a percutaneous transluminal angioplasty. In this procedure, a catheter (a flexible tube) is inserted into the artery to reduce the blockage and improve blood flow.<br />
<br />
'''How does cilostazol work?'''<br />
<br />
*The exact way that many drugs work is not well understood. Although how cilostazol works is not completely clear, its main effects are to dilate (widen) the arteries supplying blood to the legs and to decrease the ability of platelets in the blood to stick together. Platelets are particles that circulate in the blood and play a role in clotting.<br />
*Cilostazol may reduce the leg pain that patients with intermittent claudication experience, allowing them to walk farther before their leg pain occurs.<br />
*Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks. If you have not noticed any benefit from cilostazol tablets after 12 weeks you and your doctor may wish to discuss other forms of treatment.<br />
*Sometimes blood vessel disease of the legs causes pain at rest or breakdown of skin in the leg. Cilostazol has not been shown to work in patients with these problems.<br />
<br />
'''Who should not take cilostazol tablets?'''<br />
<br />
*Patients who have congestive heart failure (CHF) must not take cilostazol tablets. The most common symptoms of CHF are shortness of breath and swelling of the legs. However, other conditions may also cause these symptoms. It is important that you discuss with your doctor whether you have CHF.<br />
*Over 1,300 patients took cilostazol in studies that lasted for 3 to 6 months. The mortality rate in these patients was similar to placebo (less than 1%). These studies were too small to be sure there is not some increased risk of dying with longer use or in patients sicker than those in the studies.<br />
<br />
'''How should cilostazol tablets be taken?'''<br />
<br />
*Follow your doctor’s advice about how to take cilostazol tablets.<br />
*You should take cilostazol tablets twice a day, at least one half-hour before or two hours after breakfast and dinner. Take cilostazol tablets at about the same times each day.<br />
*Do not share cilostazol tablets with anyone else. It was prescribed only for you.<br />
*Keep cilostazol tablets and all drugs out of the reach of children.<br />
<br />
'''Can cilostazol tablets be taken with other drugs?'''<br />
<br />
Certain drugs and foods can increase the amount of cilostazol in the blood. Because of this, your doctor may adjust your dose of cilostazol or even stop it if you are taking or are going to take one of the following medications.<br />
Drugs Interacting with Cilostazol<br />
Generic Name (Brand Names)Type of Drug<br />
[[erythromycin]] (such as E.E.S.®, Erythrocin®) Antibiotic<br />
[[ketoconazole]] (Nizoral®), [[itraconazole]] (Sporanox®) Antifungal<br />
[[diltiazem]] (Cardizem®) Antihypertensive<br />
[[omeprazole]] (Prilosec®) Gastric acid reducer<br />
This list does not include every drug that may interact with cilostazol tablets. Therefore, you should tell your doctor about all medications that you are taking, including vitamins, herbal supplements and over-the-counter drugs you can buy without a prescription. You should also check with your doctor before taking a new medication after you have begun cilostazol tablets.<br />
<br />
'''What are the possible side effects of cilostazol tablets?'''<br />
<br />
Cilostazol tablets may cause side effects including headache, diarrhea, abnormal stools, increased heart rate and palpitations.<br />
You should discuss possible side effects with your doctor before taking cilostazol tablets and any time you think you are having a side effect.<br />
This provides only a summary of information about cilostazol tablets. If you have any questions about cilostazol tablets, talk to your doctor.<br />
'''Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.'''<br />
<br />
===Patient Information from NLM===<br />
<br />
For patient information about Cilostazol from NLM, click [[Cilostazol (patient information)|here]].<br />
<br />
==Precautions with Alcohol==<br />
<br />
Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
<br />
==Brand Names==<br />
<br />
Cilostazol®, Platel®.<br />
<br />
==Look-Alike Drug Names==<br />
<br />
* (Paired Confused Name 1a) — (Paired Confused Name 1b)<br />
* (Paired Confused Name 2a) — (Paired Confused Name 2b)<br />
* (Paired Confused Name 3a) — (Paired Confused Name 3b)<br />
<br />
==[http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm Drug Shortage Status]==<br />
<br />
==[http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price Price]==<br />
<br />
==References==<br />
<br />
{{reflist}}<br />
<br />
</div></div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=Cilostazol&diff=961716Cilostazol2014-04-02T10:59:15Z<p>Abdurahman Khalil: /* Respiratory */</p>
<hr />
<div>{|class="infobox" style="position: fixed; top: 180px; right: 20px; margin: 0 0 0 0; border: 0; float: right; width: 15%; background: #104E8B; border-radius: 10px 10px 10px 10px;" cellpadding="0" cellspacing="0";<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #104E8B;" | [[{{PAGENAME}}|{{fontcolor|#F8F8FF|{{PAGENAME}}®}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #000000; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|Black Box Warning}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adult Indications and Dosage|{{fontcolor|#F8F8FF|Adult Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pediatric Indications and Dosage|{{fontcolor|#F8F8FF|Pediatric Indications and Dosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Contraindications|{{fontcolor|#F8F8FF|Contraindications}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Warnings|{{fontcolor|#F8F8FF|Warnings}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Adverse Reactions|{{fontcolor|#F8F8FF|Adverse Reactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Drug Interactions|{{fontcolor|#F8F8FF|Drug Interactions}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Use in Specific Populations|{{fontcolor|#F8F8FF|Use in Specific Populations}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Administration and Monitoring|{{fontcolor|#F8F8FF|Administration and Monitoring}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#IV Compatibility|{{fontcolor|#F8F8FF|IV Compatibility}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Overdosage|{{fontcolor|#F8F8FF|Overdosage}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Pharmacology|{{fontcolor|#F8F8FF|Pharmacology}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Clinical Studies|{{fontcolor|#F8F8FF|Clinical Studies}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#How Supplied|{{fontcolor|#F8F8FF|How Supplied}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Images|{{fontcolor|#F8F8FF|Images}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Patient Information|{{fontcolor|#F8F8FF|Patient information}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Precautions with Alcohol|{{fontcolor|#F8F8FF|Precautions with Alcohol}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Brand Names|{{fontcolor|#F8F8FF|Brand Names}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [[{{PAGENAME}}#Look-Alike Drug Names|{{fontcolor|#F8F8FF|Look-Alike Drug Names}}]]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm {{fontcolor|#F8F8FF|Drug Shortage Status}}]<br />
|-<br />
! style="font-size: 80%; padding: 0 5px; background: #6D9CC9; border-radius: 5px 5px 5px 5px;" align=left | [http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price {{fontcolor|#F8F8FF|Price}}]<br />
|-<br />
|}<br />
<div style="width: 80%"><br />
__NOTOC__<br />
{{CMG}}<br />
<br />
{{SB}} Cilostazol®, Pletal®<br />
<br />
==Disclaimer==<br />
<br />
'''''WikiDoc Drug Project is a constellation of drug information for healthcare providers and patients vigorously vetted on the basis of FDA package insert, MedlinePlus, Practice Guidelines, Scientific Statements, and scholarly medical literature. The information provided is not a medical advice or treatment. WikiDoc does not promote any medication or off-label use of drugs. Please read our full disclaimer [[wikidoc:General_disclaimer|{{fontcolor|#FF0000|here}}]].'''''<br />
<br />
==<span style="color:#FF0000; background:#000000;">Black Box Warning</span>==<br />
<br />
FDA Package Insert for {{PAGENAME}} contains no information regarding ''Black Box Warning''.<br />
<br />
{| style="border: 3px solid #696969;"<br />
| style="background: #000000; border: 0px; padding: 20px 20px; width: 800px;" |<br />
<center><br />
<font color="#F8F8FF" style="font-weight: bold;">CONTRAINDICATION</font><br />
</center><br />
<br />
<center><br />
<font color="#F8F8FF" size="1" style="font-style: italic;">See full prescribing information for complete boxed warning.</font><br />
</center><br />
<br />
<font color="#F8F8FF" style="font-weight: bold;"><br />
''{{fontcolor|#FF0000|Condition Name:}}'' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
</font><br />
|}<br />
<br />
==Overview==<br />
<br />
{{PAGENAME}} is a_Phosphodiesterase 3 Inhibitor drug that is FDA approved for the treatment of intermittent claudication. There is a Black Box Warning for this drug as shown <span style="background:#000000;">'''[[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|here}}]]'''</span>. Common adverse reactions include headache, dizziness, palpitation, diarrhea, rhinitis and pharyngitis.<br />
<br />
==Adult Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Adult)===<br />
<br />
=====Intermittent claudication=====<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
===Off-Label Use and Dosage (Adult)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* There is limited information about ''Off-Label Non–Guideline-Supported Use'' of {{PAGENAME}} in adult patients.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Pediatric Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Pediatric)===<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
===Off-Label Use and Dosage (Pediatric)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Contraindications==<br />
* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
<br />
==Warnings==<br />
<br />
=====Conidition 1=====<br />
<br />
(Description)<br />
<br />
=====Conidition 2=====<br />
<br />
(Description)<br />
<br />
=====Conidition 3=====<br />
<br />
(Description)<br />
<br />
==Adverse Reactions==<br />
<br />
===Clinical Trials Experience===<br />
<br />
=====Condition 1=====<br />
<br />
======Central Nervous System======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Miscellaneous======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
=====Condition 2=====<br />
<br />
======Central Nervous System======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Cardiovascular======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Respiratory======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Gastrointestinal======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Miscellaneous======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
===Postmarketing Experience===<br />
<br />
(Description)<br />
<br />
==Drug Interactions==<br />
<br />
* Drug 1<br />
* Drug 2<br />
* Drug 3<br />
* Drug 4<br />
* Drug 5<br />
<br />
=====Drug 1=====<br />
<br />
(Description)<br />
<br />
=====Drug 2=====<br />
<br />
(Description)<br />
<br />
=====Drug 3=====<br />
<br />
(Description)<br />
<br />
=====Drug 4=====<br />
<br />
(Description)<br />
<br />
=====Drug 5=====<br />
<br />
(Description)<br />
<br />
==Use in Specific Populations==<br />
<br />
====Pregnancy====<br />
<br />
* '''[[Pregnancy category#United States|Pregnancy Category (FDA)]]: C'''<br />
<br />
* '''[[Pregnancy category#Australia|Pregnancy Category (AUS)]]: {{PAGENAME}} is not included in Australian Drug Evaluation Committee (ADEC) Pregnancy Categories.'''<br />
<br />
In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
<br />
====Labor and Delivery====<br />
<br />
(Description)<br />
<br />
====Nursing Mothers====<br />
<br />
Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
<br />
====Pediatric Use====<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
====Geriatric Use====<br />
Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
====Gender====<br />
<br />
The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range<br />
<br />
====Race====<br />
<br />
(Description)<br />
<br />
====Renal Impairment====<br />
<br />
Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
<br />
====Hepatic Impairment====<br />
<br />
Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
<br />
====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the exposure in humans at the MRHD.<br />
<br />
====Immunocompromised Patients====<br />
<br />
(Description)<br />
<br />
====Miscellaneous====<br />
<br />
=====Smokers=====<br />
Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
<br />
==Administration and Monitoring==<br />
<br />
====Administration====<br />
<br />
Oral<br />
<br />
====Monitoring====<br />
<br />
<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability).<br />
<br />
==IV Compatibility==<br />
<br />
===Solution===<br />
<br />
====Compatible====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Not Tested====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Variable====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Incompatible====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
===Y-Site===<br />
<br />
====Compatible====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Not Tested====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Variable====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Incompatible====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
===Admixture===<br />
<br />
====Compatible====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Not Tested====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Variable====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Incompatible====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
===Syringe===<br />
<br />
====Compatible====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Not Tested====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Variable====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Incompatible====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
===TPN/TNA===<br />
<br />
====Compatible====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Not Tested====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Variable====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Incompatible====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
==Overdosage==<br />
<br />
===Acute Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
<br />
====Management====<br />
<br />
(Description)<br />
<br />
===Chronic Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
(Description)<br />
<br />
====Management====<br />
<br />
(Description)<br />
<br />
==Pharmacology==<br />
<br />
{{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
<br />
===Mechanism of Action===<br />
<br />
The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
<br />
===Structure===<br />
<br />
*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
<br />
<br />
===Pharmacodynamics===<br />
<br />
(Description)<br />
<br />
===Pharmacokinetics===<br />
<br />
Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
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====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4‑dehydro‑cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4‑dehydro‑cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
<br />
===Nonclinical Toxicology===<br />
<br />
==Clinical Studies==<br />
<br />
*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
<br />
{|<br />
| [[image:Cilo2.png|400px|thumb]]<br />
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<br />
<br />
*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
<br />
==How Supplied==<br />
<br />
'''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
<br />
<br />
'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other and supplied as:<br />
<br />
* National Drug Code (NDC): 0185-0223-60 bottles of 60 and 0185-0223-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
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==Images==<br />
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===Package and Label Display Panel===<br />
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==Patient Information==<br />
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===Patient Information from FDA===<br />
(sil-OS-tah-zol)<br />
<br />
Please read this leaflet before you start taking cilostazol tablets and each time you renew it in case anything has changed. This leaflet does not replace careful discussions with your doctor. You and your doctor should discuss cilostazol when you start taking it and at regular check-ups. You should follow your doctor’s advice about when to have check-ups.<br />
What is cilostazol for?<br />
Cilostazol may improve the symptoms of patients with a medical condition called intermittent claudication.<br />
What is intermittent claudication?<br />
Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. It occurs because narrowing or blockage of the arteries decreases blood flow to the legs. The decreased blood flow does not supply enough oxygen to the leg muscles during walking, resulting in these painful leg cramps.<br />
<br />
'''What treatments are available for intermittent claudication?'''<br />
<br />
The three main treatments available for intermittent claudication are:<br />
*Exercise. Your doctor may advise an exercise program.<br />
*Medication. Your doctor may prescribe a medication such as cilostazol. (See Who should not take cilostazol tablets?)<br />
*Surgery. Your doctor may recommend a surgical procedure to bypass the blocked segment of the artery. Another procedure is called a percutaneous transluminal angioplasty. In this procedure, a catheter (a flexible tube) is inserted into the artery to reduce the blockage and improve blood flow.<br />
<br />
'''How does cilostazol work?'''<br />
<br />
*The exact way that many drugs work is not well understood. Although how cilostazol works is not completely clear, its main effects are to dilate (widen) the arteries supplying blood to the legs and to decrease the ability of platelets in the blood to stick together. Platelets are particles that circulate in the blood and play a role in clotting.<br />
*Cilostazol may reduce the leg pain that patients with intermittent claudication experience, allowing them to walk farther before their leg pain occurs.<br />
*Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks. If you have not noticed any benefit from cilostazol tablets after 12 weeks you and your doctor may wish to discuss other forms of treatment.<br />
*Sometimes blood vessel disease of the legs causes pain at rest or breakdown of skin in the leg. Cilostazol has not been shown to work in patients with these problems.<br />
<br />
'''Who should not take cilostazol tablets?'''<br />
<br />
*Patients who have congestive heart failure (CHF) must not take cilostazol tablets. The most common symptoms of CHF are shortness of breath and swelling of the legs. However, other conditions may also cause these symptoms. It is important that you discuss with your doctor whether you have CHF.<br />
*Over 1,300 patients took cilostazol in studies that lasted for 3 to 6 months. The mortality rate in these patients was similar to placebo (less than 1%). These studies were too small to be sure there is not some increased risk of dying with longer use or in patients sicker than those in the studies.<br />
<br />
'''How should cilostazol tablets be taken?'''<br />
<br />
*Follow your doctor’s advice about how to take cilostazol tablets.<br />
*You should take cilostazol tablets twice a day, at least one half-hour before or two hours after breakfast and dinner. Take cilostazol tablets at about the same times each day.<br />
*Do not share cilostazol tablets with anyone else. It was prescribed only for you.<br />
*Keep cilostazol tablets and all drugs out of the reach of children.<br />
<br />
'''Can cilostazol tablets be taken with other drugs?'''<br />
<br />
Certain drugs and foods can increase the amount of cilostazol in the blood. Because of this, your doctor may adjust your dose of cilostazol or even stop it if you are taking or are going to take one of the following medications.<br />
Drugs Interacting with Cilostazol<br />
Generic Name (Brand Names)Type of Drug<br />
[[erythromycin]] (such as E.E.S.®, Erythrocin®) Antibiotic<br />
[[ketoconazole]] (Nizoral®), [[itraconazole]] (Sporanox®) Antifungal<br />
[[diltiazem]] (Cardizem®) Antihypertensive<br />
[[omeprazole]] (Prilosec®) Gastric acid reducer<br />
This list does not include every drug that may interact with cilostazol tablets. Therefore, you should tell your doctor about all medications that you are taking, including vitamins, herbal supplements and over-the-counter drugs you can buy without a prescription. You should also check with your doctor before taking a new medication after you have begun cilostazol tablets.<br />
<br />
'''What are the possible side effects of cilostazol tablets?'''<br />
<br />
Cilostazol tablets may cause side effects including headache, diarrhea, abnormal stools, increased heart rate and palpitations.<br />
You should discuss possible side effects with your doctor before taking cilostazol tablets and any time you think you are having a side effect.<br />
This provides only a summary of information about cilostazol tablets. If you have any questions about cilostazol tablets, talk to your doctor.<br />
'''Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.'''<br />
<br />
===Patient Information from NLM===<br />
<br />
For patient information about Cilostazol from NLM, click [[Cilostazol (patient information)|here]].<br />
<br />
==Precautions with Alcohol==<br />
<br />
Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
<br />
==Brand Names==<br />
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Cilostazol®, Platel®.<br />
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==Look-Alike Drug Names==<br />
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* (Paired Confused Name 1a) — (Paired Confused Name 1b)<br />
* (Paired Confused Name 2a) — (Paired Confused Name 2b)<br />
* (Paired Confused Name 3a) — (Paired Confused Name 3b)<br />
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==[http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm Drug Shortage Status]==<br />
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==[http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price Price]==<br />
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==References==<br />
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{{reflist}}<br />
<br />
</div></div>Abdurahman Khalilhttps://www.wikidoc.org/index.php?title=Cilostazol&diff=961715Cilostazol2014-04-02T10:58:44Z<p>Abdurahman Khalil: /* Respiratory */</p>
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__NOTOC__<br />
{{CMG}}<br />
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{{SB}} Cilostazol®, Pletal®<br />
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==<span style="color:#FF0000; background:#000000;">Black Box Warning</span>==<br />
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FDA Package Insert for {{PAGENAME}} contains no information regarding ''Black Box Warning''.<br />
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<br />
<font color="#F8F8FF" style="font-weight: bold;"><br />
''{{fontcolor|#FF0000|Condition Name:}}'' Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV[[ congestive heart failure]]. Cilostazol tablets are contraindicated in patients with [[congestive heart failure]] of any severity.<br />
</font><br />
|}<br />
<br />
==Overview==<br />
<br />
{{PAGENAME}} is a_Phosphodiesterase 3 Inhibitor drug that is FDA approved for the treatment of intermittent claudication. There is a Black Box Warning for this drug as shown <span style="background:#000000;">'''[[{{PAGENAME}}#Black Box Warning|{{fontcolor|#FF0000|here}}]]'''</span>. Common adverse reactions include headache, dizziness, palpitation, diarrhea, rhinitis and pharyngitis.<br />
<br />
==Adult Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Adult)===<br />
<br />
=====Intermittent claudication=====<br />
<br />
* Dosing Information<br />
<br />
:* '''100 mg q12h PO''' taken at least half an hour before or two hours after breakfast and dinner.<br />
:* '''50 mg q12h PO''' should be considered during co-administration of such inhibitors of CYP3A4 as [[ketoconazole]], [[itraconazole]], [[erythromycin]] and [[diltiazem]] and during co-administration of such inhibitors of CYP2C19 as [[omeprazole]].<br />
<br />
Patients may respond as early as 2 to 4 weeks after the initiation of therapy, but treatment for up to 12 weeks may be needed before a beneficial effect is experienced.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
===Off-Label Use and Dosage (Adult)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* There is limited information about ''Off-Label Non–Guideline-Supported Use'' of {{PAGENAME}} in adult patients.<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Pediatric Indications and Dosage==<br />
<br />
===FDA-Labeled Indications and Dosage (Pediatric)===<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
===Off-Label Use and Dosage (Pediatric)===<br />
<br />
====Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Developed by: (Organisation)<br />
<br />
* Class of Recommendation: (Class) (Link)<br />
<br />
* Strength of Evidence: (Category A/B/C) (Link)<br />
<br />
* Dosing Information/Recommendation<br />
<br />
:* (Dosage)<br />
<br />
====Non–Guideline-Supported Use====<br />
<br />
=====Condition 1=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 2=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
=====Condition 3=====<br />
<br />
* Dosing Information<br />
<br />
:* (Dosage)<br />
<br />
==Contraindications==<br />
* [[congestive heart failure]].<br />
* Haemostatic disorders or active pathologic bleeding.<br />
* [[peptic ulcer]].<br />
* [[Intracranial bleeding]].<br />
* Hypersensitivity to any of its components.<br />
<br />
==Warnings==<br />
<br />
=====Conidition 1=====<br />
<br />
(Description)<br />
<br />
=====Conidition 2=====<br />
<br />
(Description)<br />
<br />
=====Conidition 3=====<br />
<br />
(Description)<br />
<br />
==Adverse Reactions==<br />
<br />
===Clinical Trials Experience===<br />
<br />
=====Condition 1=====<br />
<br />
======Central Nervous System======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Cardiovascular======<br />
<br />
*Common:<br />
:*Palpitation<br />
:*Tachycardia<br />
<br />
*Less common:<br />
[[Atrial fibrillation]], [[atrial flutter]], cerebral [[infarct]],[[ cerebral ischemia]], [[congestive heart failure]], [[Cardiac arrest|heart arrest]],[[ haemorrhage]], [[hypotension]], [[myocardial infarction]], [[myocardial ischemia]], nodal arrhythmia, [[postural hypotension]], [[supraventricular tachycardia]], [[syncope]], [[varicose vein]], [[vasodilation]], [[ventricular extrasystoles]], [[ventricular tachycardia]].<br />
<br />
======Respiratory======<br />
<br />
*Common:<br />
:*[[Cough]]<br />
<br />
:*[[Pharyngitis]]<br />
<br />
:*[[Rhinitis]]<br />
<br />
<br />
*Less common:<br />
[[Asthma]], [[epistaxis]], [[hemoptysis]], [[pneumonia]], [[sinusitis]].<br />
<br />
======Gastrointestinal======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Miscellaneous======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
=====Condition 2=====<br />
<br />
======Central Nervous System======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Cardiovascular======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Respiratory======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Gastrointestinal======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Hypersensitive Reactions======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
======Miscellaneous======<br />
<br />
: (list/description of adverse reactions)<br />
<br />
===Postmarketing Experience===<br />
<br />
(Description)<br />
<br />
==Drug Interactions==<br />
<br />
* Drug 1<br />
* Drug 2<br />
* Drug 3<br />
* Drug 4<br />
* Drug 5<br />
<br />
=====Drug 1=====<br />
<br />
(Description)<br />
<br />
=====Drug 2=====<br />
<br />
(Description)<br />
<br />
=====Drug 3=====<br />
<br />
(Description)<br />
<br />
=====Drug 4=====<br />
<br />
(Description)<br />
<br />
=====Drug 5=====<br />
<br />
(Description)<br />
<br />
==Use in Specific Populations==<br />
<br />
====Pregnancy====<br />
<br />
* '''[[Pregnancy category#United States|Pregnancy Category (FDA)]]: C'''<br />
<br />
* '''[[Pregnancy category#Australia|Pregnancy Category (AUS)]]: {{PAGENAME}} is not included in Australian Drug Evaluation Committee (ADEC) Pregnancy Categories.'''<br />
<br />
In a rat developmental toxicity study, oral administration of 1000 mg cilostazol/kg/day was associated with decreased fetal weights and increased incidences of cardiovascular, renal and skeletal anomalies (ventricular septal, aortic arch and subclavian artery abnormalities, renal pelvic dilation, 14th rib and retarded ossification). At this dose, systemic exposure to unbound cilostazol in nonpregnant rats was about 5 times the exposure in humans given the MRHD. Increased incidences of ventricular septal defect and retarded ossification were also noted at 150 mg/kg/day (5 times the MRHD on a systemic exposure basis). In a rabbit developmental toxicity study, an increased incidence of retardation of ossification of the sternum was seen at doses as low as 150 mg/kg/day. In nonpregnant rabbits given 150 mg/kg/day, exposure to unbound cilostazol was considerably lower than that seen in humans given the MRHD and exposure to 3,4-dehydro-cilostazol was barely detectable.<br />
When cilostazol was administered to rats during late pregnancy and lactation, an increased incidence of stillborn and decreased birth weights of offspring was seen at doses of 150 mg/kg/day (5 times the MRHD on a systemic exposure basis).<br />
There are no adequate and well-controlled studies in pregnant women.<br />
<br />
====Labor and Delivery====<br />
<br />
(Description)<br />
<br />
====Nursing Mothers====<br />
<br />
Transfer of cilostazol into milk has been reported in experimental animals (rats). Because of the potential risk to nursing infants, a decision should be made to discontinue nursing or to discontinue cilostazol tablets.<br />
<br />
====Pediatric Use====<br />
<br />
The safety and effectiveness of cilostazol in pediatric patients have not been established.<br />
<br />
====Geriatric Use====<br />
Of the total number of subjects (n=2,274) in clinical studies of cilostazol, 56 percent were 65-years-old and over, while 16 percent were 75-years-old and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have not disclosed any age-related effects on the absorption, distribution, metabolism and elimination of cilostazol and its metabolites.<br />
====Gender====<br />
<br />
The total and unbound oral clearances, adjusted for body weight, of cilostazol and its metabolites were not significantly different with respect to age and/or gender across a 50- to 80-year old age range<br />
<br />
====Race====<br />
<br />
(Description)<br />
<br />
====Renal Impairment====<br />
<br />
Patients on dialysis have not been studied, but, it is unlikely that cilostazol can be removed efficiently by dialysis because of its high protein binding (95% to 98%).<br />
Special caution is advised when cilostazol is used in patients with severe renal impairment: estimated creatinine clearance <25 mL/min.<br />
<br />
====Hepatic Impairment====<br />
<br />
Patients with moderate or severe hepatic impairment have not been studied in clinical trials.<br />
Special caution is advised when cilostazol is used in such patients.<br />
<br />
====Carcinogenesis, Mutagenesis, Impairment of Fertility====<br />
<br />
Dietary administration of cilostazol to male and female rats and mice for up to 104 weeks, at doses up to 500 mg/kg/day in rats and 1000 mg/kg/day in mice, revealed no evidence of carcinogenic potential. The maximum doses administered in both rat and mouse studies were, on a systemic exposure basis, less than the human exposure at the MRHD of the drug. Cilostazol tested negative in bacterial gene mutation, bacterial DNA repair, mammalian cell gene mutation and mouse in vivo bone marrow chromosomal aberration assays. It was, however, associated with a significant increase in chromosomal aberrations in the in vitro Chinese Hamster Ovary Cell assay.<br />
<br />
Cilostazol did not affect fertility or mating performance of male and female rats at doses as high as 1000 mg/kg/day. At this dose, systemic exposures (AUCs) to unbound cilostazol were less than 1.5 times in males and about 5 times in females, the exposure in humans at the MRHD.<br />
<br />
====Immunocompromised Patients====<br />
<br />
(Description)<br />
<br />
====Miscellaneous====<br />
<br />
=====Smokers=====<br />
Population pharmacokinetic analysis suggests that smoking decreased cilostazol exposure by about 20%.<br />
<br />
==Administration and Monitoring==<br />
<br />
====Administration====<br />
<br />
Oral<br />
<br />
====Monitoring====<br />
<br />
<br />
====Discontinuation of Therapy====<br />
The available data suggest that the dosage of cilostazol tablets can be reduced or discontinued without rebound (i.e., platelet hyperaggregability).<br />
<br />
==IV Compatibility==<br />
<br />
===Solution===<br />
<br />
====Compatible====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Not Tested====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Variable====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Incompatible====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
===Y-Site===<br />
<br />
====Compatible====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Not Tested====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Variable====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Incompatible====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
===Admixture===<br />
<br />
====Compatible====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Not Tested====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Variable====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Incompatible====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
===Syringe===<br />
<br />
====Compatible====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Not Tested====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Variable====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Incompatible====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
===TPN/TNA===<br />
<br />
====Compatible====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Not Tested====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Variable====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
====Incompatible====<br />
<br />
* Solution 1<br />
* Solution 2<br />
* Solution 3<br />
<br />
==Overdosage==<br />
<br />
===Acute Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
Information on acute overdosage with cilostazol tablets in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe [[headache]], [[diarrhea]], [[hypotension]], [[tachycardia]] and possibly cardiac [[arrhythmias]]. The patient should be carefully observed and given supportive treatment. Since cilostazol is highly protein-bound, it is unlikely that it can be efficiently removed by [[hemodialysis]] or [[peritoneal dialysis]]. The oral LD50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs.<br />
<br />
====Management====<br />
<br />
(Description)<br />
<br />
===Chronic Overdose===<br />
<br />
====Signs and Symptoms====<br />
<br />
(Description)<br />
<br />
====Management====<br />
<br />
(Description)<br />
<br />
==Pharmacology==<br />
<br />
{{Drugbox2<br />
| verifiedrevid = 460037234<br />
| IUPAC_name = 6-[4-(1-cyclohexyl-1''H''-tetrazol-5-yl)butoxy]-<br>3,4-dihydro-2(1''H'')-quinolinone<br />
| image = Cilostazol.JPG<br />
| width = 300<br />
<br />
<!--Clinical data--><br />
| tradename = Pletal<br />
| Drugs.com = {{drugs.com|monograph|cilostazol}}<br />
| MedlinePlus = a601038<br />
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --><br />
| pregnancy_US = C<br />
| pregnancy_category = <br />
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S8 --><br />
| legal_UK = <!-- GSL / P / POM / CD --><br />
| legal_US = <!-- OTC / Rx-only --><br />
| legal_status = <br />
| routes_of_administration = Oral<br />
<br />
<!--Pharmacokinetic data--><br />
| bioavailability = <br />
| protein_bound = 95–98%<br />
| metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C19]]-mediated)<br />
| elimination_half-life = 11–13 hours<br />
| excretion = Renal<br />
<br />
<!--Identifiers--><br />
| CASNo_Ref = {{cascite|correct|CAS}}<br />
| CAS_number_Ref = {{cascite|correct|??}}<br />
| CAS_number = 73963-72-1<br />
| ATC_prefix = B01<br />
| ATC_suffix = AC23<br />
| PubChem = 2754<br />
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}<br />
| DrugBank = DB01166<br />
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}<br />
| ChemSpiderID = 2652<br />
| UNII_Ref = {{fdacite|correct|FDA}}<br />
| UNII = N7Z035406B<br />
| KEGG_Ref = {{keggcite|correct|kegg}}<br />
| KEGG = D01896<br />
| ChEBI_Ref = {{ebicite|correct|EBI}}<br />
| ChEBI = 31401<br />
| ChEMBL_Ref = {{ebicite|correct|EBI}}<br />
| ChEMBL = 799<br />
<br />
<!--Chemical data--><br />
| C=20 | H=27 | N=5 | O=2 <br />
| molecular_weight = 369.46 g/mol<br />
| smiles = O=C4Nc3c(cc(OCCCCc1nnnn1C2CCCCC2)cc3)CC4<br />
| InChI = 1/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| InChIKey = RRGUKTPIGVIEKM-UHFFFAOYAE<br />
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChI = 1S/C20H27N5O2/c26-20-12-9-15-14-17(10-11-18(15)21-20)27-13-5-4-8-19-22-23-24-25(19)16-6-2-1-3-7-16/h10-11,14,16H,1-9,12-13H2,(H,21,26)<br />
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}<br />
| StdInChIKey = RRGUKTPIGVIEKM-UHFFFAOYSA-N<br />
}}<br />
<br />
===Mechanism of Action===<br />
<br />
The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) [[phosphodiesterase ]]III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in [[cAMP ]]in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively.<br />
<br />
Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including [[thrombin]], [[ADP]], [[collagen]], [[arachidonic acid]], [[epinephrine]], and [[shear stress]]. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in [[triglycerides ]]of 29.3 mg/dL (15%) and an increase in HDL-[[cholesterol ]]of 4.0 mg/dL (~10%).<br />
<br />
====Cardiovascular Effects====<br />
Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, [[carotid]] or [[superior mesenteric arteries]]. [[Renal arteries]] were not responsive to the effects of cilostazol.<br />
<br />
In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with [[Holter monitors]], numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained [[ventricular tachycardia]] events than did placebo-treated patients; the increases were not dose-related.<br />
<br />
===Structure===<br />
<br />
*Cilostazol is a [[quinolinone ]]derivative that inhibits cellular [[phosphodiesterase ]](more specific for phosphodiesterase III). The empirical formula of cilostazol is C20H27N5O2, and its molecular weight is 369.46. Cilostazol is 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, CAS-73963-72-1.<br />
*Cilostazol occurs as white to off-white crystals or as a crystalline powder that is slightly soluble in [[methanol ]]and [[ethanol]], and is practically insoluble in water, 0.1 N HCl, and 0.1 N NaOH.<br />
*Cilostazol tablets for oral administration are available in 50 mg and 100 mg round, white debossed tablets. Each tablet, in addition to the active ingredient, contains the following inactive ingredients: microcrystalline cellulose, pregelatinized starch, methylcellulose, carboxymethylcellulose calcium and magnesium stearate.<br />
<br />
<br />
===Pharmacodynamics===<br />
<br />
(Description)<br />
<br />
===Pharmacokinetics===<br />
<br />
Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cmax and a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD).<br />
<br />
The mean ±SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below<br />
{|<br />
|[[File:Cilostazolpharmaco.JPG|600px|thumb]]<br />
|}<br />
<br />
====Distribution====<br />
'''Plasma Protein and Erythrocyte Binding'''<br />
<br />
Cilostazol is 95-98% protein bound, predominantly to albumin. The mean percent binding for 3,4‑dehydro‑cilostazol is 97.4% and for 4´-trans-hydroxy-cilostazol is 66%. Mild hepatic impairment did not affect protein binding. The free fraction of cilostazol was 27% higher in subjects with renal impairment than in normal volunteers. The displacement of cilostazol from plasma proteins by erythromycin, quinidine, warfarin, and omeprazole was not clinically significant.<br />
<br />
====Metabolism and Excretion====<br />
Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are [[CYP3A4 ]]and, to a lesser extent, [[CYP2C19]]. The enzyme responsible for metabolism of 3,4‑dehydro‑cilostazol, the most active of the metabolites, is unknown.<br />
<br />
Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4´-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4´-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br />
<br />
===Nonclinical Toxicology===<br />
<br />
==Clinical Studies==<br />
<br />
*The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks’ duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998) and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests.<br />
*Compared to patients treated with placebo, patients treated with cilostazol tablets 50 mg or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks.<br />
*The following figure depicts the percent mean improvement in maximal walking distance, at study end for each of the eight studies.<br />
Percent Mean Improvement in Maximal Walking Distance at Study End for the Eight Randomized, Double-Blind, Placebo-Controlled Clinical Trials<br />
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*Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%.<br />
*The corresponding changes in the placebo group were –10% to 41%.<br />
*The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age and concomitant use of beta blockers or calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated.<br />
*A randomized, double-blind, placebo-controlled Phase IV study was conducted to assess the long-term effects of cilostazol, with respect to mortality and safety, in 1,439 patients with intermittent claudication and no heart failure. The trial stopped early due to enrollment difficulties and a lower than expected overall death rate. With respect to mortality, the observed 36-month Kaplan-Meier event rate for deaths on study drug with a median time on study drug of 18 months was 5.6% (95% CI of 2.8% to 8.4%) on cilostazol and 6.8% (95% CI of 1.9% to 11.5%) on placebo. These data appear to be sufficient to exclude a 75% increase in the risk of mortality on cilostazol, which was the a priori study hypothesis.<br />
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==How Supplied==<br />
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'''50 mg:''' White, round, debossed with “E” over “123” on one side and plain on the other and supplied as:<br />
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* National Drug Code (NDC): 0185-0123-60 bottles of 60 and 0185-0123-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
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'''100 mg:''' White, round, debossed with “E” over “223” on one side and plain on the other and supplied as:<br />
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* National Drug Code (NDC): 0185-0223-60 bottles of 60 and 0185-0223-05 bottles of 500<br />
* Storage: Store at 20° to 25°C (68° to 77° F) [see USP Controlled Room Temperature].<br />
* Manufactured by: Sandoz Inc.Princeton, NJ 08540<br />
* Distributed by:Bryant Ranch Prepack<br />
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==Images==<br />
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==Patient Information==<br />
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===Patient Information from FDA===<br />
(sil-OS-tah-zol)<br />
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Please read this leaflet before you start taking cilostazol tablets and each time you renew it in case anything has changed. This leaflet does not replace careful discussions with your doctor. You and your doctor should discuss cilostazol when you start taking it and at regular check-ups. You should follow your doctor’s advice about when to have check-ups.<br />
What is cilostazol for?<br />
Cilostazol may improve the symptoms of patients with a medical condition called intermittent claudication.<br />
What is intermittent claudication?<br />
Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. It occurs because narrowing or blockage of the arteries decreases blood flow to the legs. The decreased blood flow does not supply enough oxygen to the leg muscles during walking, resulting in these painful leg cramps.<br />
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'''What treatments are available for intermittent claudication?'''<br />
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The three main treatments available for intermittent claudication are:<br />
*Exercise. Your doctor may advise an exercise program.<br />
*Medication. Your doctor may prescribe a medication such as cilostazol. (See Who should not take cilostazol tablets?)<br />
*Surgery. Your doctor may recommend a surgical procedure to bypass the blocked segment of the artery. Another procedure is called a percutaneous transluminal angioplasty. In this procedure, a catheter (a flexible tube) is inserted into the artery to reduce the blockage and improve blood flow.<br />
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'''How does cilostazol work?'''<br />
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*The exact way that many drugs work is not well understood. Although how cilostazol works is not completely clear, its main effects are to dilate (widen) the arteries supplying blood to the legs and to decrease the ability of platelets in the blood to stick together. Platelets are particles that circulate in the blood and play a role in clotting.<br />
*Cilostazol may reduce the leg pain that patients with intermittent claudication experience, allowing them to walk farther before their leg pain occurs.<br />
*Improvement in symptoms may occur as soon as 2 weeks, but could take up to 12 weeks. If you have not noticed any benefit from cilostazol tablets after 12 weeks you and your doctor may wish to discuss other forms of treatment.<br />
*Sometimes blood vessel disease of the legs causes pain at rest or breakdown of skin in the leg. Cilostazol has not been shown to work in patients with these problems.<br />
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'''Who should not take cilostazol tablets?'''<br />
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*Patients who have congestive heart failure (CHF) must not take cilostazol tablets. The most common symptoms of CHF are shortness of breath and swelling of the legs. However, other conditions may also cause these symptoms. It is important that you discuss with your doctor whether you have CHF.<br />
*Over 1,300 patients took cilostazol in studies that lasted for 3 to 6 months. The mortality rate in these patients was similar to placebo (less than 1%). These studies were too small to be sure there is not some increased risk of dying with longer use or in patients sicker than those in the studies.<br />
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'''How should cilostazol tablets be taken?'''<br />
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*Follow your doctor’s advice about how to take cilostazol tablets.<br />
*You should take cilostazol tablets twice a day, at least one half-hour before or two hours after breakfast and dinner. Take cilostazol tablets at about the same times each day.<br />
*Do not share cilostazol tablets with anyone else. It was prescribed only for you.<br />
*Keep cilostazol tablets and all drugs out of the reach of children.<br />
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'''Can cilostazol tablets be taken with other drugs?'''<br />
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Certain drugs and foods can increase the amount of cilostazol in the blood. Because of this, your doctor may adjust your dose of cilostazol or even stop it if you are taking or are going to take one of the following medications.<br />
Drugs Interacting with Cilostazol<br />
Generic Name (Brand Names)Type of Drug<br />
[[erythromycin]] (such as E.E.S.®, Erythrocin®) Antibiotic<br />
[[ketoconazole]] (Nizoral®), [[itraconazole]] (Sporanox®) Antifungal<br />
[[diltiazem]] (Cardizem®) Antihypertensive<br />
[[omeprazole]] (Prilosec®) Gastric acid reducer<br />
This list does not include every drug that may interact with cilostazol tablets. Therefore, you should tell your doctor about all medications that you are taking, including vitamins, herbal supplements and over-the-counter drugs you can buy without a prescription. You should also check with your doctor before taking a new medication after you have begun cilostazol tablets.<br />
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'''What are the possible side effects of cilostazol tablets?'''<br />
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Cilostazol tablets may cause side effects including headache, diarrhea, abnormal stools, increased heart rate and palpitations.<br />
You should discuss possible side effects with your doctor before taking cilostazol tablets and any time you think you are having a side effect.<br />
This provides only a summary of information about cilostazol tablets. If you have any questions about cilostazol tablets, talk to your doctor.<br />
'''Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.'''<br />
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===Patient Information from NLM===<br />
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For patient information about Cilostazol from NLM, click [[Cilostazol (patient information)|here]].<br />
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==Precautions with Alcohol==<br />
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Alcohol-{{PAGENAME}} interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.<br />
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==Brand Names==<br />
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Cilostazol®, Platel®.<br />
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==Look-Alike Drug Names==<br />
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* (Paired Confused Name 1a) — (Paired Confused Name 1b)<br />
* (Paired Confused Name 2a) — (Paired Confused Name 2b)<br />
* (Paired Confused Name 3a) — (Paired Confused Name 3b)<br />
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==[http://www.fda.gov/drugs/drugsafety/drugshortages/ucm050792.htm Drug Shortage Status]==<br />
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==[http://www.goodrx.com/{{urlencode:{{#if:{{{1|}}}|{{{1}}}|{{PAGENAME}}}}}}/price Price]==<br />
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==References==<br />
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</div></div>Abdurahman Khalil