wikidoc - User contributions [en]

Exenatide

2015-03-19T19:49:11Z

Sree Teja Yelamanchili:

{{DrugProjectFormSinglePage
|authorTag={{SS}}; {{STY}}
|genericName=Exenatide
|aOrAn=a
|drugClass=[[GLP-1]] receptor agonist
|indicationType=treatment
|indication=[[type 2 diabetes mellitus]]
|adverseReactions=injection site mass, injection site [[pruritus]], [[injection site reaction]], [[hypoglycemia]], [[constipation]], [[diarrhea]], [[indigestion]], [[nausea]], [[vomiting]], antibody development, [[asthenia]], [[dizziness]], [[nervousness]], [[headache]]
|blackBoxWarningTitle=<b><span style="color:#FF0000;">TITLE</span></b>
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)
|fdaLIADAdult=<H4>Type 2 Diabetes Mellitus</H4>

* Dosing information
:* '''5 mg injection SC bid''' at any time within the 60-minute period before the morning and evening meals (or before the two main meals of the day, approximately 6 hours or more apart)
:* Exenatide should not be administered after a meal.
:* Based on clinical response, the dose of Exenatide can be increased to '''10 mcg SC injection bid''' after 1 month of therapy.
::* Initiation with '''5 mcg''' reduces the incidence and severity of gastrointestinal side effects. Each dose should be administered as a subcutaneous (SC) injection in the thigh, abdomen, or upper arm. Do not mix Exenatide with insulin. Do not transfer Exenatide from the pen to a syringe or a vial. No data are available on the safety or efficacy of intravenous or intramuscular injection of Exenatide.

<h4>Important limitations of use</h4>

* Exenatide is not a substitute for insulin. Exenatide should not be used for the treatment of [[type 1 diabetes]] or diabetic [[ketoacidosis]], as it would not be effective in these settings.
:* The concurrent use of Exenatide with prandial [[insulin]] has not been studied and cannot be recommended.
:* Based on post marketing data Exenatide has been associated with [[acute pancreatitis]], including fatal and non-fatal hemorrhagic or [[necrotizing pancreatitis]]. Exenatide has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk for [[pancreatitis]] while using Exenatide. Other anti diabetic therapies should be considered in patients with a history of pancreatitis.
|offLabelAdultGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of exenatide in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of exenatide in adult patients.
|fdaLIADPed=Safety and effectiveness of Exenatide have not been established in pediatric patients.
|offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of exenatide in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of exenatide in pediatric patients.
|contraindications=====Hypersensitivity====

Exenatide is contraindicated in patients with prior severe [[hypersensitivity]] reactions to exenatide or to any of the product components.
|warnings=====Never Share a Exenatide Pen between Patients====

Exenatide pens should never be shared between patients, even if the needle is changed. Pen-sharing poses a risk for transmission of blood-borne pathogens.

====Acute Pancreatitis====

*Based on post marketing data, Exenatide has been associated with [[acute pancreatitis]], including fatal and non-fatal hemorrhagic or [[necrotizing pancreatitis]].
*After initiation of Exenatide, and after dose increases, observe patients carefully for signs and symptoms of [[pancreatitis]] (including persistent severe [[abdominal pain]], sometimes radiating to the back, which may or may not be accompanied by [[vomiting]]).
*If [[pancreatitis]] is suspected, Exenatide should promptly be discontinued and appropriate management should be initiated. If [[pancreatitis]] is confirmed, Exenatide should not be restarted.
*Consider anti diabetic therapies other than Exenatide in patients with a history of [[pancreatitis]].

====Use with Medications Known to Cause Hypoglycemia====

*The risk of [[hypoglycemia]] is increased when Exenatide is used in combination with a [[sulfonylurea]]. Therefore, patients receiving Exenatide and a [[sulfonylurea]] may require a lower dose of the [[sulfonylurea]] to reduce the risk of [[hypoglycemia]].
*When Exenatide is used in combination with [[insulin]], the dose of insulin should be evaluated. In patients at increased risk of [[hypoglycemia]] consider reducing the dose of [[insulin]].
*The concurrent use of Exenatide with prandial [[insulin]] has not been studied and cannot be recommended. It is also possible that the use of Exenatide with other glucose-independent [[insulin]] secretagogues (e.g., meglitinides) could increase the risk of [[hypoglycemia]].

====Renal Impairment====

*Exenatide should not be used in patients with severe [[renal impairment]] (creatinine clearance <30 mL/min) or [[end-stage renal disease]] and should be used with caution in patients with renal transplantation .
*In patients with end-stage renal disease receiving [[dialysis]], single doses of Exenatide 5 mcg were not well tolerated due to gastrointestinal side effects.
*Because Exenatide may induce [[nausea]] and [[vomiting]] with transient [[hypovolemia]], treatment may worsen renal function. Caution should be applied when initiating or escalating doses of Exenatide from 5 to 10 mcg in patients with moderate [[renal impairment]] (creatinine clearance 30-50 mL/min).
*There have been post marketing reports of altered renal function, including increased serum creatinine, [[renal impairment]], worsened [[chronic renal failure]] and [[acute renal failure]], sometimes requiring [[hemodialysis]] or kidney transplantation.
*Some of these events occurred in patients receiving one or more pharmacologic agents known to affect renal function or [[hydration]] status, such as [[angiotensin converting enzyme inhibitors]], [[nonsteroidal anti-inflammatory drugs]], or [[diuretics]].
*Some events occurred in patients who had been experiencing [[nausea]], [[vomiting]], or [[diarrhea]], with or without [[dehydration]]. Reversibility of altered renal function has been observed in many cases with supportive treatment and discontinuation of potentially causative agents, including Exenatide.
*Exenatide has not been found to be directly nephrotoxic in preclinical or clinical studies.

====Gastrointestinal Disease====

*Exenatide has not been studied in patients with severe gastrointestinal disease, including [[gastroparesis]].
*Because Exenatide is commonly associated with gastrointestinal adverse reactions, including [[nausea]], [[vomiting]], and [[diarrhea]], the use of Exenatide is not recommended in patients with severe gastrointestinal disease.

====Immunogenicity====

*Patients may develop antibodies to exenatide following treatment with Exenatide.
*Antibody levels were measured in 90% of subjects in the 30-week, 24-week, and 16-week studies of Exenatide.
*In 3%, 4%, and 1% of these patients, respectively, antibody formation was associated with an attenuated glycemic response.
*If there is worsening glycemic control or failure to achieve targeted glycemic control, alternative anti diabetic therapy should be considered.

====Hypersensitivity====

*There have been post marketing reports of serious [[hypersensitivity reactions]] (e.g., [[anaphylaxis]] and [[angioedema]]) in patients treated with Exenatide.
*If a [[hypersensitivity]] reaction occurs, the patient should discontinue Exenatide and other suspect medications and promptly seek medical advice.

====Macrovascular Outcomes====

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Exenatide or any other anti diabetic drug.
|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

====Hypoglycemia====

Table 1 summarizes the incidence and rate of [[hypoglycemia]] with Exenatide in six placebo-controlled clinical trials.

[[File:Exenatide_adverse_01.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

====Immunogenicity====

*Antibodies were assessed in 90% of subjects in the 30-week, 24-week, and 16-week studies of Exenatide. In the 30-week controlled trials of Exenatide add-on to [[metformin]] and/or [[sulfonylurea]], antibodies were assessed at 2- to 6-week intervals.
*The mean antibody titer peaked at week 6 and was reduced by 55% by week 30. Three hundred and sixty patients (38%) had low titer antibodies (<625) to exenatide at 30 weeks.
*The level of glycemic control ([[HbA1c]]) in these patients was generally comparable to that observed in the 534 patients (56%) without antibody titers. An additional 59 patients (6%) had higher titer antibodies (≥625) at 30 weeks.
*Of these patients, 32 (3% overall) had an attenuated glycemic response to Exenatide; the remaining 27 (3% overall) had a glycemic response comparable to that of patients without antibodies.
*In the 16-week trial of Exenatide add-on to [[thiazolidinediones]], with or without [[metformin]], 36 patients (31%) had low titer antibodies to exenatide at 16 weeks.
*The level of glycemic control in these patients was generally comparable to that observed in the 69 patients (60%) without antibody titer. An additional 10 patients (9%) had higher titer antibodies at 16 weeks.
*Of these patients, 4 (4% overall) had an attenuated glycemic response to Exenatide; the remaining 6 (5% overall) had a glycemic response comparable to that of patients without antibodies.
*In the 24-week trial of Exenatide used as monotherapy, 40 patients (28%) had low titer antibodies to exenatide at 24 weeks.
*The level of glycemic control in these patients was generally comparable to that observed in the 101 patients (70%) without antibody titers. An additional 3 patients (2%) had higher titer antibodies at 24 weeks.
*Of these patients, 1 (1% overall) had an attenuated glycemic response to Exenatide; the remaining 2 (1% overall) had a glycemic response comparable to that of patients without antibodies.
*Antibodies to exenatide were not assessed in the 30-week trial of Exenatide used in combination with [[insulin]] glargine.
*Two hundred and ten patients with antibodies to exenatide in the Exenatide clinical trials were tested for the presence of cross-reactive antibodies to GLP-1 and/or glucagon.
*No treatment-emergent cross-reactive antibodies were observed across the range of titers.

====Other Adverse Reactions====

<i>Monotherapy</i>

For the 24-week placebo-controlled study of Exenatide used as a monotherapy, Table 2 summarizes adverse reactions (excluding [[hypoglycemia]]) occurring with an incidence ≥2% and occurring more frequently in Exenatide-treated patients compared with placebo-treated patients.

[[File:Exenatide_adverse_02.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

Adverse reactions reported in ≥1.0% to <2.0% of patients receiving Exenatide and reported more frequently than with placebo included decreased appetite, [[diarrhea]], and [[dizziness]]. The most frequently reported adverse reaction associated with Exenatide, [[nausea]], occurred in a dose-dependent fashion.
Two of the 155 patients treated with Exenatide withdrew due to adverse reactions of [[headache]] and [[nausea]]. No placebo-treated patients withdrew due to adverse reactions.

<i>Combination Therapy</i>

'''Add-On to Metformin and/or Sulfonylurea'''

In the three 30-week controlled trials of Exenatide add-on to [[metformin]] and/or [[sulfonylurea]], adverse reactions (excluding [[hypoglycemia]]) with an incidence ≥2% and occurring more frequently in Exenatide-treated patients compared with placebo-treated patients ] are summarized in Table 3.

[[File:Exenatide_adverse_03.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

Adverse reactions reported in ≥1.0% to <2.0% of patients receiving Exenatide and reported more frequently than with placebo included decreased appetite. [[nausea]] was the most frequently reported adverse reaction and occurred in a dose-dependent fashion. With continued therapy, the frequency and severity decreased over time in most of the patients who initially experienced [[nausea]]. Patients in the long-term uncontrolled open-label extension studies at 52 weeks reported no new types of adverse reactions than those observed in the 30-week controlled trials.
The most common adverse reactions leading to withdrawal for Exenatide-treated patients were [[nausea]] (3% of patients) and [[vomiting]] (1%). For placebo-treated patients, <1% withdrew due to [[nausea]] and none due to [[vomiting]].

'''Add-On to Thiazolidinedione with or without Metformin'''

For the 16-week placebo-controlled study of Exenatide add-on to a thiazolidinedione, with or without metformin, Table 4 summarizes the adverse reactions (excluding hypoglycemia) with an incidence of ≥2% and occurring more frequently in Exenatide-treated patients compared with placebo-treated patients.

[[File:Exenatide_adverse_04.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

Adverse reactions reported in ≥1.0% to <2.0% of patients receiving Exenatide and reported more frequently than with placebo included decreased appetite. Chills (n=4) and injection-site reactions (n=2) occurred only in Exenatide-treated patients. The two patients who reported an injection-site reaction had high titers of antibodies to exenatide. Two serious adverse events (chest pain and chronic hypersensitivity pneumonitis) were reported in the Exenatide arm. No serious adverse events were reported in the placebo arm.
The most common adverse reactions leading to withdrawal for Exenatide-treated patients were [[nausea]] (9%) and [[vomiting]] (5%). For placebo-treated patients, <1% withdrew due to [[nausea]].

'''Add-On to Insulin Glargine with or without Metformin and/or Thiazolidinedione'''

For the 30-week placebo-controlled study of Exenatide as add-on to insulin glargine with or without oral antihyperglycemic medications, Table 5 summarizes adverse reactions (excluding [[hypoglycemia]]) occurring with an incidence ≥2% and occurring more frequently in Exenatide-treated patients compared with placebo-treated patients.

[[File:Exenatide_adverse_05.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

The most frequently reported adverse reactions leading to withdrawal for Exenatide-treated patients were [[nausea]] (5.1%) and [[vomiting]] (2.9%). No placebo-treated patients withdrew due to [[nausea]] or [[vomiting]].
|postmarketing=The following additional adverse reactions have been reported during post approval use of Exenatide. Because these events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.<br>
<i>Allergy/Hypersensitivity</i>: injection-site reactions, generalized [[pruritus]] and/or [[urticaria]], macular or [[papular rash]], [[angioedema]], [[anaphylactic reaction]] .<br>
<i>Drug Interactions</i>: International normalized ratio (INR) increased with concomitant [[warfarin]] use sometimes associated with bleeding.
<br>
<i>Gastrointestinal</i>: [[nausea]], [[vomiting]], and/or [[diarrhea]] resulting in [[dehydration]]; abdominal distension, [[abdominal pain]], [[eructation]], [[constipation]], [[flatulence]], [[acute pancreatitis]], hemorrhagic and necrotizing [[pancreatitis]] sometimes resulting in death.
<i>Neurologic</i>: [[dysgeusia]]; [[somnolence]].
<br>
<i>Renal and Urinary Disorders</i>: altered renal function, including increased serum creatinine, renal impairment, worsened [[chronic renal failure]] or [[acute renal failure]] (sometimes requiring [[hemodialysis]]), [[kidney transplant]] and kidney transplant dysfunction.<br>
<i>Skin and Subcutaneous Tissue Disorders</i>: [[alopecia]].
|drugInteractions=====Orally Administered Drugs====

The effect of Exenatide to slow gastric emptying can reduce the extent and rate of absorption of orally administered drugs. Exenatide should be used with caution in patients receiving oral medications that have narrow therapeutic index or require rapid gastrointestinal absorption . For oral medications that are dependent on threshold concentrations for efficacy, such as [[contraceptives]] and [[antibiotics]], patients should be advised to take those drugs at least 1 hour before Exenatide injection. If such drugs are to be administered with food, patients should be advised to take them with a meal or snack when Exenatide is not administered .

====Warfarin====

There are post marketing reports of increased INR sometimes associated with bleeding, with concomitant use of [[warfarin]] and Exenatide . In a drug interaction study, Exenatide did not have a significant effect on INR . In patients taking [[warfarin]], prothrombin time should be monitored more frequently after initiation or alteration of Exenatide therapy. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on [[warfarin]].
|FDAPregCat=C
|useInPregnancyFDA=There are no adequate and well-controlled studies of Exenatide use in pregnant women. In animal studies, exenatide caused [[cleft palate]], irregular skeletal ossification and an increased number of neonatal deaths. Exenatide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Female mice given SC doses of 6, 68, or 760 mcg/kg/day beginning 2 weeks prior to and throughout mating until gestation day 7 had no adverse fetal effects. At the maximal dose, 760 mcg/kg/day, systemic exposures were up to 390 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.
In developmental toxicity studies, pregnant animals received exenatide subcutaneously during organogenesis. Specifically, fetuses from pregnant rabbits given SC doses of 0.2, 2, 22, 156, or 260 mcg/kg/day from gestation day 6 through 18 experienced irregular skeletal ossifications from exposures 12 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC. Moreover, fetuses from pregnant mice given SC doses of 6, 68, 460, or 760 mcg/kg/day from gestation day 6 through 15 demonstrated reduced fetal and neonatal growth, [[cleft palate]] and skeletal effects at systemic exposure 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.
Lactating mice given SC doses of 6, 68, or 760 mcg/kg/day from gestation day 6 through lactation day 20 (weaning), experienced an increased number of neonatal deaths. Deaths were observed on postpartum days 2 to 4 in dams given 6 mcg/kg/day, a systemic exposure 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.
Pregnancy Registry
A Pregnancy Registry has been implemented to monitor pregnancy outcomes of women exposed to exenatide during pregnancy. Physicians are encouraged to register patients by calling 1-800-633-9081.
|useInNursing=It is not known whether exenatide is excreted in human milk. However, exenatide is present at low concentrations (less than or equal to 2.5% of the concentration in maternal plasma following subcutaneous dosing) in the milk of lactating mice. Many drugs are excreted in human milk and because of the potential for clinically significant adverse reactions in nursing infants from exenatide, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account these potential risks against the glycemic benefits to the lactating woman. Caution should be exercised when Exenatide is administered to a nursing woman.
|useInPed=Safety and effectiveness of Exenatide have not been established in pediatric patients.
|useInGeri=Population pharmacokinetic analysis of patients ranging from 22 to 73 years of age suggests that age does not influence the pharmacokinetic properties of exenatide. Exenatide was studied in 282 patients 65 years of age or older and in 16 patients 75 years of age or older. No differences in safety or effectiveness were observed between these patients and younger patients. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in the elderly based on renal function.
|useInRenalImpair=Exenatide is not recommended for use in patients with end-stage renal disease or severe renal impairment (creatinine clearance <30 mL/min) and should be used with caution in patients with renal transplantation. No dosage adjustment of Exenatide is required in patients with mild renal impairment (creatinine clearance 50-80 mL/min). Caution should be applied when initiating or escalating doses of Exenatide from 5 to 10 mcg in patients with moderate renal impairment (creatinine clearance 30-50 mL/min)
|useInHepaticImpair=No pharmacokinetic study has been performed in patients with a diagnosis of acute or chronic hepatic impairment. Because exenatide is cleared primarily by the kidney, hepatic dysfunction is not expected to affect blood concentrations of eventide.
|administration=Injection SC
|monitoring=FDA package insert for abcixmab contains no information regarding drug monitoring.
|IVCompat=There is limited information about the IV compatibility.
|overdose=In a clinical study of Exenatide, three patients with [[type 2 diabetes]] each experienced a single overdose of 100 mcg SC (10 times the maximum recommended dose). Effects of the overdoses included severe [[nausea]], severe [[vomiting]], and rapidly declining blood glucose concentrations. One of the three patients experienced severe [[hypoglycemia]] requiring parenteral glucose administration. The three patients recovered without complication. In the event of overdose, appropriate supportive treatment should be initiated according to the patient's clinical signs and symptoms.
|drugBox={{Drugbox2
| verifiedrevid = 464189825
| IUPAC_name = ''N''-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)<br>quinazolin-4-amine
| image = Erlotinib Structural Formulae.png
| width = 250
| image2 = Erlotinib-1m17-3D-balls.png


| tradename = Tarceva
| Drugs.com = {{drugs.com|monograph|erlotinib}}
| MedlinePlus = a605008
| licence_EU = Tarceva
| licence_US = Erlotinib
| pregnancy_US = D
| legal_UK = POM
| legal_US = Rx-only
| routes_of_administration = Oral [[Tablet (pharmacy)|tablets]]


| bioavailability = 59%
| protein_bound = 95%
| metabolism = [[Liver|Hepatic]] (mainly [[CYP3A4]], less [[CYP1A2]])
| elimination_half-life = 36.2 hrs ([[median]])
| excretion = >98% as metabolites, of which >90% via [[faeces]], 9% via [[urine]]


| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 183321-74-6
| ATC_prefix = L01
| ATC_suffix = XE03
| PubChem = 176870
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00530
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 154044
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = J4T82NDH7E
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D07907
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 114785
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 553


| C=22 | H=23 | N=3 | O=4
| molecular_weight = 393.436 g/mol
| smiles = COCCOc1cc2c(cc1OCCOC)ncnc2Nc3cccc(c3)C#C
| InChI = 1/C22H23N3O4/c1-4-16-6-5-7-17(12-16)25-22-18-13-20(28-10-8-26-2)21(29-11-9-27-3)14-19(18)23-15-24-22/h1,5-7,12-15H,8-11H2,2-3H3,(H,23,24,25)
| InChIKey = AAKJLRGGTJKAMG-UHFFFAOYAM
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C22H23N3O4/c1-4-16-6-5-7-17(12-16)25-22-18-13-20(28-10-8-26-2)21(29-11-9-27-3)14-19(18)23-15-24-22/h1,5-7,12-15H,8-11H2,2-3H3,(H,23,24,25)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = AAKJLRGGTJKAMG-UHFFFAOYSA-N
}}
|mechAction=Incretins, such as glucagon-like peptide-1 (GLP-1), enhance glucose-dependent [[insulin]] secretion and exhibit other anti hyperglycemic actions following their release into the circulation from the gut. Exenatide is a GLP-1 receptor agonist that enhances glucose-dependent [[insulin]] secretion by the pancreatic beta-cell, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying.
The amino acid sequence of exenatide partially overlaps that of human GLP-1. Exenatide has been shown to bind and activate the human GLP-1 receptor in vitro. This leads to an increase in both glucose-dependent synthesis of [[insulin]], and in vivo secretion of insulin from pancreatic beta cells, by mechanisms involving cyclic AMP and/or other intracellular signaling pathways.
Exenatide improves glycemic control by reducing fasting and postprandial glucose concentrations in patients with [[type 2 diabetes]] through the actions described below.
|structure=Exenatide (exenatide) is a synthetic peptide that was originally identified in the lizard Heloderma suspectum. Exenatide differs in chemical structure and pharmacological action from insulin, sulfonylureas (including D-phenylalanine derivatives and meglitinides), [[biguanides]], [[thiazolidinediones]], [[alpha-glucosidase inhibitors]], [[amylinomimetics]] and dipeptidyl peptidase-4 inhibitors.
Exenatide is a 39-amino acid peptide amide. Exenatide has the empirical formula C184H282N50O60S and molecular weight of 4186.6 Daltons. The amino acid sequence for exenatide is shown below.
H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
Exenatide is supplied for SC injection as a sterile, preserved isotonic solution in a glass cartridge that has been assembled in a pen-injector (pen). Each milliliter (mL) contains 250 micrograms (mcg) synthetic exenatide, 2.2 mg metacresol as an antimicrobial preservative, mannitol as a tonicity-adjusting agent, and glacial acetic acid and sodium acetate trihydrate in water for injection as a buffering solution at pH 4.5. Two prefilled pens are available to deliver unit doses of 5 mcg or 10 mcg. Each prefilled pen will deliver 60 doses to provide for 30 days of twice daily administration (BID).
|PD=Glucose-Dependent Insulin Secretion

Exenatide has acute effects on pancreatic beta-cell responsiveness to glucose leading to insulin release predominantly in the presence of elevated glucose concentrations. This insulin secretion subsides as blood glucose concentrations decrease and approach [[euglycemia]]. However, Exenatide does not impair the normal glucagon response to [[hypoglycemia]].

First-Phase Insulin Response

In healthy individuals, robust insulin secretion occurs during the first 10 minutes following intravenous (IV) glucose administration. This secretion, known as the "first-phase insulin response," is characteristically absent in patients with type 2 diabetes. The loss of the first-phase insulin response is an early beta-cell defect in [[type 2 diabetes]]. Administration of Exenatide at therapeutic plasma concentrations restored first-phase insulin response to an IV bolus of glucose in patients with type 2 diabetes (Figure 1). Both first-phase insulin secretion and second-phase insulin secretion were significantly increased in patients with type 2 diabetes treated with Exenatide compared with saline (p<0.001 for both).

[[File:Exenatide_PD_01.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

Glucagon Secretion

In patients with type 2 diabetes, Exenatide moderates glucagon secretion and lowers serum glucagon concentrations during periods of [[hyperglycemia]]. Lower glucagon concentrations lead to decreased hepatic glucose output and decreased insulin demand.

Gastric Emptying

Exenatide slows gastric emptying, thereby reducing the rate at which meal-derived glucose appears in the circulation.

Food Intake

In both animals and humans, administration of exenatide has been shown to reduce food intake.

Postprandial Glucose

In patients with [[type 2 diabetes]], Exenatide reduces postprandial plasma glucose concentrations (Figure 2).

[[File:Exenatide_PD_02.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

Fasting Glucose

In a single-dose crossover study in patients with [[type 2 diabetes]] and fasting [[hyperglycemia]], immediate insulin release followed injection of Exenatide. Plasma glucose concentrations were significantly reduced with Exenatide compared with placebo (Figure 3).

[[File:Exenatide_PD_03.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

Cardiac Electrophysiology

The effect of exenatide 10 µg subcutaneously on QTc interval was evaluated in a randomized, placebo-, and active-controlled (moxifloxacin 400 mg) crossover thorough QTc study in 62 healthy subjects. In this study with demonstrated ability to detect small effects, the upper bound of the 90% confidence interval for the largest placebo-adjusted, baseline-corrected QTc was below 10 msec. Thus, Exenatide (10 mcg single dose) was not associated with clinically meaningful prolongation of the QTc interval.
|PK='''Absorption'''

Following SC administration to patients with [[type 2 diabetes]], exenatide reaches median peak plasma concentrations in 2.1 hours. The mean peak exenatide concentration (Cmax) was 211 pg/mL and overall mean area under the time-concentration curve (AUC0-inf) was 1036 pg∙h/mL following SC administration of a 10-mcg dose of Exenatide. Exenatide exposure (AUC) increased proportionally over the therapeutic dose range of 5 to 10 mcg. The Cmax values increased less than proportionally over the same range. Similar exposure is achieved with SC administration of Exenatide in the abdomen, thigh, or upper arm.

'''Distribution'''

The mean apparent volume of distribution of exenatide following SC administration of a single dose of Exenatide is 28.3 L.

'''Metabolism and Elimination'''

Nonclinical studies have shown that exenatide is predominantly eliminated by glomerular filtration with subsequent proteolytic degradation. The mean apparent clearance of exenatide in humans is 9.1 L/hour and the mean terminal half-life is 2.4 hours. These pharmacokinetic characteristics of exenatide are independent of the dose. In most individuals, exenatide concentrations are measurable for approximately 10 hours post-dose.

'''Drug Interactions'''

<i>Acetaminophen</i>

When 1000 mg [[acetaminophen]] elixir was given with 10 mcg Exenatide (0 hour) and 1 hour, 2 hours, and 4 hours after Exenatide injection, [[acetaminophen]] AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; Cmax was decreased by 37%, 56%, 54%, and 41%, respectively; Tmax was increased from 0.6 hour in the control period to 0.9 hour, 4.2 hours, 3.3 hours, and 1.6 hours, respectively. [[acetaminophen]] AUC, Cmax and Tmax were not significantly changed when [[acetaminophen]] was given 1 hour before Exenatide injection.

<i>Digoxin</i>

Administration of repeated doses of Exenatide (10 mcg BID) 30 minutes before oral [[digoxin]] (0.25 mg once daily) decreased the Cmax of [[digoxin]] by 17% and delayed the Tmax of [[digoxin]] by approximately 2.5 hours; however, the overall steady-state pharmacokinetic exposure (e.g., AUC) of [[digoxin]] was not changed.

<i>Lovastatin</i>

Administration of Exenatide (10 mcg BID) 30 minutes before a single oral dose of [[lovastatin]] (40 mg) decreased the AUC and Cmax of [[lovastatin]] by approximately 40% and 28%, respectively, and delayed the Tmax by about 4 hours compared with [[lovastatin]] administered alone. In the 30-week controlled clinical trials of Exenatide, the use of Exenatide in patients already receiving [[HMG CoA reductase]] inhibitors was not associated with consistent changes in lipid profiles compared to baseline.

<i>Lisinopril</i>

In patients with mild to moderate hypertension stabilized on [[lisinopril]] (5-20 mg/day), Exenatide (10 mcg BID) did not alter steady-state Cmax or AUC of [[lisinopril]]. [[lisinopril]] steady-state Tmax was delayed by 2 hours. There were no changes in 24-hour mean systolic and diastolic blood pressure.

<i>Oral Contraceptives</i>

The effect of Exenatide (10 mcg BID) on single and on multiple doses of a combination [[oral contraceptive]] (30 mcg ethinyl estradiol plus 150 mcg levonorgestrel) was studied in healthy female subjects. Repeated daily doses of the oral contraceptive (OC) given 30 minutes after Exenatide administration decreased the Cmax of ethinyl estradiol and levonorgestrel by 45% and 27%, respectively and delayed the Tmax of ethinyl estradiol and levonorgestrel by 3.0 hours and 3.5 hours, respectively, as compared to the oral contraceptive administered alone. Administration of repeated daily doses of the OC one hour prior to Exenatide administration decreased the mean Cmax of ethinyl estradiol by 15% but the mean Cmax of levonorgestrel was not significantly changed as compared to when the OC was given alone. Exenatide did not alter the mean trough concentrations of levonorgestrel after repeated daily dosing of the oral contraceptive for both regimens. However, the mean trough concentration of ethinyl estradiol was increased by 20% when the OC was administered 30 minutes after Exenatide administration injection as compared to when the OC was given alone. The effect of Exenatide on OC pharmacokinetics is confounded by the possible food effect on OC in this study. Therefore, OC products should be administered at least one hour prior to Exenatide injection.

<i>warfarin</i>

Administration of [[warfarin]] (25 mg) 35 minutes after repeated doses of Exenatide (5 mcg BID on days 1-2 and 10 mcg BID on days 3-9) in healthy volunteers delayed [[warfarin]] Tmax by approximately 2 hours. No clinically relevant effects on Cmax or AUC of S- and R-enantiomers of [[warfarin]] were observed. Exenatide did not significantly alter the pharmacodynamic properties (e.g., international normalized ratio) of [[warfarin]] [see Drug Interactions (7.2)].

'''Specific Populations'''

<i>Renal Impairment</i>

Pharmacokinetics of exenatide was studied in subjects with normal, mild, or moderate renal impairment and subjects with end-stage renal disease. In subjects with mild to moderate renal impairment (creatinine clearance 30-80 mL/min), exenatide exposure was similar to that of subjects with normal renal function. However, in subjects with end-stage renal disease receiving dialysis, mean exenatide exposure increased by 3.37-fold compared to that of subjects with normal renal function.

<i>Hepatic Impairment</i>
No pharmacokinetic study has been performed in patients with a diagnosis of acute or chronic hepatic impairment.

<i>Age</i>

Population pharmacokinetic analysis of patients ranging from 22 to 73 years of age suggests that age does not influence the pharmacokinetic properties of exenatide [see Use in Specific Population (8.5)].

<i>Gender</i>

Population pharmacokinetic analysis of male and female patients suggests that gender does not influence the distribution and elimination of exenatide.

<i>Race</i>

Population pharmacokinetic analysis of samples from Caucasian, Hispanic, Asian, and Black patients suggests that race has no significant influence on the pharmacokinetics of exenatide.

<i>Body Mass Index</i>

Population pharmacokinetic analysis of patients with body mass indices (BMI) ≥30 kg/m2 and <30 kg/m2 suggests that BMI has no significant effect on the pharmacokinetics of exenatide.
|nonClinToxic=====Carcinogenesis, Mutagenesis, Impairment of Fertility====

A 104-week carcinogenicity study was conducted in male and female rats at doses of 18, 70, or 250 mcg/kg/day administered by bolus SC injection. Benign thyroid C-cell adenomas were observed in female rats at all exenatide doses. The incidences in female rats were 8% and 5% in the two control groups and 14%, 11%, and 23% in the low-, medium-, and high-dose groups with systemic exposures of 5, 22, and 130 times, respectively, the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on plasma area under the curve (AUC).
In a 104-week carcinogenicity study in mice at doses of 18, 70, or 250 mcg/kg/day administered by bolus SC injection, no evidence of tumors was observed at doses up to 250 mcg/kg/day, a systemic exposure up to 95 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.
Exenatide was not mutagenic or clastogenic, with or without metabolic activation, in the Ames bacterial mutagenicity assay or chromosomal aberration assay in Chinese hamster ovary cells. Exenatide was negative in the in vivo mouse micronucleus assay.
In mouse fertility studies with SC doses of 6, 68, or 760 mcg/kg/day, males were treated for 4 weeks prior to and throughout mating, and females were treated 2 weeks prior to mating and throughout mating until gestation day 7. No adverse effect on fertility was observed at 760 mcg/kg/day, a systemic exposure 390 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.

====Reproductive and Developmental Toxicology====

In female mice given SC doses of 6, 68, or 760 mcg/kg/day beginning 2 weeks prior to and throughout mating until gestation day 7, there were no adverse fetal effects at doses up to 760 mcg/kg/day, systemic exposures up to 390 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.
In pregnant mice given SC doses of 6, 68, 460, or 760 mcg/kg/day from gestation day 6 through 15 (organogenesis), [[cleft palate]] (some with holes) and irregular fetal skeletal ossification of rib and skull bones were observed at 6 mcg/kg/day, a systemic exposure 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.
In pregnant rabbits given SC doses of 0.2, 2, 22, 156, or 260 mcg/kg/day from gestation day 6 through 18 (organogenesis), irregular fetal skeletal ossifications were observed at 2 mcg/kg/day, a systemic exposure 12 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.
In pregnant mice given SC doses of 6, 68, or 760 mcg/kg/day from gestation day 6 through lactation day 20 (weaning), an increased number of neonatal deaths was observed on postpartum days 2-4 in dams given 6 mcg/kg/day, a systemic exposure 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.
|clinicalStudies=Exenatide has been studied as monotherapy and in combination with [[metformin]], a [[sulfonylurea]], a [[thiazolidinedione]], a combination of [[metformin]] and a [[sulfonylurea]], a combination of [[metformin]] and a [[thiazolidinedione]], or in combination with [[insulin]] glargine with or without [[metformin]] and/or [[thiazolidinedione]].

====Monotherapy====

In a randomized, double-blind, placebo-controlled trial of 24 weeks duration, Exenatide 5 mcg BID (n=77), Exenatide 10 mcg BID (n=78), or placebo BID (n=77) was used as monotherapy in patients with entry [[HbA1c]] ranging from 6.5% to 10%. All patients assigned to Exenatide initially received 5 mcg BID for 4 weeks. After 4 weeks, those patients either continued to receive Exenatide 5 mcg BID or had their dose increased to 10 mcg BID. Patients assigned to placebo received placebo BID throughout the trial. Exenatide or placebo was injected subcutaneously before the morning and evening meals. The majority of patients (68%) were Caucasian, 26% West Asian, 3% Hispanic, 3% Black, and 0.4% East Asian.
The primary endpoint was the change in [[HbA1c]] from baseline to Week 24 (or the last value at time of early discontinuation). Compared to placebo, Exenatide 5 mcg BID and 10 mcg BID resulted in statistically significant reductions in [[HbA1c]] from baseline at Week 24 (Table 6).

[[File:Exenatide_clinical studies_01.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

====Combination Therapy with Oral Antihyperglycemic Medicines====

Three 30-week, double-blind, placebo-controlled trials were conducted to evaluate the safety and efficacy of Exenatide in patients with [[type 2 diabetes]] whose glycemic control was inadequate with [[metformin]] alone, a [[sulfonylurea]] alone, or [[metformin]] in combination with a [[sulfonylurea]]. In addition, a 16-week, placebo-controlled trial was conducted where Exenatide was added to existing [[thiazolidinedione]] ([[pioglitazone]] or [[rosiglitazone]]) treatment, with or without [[metformin]], in patients with [[type 2 diabetes]] with inadequate glycemic control.
In the 30-week trials, after a 4-week placebo lead-in period, patients were randomly assigned to receive Exenatide 5 mcg bid, Exenatide 10 mcg bid, or placebo bid before the morning and evening meals, in addition to their existing oral anti diabetic agent. All patients assigned to Exenatide initially received 5 mcg bid for 4 weeks. After 4 weeks, those patients either continued to receive Exenatide 5 mcg BID or had their dose increased to 10 mcg bid. Patients assigned to placebo received placebo bid throughout the study. A total of 1446 patients were randomized in the three 30-week trials: 991 (69%) were Caucasian, 224 (16%) Hispanic, and 174 (12%) Black. Mean [[HbA1c]] values at baseline for the trials ranged from 8.2% to 8.7%.
In the placebo-controlled trial of 16 weeks duration, Exenatide (n=121) or placebo (n=112) was added to existing [[thiazolidinedione]] ([[pioglitazone]] or [[rosiglitazone]]) treatment, with or without [[metformin]]. Randomization to Exenatide or placebo was stratified based on whether the patients were receiving [[metformin]]. Exenatide treatment was initiated at a dose of 5 mcg bid for 4 weeks then increased to 10 mcg bid for 12 more weeks. Patients assigned to placebo received placebo BID throughout the study. Exenatide or placebo was injected subcutaneously before the morning and evening meals. In this trial, 79% of patients were taking a [[thiazolidinedione]] and [[metformin]] and 21% were taking a [[thiazolidinedione]] alone. The majority of patients (84%) were Caucasian, 8% Hispanic, and 3% Black. The mean baseline [[HbA1c]] values were 7.9% for Exenatide and placebo.
The primary endpoint in each study was the mean change in [[HbA1c]] from baseline to study end (or early discontinuation). Table 7 summarizes the study results for the 30- and 16-week clinical trials.

[[File:Exenatide_clinical studies_02.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

[[File:Exenatide_clinical studies_03.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

HbA1c

The addition of Exenatide to a regimen of [[metformin]], a [[sulfonylurea]], or both, resulted in statistically significant reductions from baseline in [[HbA1c]] compared with patients receiving placebo added to these agents in the three controlled trials (Table 7).
In the 16-week trial of Exenatide add-on to [[thiazolidinediones]], with or without [[metformin]], Exenatide resulted in statistically significant reductions from baseline in [[HbA1c]] compared with patients receiving placebo (Table 7).

Postprandial Glucose

Postprandial glucose was measured after a mixed meal tolerance test in 9.5% of patients participating in the 30-week add-on to [[metformin]], add-on to [[sulfonylurea]], and add-on to [[metformin]] in combination with [[sulfonylurea]] clinical trials. In this pooled subset of patients, Exenatide reduced postprandial plasma glucose concentrations in a dose-dependent manner. The mean (SD) change in 2-hour postprandial glucose concentration following administration of Exenatide at Week 30 relative to baseline was −63 (65) mg/dL for 5 mcg BID (n=42), −71 (73) mg/dL for 10 mcg BID (n=52), and +11 (69) mg/dL for placebo BID (n=44).

====Combination with Insulin Glargine====

A 30-week, double-blind, placebo-controlled trial was conducted to evaluate the efficacy and safety of Exenatide (n=137) versus placebo (n=122) when added to titrated [[insulin]] glargine, with or without [[metformin]] and/or [[thiazolidinedione]], in patients with [[type 2 diabetes]] with inadequate glycemic control.
All patients assigned to Exenatide initially received 5 mcg bid for 4 weeks. After 4 weeks, those patients assigned to Exenatide had their dose increased to 10 mcg bid. Patients assigned to placebo received placebo bid throughout the trial. Exenatide or placebo was injected subcutaneously before the morning and evening meals. Patients with an [[HbA1c]] ≤8.0% decreased their prestudy dose of [[insulin]] glargine by 20% and patients with an [[HbA1c]] ≥8.1% maintained their current dose of [[insulin]] glargine. Five weeks after initiating randomized treatment, [[insulin]] doses were titrated with guidance from the investigator toward predefined fasting glucose targets according to the dose titration algorithm provided in Table 9. The majority of patients (78%) were Caucasian, 10% American Indian or Alaska Native, 9% Black, 3% Asian, and 0.8% of multiple origins.
The primary endpoint was the change in [[HbA1c]] from baseline to Week 30. Compared to placebo, Exenatide 10 mcg bid resulted in statistically significant reductions in [[HbA1c]] from baseline at Week 30 (Table 8) in patients receiving titrated [[insulin]] glargine.

[[File:Exenatide_clinical studies_04.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

[[File:Exenatide_clinical studies_05.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|howSupplied=Exenatide is supplied as a sterile solution for subcutaneous injection containing 250 mcg/mL exenatide.
The following packages are available:

5 mcg per dose, 60 doses, 1.2 mL prefilled pen, NDC 66780-210-07

10 mcg per dose, 60 doses, 2.4 mL prefilled pen, NDC 66780-212-01
|storage=* Prior to first use, Exenatide must be stored refrigerated at 36°F to 46°F (2°C to 8°C).
* After first use, Exenatide can be kept at a temperature not to exceed 77°F (25°C).
* Do not freeze. Do not use Exenatide if it has been frozen.
* Exenatide should be protected from light.
* The pen should be discarded 30 days after first use, even if some drug remains in the pen.
* Use a puncture-resistant container to discard the needles. Do not reuse or share needles.
* Exenatide should not be used past the expiration date.
|fdaPatientInfo=[[File:Exenatide_patient information_01.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|alcohol=Alcohol-Exenatide interaction has not been established. Talk to your doctor about the effects of taking [[alcohol]] with this medication.
|brandNames=* Exenatide
* Bydureon
|lookAlike=There is limited information about the Look-alike drug names.
}}
{{LabelImage
|fileName=Exenatide_label_01.jpg
}}
{{LabelImage
|fileName=Exenatide_label_02.jpg
}}
{{LabelImage
|fileName=Exenatide_panel_01.png
}}
{{LabelImage
|fileName=Exenatide_panel_02.png
}}

Exenatide

2015-03-19T19:48:22Z

Sree Teja Yelamanchili:

{{DrugProjectFormSinglePage
|authorTag={{SS}}; {{STY}}
|genericName=Exenatide
|aOrAn=a
|drugClass=[[GLP-1]] receptor agonist
|indicationType=treatment
|indication=[[type 2 diabetes mellitus]]
|adverseReactions=injection site mass, injection site [[pruritus]], [[injection site reaction]], [[hypoglycemia]], [[constipation]], [[diarrhea]], [[indigestion]], [[nausea]], [[vomiting]], antibody development, [[asthenia]], [[dizziness]], [[nervousness]], [[headache]]
|blackBoxWarningTitle=<b><span style="color:#FF0000;">TITLE</span></b>
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)
|fdaLIADAdult=<H4>Type 2 Diabetes Mellitus</H4>

* Dosing information
:* '''5 mg injection SC bid''' at any time within the 60-minute period before the morning and evening meals (or before the two main meals of the day, approximately 6 hours or more apart)
:* BYETTA should not be administered after a meal.
:* Based on clinical response, the dose of BYETTA can be increased to '''10 mcg SC injection bid''' after 1 month of therapy.
::* Initiation with '''5 mcg''' reduces the incidence and severity of gastrointestinal side effects. Each dose should be administered as a subcutaneous (SC) injection in the thigh, abdomen, or upper arm. Do not mix BYETTA with insulin. Do not transfer BYETTA from the pen to a syringe or a vial. No data are available on the safety or efficacy of intravenous or intramuscular injection of BYETTA.

<h4>Important limitations of use</h4>

* BYETTA is not a substitute for insulin. BYETTA should not be used for the treatment of [[type 1 diabetes]] or diabetic [[ketoacidosis]], as it would not be effective in these settings.
:* The concurrent use of BYETTA with prandial [[insulin]] has not been studied and cannot be recommended.
:* Based on post marketing data BYETTA has been associated with [[acute pancreatitis]], including fatal and non-fatal hemorrhagic or [[necrotizing pancreatitis]]. BYETTA has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk for [[pancreatitis]] while using BYETTA. Other anti diabetic therapies should be considered in patients with a history of pancreatitis.
|offLabelAdultGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of exenatide in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of exenatide in adult patients.
|fdaLIADPed=Safety and effectiveness of BYETTA have not been established in pediatric patients.
|offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of exenatide in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of exenatide in pediatric patients.
|contraindications=====Hypersensitivity====

BYETTA is contraindicated in patients with prior severe [[hypersensitivity]] reactions to exenatide or to any of the product components.
|warnings=====Never Share a BYETTA Pen between Patients====

BYETTA pens should never be shared between patients, even if the needle is changed. Pen-sharing poses a risk for transmission of blood-borne pathogens.

====Acute Pancreatitis====

*Based on post marketing data, BYETTA has been associated with [[acute pancreatitis]], including fatal and non-fatal hemorrhagic or [[necrotizing pancreatitis]].
*After initiation of BYETTA, and after dose increases, observe patients carefully for signs and symptoms of [[pancreatitis]] (including persistent severe [[abdominal pain]], sometimes radiating to the back, which may or may not be accompanied by [[vomiting]]).
*If [[pancreatitis]] is suspected, BYETTA should promptly be discontinued and appropriate management should be initiated. If [[pancreatitis]] is confirmed, BYETTA should not be restarted.
*Consider anti diabetic therapies other than BYETTA in patients with a history of [[pancreatitis]].

====Use with Medications Known to Cause Hypoglycemia====

*The risk of [[hypoglycemia]] is increased when BYETTA is used in combination with a [[sulfonylurea]]. Therefore, patients receiving BYETTA and a [[sulfonylurea]] may require a lower dose of the [[sulfonylurea]] to reduce the risk of [[hypoglycemia]].
*When BYETTA is used in combination with [[insulin]], the dose of insulin should be evaluated. In patients at increased risk of [[hypoglycemia]] consider reducing the dose of [[insulin]].
*The concurrent use of BYETTA with prandial [[insulin]] has not been studied and cannot be recommended. It is also possible that the use of BYETTA with other glucose-independent [[insulin]] secretagogues (e.g., meglitinides) could increase the risk of [[hypoglycemia]].

====Renal Impairment====

*BYETTA should not be used in patients with severe [[renal impairment]] (creatinine clearance <30 mL/min) or [[end-stage renal disease]] and should be used with caution in patients with renal transplantation .
*In patients with end-stage renal disease receiving [[dialysis]], single doses of BYETTA 5 mcg were not well tolerated due to gastrointestinal side effects.
*Because BYETTA may induce [[nausea]] and [[vomiting]] with transient [[hypovolemia]], treatment may worsen renal function. Caution should be applied when initiating or escalating doses of BYETTA from 5 to 10 mcg in patients with moderate [[renal impairment]] (creatinine clearance 30-50 mL/min).
*There have been post marketing reports of altered renal function, including increased serum creatinine, [[renal impairment]], worsened [[chronic renal failure]] and [[acute renal failure]], sometimes requiring [[hemodialysis]] or kidney transplantation.
*Some of these events occurred in patients receiving one or more pharmacologic agents known to affect renal function or [[hydration]] status, such as [[angiotensin converting enzyme inhibitors]], [[nonsteroidal anti-inflammatory drugs]], or [[diuretics]].
*Some events occurred in patients who had been experiencing [[nausea]], [[vomiting]], or [[diarrhea]], with or without [[dehydration]]. Reversibility of altered renal function has been observed in many cases with supportive treatment and discontinuation of potentially causative agents, including BYETTA.
*Exenatide has not been found to be directly nephrotoxic in preclinical or clinical studies.

====Gastrointestinal Disease====

*BYETTA has not been studied in patients with severe gastrointestinal disease, including [[gastroparesis]].
*Because BYETTA is commonly associated with gastrointestinal adverse reactions, including [[nausea]], [[vomiting]], and [[diarrhea]], the use of BYETTA is not recommended in patients with severe gastrointestinal disease.

====Immunogenicity====

*Patients may develop antibodies to exenatide following treatment with BYETTA.
*Antibody levels were measured in 90% of subjects in the 30-week, 24-week, and 16-week studies of BYETTA.
*In 3%, 4%, and 1% of these patients, respectively, antibody formation was associated with an attenuated glycemic response.
*If there is worsening glycemic control or failure to achieve targeted glycemic control, alternative anti diabetic therapy should be considered.

====Hypersensitivity====

*There have been post marketing reports of serious [[hypersensitivity reactions]] (e.g., [[anaphylaxis]] and [[angioedema]]) in patients treated with BYETTA.
*If a [[hypersensitivity]] reaction occurs, the patient should discontinue BYETTA and other suspect medications and promptly seek medical advice.

====Macrovascular Outcomes====

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with BYETTA or any other anti diabetic drug.
|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

====Hypoglycemia====

Table 1 summarizes the incidence and rate of [[hypoglycemia]] with BYETTA in six placebo-controlled clinical trials.

[[File:Exenatide_adverse_01.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

====Immunogenicity====

*Antibodies were assessed in 90% of subjects in the 30-week, 24-week, and 16-week studies of BYETTA. In the 30-week controlled trials of BYETTA add-on to [[metformin]] and/or [[sulfonylurea]], antibodies were assessed at 2- to 6-week intervals.
*The mean antibody titer peaked at week 6 and was reduced by 55% by week 30. Three hundred and sixty patients (38%) had low titer antibodies (<625) to exenatide at 30 weeks.
*The level of glycemic control ([[HbA1c]]) in these patients was generally comparable to that observed in the 534 patients (56%) without antibody titers. An additional 59 patients (6%) had higher titer antibodies (≥625) at 30 weeks.
*Of these patients, 32 (3% overall) had an attenuated glycemic response to BYETTA; the remaining 27 (3% overall) had a glycemic response comparable to that of patients without antibodies.
*In the 16-week trial of BYETTA add-on to [[thiazolidinediones]], with or without [[metformin]], 36 patients (31%) had low titer antibodies to exenatide at 16 weeks.
*The level of glycemic control in these patients was generally comparable to that observed in the 69 patients (60%) without antibody titer. An additional 10 patients (9%) had higher titer antibodies at 16 weeks.
*Of these patients, 4 (4% overall) had an attenuated glycemic response to BYETTA; the remaining 6 (5% overall) had a glycemic response comparable to that of patients without antibodies.
*In the 24-week trial of BYETTA used as monotherapy, 40 patients (28%) had low titer antibodies to exenatide at 24 weeks.
*The level of glycemic control in these patients was generally comparable to that observed in the 101 patients (70%) without antibody titers. An additional 3 patients (2%) had higher titer antibodies at 24 weeks.
*Of these patients, 1 (1% overall) had an attenuated glycemic response to BYETTA; the remaining 2 (1% overall) had a glycemic response comparable to that of patients without antibodies.
*Antibodies to exenatide were not assessed in the 30-week trial of BYETTA used in combination with [[insulin]] glargine.
*Two hundred and ten patients with antibodies to exenatide in the BYETTA clinical trials were tested for the presence of cross-reactive antibodies to GLP-1 and/or glucagon.
*No treatment-emergent cross-reactive antibodies were observed across the range of titers.

====Other Adverse Reactions====

<i>Monotherapy</i>

For the 24-week placebo-controlled study of BYETTA used as a monotherapy, Table 2 summarizes adverse reactions (excluding [[hypoglycemia]]) occurring with an incidence ≥2% and occurring more frequently in BYETTA-treated patients compared with placebo-treated patients.

[[File:Exenatide_adverse_02.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

Adverse reactions reported in ≥1.0% to <2.0% of patients receiving BYETTA and reported more frequently than with placebo included decreased appetite, [[diarrhea]], and [[dizziness]]. The most frequently reported adverse reaction associated with BYETTA, [[nausea]], occurred in a dose-dependent fashion.
Two of the 155 patients treated with BYETTA withdrew due to adverse reactions of [[headache]] and [[nausea]]. No placebo-treated patients withdrew due to adverse reactions.

<i>Combination Therapy</i>

'''Add-On to Metformin and/or Sulfonylurea'''

In the three 30-week controlled trials of BYETTA add-on to [[metformin]] and/or [[sulfonylurea]], adverse reactions (excluding [[hypoglycemia]]) with an incidence ≥2% and occurring more frequently in BYETTA-treated patients compared with placebo-treated patients ] are summarized in Table 3.

[[File:Exenatide_adverse_03.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

Adverse reactions reported in ≥1.0% to <2.0% of patients receiving BYETTA and reported more frequently than with placebo included decreased appetite. [[nausea]] was the most frequently reported adverse reaction and occurred in a dose-dependent fashion. With continued therapy, the frequency and severity decreased over time in most of the patients who initially experienced [[nausea]]. Patients in the long-term uncontrolled open-label extension studies at 52 weeks reported no new types of adverse reactions than those observed in the 30-week controlled trials.
The most common adverse reactions leading to withdrawal for BYETTA-treated patients were [[nausea]] (3% of patients) and [[vomiting]] (1%). For placebo-treated patients, <1% withdrew due to [[nausea]] and none due to [[vomiting]].

'''Add-On to Thiazolidinedione with or without Metformin'''

For the 16-week placebo-controlled study of BYETTA add-on to a thiazolidinedione, with or without metformin, Table 4 summarizes the adverse reactions (excluding hypoglycemia) with an incidence of ≥2% and occurring more frequently in BYETTA-treated patients compared with placebo-treated patients.

[[File:Exenatide_adverse_04.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

Adverse reactions reported in ≥1.0% to <2.0% of patients receiving BYETTA and reported more frequently than with placebo included decreased appetite. Chills (n=4) and injection-site reactions (n=2) occurred only in BYETTA-treated patients. The two patients who reported an injection-site reaction had high titers of antibodies to exenatide. Two serious adverse events (chest pain and chronic hypersensitivity pneumonitis) were reported in the BYETTA arm. No serious adverse events were reported in the placebo arm.
The most common adverse reactions leading to withdrawal for BYETTA-treated patients were [[nausea]] (9%) and [[vomiting]] (5%). For placebo-treated patients, <1% withdrew due to [[nausea]].

'''Add-On to Insulin Glargine with or without Metformin and/or Thiazolidinedione'''

For the 30-week placebo-controlled study of BYETTA as add-on to insulin glargine with or without oral antihyperglycemic medications, Table 5 summarizes adverse reactions (excluding [[hypoglycemia]]) occurring with an incidence ≥2% and occurring more frequently in BYETTA-treated patients compared with placebo-treated patients.

[[File:Exenatide_adverse_05.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

The most frequently reported adverse reactions leading to withdrawal for BYETTA-treated patients were [[nausea]] (5.1%) and [[vomiting]] (2.9%). No placebo-treated patients withdrew due to [[nausea]] or [[vomiting]].
|postmarketing=The following additional adverse reactions have been reported during post approval use of BYETTA. Because these events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.<br>
<i>Allergy/Hypersensitivity</i>: injection-site reactions, generalized [[pruritus]] and/or [[urticaria]], macular or [[papular rash]], [[angioedema]], [[anaphylactic reaction]] .<br>
<i>Drug Interactions</i>: International normalized ratio (INR) increased with concomitant [[warfarin]] use sometimes associated with bleeding.
<br>
<i>Gastrointestinal</i>: [[nausea]], [[vomiting]], and/or [[diarrhea]] resulting in [[dehydration]]; abdominal distension, [[abdominal pain]], [[eructation]], [[constipation]], [[flatulence]], [[acute pancreatitis]], hemorrhagic and necrotizing [[pancreatitis]] sometimes resulting in death.
<i>Neurologic</i>: [[dysgeusia]]; [[somnolence]].
<br>
<i>Renal and Urinary Disorders</i>: altered renal function, including increased serum creatinine, renal impairment, worsened [[chronic renal failure]] or [[acute renal failure]] (sometimes requiring [[hemodialysis]]), [[kidney transplant]] and kidney transplant dysfunction.<br>
<i>Skin and Subcutaneous Tissue Disorders</i>: [[alopecia]].
|drugInteractions=====Orally Administered Drugs====

The effect of BYETTA to slow gastric emptying can reduce the extent and rate of absorption of orally administered drugs. BYETTA should be used with caution in patients receiving oral medications that have narrow therapeutic index or require rapid gastrointestinal absorption . For oral medications that are dependent on threshold concentrations for efficacy, such as [[contraceptives]] and [[antibiotics]], patients should be advised to take those drugs at least 1 hour before BYETTA injection. If such drugs are to be administered with food, patients should be advised to take them with a meal or snack when BYETTA is not administered .

====Warfarin====

There are post marketing reports of increased INR sometimes associated with bleeding, with concomitant use of [[warfarin]] and BYETTA . In a drug interaction study, BYETTA did not have a significant effect on INR . In patients taking [[warfarin]], prothrombin time should be monitored more frequently after initiation or alteration of BYETTA therapy. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on [[warfarin]].
|FDAPregCat=C
|useInPregnancyFDA=There are no adequate and well-controlled studies of BYETTA use in pregnant women. In animal studies, exenatide caused [[cleft palate]], irregular skeletal ossification and an increased number of neonatal deaths. BYETTA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Female mice given SC doses of 6, 68, or 760 mcg/kg/day beginning 2 weeks prior to and throughout mating until gestation day 7 had no adverse fetal effects. At the maximal dose, 760 mcg/kg/day, systemic exposures were up to 390 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.
In developmental toxicity studies, pregnant animals received exenatide subcutaneously during organogenesis. Specifically, fetuses from pregnant rabbits given SC doses of 0.2, 2, 22, 156, or 260 mcg/kg/day from gestation day 6 through 18 experienced irregular skeletal ossifications from exposures 12 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC. Moreover, fetuses from pregnant mice given SC doses of 6, 68, 460, or 760 mcg/kg/day from gestation day 6 through 15 demonstrated reduced fetal and neonatal growth, [[cleft palate]] and skeletal effects at systemic exposure 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.
Lactating mice given SC doses of 6, 68, or 760 mcg/kg/day from gestation day 6 through lactation day 20 (weaning), experienced an increased number of neonatal deaths. Deaths were observed on postpartum days 2 to 4 in dams given 6 mcg/kg/day, a systemic exposure 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.
Pregnancy Registry
A Pregnancy Registry has been implemented to monitor pregnancy outcomes of women exposed to exenatide during pregnancy. Physicians are encouraged to register patients by calling 1-800-633-9081.
|useInNursing=It is not known whether exenatide is excreted in human milk. However, exenatide is present at low concentrations (less than or equal to 2.5% of the concentration in maternal plasma following subcutaneous dosing) in the milk of lactating mice. Many drugs are excreted in human milk and because of the potential for clinically significant adverse reactions in nursing infants from exenatide, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account these potential risks against the glycemic benefits to the lactating woman. Caution should be exercised when BYETTA is administered to a nursing woman.
|useInPed=Safety and effectiveness of BYETTA have not been established in pediatric patients.
|useInGeri=Population pharmacokinetic analysis of patients ranging from 22 to 73 years of age suggests that age does not influence the pharmacokinetic properties of exenatide. BYETTA was studied in 282 patients 65 years of age or older and in 16 patients 75 years of age or older. No differences in safety or effectiveness were observed between these patients and younger patients. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in the elderly based on renal function.
|useInRenalImpair=BYETTA is not recommended for use in patients with end-stage renal disease or severe renal impairment (creatinine clearance <30 mL/min) and should be used with caution in patients with renal transplantation. No dosage adjustment of BYETTA is required in patients with mild renal impairment (creatinine clearance 50-80 mL/min). Caution should be applied when initiating or escalating doses of BYETTA from 5 to 10 mcg in patients with moderate renal impairment (creatinine clearance 30-50 mL/min)
|useInHepaticImpair=No pharmacokinetic study has been performed in patients with a diagnosis of acute or chronic hepatic impairment. Because exenatide is cleared primarily by the kidney, hepatic dysfunction is not expected to affect blood concentrations of eventide.
|administration=Injection SC
|monitoring=FDA package insert for abcixmab contains no information regarding drug monitoring.
|IVCompat=There is limited information about the IV compatibility.
|overdose=In a clinical study of BYETTA, three patients with [[type 2 diabetes]] each experienced a single overdose of 100 mcg SC (10 times the maximum recommended dose). Effects of the overdoses included severe [[nausea]], severe [[vomiting]], and rapidly declining blood glucose concentrations. One of the three patients experienced severe [[hypoglycemia]] requiring parenteral glucose administration. The three patients recovered without complication. In the event of overdose, appropriate supportive treatment should be initiated according to the patient's clinical signs and symptoms.
|drugBox={{Drugbox2
| verifiedrevid = 464189825
| IUPAC_name = ''N''-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)<br>quinazolin-4-amine
| image = Erlotinib Structural Formulae.png
| width = 250
| image2 = Erlotinib-1m17-3D-balls.png


| tradename = Tarceva
| Drugs.com = {{drugs.com|monograph|erlotinib}}
| MedlinePlus = a605008
| licence_EU = Tarceva
| licence_US = Erlotinib
| pregnancy_US = D
| legal_UK = POM
| legal_US = Rx-only
| routes_of_administration = Oral [[Tablet (pharmacy)|tablets]]


| bioavailability = 59%
| protein_bound = 95%
| metabolism = [[Liver|Hepatic]] (mainly [[CYP3A4]], less [[CYP1A2]])
| elimination_half-life = 36.2 hrs ([[median]])
| excretion = >98% as metabolites, of which >90% via [[faeces]], 9% via [[urine]]


| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 183321-74-6
| ATC_prefix = L01
| ATC_suffix = XE03
| PubChem = 176870
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00530
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 154044
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = J4T82NDH7E
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D07907
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 114785
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 553


| C=22 | H=23 | N=3 | O=4
| molecular_weight = 393.436 g/mol
| smiles = COCCOc1cc2c(cc1OCCOC)ncnc2Nc3cccc(c3)C#C
| InChI = 1/C22H23N3O4/c1-4-16-6-5-7-17(12-16)25-22-18-13-20(28-10-8-26-2)21(29-11-9-27-3)14-19(18)23-15-24-22/h1,5-7,12-15H,8-11H2,2-3H3,(H,23,24,25)
| InChIKey = AAKJLRGGTJKAMG-UHFFFAOYAM
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C22H23N3O4/c1-4-16-6-5-7-17(12-16)25-22-18-13-20(28-10-8-26-2)21(29-11-9-27-3)14-19(18)23-15-24-22/h1,5-7,12-15H,8-11H2,2-3H3,(H,23,24,25)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = AAKJLRGGTJKAMG-UHFFFAOYSA-N
}}
|mechAction=Incretins, such as glucagon-like peptide-1 (GLP-1), enhance glucose-dependent [[insulin]] secretion and exhibit other anti hyperglycemic actions following their release into the circulation from the gut. BYETTA is a GLP-1 receptor agonist that enhances glucose-dependent [[insulin]] secretion by the pancreatic beta-cell, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying.
The amino acid sequence of exenatide partially overlaps that of human GLP-1. Exenatide has been shown to bind and activate the human GLP-1 receptor in vitro. This leads to an increase in both glucose-dependent synthesis of [[insulin]], and in vivo secretion of insulin from pancreatic beta cells, by mechanisms involving cyclic AMP and/or other intracellular signaling pathways.
BYETTA improves glycemic control by reducing fasting and postprandial glucose concentrations in patients with [[type 2 diabetes]] through the actions described below.
|structure=BYETTA (exenatide) is a synthetic peptide that was originally identified in the lizard Heloderma suspectum. Exenatide differs in chemical structure and pharmacological action from insulin, sulfonylureas (including D-phenylalanine derivatives and meglitinides), [[biguanides]], [[thiazolidinediones]], [[alpha-glucosidase inhibitors]], [[amylinomimetics]] and dipeptidyl peptidase-4 inhibitors.
Exenatide is a 39-amino acid peptide amide. Exenatide has the empirical formula C184H282N50O60S and molecular weight of 4186.6 Daltons. The amino acid sequence for exenatide is shown below.
H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
BYETTA is supplied for SC injection as a sterile, preserved isotonic solution in a glass cartridge that has been assembled in a pen-injector (pen). Each milliliter (mL) contains 250 micrograms (mcg) synthetic exenatide, 2.2 mg metacresol as an antimicrobial preservative, mannitol as a tonicity-adjusting agent, and glacial acetic acid and sodium acetate trihydrate in water for injection as a buffering solution at pH 4.5. Two prefilled pens are available to deliver unit doses of 5 mcg or 10 mcg. Each prefilled pen will deliver 60 doses to provide for 30 days of twice daily administration (BID).
|PD=Glucose-Dependent Insulin Secretion

BYETTA has acute effects on pancreatic beta-cell responsiveness to glucose leading to insulin release predominantly in the presence of elevated glucose concentrations. This insulin secretion subsides as blood glucose concentrations decrease and approach [[euglycemia]]. However, BYETTA does not impair the normal glucagon response to [[hypoglycemia]].

First-Phase Insulin Response

In healthy individuals, robust insulin secretion occurs during the first 10 minutes following intravenous (IV) glucose administration. This secretion, known as the "first-phase insulin response," is characteristically absent in patients with type 2 diabetes. The loss of the first-phase insulin response is an early beta-cell defect in [[type 2 diabetes]]. Administration of BYETTA at therapeutic plasma concentrations restored first-phase insulin response to an IV bolus of glucose in patients with type 2 diabetes (Figure 1). Both first-phase insulin secretion and second-phase insulin secretion were significantly increased in patients with type 2 diabetes treated with BYETTA compared with saline (p<0.001 for both).

[[File:Exenatide_PD_01.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

Glucagon Secretion

In patients with type 2 diabetes, BYETTA moderates glucagon secretion and lowers serum glucagon concentrations during periods of [[hyperglycemia]]. Lower glucagon concentrations lead to decreased hepatic glucose output and decreased insulin demand.

Gastric Emptying

BYETTA slows gastric emptying, thereby reducing the rate at which meal-derived glucose appears in the circulation.

Food Intake

In both animals and humans, administration of exenatide has been shown to reduce food intake.

Postprandial Glucose

In patients with [[type 2 diabetes]], BYETTA reduces postprandial plasma glucose concentrations (Figure 2).

[[File:Exenatide_PD_02.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

Fasting Glucose

In a single-dose crossover study in patients with [[type 2 diabetes]] and fasting [[hyperglycemia]], immediate insulin release followed injection of BYETTA. Plasma glucose concentrations were significantly reduced with BYETTA compared with placebo (Figure 3).

[[File:Exenatide_PD_03.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

Cardiac Electrophysiology

The effect of exenatide 10 µg subcutaneously on QTc interval was evaluated in a randomized, placebo-, and active-controlled (moxifloxacin 400 mg) crossover thorough QTc study in 62 healthy subjects. In this study with demonstrated ability to detect small effects, the upper bound of the 90% confidence interval for the largest placebo-adjusted, baseline-corrected QTc was below 10 msec. Thus, BYETTA (10 mcg single dose) was not associated with clinically meaningful prolongation of the QTc interval.
|PK='''Absorption'''

Following SC administration to patients with [[type 2 diabetes]], exenatide reaches median peak plasma concentrations in 2.1 hours. The mean peak exenatide concentration (Cmax) was 211 pg/mL and overall mean area under the time-concentration curve (AUC0-inf) was 1036 pg∙h/mL following SC administration of a 10-mcg dose of BYETTA. Exenatide exposure (AUC) increased proportionally over the therapeutic dose range of 5 to 10 mcg. The Cmax values increased less than proportionally over the same range. Similar exposure is achieved with SC administration of BYETTA in the abdomen, thigh, or upper arm.

'''Distribution'''

The mean apparent volume of distribution of exenatide following SC administration of a single dose of BYETTA is 28.3 L.

'''Metabolism and Elimination'''

Nonclinical studies have shown that exenatide is predominantly eliminated by glomerular filtration with subsequent proteolytic degradation. The mean apparent clearance of exenatide in humans is 9.1 L/hour and the mean terminal half-life is 2.4 hours. These pharmacokinetic characteristics of exenatide are independent of the dose. In most individuals, exenatide concentrations are measurable for approximately 10 hours post-dose.

'''Drug Interactions'''

<i>Acetaminophen</i>

When 1000 mg [[acetaminophen]] elixir was given with 10 mcg BYETTA (0 hour) and 1 hour, 2 hours, and 4 hours after BYETTA injection, [[acetaminophen]] AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; Cmax was decreased by 37%, 56%, 54%, and 41%, respectively; Tmax was increased from 0.6 hour in the control period to 0.9 hour, 4.2 hours, 3.3 hours, and 1.6 hours, respectively. [[acetaminophen]] AUC, Cmax and Tmax were not significantly changed when [[acetaminophen]] was given 1 hour before BYETTA injection.

<i>Digoxin</i>

Administration of repeated doses of BYETTA (10 mcg BID) 30 minutes before oral [[digoxin]] (0.25 mg once daily) decreased the Cmax of [[digoxin]] by 17% and delayed the Tmax of [[digoxin]] by approximately 2.5 hours; however, the overall steady-state pharmacokinetic exposure (e.g., AUC) of [[digoxin]] was not changed.

<i>Lovastatin</i>

Administration of BYETTA (10 mcg BID) 30 minutes before a single oral dose of [[lovastatin]] (40 mg) decreased the AUC and Cmax of [[lovastatin]] by approximately 40% and 28%, respectively, and delayed the Tmax by about 4 hours compared with [[lovastatin]] administered alone. In the 30-week controlled clinical trials of BYETTA, the use of BYETTA in patients already receiving [[HMG CoA reductase]] inhibitors was not associated with consistent changes in lipid profiles compared to baseline.

<i>Lisinopril</i>

In patients with mild to moderate hypertension stabilized on [[lisinopril]] (5-20 mg/day), BYETTA (10 mcg BID) did not alter steady-state Cmax or AUC of [[lisinopril]]. [[lisinopril]] steady-state Tmax was delayed by 2 hours. There were no changes in 24-hour mean systolic and diastolic blood pressure.

<i>Oral Contraceptives</i>

The effect of BYETTA (10 mcg BID) on single and on multiple doses of a combination [[oral contraceptive]] (30 mcg ethinyl estradiol plus 150 mcg levonorgestrel) was studied in healthy female subjects. Repeated daily doses of the oral contraceptive (OC) given 30 minutes after BYETTA administration decreased the Cmax of ethinyl estradiol and levonorgestrel by 45% and 27%, respectively and delayed the Tmax of ethinyl estradiol and levonorgestrel by 3.0 hours and 3.5 hours, respectively, as compared to the oral contraceptive administered alone. Administration of repeated daily doses of the OC one hour prior to BYETTA administration decreased the mean Cmax of ethinyl estradiol by 15% but the mean Cmax of levonorgestrel was not significantly changed as compared to when the OC was given alone. BYETTA did not alter the mean trough concentrations of levonorgestrel after repeated daily dosing of the oral contraceptive for both regimens. However, the mean trough concentration of ethinyl estradiol was increased by 20% when the OC was administered 30 minutes after BYETTA administration injection as compared to when the OC was given alone. The effect of BYETTA on OC pharmacokinetics is confounded by the possible food effect on OC in this study. Therefore, OC products should be administered at least one hour prior to BYETTA injection.

<i>warfarin</i>

Administration of [[warfarin]] (25 mg) 35 minutes after repeated doses of BYETTA (5 mcg BID on days 1-2 and 10 mcg BID on days 3-9) in healthy volunteers delayed [[warfarin]] Tmax by approximately 2 hours. No clinically relevant effects on Cmax or AUC of S- and R-enantiomers of [[warfarin]] were observed. BYETTA did not significantly alter the pharmacodynamic properties (e.g., international normalized ratio) of [[warfarin]] [see Drug Interactions (7.2)].

'''Specific Populations'''

<i>Renal Impairment</i>

Pharmacokinetics of exenatide was studied in subjects with normal, mild, or moderate renal impairment and subjects with end-stage renal disease. In subjects with mild to moderate renal impairment (creatinine clearance 30-80 mL/min), exenatide exposure was similar to that of subjects with normal renal function. However, in subjects with end-stage renal disease receiving dialysis, mean exenatide exposure increased by 3.37-fold compared to that of subjects with normal renal function.

<i>Hepatic Impairment</i>
No pharmacokinetic study has been performed in patients with a diagnosis of acute or chronic hepatic impairment.

<i>Age</i>

Population pharmacokinetic analysis of patients ranging from 22 to 73 years of age suggests that age does not influence the pharmacokinetic properties of exenatide [see Use in Specific Population (8.5)].

<i>Gender</i>

Population pharmacokinetic analysis of male and female patients suggests that gender does not influence the distribution and elimination of exenatide.

<i>Race</i>

Population pharmacokinetic analysis of samples from Caucasian, Hispanic, Asian, and Black patients suggests that race has no significant influence on the pharmacokinetics of exenatide.

<i>Body Mass Index</i>

Population pharmacokinetic analysis of patients with body mass indices (BMI) ≥30 kg/m2 and <30 kg/m2 suggests that BMI has no significant effect on the pharmacokinetics of exenatide.
|nonClinToxic=====Carcinogenesis, Mutagenesis, Impairment of Fertility====

A 104-week carcinogenicity study was conducted in male and female rats at doses of 18, 70, or 250 mcg/kg/day administered by bolus SC injection. Benign thyroid C-cell adenomas were observed in female rats at all exenatide doses. The incidences in female rats were 8% and 5% in the two control groups and 14%, 11%, and 23% in the low-, medium-, and high-dose groups with systemic exposures of 5, 22, and 130 times, respectively, the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on plasma area under the curve (AUC).
In a 104-week carcinogenicity study in mice at doses of 18, 70, or 250 mcg/kg/day administered by bolus SC injection, no evidence of tumors was observed at doses up to 250 mcg/kg/day, a systemic exposure up to 95 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.
Exenatide was not mutagenic or clastogenic, with or without metabolic activation, in the Ames bacterial mutagenicity assay or chromosomal aberration assay in Chinese hamster ovary cells. Exenatide was negative in the in vivo mouse micronucleus assay.
In mouse fertility studies with SC doses of 6, 68, or 760 mcg/kg/day, males were treated for 4 weeks prior to and throughout mating, and females were treated 2 weeks prior to mating and throughout mating until gestation day 7. No adverse effect on fertility was observed at 760 mcg/kg/day, a systemic exposure 390 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.

====Reproductive and Developmental Toxicology====

In female mice given SC doses of 6, 68, or 760 mcg/kg/day beginning 2 weeks prior to and throughout mating until gestation day 7, there were no adverse fetal effects at doses up to 760 mcg/kg/day, systemic exposures up to 390 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.
In pregnant mice given SC doses of 6, 68, 460, or 760 mcg/kg/day from gestation day 6 through 15 (organogenesis), [[cleft palate]] (some with holes) and irregular fetal skeletal ossification of rib and skull bones were observed at 6 mcg/kg/day, a systemic exposure 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.
In pregnant rabbits given SC doses of 0.2, 2, 22, 156, or 260 mcg/kg/day from gestation day 6 through 18 (organogenesis), irregular fetal skeletal ossifications were observed at 2 mcg/kg/day, a systemic exposure 12 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.
In pregnant mice given SC doses of 6, 68, or 760 mcg/kg/day from gestation day 6 through lactation day 20 (weaning), an increased number of neonatal deaths was observed on postpartum days 2-4 in dams given 6 mcg/kg/day, a systemic exposure 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.
|clinicalStudies=BYETTA has been studied as monotherapy and in combination with [[metformin]], a [[sulfonylurea]], a [[thiazolidinedione]], a combination of [[metformin]] and a [[sulfonylurea]], a combination of [[metformin]] and a [[thiazolidinedione]], or in combination with [[insulin]] glargine with or without [[metformin]] and/or [[thiazolidinedione]].

====Monotherapy====

In a randomized, double-blind, placebo-controlled trial of 24 weeks duration, BYETTA 5 mcg BID (n=77), BYETTA 10 mcg BID (n=78), or placebo BID (n=77) was used as monotherapy in patients with entry [[HbA1c]] ranging from 6.5% to 10%. All patients assigned to BYETTA initially received 5 mcg BID for 4 weeks. After 4 weeks, those patients either continued to receive BYETTA 5 mcg BID or had their dose increased to 10 mcg BID. Patients assigned to placebo received placebo BID throughout the trial. BYETTA or placebo was injected subcutaneously before the morning and evening meals. The majority of patients (68%) were Caucasian, 26% West Asian, 3% Hispanic, 3% Black, and 0.4% East Asian.
The primary endpoint was the change in [[HbA1c]] from baseline to Week 24 (or the last value at time of early discontinuation). Compared to placebo, BYETTA 5 mcg BID and 10 mcg BID resulted in statistically significant reductions in [[HbA1c]] from baseline at Week 24 (Table 6).

[[File:Exenatide_clinical studies_01.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

====Combination Therapy with Oral Antihyperglycemic Medicines====

Three 30-week, double-blind, placebo-controlled trials were conducted to evaluate the safety and efficacy of BYETTA in patients with [[type 2 diabetes]] whose glycemic control was inadequate with [[metformin]] alone, a [[sulfonylurea]] alone, or [[metformin]] in combination with a [[sulfonylurea]]. In addition, a 16-week, placebo-controlled trial was conducted where BYETTA was added to existing [[thiazolidinedione]] ([[pioglitazone]] or [[rosiglitazone]]) treatment, with or without [[metformin]], in patients with [[type 2 diabetes]] with inadequate glycemic control.
In the 30-week trials, after a 4-week placebo lead-in period, patients were randomly assigned to receive BYETTA 5 mcg bid, BYETTA 10 mcg bid, or placebo bid before the morning and evening meals, in addition to their existing oral anti diabetic agent. All patients assigned to BYETTA initially received 5 mcg bid for 4 weeks. After 4 weeks, those patients either continued to receive BYETTA 5 mcg BID or had their dose increased to 10 mcg bid. Patients assigned to placebo received placebo bid throughout the study. A total of 1446 patients were randomized in the three 30-week trials: 991 (69%) were Caucasian, 224 (16%) Hispanic, and 174 (12%) Black. Mean [[HbA1c]] values at baseline for the trials ranged from 8.2% to 8.7%.
In the placebo-controlled trial of 16 weeks duration, BYETTA (n=121) or placebo (n=112) was added to existing [[thiazolidinedione]] ([[pioglitazone]] or [[rosiglitazone]]) treatment, with or without [[metformin]]. Randomization to BYETTA or placebo was stratified based on whether the patients were receiving [[metformin]]. BYETTA treatment was initiated at a dose of 5 mcg bid for 4 weeks then increased to 10 mcg bid for 12 more weeks. Patients assigned to placebo received placebo BID throughout the study. BYETTA or placebo was injected subcutaneously before the morning and evening meals. In this trial, 79% of patients were taking a [[thiazolidinedione]] and [[metformin]] and 21% were taking a [[thiazolidinedione]] alone. The majority of patients (84%) were Caucasian, 8% Hispanic, and 3% Black. The mean baseline [[HbA1c]] values were 7.9% for BYETTA and placebo.
The primary endpoint in each study was the mean change in [[HbA1c]] from baseline to study end (or early discontinuation). Table 7 summarizes the study results for the 30- and 16-week clinical trials.

[[File:Exenatide_clinical studies_02.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

[[File:Exenatide_clinical studies_03.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

HbA1c

The addition of BYETTA to a regimen of [[metformin]], a [[sulfonylurea]], or both, resulted in statistically significant reductions from baseline in [[HbA1c]] compared with patients receiving placebo added to these agents in the three controlled trials (Table 7).
In the 16-week trial of BYETTA add-on to [[thiazolidinediones]], with or without [[metformin]], BYETTA resulted in statistically significant reductions from baseline in [[HbA1c]] compared with patients receiving placebo (Table 7).

Postprandial Glucose

Postprandial glucose was measured after a mixed meal tolerance test in 9.5% of patients participating in the 30-week add-on to [[metformin]], add-on to [[sulfonylurea]], and add-on to [[metformin]] in combination with [[sulfonylurea]] clinical trials. In this pooled subset of patients, BYETTA reduced postprandial plasma glucose concentrations in a dose-dependent manner. The mean (SD) change in 2-hour postprandial glucose concentration following administration of BYETTA at Week 30 relative to baseline was −63 (65) mg/dL for 5 mcg BID (n=42), −71 (73) mg/dL for 10 mcg BID (n=52), and +11 (69) mg/dL for placebo BID (n=44).

====Combination with Insulin Glargine====

A 30-week, double-blind, placebo-controlled trial was conducted to evaluate the efficacy and safety of BYETTA (n=137) versus placebo (n=122) when added to titrated [[insulin]] glargine, with or without [[metformin]] and/or [[thiazolidinedione]], in patients with [[type 2 diabetes]] with inadequate glycemic control.
All patients assigned to BYETTA initially received 5 mcg bid for 4 weeks. After 4 weeks, those patients assigned to BYETTA had their dose increased to 10 mcg bid. Patients assigned to placebo received placebo bid throughout the trial. BYETTA or placebo was injected subcutaneously before the morning and evening meals. Patients with an [[HbA1c]] ≤8.0% decreased their prestudy dose of [[insulin]] glargine by 20% and patients with an [[HbA1c]] ≥8.1% maintained their current dose of [[insulin]] glargine. Five weeks after initiating randomized treatment, [[insulin]] doses were titrated with guidance from the investigator toward predefined fasting glucose targets according to the dose titration algorithm provided in Table 9. The majority of patients (78%) were Caucasian, 10% American Indian or Alaska Native, 9% Black, 3% Asian, and 0.8% of multiple origins.
The primary endpoint was the change in [[HbA1c]] from baseline to Week 30. Compared to placebo, BYETTA 10 mcg bid resulted in statistically significant reductions in [[HbA1c]] from baseline at Week 30 (Table 8) in patients receiving titrated [[insulin]] glargine.

[[File:Exenatide_clinical studies_04.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

[[File:Exenatide_clinical studies_05.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|howSupplied=BYETTA is supplied as a sterile solution for subcutaneous injection containing 250 mcg/mL exenatide.
The following packages are available:

5 mcg per dose, 60 doses, 1.2 mL prefilled pen, NDC 66780-210-07

10 mcg per dose, 60 doses, 2.4 mL prefilled pen, NDC 66780-212-01
|storage=* Prior to first use, BYETTA must be stored refrigerated at 36°F to 46°F (2°C to 8°C).
* After first use, BYETTA can be kept at a temperature not to exceed 77°F (25°C).
* Do not freeze. Do not use BYETTA if it has been frozen.
* BYETTA should be protected from light.
* The pen should be discarded 30 days after first use, even if some drug remains in the pen.
* Use a puncture-resistant container to discard the needles. Do not reuse or share needles.
* BYETTA should not be used past the expiration date.
|fdaPatientInfo=[[File:Exenatide_patient information_01.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|alcohol=Alcohol-Exenatide interaction has not been established. Talk to your doctor about the effects of taking [[alcohol]] with this medication.
|brandNames=* Byetta
* Bydureon
|lookAlike=There is limited information about the Look-alike drug names.
}}
{{LabelImage
|fileName=Exenatide_label_01.jpg
}}
{{LabelImage
|fileName=Exenatide_label_02.jpg
}}
{{LabelImage
|fileName=Exenatide_panel_01.png
}}
{{LabelImage
|fileName=Exenatide_panel_02.png
}}

Exenatide

2015-03-19T19:47:40Z

Sree Teja Yelamanchili:

{{DrugProjectFormSinglePage
|authorTag={{SS}}
|genericName=Exenatide
|aOrAn=a
|drugClass=[[GLP-1]] receptor agonist
|indicationType=treatment
|indication=[[type 2 diabetes mellitus]]
|adverseReactions=injection site mass, injection site [[pruritus]], [[injection site reaction]], [[hypoglycemia]], [[constipation]], [[diarrhea]], [[indigestion]], [[nausea]], [[vomiting]], antibody development, [[asthenia]], [[dizziness]], [[nervousness]], [[headache]]
|blackBoxWarningTitle=<b><span style="color:#FF0000;">TITLE</span></b>
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)
|fdaLIADAdult=<H4>Type 2 Diabetes Mellitus</H4>

* Dosing information
:* '''5 mg injection SC bid''' at any time within the 60-minute period before the morning and evening meals (or before the two main meals of the day, approximately 6 hours or more apart)
:* BYETTA should not be administered after a meal.
:* Based on clinical response, the dose of BYETTA can be increased to '''10 mcg SC injection bid''' after 1 month of therapy.
::* Initiation with '''5 mcg''' reduces the incidence and severity of gastrointestinal side effects. Each dose should be administered as a subcutaneous (SC) injection in the thigh, abdomen, or upper arm. Do not mix BYETTA with insulin. Do not transfer BYETTA from the pen to a syringe or a vial. No data are available on the safety or efficacy of intravenous or intramuscular injection of BYETTA.

<h4>Important limitations of use</h4>

* BYETTA is not a substitute for insulin. BYETTA should not be used for the treatment of [[type 1 diabetes]] or diabetic [[ketoacidosis]], as it would not be effective in these settings.
:* The concurrent use of BYETTA with prandial [[insulin]] has not been studied and cannot be recommended.
:* Based on post marketing data BYETTA has been associated with [[acute pancreatitis]], including fatal and non-fatal hemorrhagic or [[necrotizing pancreatitis]]. BYETTA has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk for [[pancreatitis]] while using BYETTA. Other anti diabetic therapies should be considered in patients with a history of pancreatitis.
|offLabelAdultGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of exenatide in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of exenatide in adult patients.
|fdaLIADPed=Safety and effectiveness of BYETTA have not been established in pediatric patients.
|offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of exenatide in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of exenatide in pediatric patients.
|contraindications=====Hypersensitivity====

BYETTA is contraindicated in patients with prior severe [[hypersensitivity]] reactions to exenatide or to any of the product components.
|warnings=====Never Share a BYETTA Pen between Patients====

BYETTA pens should never be shared between patients, even if the needle is changed. Pen-sharing poses a risk for transmission of blood-borne pathogens.

====Acute Pancreatitis====

*Based on post marketing data, BYETTA has been associated with [[acute pancreatitis]], including fatal and non-fatal hemorrhagic or [[necrotizing pancreatitis]].
*After initiation of BYETTA, and after dose increases, observe patients carefully for signs and symptoms of [[pancreatitis]] (including persistent severe [[abdominal pain]], sometimes radiating to the back, which may or may not be accompanied by [[vomiting]]).
*If [[pancreatitis]] is suspected, BYETTA should promptly be discontinued and appropriate management should be initiated. If [[pancreatitis]] is confirmed, BYETTA should not be restarted.
*Consider anti diabetic therapies other than BYETTA in patients with a history of [[pancreatitis]].

====Use with Medications Known to Cause Hypoglycemia====

*The risk of [[hypoglycemia]] is increased when BYETTA is used in combination with a [[sulfonylurea]]. Therefore, patients receiving BYETTA and a [[sulfonylurea]] may require a lower dose of the [[sulfonylurea]] to reduce the risk of [[hypoglycemia]].
*When BYETTA is used in combination with [[insulin]], the dose of insulin should be evaluated. In patients at increased risk of [[hypoglycemia]] consider reducing the dose of [[insulin]].
*The concurrent use of BYETTA with prandial [[insulin]] has not been studied and cannot be recommended. It is also possible that the use of BYETTA with other glucose-independent [[insulin]] secretagogues (e.g., meglitinides) could increase the risk of [[hypoglycemia]].

====Renal Impairment====

*BYETTA should not be used in patients with severe [[renal impairment]] (creatinine clearance <30 mL/min) or [[end-stage renal disease]] and should be used with caution in patients with renal transplantation .
*In patients with end-stage renal disease receiving [[dialysis]], single doses of BYETTA 5 mcg were not well tolerated due to gastrointestinal side effects.
*Because BYETTA may induce [[nausea]] and [[vomiting]] with transient [[hypovolemia]], treatment may worsen renal function. Caution should be applied when initiating or escalating doses of BYETTA from 5 to 10 mcg in patients with moderate [[renal impairment]] (creatinine clearance 30-50 mL/min).
*There have been post marketing reports of altered renal function, including increased serum creatinine, [[renal impairment]], worsened [[chronic renal failure]] and [[acute renal failure]], sometimes requiring [[hemodialysis]] or kidney transplantation.
*Some of these events occurred in patients receiving one or more pharmacologic agents known to affect renal function or [[hydration]] status, such as [[angiotensin converting enzyme inhibitors]], [[nonsteroidal anti-inflammatory drugs]], or [[diuretics]].
*Some events occurred in patients who had been experiencing [[nausea]], [[vomiting]], or [[diarrhea]], with or without [[dehydration]]. Reversibility of altered renal function has been observed in many cases with supportive treatment and discontinuation of potentially causative agents, including BYETTA.
*Exenatide has not been found to be directly nephrotoxic in preclinical or clinical studies.

====Gastrointestinal Disease====

*BYETTA has not been studied in patients with severe gastrointestinal disease, including [[gastroparesis]].
*Because BYETTA is commonly associated with gastrointestinal adverse reactions, including [[nausea]], [[vomiting]], and [[diarrhea]], the use of BYETTA is not recommended in patients with severe gastrointestinal disease.

====Immunogenicity====

*Patients may develop antibodies to exenatide following treatment with BYETTA.
*Antibody levels were measured in 90% of subjects in the 30-week, 24-week, and 16-week studies of BYETTA.
*In 3%, 4%, and 1% of these patients, respectively, antibody formation was associated with an attenuated glycemic response.
*If there is worsening glycemic control or failure to achieve targeted glycemic control, alternative anti diabetic therapy should be considered.

====Hypersensitivity====

*There have been post marketing reports of serious [[hypersensitivity reactions]] (e.g., [[anaphylaxis]] and [[angioedema]]) in patients treated with BYETTA.
*If a [[hypersensitivity]] reaction occurs, the patient should discontinue BYETTA and other suspect medications and promptly seek medical advice.

====Macrovascular Outcomes====

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with BYETTA or any other anti diabetic drug.
|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

====Hypoglycemia====

Table 1 summarizes the incidence and rate of [[hypoglycemia]] with BYETTA in six placebo-controlled clinical trials.

[[File:Exenatide_adverse_01.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

====Immunogenicity====

*Antibodies were assessed in 90% of subjects in the 30-week, 24-week, and 16-week studies of BYETTA. In the 30-week controlled trials of BYETTA add-on to [[metformin]] and/or [[sulfonylurea]], antibodies were assessed at 2- to 6-week intervals.
*The mean antibody titer peaked at week 6 and was reduced by 55% by week 30. Three hundred and sixty patients (38%) had low titer antibodies (<625) to exenatide at 30 weeks.
*The level of glycemic control ([[HbA1c]]) in these patients was generally comparable to that observed in the 534 patients (56%) without antibody titers. An additional 59 patients (6%) had higher titer antibodies (≥625) at 30 weeks.
*Of these patients, 32 (3% overall) had an attenuated glycemic response to BYETTA; the remaining 27 (3% overall) had a glycemic response comparable to that of patients without antibodies.
*In the 16-week trial of BYETTA add-on to [[thiazolidinediones]], with or without [[metformin]], 36 patients (31%) had low titer antibodies to exenatide at 16 weeks.
*The level of glycemic control in these patients was generally comparable to that observed in the 69 patients (60%) without antibody titer. An additional 10 patients (9%) had higher titer antibodies at 16 weeks.
*Of these patients, 4 (4% overall) had an attenuated glycemic response to BYETTA; the remaining 6 (5% overall) had a glycemic response comparable to that of patients without antibodies.
*In the 24-week trial of BYETTA used as monotherapy, 40 patients (28%) had low titer antibodies to exenatide at 24 weeks.
*The level of glycemic control in these patients was generally comparable to that observed in the 101 patients (70%) without antibody titers. An additional 3 patients (2%) had higher titer antibodies at 24 weeks.
*Of these patients, 1 (1% overall) had an attenuated glycemic response to BYETTA; the remaining 2 (1% overall) had a glycemic response comparable to that of patients without antibodies.
*Antibodies to exenatide were not assessed in the 30-week trial of BYETTA used in combination with [[insulin]] glargine.
*Two hundred and ten patients with antibodies to exenatide in the BYETTA clinical trials were tested for the presence of cross-reactive antibodies to GLP-1 and/or glucagon.
*No treatment-emergent cross-reactive antibodies were observed across the range of titers.

====Other Adverse Reactions====

<i>Monotherapy</i>

For the 24-week placebo-controlled study of BYETTA used as a monotherapy, Table 2 summarizes adverse reactions (excluding [[hypoglycemia]]) occurring with an incidence ≥2% and occurring more frequently in BYETTA-treated patients compared with placebo-treated patients.

[[File:Exenatide_adverse_02.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

Adverse reactions reported in ≥1.0% to <2.0% of patients receiving BYETTA and reported more frequently than with placebo included decreased appetite, [[diarrhea]], and [[dizziness]]. The most frequently reported adverse reaction associated with BYETTA, [[nausea]], occurred in a dose-dependent fashion.
Two of the 155 patients treated with BYETTA withdrew due to adverse reactions of [[headache]] and [[nausea]]. No placebo-treated patients withdrew due to adverse reactions.

<i>Combination Therapy</i>

'''Add-On to Metformin and/or Sulfonylurea'''

In the three 30-week controlled trials of BYETTA add-on to [[metformin]] and/or [[sulfonylurea]], adverse reactions (excluding [[hypoglycemia]]) with an incidence ≥2% and occurring more frequently in BYETTA-treated patients compared with placebo-treated patients ] are summarized in Table 3.

[[File:Exenatide_adverse_03.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

Adverse reactions reported in ≥1.0% to <2.0% of patients receiving BYETTA and reported more frequently than with placebo included decreased appetite. [[nausea]] was the most frequently reported adverse reaction and occurred in a dose-dependent fashion. With continued therapy, the frequency and severity decreased over time in most of the patients who initially experienced [[nausea]]. Patients in the long-term uncontrolled open-label extension studies at 52 weeks reported no new types of adverse reactions than those observed in the 30-week controlled trials.
The most common adverse reactions leading to withdrawal for BYETTA-treated patients were [[nausea]] (3% of patients) and [[vomiting]] (1%). For placebo-treated patients, <1% withdrew due to [[nausea]] and none due to [[vomiting]].

'''Add-On to Thiazolidinedione with or without Metformin'''

For the 16-week placebo-controlled study of BYETTA add-on to a thiazolidinedione, with or without metformin, Table 4 summarizes the adverse reactions (excluding hypoglycemia) with an incidence of ≥2% and occurring more frequently in BYETTA-treated patients compared with placebo-treated patients.

[[File:Exenatide_adverse_04.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

Adverse reactions reported in ≥1.0% to <2.0% of patients receiving BYETTA and reported more frequently than with placebo included decreased appetite. Chills (n=4) and injection-site reactions (n=2) occurred only in BYETTA-treated patients. The two patients who reported an injection-site reaction had high titers of antibodies to exenatide. Two serious adverse events (chest pain and chronic hypersensitivity pneumonitis) were reported in the BYETTA arm. No serious adverse events were reported in the placebo arm.
The most common adverse reactions leading to withdrawal for BYETTA-treated patients were [[nausea]] (9%) and [[vomiting]] (5%). For placebo-treated patients, <1% withdrew due to [[nausea]].

'''Add-On to Insulin Glargine with or without Metformin and/or Thiazolidinedione'''

For the 30-week placebo-controlled study of BYETTA as add-on to insulin glargine with or without oral antihyperglycemic medications, Table 5 summarizes adverse reactions (excluding [[hypoglycemia]]) occurring with an incidence ≥2% and occurring more frequently in BYETTA-treated patients compared with placebo-treated patients.

[[File:Exenatide_adverse_05.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

The most frequently reported adverse reactions leading to withdrawal for BYETTA-treated patients were [[nausea]] (5.1%) and [[vomiting]] (2.9%). No placebo-treated patients withdrew due to [[nausea]] or [[vomiting]].
|postmarketing=The following additional adverse reactions have been reported during post approval use of BYETTA. Because these events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.<br>
<i>Allergy/Hypersensitivity</i>: injection-site reactions, generalized [[pruritus]] and/or [[urticaria]], macular or [[papular rash]], [[angioedema]], [[anaphylactic reaction]] .<br>
<i>Drug Interactions</i>: International normalized ratio (INR) increased with concomitant [[warfarin]] use sometimes associated with bleeding.
<br>
<i>Gastrointestinal</i>: [[nausea]], [[vomiting]], and/or [[diarrhea]] resulting in [[dehydration]]; abdominal distension, [[abdominal pain]], [[eructation]], [[constipation]], [[flatulence]], [[acute pancreatitis]], hemorrhagic and necrotizing [[pancreatitis]] sometimes resulting in death.
<i>Neurologic</i>: [[dysgeusia]]; [[somnolence]].
<br>
<i>Renal and Urinary Disorders</i>: altered renal function, including increased serum creatinine, renal impairment, worsened [[chronic renal failure]] or [[acute renal failure]] (sometimes requiring [[hemodialysis]]), [[kidney transplant]] and kidney transplant dysfunction.<br>
<i>Skin and Subcutaneous Tissue Disorders</i>: [[alopecia]].
|drugInteractions=====Orally Administered Drugs====

The effect of BYETTA to slow gastric emptying can reduce the extent and rate of absorption of orally administered drugs. BYETTA should be used with caution in patients receiving oral medications that have narrow therapeutic index or require rapid gastrointestinal absorption . For oral medications that are dependent on threshold concentrations for efficacy, such as [[contraceptives]] and [[antibiotics]], patients should be advised to take those drugs at least 1 hour before BYETTA injection. If such drugs are to be administered with food, patients should be advised to take them with a meal or snack when BYETTA is not administered .

====Warfarin====

There are post marketing reports of increased INR sometimes associated with bleeding, with concomitant use of [[warfarin]] and BYETTA . In a drug interaction study, BYETTA did not have a significant effect on INR . In patients taking [[warfarin]], prothrombin time should be monitored more frequently after initiation or alteration of BYETTA therapy. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on [[warfarin]].
|FDAPregCat=C
|useInPregnancyFDA=There are no adequate and well-controlled studies of BYETTA use in pregnant women. In animal studies, exenatide caused [[cleft palate]], irregular skeletal ossification and an increased number of neonatal deaths. BYETTA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Female mice given SC doses of 6, 68, or 760 mcg/kg/day beginning 2 weeks prior to and throughout mating until gestation day 7 had no adverse fetal effects. At the maximal dose, 760 mcg/kg/day, systemic exposures were up to 390 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.
In developmental toxicity studies, pregnant animals received exenatide subcutaneously during organogenesis. Specifically, fetuses from pregnant rabbits given SC doses of 0.2, 2, 22, 156, or 260 mcg/kg/day from gestation day 6 through 18 experienced irregular skeletal ossifications from exposures 12 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC. Moreover, fetuses from pregnant mice given SC doses of 6, 68, 460, or 760 mcg/kg/day from gestation day 6 through 15 demonstrated reduced fetal and neonatal growth, [[cleft palate]] and skeletal effects at systemic exposure 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.
Lactating mice given SC doses of 6, 68, or 760 mcg/kg/day from gestation day 6 through lactation day 20 (weaning), experienced an increased number of neonatal deaths. Deaths were observed on postpartum days 2 to 4 in dams given 6 mcg/kg/day, a systemic exposure 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.
Pregnancy Registry
A Pregnancy Registry has been implemented to monitor pregnancy outcomes of women exposed to exenatide during pregnancy. Physicians are encouraged to register patients by calling 1-800-633-9081.
|useInNursing=It is not known whether exenatide is excreted in human milk. However, exenatide is present at low concentrations (less than or equal to 2.5% of the concentration in maternal plasma following subcutaneous dosing) in the milk of lactating mice. Many drugs are excreted in human milk and because of the potential for clinically significant adverse reactions in nursing infants from exenatide, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account these potential risks against the glycemic benefits to the lactating woman. Caution should be exercised when BYETTA is administered to a nursing woman.
|useInPed=Safety and effectiveness of BYETTA have not been established in pediatric patients.
|useInGeri=Population pharmacokinetic analysis of patients ranging from 22 to 73 years of age suggests that age does not influence the pharmacokinetic properties of exenatide. BYETTA was studied in 282 patients 65 years of age or older and in 16 patients 75 years of age or older. No differences in safety or effectiveness were observed between these patients and younger patients. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in the elderly based on renal function.
|useInRenalImpair=BYETTA is not recommended for use in patients with end-stage renal disease or severe renal impairment (creatinine clearance <30 mL/min) and should be used with caution in patients with renal transplantation. No dosage adjustment of BYETTA is required in patients with mild renal impairment (creatinine clearance 50-80 mL/min). Caution should be applied when initiating or escalating doses of BYETTA from 5 to 10 mcg in patients with moderate renal impairment (creatinine clearance 30-50 mL/min)
|useInHepaticImpair=No pharmacokinetic study has been performed in patients with a diagnosis of acute or chronic hepatic impairment. Because exenatide is cleared primarily by the kidney, hepatic dysfunction is not expected to affect blood concentrations of eventide.
|administration=Injection SC
|monitoring=FDA package insert for abcixmab contains no information regarding drug monitoring.
|IVCompat=There is limited information about the IV compatibility.
|overdose=In a clinical study of BYETTA, three patients with [[type 2 diabetes]] each experienced a single overdose of 100 mcg SC (10 times the maximum recommended dose). Effects of the overdoses included severe [[nausea]], severe [[vomiting]], and rapidly declining blood glucose concentrations. One of the three patients experienced severe [[hypoglycemia]] requiring parenteral glucose administration. The three patients recovered without complication. In the event of overdose, appropriate supportive treatment should be initiated according to the patient's clinical signs and symptoms.
|drugBox={{Drugbox2
| verifiedrevid = 464189825
| IUPAC_name = ''N''-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)<br>quinazolin-4-amine
| image = Erlotinib Structural Formulae.png
| width = 250
| image2 = Erlotinib-1m17-3D-balls.png


| tradename = Tarceva
| Drugs.com = {{drugs.com|monograph|erlotinib}}
| MedlinePlus = a605008
| licence_EU = Tarceva
| licence_US = Erlotinib
| pregnancy_US = D
| legal_UK = POM
| legal_US = Rx-only
| routes_of_administration = Oral [[Tablet (pharmacy)|tablets]]


| bioavailability = 59%
| protein_bound = 95%
| metabolism = [[Liver|Hepatic]] (mainly [[CYP3A4]], less [[CYP1A2]])
| elimination_half-life = 36.2 hrs ([[median]])
| excretion = >98% as metabolites, of which >90% via [[faeces]], 9% via [[urine]]


| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 183321-74-6
| ATC_prefix = L01
| ATC_suffix = XE03
| PubChem = 176870
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00530
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 154044
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = J4T82NDH7E
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D07907
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 114785
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 553


| C=22 | H=23 | N=3 | O=4
| molecular_weight = 393.436 g/mol
| smiles = COCCOc1cc2c(cc1OCCOC)ncnc2Nc3cccc(c3)C#C
| InChI = 1/C22H23N3O4/c1-4-16-6-5-7-17(12-16)25-22-18-13-20(28-10-8-26-2)21(29-11-9-27-3)14-19(18)23-15-24-22/h1,5-7,12-15H,8-11H2,2-3H3,(H,23,24,25)
| InChIKey = AAKJLRGGTJKAMG-UHFFFAOYAM
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C22H23N3O4/c1-4-16-6-5-7-17(12-16)25-22-18-13-20(28-10-8-26-2)21(29-11-9-27-3)14-19(18)23-15-24-22/h1,5-7,12-15H,8-11H2,2-3H3,(H,23,24,25)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = AAKJLRGGTJKAMG-UHFFFAOYSA-N
}}
|mechAction=Incretins, such as glucagon-like peptide-1 (GLP-1), enhance glucose-dependent [[insulin]] secretion and exhibit other anti hyperglycemic actions following their release into the circulation from the gut. BYETTA is a GLP-1 receptor agonist that enhances glucose-dependent [[insulin]] secretion by the pancreatic beta-cell, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying.
The amino acid sequence of exenatide partially overlaps that of human GLP-1. Exenatide has been shown to bind and activate the human GLP-1 receptor in vitro. This leads to an increase in both glucose-dependent synthesis of [[insulin]], and in vivo secretion of insulin from pancreatic beta cells, by mechanisms involving cyclic AMP and/or other intracellular signaling pathways.
BYETTA improves glycemic control by reducing fasting and postprandial glucose concentrations in patients with [[type 2 diabetes]] through the actions described below.
|structure=BYETTA (exenatide) is a synthetic peptide that was originally identified in the lizard Heloderma suspectum. Exenatide differs in chemical structure and pharmacological action from insulin, sulfonylureas (including D-phenylalanine derivatives and meglitinides), [[biguanides]], [[thiazolidinediones]], [[alpha-glucosidase inhibitors]], [[amylinomimetics]] and dipeptidyl peptidase-4 inhibitors.
Exenatide is a 39-amino acid peptide amide. Exenatide has the empirical formula C184H282N50O60S and molecular weight of 4186.6 Daltons. The amino acid sequence for exenatide is shown below.
H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2
BYETTA is supplied for SC injection as a sterile, preserved isotonic solution in a glass cartridge that has been assembled in a pen-injector (pen). Each milliliter (mL) contains 250 micrograms (mcg) synthetic exenatide, 2.2 mg metacresol as an antimicrobial preservative, mannitol as a tonicity-adjusting agent, and glacial acetic acid and sodium acetate trihydrate in water for injection as a buffering solution at pH 4.5. Two prefilled pens are available to deliver unit doses of 5 mcg or 10 mcg. Each prefilled pen will deliver 60 doses to provide for 30 days of twice daily administration (BID).
|PD=Glucose-Dependent Insulin Secretion

BYETTA has acute effects on pancreatic beta-cell responsiveness to glucose leading to insulin release predominantly in the presence of elevated glucose concentrations. This insulin secretion subsides as blood glucose concentrations decrease and approach [[euglycemia]]. However, BYETTA does not impair the normal glucagon response to [[hypoglycemia]].

First-Phase Insulin Response

In healthy individuals, robust insulin secretion occurs during the first 10 minutes following intravenous (IV) glucose administration. This secretion, known as the "first-phase insulin response," is characteristically absent in patients with type 2 diabetes. The loss of the first-phase insulin response is an early beta-cell defect in [[type 2 diabetes]]. Administration of BYETTA at therapeutic plasma concentrations restored first-phase insulin response to an IV bolus of glucose in patients with type 2 diabetes (Figure 1). Both first-phase insulin secretion and second-phase insulin secretion were significantly increased in patients with type 2 diabetes treated with BYETTA compared with saline (p<0.001 for both).

[[File:Exenatide_PD_01.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

Glucagon Secretion

In patients with type 2 diabetes, BYETTA moderates glucagon secretion and lowers serum glucagon concentrations during periods of [[hyperglycemia]]. Lower glucagon concentrations lead to decreased hepatic glucose output and decreased insulin demand.

Gastric Emptying

BYETTA slows gastric emptying, thereby reducing the rate at which meal-derived glucose appears in the circulation.

Food Intake

In both animals and humans, administration of exenatide has been shown to reduce food intake.

Postprandial Glucose

In patients with [[type 2 diabetes]], BYETTA reduces postprandial plasma glucose concentrations (Figure 2).

[[File:Exenatide_PD_02.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

Fasting Glucose

In a single-dose crossover study in patients with [[type 2 diabetes]] and fasting [[hyperglycemia]], immediate insulin release followed injection of BYETTA. Plasma glucose concentrations were significantly reduced with BYETTA compared with placebo (Figure 3).

[[File:Exenatide_PD_03.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

Cardiac Electrophysiology

The effect of exenatide 10 µg subcutaneously on QTc interval was evaluated in a randomized, placebo-, and active-controlled (moxifloxacin 400 mg) crossover thorough QTc study in 62 healthy subjects. In this study with demonstrated ability to detect small effects, the upper bound of the 90% confidence interval for the largest placebo-adjusted, baseline-corrected QTc was below 10 msec. Thus, BYETTA (10 mcg single dose) was not associated with clinically meaningful prolongation of the QTc interval.
|PK='''Absorption'''

Following SC administration to patients with [[type 2 diabetes]], exenatide reaches median peak plasma concentrations in 2.1 hours. The mean peak exenatide concentration (Cmax) was 211 pg/mL and overall mean area under the time-concentration curve (AUC0-inf) was 1036 pg∙h/mL following SC administration of a 10-mcg dose of BYETTA. Exenatide exposure (AUC) increased proportionally over the therapeutic dose range of 5 to 10 mcg. The Cmax values increased less than proportionally over the same range. Similar exposure is achieved with SC administration of BYETTA in the abdomen, thigh, or upper arm.

'''Distribution'''

The mean apparent volume of distribution of exenatide following SC administration of a single dose of BYETTA is 28.3 L.

'''Metabolism and Elimination'''

Nonclinical studies have shown that exenatide is predominantly eliminated by glomerular filtration with subsequent proteolytic degradation. The mean apparent clearance of exenatide in humans is 9.1 L/hour and the mean terminal half-life is 2.4 hours. These pharmacokinetic characteristics of exenatide are independent of the dose. In most individuals, exenatide concentrations are measurable for approximately 10 hours post-dose.

'''Drug Interactions'''

<i>Acetaminophen</i>

When 1000 mg [[acetaminophen]] elixir was given with 10 mcg BYETTA (0 hour) and 1 hour, 2 hours, and 4 hours after BYETTA injection, [[acetaminophen]] AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; Cmax was decreased by 37%, 56%, 54%, and 41%, respectively; Tmax was increased from 0.6 hour in the control period to 0.9 hour, 4.2 hours, 3.3 hours, and 1.6 hours, respectively. [[acetaminophen]] AUC, Cmax and Tmax were not significantly changed when [[acetaminophen]] was given 1 hour before BYETTA injection.

<i>Digoxin</i>

Administration of repeated doses of BYETTA (10 mcg BID) 30 minutes before oral [[digoxin]] (0.25 mg once daily) decreased the Cmax of [[digoxin]] by 17% and delayed the Tmax of [[digoxin]] by approximately 2.5 hours; however, the overall steady-state pharmacokinetic exposure (e.g., AUC) of [[digoxin]] was not changed.

<i>Lovastatin</i>

Administration of BYETTA (10 mcg BID) 30 minutes before a single oral dose of [[lovastatin]] (40 mg) decreased the AUC and Cmax of [[lovastatin]] by approximately 40% and 28%, respectively, and delayed the Tmax by about 4 hours compared with [[lovastatin]] administered alone. In the 30-week controlled clinical trials of BYETTA, the use of BYETTA in patients already receiving [[HMG CoA reductase]] inhibitors was not associated with consistent changes in lipid profiles compared to baseline.

<i>Lisinopril</i>

In patients with mild to moderate hypertension stabilized on [[lisinopril]] (5-20 mg/day), BYETTA (10 mcg BID) did not alter steady-state Cmax or AUC of [[lisinopril]]. [[lisinopril]] steady-state Tmax was delayed by 2 hours. There were no changes in 24-hour mean systolic and diastolic blood pressure.

<i>Oral Contraceptives</i>

The effect of BYETTA (10 mcg BID) on single and on multiple doses of a combination [[oral contraceptive]] (30 mcg ethinyl estradiol plus 150 mcg levonorgestrel) was studied in healthy female subjects. Repeated daily doses of the oral contraceptive (OC) given 30 minutes after BYETTA administration decreased the Cmax of ethinyl estradiol and levonorgestrel by 45% and 27%, respectively and delayed the Tmax of ethinyl estradiol and levonorgestrel by 3.0 hours and 3.5 hours, respectively, as compared to the oral contraceptive administered alone. Administration of repeated daily doses of the OC one hour prior to BYETTA administration decreased the mean Cmax of ethinyl estradiol by 15% but the mean Cmax of levonorgestrel was not significantly changed as compared to when the OC was given alone. BYETTA did not alter the mean trough concentrations of levonorgestrel after repeated daily dosing of the oral contraceptive for both regimens. However, the mean trough concentration of ethinyl estradiol was increased by 20% when the OC was administered 30 minutes after BYETTA administration injection as compared to when the OC was given alone. The effect of BYETTA on OC pharmacokinetics is confounded by the possible food effect on OC in this study. Therefore, OC products should be administered at least one hour prior to BYETTA injection.

<i>warfarin</i>

Administration of [[warfarin]] (25 mg) 35 minutes after repeated doses of BYETTA (5 mcg BID on days 1-2 and 10 mcg BID on days 3-9) in healthy volunteers delayed [[warfarin]] Tmax by approximately 2 hours. No clinically relevant effects on Cmax or AUC of S- and R-enantiomers of [[warfarin]] were observed. BYETTA did not significantly alter the pharmacodynamic properties (e.g., international normalized ratio) of [[warfarin]] [see Drug Interactions (7.2)].

'''Specific Populations'''

<i>Renal Impairment</i>

Pharmacokinetics of exenatide was studied in subjects with normal, mild, or moderate renal impairment and subjects with end-stage renal disease. In subjects with mild to moderate renal impairment (creatinine clearance 30-80 mL/min), exenatide exposure was similar to that of subjects with normal renal function. However, in subjects with end-stage renal disease receiving dialysis, mean exenatide exposure increased by 3.37-fold compared to that of subjects with normal renal function.

<i>Hepatic Impairment</i>
No pharmacokinetic study has been performed in patients with a diagnosis of acute or chronic hepatic impairment.

<i>Age</i>

Population pharmacokinetic analysis of patients ranging from 22 to 73 years of age suggests that age does not influence the pharmacokinetic properties of exenatide [see Use in Specific Population (8.5)].

<i>Gender</i>

Population pharmacokinetic analysis of male and female patients suggests that gender does not influence the distribution and elimination of exenatide.

<i>Race</i>

Population pharmacokinetic analysis of samples from Caucasian, Hispanic, Asian, and Black patients suggests that race has no significant influence on the pharmacokinetics of exenatide.

<i>Body Mass Index</i>

Population pharmacokinetic analysis of patients with body mass indices (BMI) ≥30 kg/m2 and <30 kg/m2 suggests that BMI has no significant effect on the pharmacokinetics of exenatide.
|nonClinToxic=====Carcinogenesis, Mutagenesis, Impairment of Fertility====

A 104-week carcinogenicity study was conducted in male and female rats at doses of 18, 70, or 250 mcg/kg/day administered by bolus SC injection. Benign thyroid C-cell adenomas were observed in female rats at all exenatide doses. The incidences in female rats were 8% and 5% in the two control groups and 14%, 11%, and 23% in the low-, medium-, and high-dose groups with systemic exposures of 5, 22, and 130 times, respectively, the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on plasma area under the curve (AUC).
In a 104-week carcinogenicity study in mice at doses of 18, 70, or 250 mcg/kg/day administered by bolus SC injection, no evidence of tumors was observed at doses up to 250 mcg/kg/day, a systemic exposure up to 95 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.
Exenatide was not mutagenic or clastogenic, with or without metabolic activation, in the Ames bacterial mutagenicity assay or chromosomal aberration assay in Chinese hamster ovary cells. Exenatide was negative in the in vivo mouse micronucleus assay.
In mouse fertility studies with SC doses of 6, 68, or 760 mcg/kg/day, males were treated for 4 weeks prior to and throughout mating, and females were treated 2 weeks prior to mating and throughout mating until gestation day 7. No adverse effect on fertility was observed at 760 mcg/kg/day, a systemic exposure 390 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.

====Reproductive and Developmental Toxicology====

In female mice given SC doses of 6, 68, or 760 mcg/kg/day beginning 2 weeks prior to and throughout mating until gestation day 7, there were no adverse fetal effects at doses up to 760 mcg/kg/day, systemic exposures up to 390 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.
In pregnant mice given SC doses of 6, 68, 460, or 760 mcg/kg/day from gestation day 6 through 15 (organogenesis), [[cleft palate]] (some with holes) and irregular fetal skeletal ossification of rib and skull bones were observed at 6 mcg/kg/day, a systemic exposure 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.
In pregnant rabbits given SC doses of 0.2, 2, 22, 156, or 260 mcg/kg/day from gestation day 6 through 18 (organogenesis), irregular fetal skeletal ossifications were observed at 2 mcg/kg/day, a systemic exposure 12 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.
In pregnant mice given SC doses of 6, 68, or 760 mcg/kg/day from gestation day 6 through lactation day 20 (weaning), an increased number of neonatal deaths was observed on postpartum days 2-4 in dams given 6 mcg/kg/day, a systemic exposure 3 times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.
|clinicalStudies=BYETTA has been studied as monotherapy and in combination with [[metformin]], a [[sulfonylurea]], a [[thiazolidinedione]], a combination of [[metformin]] and a [[sulfonylurea]], a combination of [[metformin]] and a [[thiazolidinedione]], or in combination with [[insulin]] glargine with or without [[metformin]] and/or [[thiazolidinedione]].

====Monotherapy====

In a randomized, double-blind, placebo-controlled trial of 24 weeks duration, BYETTA 5 mcg BID (n=77), BYETTA 10 mcg BID (n=78), or placebo BID (n=77) was used as monotherapy in patients with entry [[HbA1c]] ranging from 6.5% to 10%. All patients assigned to BYETTA initially received 5 mcg BID for 4 weeks. After 4 weeks, those patients either continued to receive BYETTA 5 mcg BID or had their dose increased to 10 mcg BID. Patients assigned to placebo received placebo BID throughout the trial. BYETTA or placebo was injected subcutaneously before the morning and evening meals. The majority of patients (68%) were Caucasian, 26% West Asian, 3% Hispanic, 3% Black, and 0.4% East Asian.
The primary endpoint was the change in [[HbA1c]] from baseline to Week 24 (or the last value at time of early discontinuation). Compared to placebo, BYETTA 5 mcg BID and 10 mcg BID resulted in statistically significant reductions in [[HbA1c]] from baseline at Week 24 (Table 6).

[[File:Exenatide_clinical studies_01.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

====Combination Therapy with Oral Antihyperglycemic Medicines====

Three 30-week, double-blind, placebo-controlled trials were conducted to evaluate the safety and efficacy of BYETTA in patients with [[type 2 diabetes]] whose glycemic control was inadequate with [[metformin]] alone, a [[sulfonylurea]] alone, or [[metformin]] in combination with a [[sulfonylurea]]. In addition, a 16-week, placebo-controlled trial was conducted where BYETTA was added to existing [[thiazolidinedione]] ([[pioglitazone]] or [[rosiglitazone]]) treatment, with or without [[metformin]], in patients with [[type 2 diabetes]] with inadequate glycemic control.
In the 30-week trials, after a 4-week placebo lead-in period, patients were randomly assigned to receive BYETTA 5 mcg bid, BYETTA 10 mcg bid, or placebo bid before the morning and evening meals, in addition to their existing oral anti diabetic agent. All patients assigned to BYETTA initially received 5 mcg bid for 4 weeks. After 4 weeks, those patients either continued to receive BYETTA 5 mcg BID or had their dose increased to 10 mcg bid. Patients assigned to placebo received placebo bid throughout the study. A total of 1446 patients were randomized in the three 30-week trials: 991 (69%) were Caucasian, 224 (16%) Hispanic, and 174 (12%) Black. Mean [[HbA1c]] values at baseline for the trials ranged from 8.2% to 8.7%.
In the placebo-controlled trial of 16 weeks duration, BYETTA (n=121) or placebo (n=112) was added to existing [[thiazolidinedione]] ([[pioglitazone]] or [[rosiglitazone]]) treatment, with or without [[metformin]]. Randomization to BYETTA or placebo was stratified based on whether the patients were receiving [[metformin]]. BYETTA treatment was initiated at a dose of 5 mcg bid for 4 weeks then increased to 10 mcg bid for 12 more weeks. Patients assigned to placebo received placebo BID throughout the study. BYETTA or placebo was injected subcutaneously before the morning and evening meals. In this trial, 79% of patients were taking a [[thiazolidinedione]] and [[metformin]] and 21% were taking a [[thiazolidinedione]] alone. The majority of patients (84%) were Caucasian, 8% Hispanic, and 3% Black. The mean baseline [[HbA1c]] values were 7.9% for BYETTA and placebo.
The primary endpoint in each study was the mean change in [[HbA1c]] from baseline to study end (or early discontinuation). Table 7 summarizes the study results for the 30- and 16-week clinical trials.

[[File:Exenatide_clinical studies_02.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

[[File:Exenatide_clinical studies_03.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

HbA1c

The addition of BYETTA to a regimen of [[metformin]], a [[sulfonylurea]], or both, resulted in statistically significant reductions from baseline in [[HbA1c]] compared with patients receiving placebo added to these agents in the three controlled trials (Table 7).
In the 16-week trial of BYETTA add-on to [[thiazolidinediones]], with or without [[metformin]], BYETTA resulted in statistically significant reductions from baseline in [[HbA1c]] compared with patients receiving placebo (Table 7).

Postprandial Glucose

Postprandial glucose was measured after a mixed meal tolerance test in 9.5% of patients participating in the 30-week add-on to [[metformin]], add-on to [[sulfonylurea]], and add-on to [[metformin]] in combination with [[sulfonylurea]] clinical trials. In this pooled subset of patients, BYETTA reduced postprandial plasma glucose concentrations in a dose-dependent manner. The mean (SD) change in 2-hour postprandial glucose concentration following administration of BYETTA at Week 30 relative to baseline was −63 (65) mg/dL for 5 mcg BID (n=42), −71 (73) mg/dL for 10 mcg BID (n=52), and +11 (69) mg/dL for placebo BID (n=44).

====Combination with Insulin Glargine====

A 30-week, double-blind, placebo-controlled trial was conducted to evaluate the efficacy and safety of BYETTA (n=137) versus placebo (n=122) when added to titrated [[insulin]] glargine, with or without [[metformin]] and/or [[thiazolidinedione]], in patients with [[type 2 diabetes]] with inadequate glycemic control.
All patients assigned to BYETTA initially received 5 mcg bid for 4 weeks. After 4 weeks, those patients assigned to BYETTA had their dose increased to 10 mcg bid. Patients assigned to placebo received placebo bid throughout the trial. BYETTA or placebo was injected subcutaneously before the morning and evening meals. Patients with an [[HbA1c]] ≤8.0% decreased their prestudy dose of [[insulin]] glargine by 20% and patients with an [[HbA1c]] ≥8.1% maintained their current dose of [[insulin]] glargine. Five weeks after initiating randomized treatment, [[insulin]] doses were titrated with guidance from the investigator toward predefined fasting glucose targets according to the dose titration algorithm provided in Table 9. The majority of patients (78%) were Caucasian, 10% American Indian or Alaska Native, 9% Black, 3% Asian, and 0.8% of multiple origins.
The primary endpoint was the change in [[HbA1c]] from baseline to Week 30. Compared to placebo, BYETTA 10 mcg bid resulted in statistically significant reductions in [[HbA1c]] from baseline at Week 30 (Table 8) in patients receiving titrated [[insulin]] glargine.

[[File:Exenatide_clinical studies_04.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

[[File:Exenatide_clinical studies_05.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|howSupplied=BYETTA is supplied as a sterile solution for subcutaneous injection containing 250 mcg/mL exenatide.
The following packages are available:

5 mcg per dose, 60 doses, 1.2 mL prefilled pen, NDC 66780-210-07

10 mcg per dose, 60 doses, 2.4 mL prefilled pen, NDC 66780-212-01
|storage=* Prior to first use, BYETTA must be stored refrigerated at 36°F to 46°F (2°C to 8°C).
* After first use, BYETTA can be kept at a temperature not to exceed 77°F (25°C).
* Do not freeze. Do not use BYETTA if it has been frozen.
* BYETTA should be protected from light.
* The pen should be discarded 30 days after first use, even if some drug remains in the pen.
* Use a puncture-resistant container to discard the needles. Do not reuse or share needles.
* BYETTA should not be used past the expiration date.
|fdaPatientInfo=[[File:Exenatide_patient information_01.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|alcohol=Alcohol-Exenatide interaction has not been established. Talk to your doctor about the effects of taking [[alcohol]] with this medication.
|brandNames=* Byetta
* Bydureon
|lookAlike=There is limited information about the Look-alike drug names.
}}
{{LabelImage
|fileName=Exenatide_label_01.jpg
}}
{{LabelImage
|fileName=Exenatide_label_02.jpg
}}
{{LabelImage
|fileName=Exenatide_panel_01.png
}}
{{LabelImage
|fileName=Exenatide_panel_02.png
}}

Clopidogrel

2015-03-19T19:02:09Z

Sree Teja Yelamanchili:

{{DrugProjectFormSinglePage
|authorTag={{SS}}; {{STY}}
|genericName=Clopidogrel
|aOrAn=a
|drugClass=[[P2Y12]] platelet inhibitor, [[platelet aggregation inhibitor]]
|indicationType=treatment
|indication=[[acute coronary syndrome]] ([[ACS]]), recent [[MI]], recent [[stroke]], or established [[peripheral arterial disease]]
|hasBlackBoxWarning=Yes
|adverseReactions=non-major [[bleeding]]
|blackBoxWarningTitle=<span style="color:#FF0000;">WARNING: DIMINISHED EFFECTIVENESS IN POOR METABOLIZERS</span>
|blackBoxWarningBody=* Effectiveness of clopidogrel depends on activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19.
* Poor metabolizers treated with clopidogrel at recommended doses exhibit higher cardiovascular event rates following acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) than patients with normal CYP2C19 function.
* Tests are available to identify a patient's CYP2C19 genotype and can be used as an aid in determining therapeutic strategy.
* Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers.
|fdaLIADAdult=<h4>Acute Coronary Syndrome</h4>

* For patients with [[NSTEMI|non-ST-elevation]] [[ACS]]

:* Initial loading dosage: '''300 mg PO '''
:* Maitaining dosage: '''75 mg PO qd'''
:* In combination with: '''Aspirin 75-300 mg PO qd'''

* For patients with [[STEMI]]

:* Recommended dosage: '''75 mg PO qd''' (With or without the loading dosage)
:* In combination with: '''Aspirin 75-300 mg PO qd'''

<h4>Recent MI, Recent Stroke, or Established Peripheral Arterial Disease</h4>

* Dosing information

:* '''75 mg PO qd'''
|offLabelAdultGuideSupport=There is limited information about the guideline-supported use.
|offLabelAdultNoGuideSupport=<b>Prophylaxis of [[Thrombosis]] in patient with [[Atrial Fibrillation]]</b>

* Dosing Information

:* '''75 mg/day''' incombination with '''[[aspirin]] 75-100 mg'''<ref name="pmid19336502">ACTIVE Investigators. Connolly SJ, Pogue J, Hart RG, Hohnloser SH, Pfeffer M et al. (2009) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=19336502 Effect of clopidogrel added to aspirin in patients with atrial fibrillation.] ''N Engl J Med'' 360 (20):2066-78. [http://dx.doi.org/10.1056/NEJMoa0901301 DOI:10.1056/NEJMoa0901301] PMID: [http://pubmed.gov/19336502 19336502]</ref>

<b>Prophylaxis of [[Thrombosis]] in patient with [[CHF|Chronic Heart failure]]</b>

* Dosing information

:* '''75 mg/day'''<ref name="pmid19289640">Massie BM, Collins JF, Ammon SE, Armstrong PW, Cleland JG, Ezekowitz M et al. (2009) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=19289640 Randomized trial of warfarin, aspirin, and clopidogrel in patients with chronic heart failure: the Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial.] ''Circulation'' 119 (12):1616-24. [http://dx.doi.org/10.1161/CIRCULATIONAHA.108.801753 DOI:10.1161/CIRCULATIONAHA.108.801753] PMID: [http://pubmed.gov/19289640 19289640]</ref>

<b>[[Stasis ulcer]]</b>

* Dosing information

:* Recommended dosage: '''75 mg/day for 2-4 weeks'''<ref name="pmid11190899">Bick RL, Scott RG (2001) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=11190899 Stasis ulcers refractory to therapy--accelerated healing by treatment with clopidogrel +/- dalteparin: a preliminary report.] ''Clin Appl Thromb Hemost'' 7 (1):21-4. PMID: [http://pubmed.gov/11190899 11190899]</ref>
|offLabelPedGuideSupport=There is limited information about the guideline-supported use.
|offLabelPedNoGuideSupport=<b>Prophylaxis of Arterial thrombosis</b>

* Dosing Information

:* Recommended dosage: '''0.2 mg/kg/day'''<ref name="pmid18195173">Li JS, Yow E, Berezny KY, Bokesch PM, Takahashi M, Graham TP et al. (2008) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=18195173 Dosing of clopidogrel for platelet inhibition in infants and young children: primary results of the Platelet Inhibition in Children On Clopidogrel (PICOLO) trial.] ''Circulation'' 117 (4):553-9. [http://dx.doi.org/10.1161/CIRCULATIONAHA.107.715821 DOI:10.1161/CIRCULATIONAHA.107.715821] PMID: [http://pubmed.gov/18195173 18195173]</ref>
|contraindications=* Active [[Bleeding]]

:* Clopidogrel is contraindicated in patients with active pathological bleeding such as [[peptic ulcer]] or [[intracranial hemorrhage]].

* [[Hypersensitivity]]

:* Clopidogrel tablets are contraindicated in patients with [[hypersensitivity]] (e.g., [[anaphylaxis]]) to clopidogrel or any component of the product.
|warnings=*'''Diminished Antiplatelet Activity Due to Impaired CYP2C19 Function'''

:* Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is achieved through an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by genetic variations in CYP2C19 and by concomitant medications that interfere with CYP2C19.

* '''Proton Pump Inhibitors'''

:* Avoid concomitant use of clopidogrel with [[omeprazole]] or [[esomeprazole]] because both significantly reduce the antiplatelet activity of clopidogrel.

* '''General Risk of Bleeding'''

:* [[Thienopyridines]], including clopidogrel, increase the risk of bleeding. If a patient is to undergo surgery and an antiplatelet effect is not desired, discontinue clopidogrel five days prior to surgery. In patients who stopped therapy more than five days prior to [[CABG]] the rates of major bleeding were similar (event rate 4.4% clopidogrel + [[aspirin]]; 5.3% placebo + [[aspirin]]). In patients who remained on therapy within five days of CABG, the major bleeding rate was 9.6% for clopidogrel + [[aspirin]], and 6.3% for placebo + [[aspirin]].
:* [[Thienopyridines]] inhibit platelet aggregation for the lifetime of the platelet (7 to 10 days), so withholding a dose will not be useful in managing a bleeding event or the risk of bleeding associated with an invasive procedure. Because the half-life of clopidogrel's active metabolite is short, it may be possible to restore hemostasis by administering exogenous platelets; however, platelet transfusions within 4 hours of the loading dose or 2 hours of the maintenance dose may be less effective.

* '''Discontinuation of Clopidogrel'''

:* Avoid lapses in therapy, and if clopidogrel must be temporarily discontinued, restart as soon as possible. Premature discontinuation of clopidogrel may increase the risk of cardiovascular events.

* '''Patients With Recent Transient Ischemic Attack (TIA) or Stroke'''

:* In patients with recent [[TIA]] or [[stroke]] who are at high risk for recurrent ischemic events, the combination of [[aspirin]] and clopidogrel has not been shown to be more effective than clopidogrel alone, but the combination has been shown to increase major bleeding.

* '''Thrombotic Thrombocytopenic Purpura (TTP)'''

:* [[Thrombotic Thrombocytopenic Purpura|TTP]], sometimes fatal, has been reported following use of clopidogrel, sometimes after a short exposure (< 2 weeks). TTP is a serious condition that requires urgent treatment including [[plasmapheresis]] (plasma exchange). It is characterized by [[thrombocytopenia]], [[microangiopathic hemolytic anemia]] ([[schistocytes]] [fragmented RBCs] seen on peripheral smear), neurological findings, renal dysfunction, and fever.

* '''Cross-Reactivity Among Thienopyridines'''

:* [[Hypersensitivity]] including [[rash]], [[angioedema]] or hematologic reaction have been reported in patients receiving clopidogrel, including patients with a history of [[hypersensitivity]] or hematologic reaction to other [[thienopyridines]].
|clinicalTrials=*Because clinical trials are conducted under widely varying conditions and durations of follow up, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
*Clopidogrel bisulfate has been evaluated for safety in more than 54,000 patients, including over 21,000 patients treated for 1 year or more.
*The clinically important adverse reactions observed in trials comparing clopidogrel plus aspirin to placebo plus aspirin and trials comparing clopidogrel bisulfate alone to aspirin alone are discussed below.

'''''Bleeding'''''

* '''CURE'''

:* In CURE, clopidogrel bisulfate use with aspirin was associated with an increase in major bleeding (primarily [[gastrointestinal bleeding]] and at puncture sites) compared to placebo with aspirin. The incidence of [[intracranial hemorrhage]] (0.1%) and fatal bleeding (0.2%) were the same in both groups. Other bleeding events that were reported more frequently in the clopidogrel group were [[epistaxis]], [[hematuria]], and bruise.
The overall incidence of bleeding is described in Table 1.
:* Ninety-two percent (92%) of the patients in the CURE study received [[heparin]] or [[low molecular weight heparin]] (LMWH), and the rate of bleeding in these patients was similar to the overall results.

* '''COMMIT'''
:* In COMMIT, similar rates of major bleeding were observed in the clopidogrel bisulfate and placebo groups, both of which also received aspirin.

[[File:Clopidogrel_adverse_01.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

:* Ninety-two percent (92%) of the patients in the CURE study received heparin or low molecular weight heparin (LMWH), and the rate of bleeding in these patients was similar to the overall results.

'''''COMMIT'''''

:* In COMMIT, similar rates of major bleeding were observed in the clopidogrel bisulfate and placebo groups, both of which also received aspirin.

[[File:Clopidogrel_adverse_02.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

* '''CAPRIE (Clopidogrel bisulfate vs. Aspirin)'''

:* In CAPRIE, [[gastrointestinal hemorrhage]] occurred at a rate of 2.0% in those taking clopidogrel bisulfate vs. 2.7% in those taking aspirin; bleeding requiring hospitalization occurred in 0.7% and 1.1%, respectively. The incidence of [[intracranial hemorrhage]] was 0.4% for clopidogrel bisulfate compared to 0.5% for aspirin.
:* Other bleeding events that were reported more frequently in the clopidogrel bisulfate group were [[epistaxis]] and [[hematoma]].

* <sub>Other Adverse Events</sub>

:* In CURE and CHARISMA, which compared clopidogrel bisulfate plus aspirin to aspirin alone, there was no difference in the rate of adverse events (other than bleeding) between clopidogrel bisulfate and placebo.
:* In CAPRIE, which compared clopidogrel bisulfate to aspirin, [[pruritus]] was more frequently reported in those taking clopidogrel bisulfate. No other difference in the rate of adverse events (other than bleeding) was reported.
|postmarketing=The following adverse reactions have been identified during post-approval use of clopidogrel. Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Blood and lymphatic system disorders: [[Agranulocytosis]], [[aplastic anemia]]/[[pancytopenia]], [[thrombotic thrombocytopenic purpura]] ([[TTP]]), acquired [[hemophilia A]]
* Eye disorders: Eye (conjunctival, ocular, retinal) bleeding
* Gastrointestinal disorders: Gastrointestinal and [[retroperitoneal hemorrhage]] with fatal outcome, [[colitis]] (including ulcerative or [[lymphocytic colitis]]), [[pancreatitis]], [[stomatitis]], gastric/duodenal ulcer, [[diarrhea]]
* General disorders and administration site condition: [[Fever]], [[hemorrhage]] of operative wound
* Hepato-biliary disorders: [[Acute liver failure]], [[hepatitis]] (non-infectious), abnormal liver function test
* Immune system disorders: [[Hypersensitivity reactions]], [[anaphylactoid reactions]], [[serum sickness]]
* Musculoskeletal, connective tissue and bone disorders: Musculoskeletal bleeding, [[myalgia]], [[arthralgia]], [[arthritis]]
* Nervous system disorders: Taste disorders, fatal [[intracranial bleeding]], [[headache]]
* Psychiatric disorders: [[Confusion]], [[hallucinations]]
* Respiratory, thoracic and mediastinal disorders: [[Bronchospasm]], [[interstitial pneumonitis]], [[respiratory tract bleeding]], [[eosinophilic pneumonia]]
* Renal and urinary disorders: Increased creatinine levels
* Skin and subcutaneous tissue disorders: [[Maculopapular]], [[erythematous]] or [[exfoliative skin disorder|exfoliative rash]], [[urticaria]], [[bullous dermatitis]], [[eczema]], [[toxic epidermal necrolysis]], [[Stevens-Johnson syndrome]], [[angioedema]], drug-induced hypersensitivity syndrome, [[drug rash]] with [[eosinophilia]] and systemic symptoms (DRESS), [[erythema multiforme]], skin bleeding, [[lichen planus]], [[generalized pruritus]]
* Vascular disorders: [[Vasculitis]], [[hypotension]]
|drugInteractions======CYP2C19 Inhibitors=====
:* Clopidogrel is metabolized to its active metabolite in part by [[CYP2C19]]. Concomitant use of certain drugs that inhibit the activity of this enzyme results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition.

=====Proton Pump Inhibitors (PPI)=====

::* Avoid concomitant use of clopidogrel with [[omeprazole]] or [[esomeprazole]]. In clinical studies, [[omeprazole]] was shown to reduce the antiplatelet activity of clopidogrel when given concomitantly or 12 hours apart. A higher dose regimen of clopidogrel concomitantly administered with [[omeprazole]] increases antiplatelet response; an appropriate dose regimen has not been established. A similar reduction in antiplatelet activity was observed with [[esomeprazole]] when given concomitantly with clopidogrel. Consider using another acid-reducing agent with minimal or no CYP2C19 inhibitory effect on the formation of clopidogrel active metabolite. [[Dexlansoprazole]], [[lansoprazole]] and [[pantoprazole]] had less effect on the antiplatelet activity of clopidogrel than did [[omeprazole]] or [[esomeprazole]].

=====Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)=====
:* Coadministration of clopidogrel and [[NSAIDs]] increases the risk of [[gastrointestinal bleeding]].

=====Warfarin (CYP2C9 Substrates)=====
:* Although the administration of clopidogrel 75 mg per day did not modify the pharmacokinetics of S-warfarin (a [[CYP2C9]] substrate) or INR in patients receiving long-term [[warfarin]] therapy, coadministration of clopidogrel with warfarin increases the risk of bleeding because of independent effects on [[hemostasis]].
:* However, at high concentrations in vitro, clopidogrel inhibits [[CYP2C9]].

=====SSRIs and SNRIs=====
:* Since [[selective serotonin reuptake inhibitors]] ([[SSRIs]]) and [[serotonin norepinephrine reuptake inhibitors]] ([[SNRIs]]) affect platelet activation, the concomitant administration of SSRIs and SNRIs with clopidogrel may increase the risk of bleeding.
|FDAPregCat=B
|useInPregnancyFDA=Reproduction studies performed in rats and rabbits at doses up to 500 and 300 mg/kg/day, respectively (65 and 78 times the recommended daily human dose, respectively, on a mg/m2 basis), revealed no evidence of impaired fertility or fetotoxicity due to clopidogrel. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of a human response, clopidogrel should be used during pregnancy only if clearly needed.
|useInNursing=Studies in rats have shown that clopidogrel and/or its metabolites are excreted in the milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from clopidogrel, 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.
|useInPed=Safety and effectiveness in pediatric populations have not been established.
Additional information describing a clinical study in which efficacy was not demonstrated in neonates and infants is approved in the package insert for Bristol-Myers Squibb’s clopidogrel tablets. However, due to Bristol-Myers Squibb’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.
|useInGeri=Of the total number of subjects in the CAPRIE and CURE controlled clinical studies, approximately 50% of patients treated with clopidogrel were 65 years of age and older, and 15% were 75 years and older. In COMMIT, approximately 58% of the patients treated with clopidogrel were 60 years and older, 26% of whom were 70 years and older.
The observed risk of bleeding events with clopidogrel plus aspirin versus placebo plus aspirin by age category is provided in Table 1 and Table 2 for the CURE and COMMIT trials, respectively. No dosage adjustment is necessary in elderly patients.
|useInRenalImpair=Experience is limited in patients with severe and moderate [[renal impairment]].
|useInHepaticImpair=No dosage adjustment is necessary in patients with [[hepatic impairment]].
|administration======Acute Coronary Syndrome=====

Clopidogrel tablets USP can be administered with or without food.
For patients with [[NSTEMI|non-ST-elevation]] ACS (UA/[[NSTEMI]]), initiate clopidogrel tablets USP with a single 300 mg oral loading dose and then continue at 75 mg once daily. Initiate [[aspirin]] (75 to 325 mg once daily) and continue in combination with clopidogrel tablets USP.
For patients with STEMI, the recommended dose of clopidogrel tablets USP is 75 mg once daily orally, administered in combination with [[aspirin]] (75 to 325 mg once daily), with or without thrombolytics. Clopidogrel tablets USP may be initiated with or without a loading dose.

=====Recent MI, Recent Stroke, or Established Peripheral Arterial Disease=====

The recommended daily dose of clopidogrel tablets USP is 75 mg once daily orally, with or without food.

=====CYP2C19 Poor Metabolizers=====

CYP2C19 poor metabolizer status is associated with diminished antiplatelet response to clopidogrel. Although a higher dose regimen in poor metabolizers increases antiplatelet response, an appropriate dose regimen for this patient population has not been established.

=====Use With Proton Pump Inhibitors (PPI)=====

Avoid using [[omeprazole]] or [[esomeprazole]] with clopidogrel tablets USP. [[Omeprazole]] and [[esomeprazole]] significantly reduce the antiplatelet activity of clopidogrel tablets USP. When concomitant administration of a PPI is required, consider using another acid-reducing agent with minimal or no CYP2C19 inhibitory effect on the formation of clopidogrel active metabolite.
|overdose=Platelet inhibition by clopidogrel is irreversible and will last for the life of the platelet. Overdose following clopidogrel administration may result in bleeding complications. A single oral dose of clopidogrel at 1500 or 2000 mg/kg was lethal to mice and to rats and at 3000 mg/kg to baboons. Symptoms of acute toxicity were [[vomiting]], [[prostration]], difficult breathing, and [[gastrointestinal hemorrhage]] in animals.
Based on biological plausibility, platelet transfusion may restore clotting ability.
|drugBox={{drugbox2 | verifiedrevid = 460044539
| IUPAC_name = (+)-(''S'')-methyl 2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-''c'']pyridin-5(4''H'')-yl)acetate
| image = S-Clopidogrel structure.svg
| width = 200
| image2 = Clopidogrel 3D.png
| width2 = 200


| tradename = Plavix
| Drugs.com = {{drugs.com|monograph|plavix}}
| MedlinePlus = a601040
| pregnancy_AU = B1
| pregnancy_US = B
| pregnancy_category =
| legal_AU = S4
| legal_UK = POM
| legal_US = Rx-only
| legal_status =
| routes_of_administration = Oral
| licence_US = Plavix


| bioavailability = >50%
| protein_bound = 94–98%
| metabolism = [[Liver|Hepatic]]
| elimination_half-life = 7–8 hours (inactive metabolite)
| excretion = 50% [[renal]]<br />46% [[biliary]]


| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 113665-84-2
| ATC_prefix = B01
| ATC_suffix = AC04
| PubChem = 60606
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00758
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 54632
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = A74586SNO7
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D07729
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 37941
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1771


| C=16 | H=16 | Cl=1 | N=1 | O=2 | S=1
| molecular_weight = 321.82 g/mol
| smiles = COC(=O)[C@H](c1ccccc1Cl)N2CCc3c(ccs3)C2
| InChI = 1/C16H16ClNO2S/c1-20-16(19)15(12-4-2-3-5-13(12)17)18-8-6-14-11(10-18)7-9-21-14/h2-5,7,9,15H,6,8,10H2,1H3/t15-/m0/s1
| InChIKey = GKTWGGQPFAXNFI-HNNXBMFYBE
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C16H16ClNO2S/c1-20-16(19)15(12-4-2-3-5-13(12)17)18-8-6-14-11(10-18)7-9-21-14/h2-5,7,9,15H,6,8,10H2,1H3/t15-/m0/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = GKTWGGQPFAXNFI-HNNXBMFYSA-N
}}
|mechAction=Clopidogrel is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Y12 class of ADP receptors on platelets.
|structure=Clopidogrel bisulfate, USP is a thienopyridine class inhibitor of P2Y12 ADP platelet receptors. Chemically it is methyl (+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate sulfate (1:1).
The structural formula is as follows:

[[File:Clopidogrel_pharmacology_01.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

C16H16ClNO2S•H2SO4 M.W. 419.9
Clopidogrel bisulfate, USP is a white to off-white powder. It is practically insoluble in water at neutral pH but freely soluble at pH 1. It also dissolves freely in methanol, dissolves sparingly in methylene chloride, and is practically insoluble in ethyl ether. It has a specific optical rotation of about +56°.
Clopidogrel bisulfate, USP for oral administration is provided as light-pink to pink, debossed, film-coated, capsule shaped tablets containing 97.875 mg of clopidogrel bisulfate, USP which is the molar equivalent of 75 mg of clopidogrel base.
Each tablet contains the following inactive ingredients: crospovidone, hydrogenated vegetable oil, hydroxypropyl cellulose, hypromellose, indigo carmine aluminum lake FD&C blue #2, iron oxide red, iron oxide yellow, lactose, lactose monohydrate, microcrystalline cellulose, polyethylene glycol, sodium lauryl sulfate, and titanium dioxide.
|PD=Clopidogrel must be metabolized by CYP450 enzymes to produce the active metabolite that inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y12 receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. This action is irreversible. Consequently, platelets exposed to clopidogrel’s active metabolite are affected for the remainder of their lifespan (about 7 to 10 days). Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of platelet activation by released ADP.
Dose-dependent inhibition of platelet aggregation can be seen 2 hours after single oral doses of clopidogrel. Repeated doses of 75 mg clopidogrel per day inhibit ADP-induced platelet aggregation on the first day, and inhibition reaches steady state between Day 3 and Day 7. At steady state, the average inhibition level observed with a dose of 75 mg clopidogrel per day was between 40% and 60%. Platelet aggregation and bleeding time gradually return to baseline values after treatment is discontinued, generally in about 5 days.

'''''Geriatric Patients'''''

Elderly (≥ 75 years) and young healthy subjects had similar effects on platelet aggregation.

'''''Renally-Impaired Patients'''''

After repeated doses of 75 mg clopidogrel per day, patients with severe renal impairment (creatinine clearance from 5 to 15 mL/min) and moderate renal impairment (creatinine clearance from 30 to 60 mL/min) showed low (25%) inhibition of ADP-induced platelet aggregation.

'''''Hepatically-Impaired Patients'''''

After repeated doses of 75 mg clopidogrel per day for 10 days in patients with severe hepatic impairment, inhibition of ADP-induced platelet aggregation was similar to that observed in healthy subjects.

'''''Gender'''''

In a small study comparing men and women, less inhibition of ADP-induced platelet aggregation was observed in women.
|PK=Clopidogrel is a prodrug and is metabolized to a pharmacologically active metabolite and inactive metabolites.

'''''Absorption'''''
* After single and repeated oral doses of 75 mg per day, clopidogrel is rapidly absorbed. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites.

'''''Effect of Food'''''
* Clopidogrel can be administered with or without food. In a study in healthy male subjects when clopidogrel 75 mg per day was given with a standard breakfast, mean inhibition of ADP-induced platelet aggregation was reduced by less than 9%. The active metabolite AUC0-24 was unchanged in the presence of food, while there was a 57% decrease in active metabolite Cmax. Similar results were observed when a clopidogrel 300 mg loading dose was administered with a high-fat breakfast.

'''''Metabolism'''''
* Clopidogrel is extensively metabolized by two main metabolic pathways: one mediated by esterases and leading to hydrolysis into an inactive carboxylic acid derivative (85% of circulating metabolites) and one mediated by multiple cytochrome P450 enzymes. Cytochromes first oxidize clopidogrel to a 2-oxo-clopidogrel intermediate metabolite. Subsequent metabolism of the 2-oxo-clopidogrel intermediate metabolite results in formation of the active metabolite, a thiol derivative of clopidogrel. This metabolic pathway is mediated by CYP2C19, CYP3A, CYP2B6 and CYP1A2. The active thiol metabolite binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation for the lifespan of the platelet.

* The Cmax of the active metabolite is twice as high following a single 300 mg clopidogrel loading dose as it is after four days of 75 mg maintenance dose. Cmax occurs approximately 30 to 60 minutes after dosing. In the 75 to 300 mg dose range, the pharmacokinetics of the active metabolite deviates from dose proportionality: increasing the dose by a factor of four results in 2.0 and 2.7 fold increases in Cmax and AUC, respectively.

'''''Elimination'''''

* Following an oral dose of 14C-labeled clopidogrel in humans, approximately 50% of total radioactivity was excreted in urine and approximately 46% in feces over the 5 days post-dosing. After a single, oral dose of 75 mg, clopidogrel has a half-life of approximately 6 hours. The half-life of the active metabolite is about 30 minutes.

'''''Drug Interactions'''''

* Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of certain inhibitors of this enzyme results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition.

'''''Proton Pump Inhibitors (PPI)'''''

* The effect of proton pump inhibitors (PPI) on the systemic exposure to the clopidogrel active metabolite following multiple doses of clopidogrel 75 mg evaluated in dedicated drug interaction studies is presented in Figure 1.
|nonClinToxic=There was no evidence of tumorigenicity when clopidogrel was administered for 78 weeks to mice and 104 weeks to rats at dosages up to 77 mg/kg per day, which afforded plasma exposures > 25 times that in humans at the recommended daily dose of 75 mg.
Clopidogrel was not genotoxic in four in vitro tests (Ames test, DNA-repair test in rat hepatocytes, gene mutation assay in Chinese hamster fibroblasts, and metaphase chromosome analysis of human lymphocytes) and in one in vivo test (micronucleus test by oral route in mice).
Clopidogrel was found to have no effect on fertility of male and female rats at oral doses up to 400 mg/kg per day (52 times the recommended human dose on a mg/m2 basis).
|clinicalStudies======Acute Coronary Syndrome=====

''CURE''

The CURE study included 12,562 patients with ACS without ST-elevation (UA or NSTEMI) and presenting within 24 hours of onset of the most recent episode of chest pain or symptoms consistent with ischemia. Patients were required to have either ECG changes compatible with new ischemia (without ST-elevation) or elevated cardiac enzymes or troponin I or T to at least twice the upper limit of normal. The patient population was largely Caucasian (82%) and included 38% women, and 52% patients ≥ 65 years of age.
Patients were randomized to receive clopidogrel (300 mg loading dose followed by 75 mg once daily) or placebo, and were treated for up to one year. Patients also received aspirin (75 to 325 mg once daily) and other standard therapies such as heparin. The use of GPIIb/IIIa inhibitors was not permitted for three days prior to randomization.
The number of patients experiencing the primary outcome (CV death, MI, or stroke) was 582 (9.3%) in the clopidogrel-treated group and 719 (11.4%) in the placebo-treated group, a 20% relative risk reduction (95% CI of 10% to 28%; p < 0.001) for the clopidogrel-treated group.

[[File:Clopidogrel_pharmacology_01.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

Most of the benefit of clopidogrel occurred in the first two months, but the difference from placebo was maintained throughout the course of the trial (up to 12 months).

[[File:Clopidogrel_pharmacology_02.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

In CURE, the use of clopidogrel was associated with a lower incidence of CV death, MI or stroke in patient populations with different characteristics, as shown in Figure 3. The benefits associated with clopidogrel were independent of the use of other acute and long-term cardiovascular therapies, including heparin/LMWH, intravenous glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors, lipid-lowering drugs, beta-blockers, and ACE-inhibitors. The efficacy of clopidogrel was observed independently of the dose of aspirin (75 to 325 mg once daily). The use of oral anticoagulants, non-study antiplatelet drugs, and chronic NSAIDs was not allowed in CURE.

[[File:Clopidogrel_pharmacology_03.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

The use of clopidogrel in CURE was associated with a decrease in the use of thrombolytic therapy (71 patients [1.1%] in the clopidogrel group, 126 patients [2.0%] in the placebo group; relative risk reduction of 43%), and GPIIb/IIIa inhibitors (369 patients [5.9%] in the clopidogrel group, 454 patients [7.2%] in the placebo group, relative risk reduction of 18%). The use of clopidogrel in CURE did not affect the number of patients treated with CABG or PCI (with or without stenting), (2253 patients [36.0%] in the clopidogrel group, 2324 patients [36.9%] in the placebo group; relative risk reduction of 4.0%).

''COMMIT''

In patients with STEMI, the safety and efficacy of clopidogrel were evaluated in the randomized, placebo-controlled, double-blind study, COMMIT. COMMIT included 45,852 patients presenting within 24 hours of the onset of the symptoms of myocardial infarction with supporting ECG abnormalities (i.e., ST-elevation, ST-depression or left bundle-branch block). Patients were randomized to receive clopidogrel (75 mg once daily) or placebo, in combination with aspirin (162 mg per day), for 28 days or until hospital discharge, whichever came first.
The primary endpoints were death from any cause and the first occurrence of re-infarction, stroke or death.
The patient population included 28% women, 58% age ≥ 60 years (26% age ≥ 70 years), 55% patients who received thrombolytics, 68% who received ACE-inhibitors, and only 3% who underwent PCI.
As shown in Table 5 and Figures 4 and 5 below, clopidogrel significantly reduced the relative risk of death from any cause by 7% (p = 0.029), and the relative risk of the combination of re-infarction, stroke or death by 9% (p = 0.002).

[[File:Clopidogrel_pharmacology_04.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

[[File:Clopidogrel_pharmacology_05.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

[[File:Clopidogrel_pharmacology_06.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

* All treated patients received aspirin.

The effect of clopidogrel did not differ significantly in various pre-specified subgroups as shown in Figure 6. The effect was also similar in non-prespecified subgroups including those based on infarct location, Killip class or prior MI history. Such subgroup analyses should be interpreted cautiously.

[[File:Clopidogrel_pharmacology_07.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

* Three similar-sized prognostic index groups were based on absolute risk of primary composite outcome for each patient calculated from baseline prognostic variables (excluding allocated treatments) with a Cox regression model.

[[File:Clopidogrel_pharmacology_08.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

=====Recent Myocardial Infarction, Recent Stroke, or Established Peripheral Arterial Disease=====

''CAPRIE''

The CAPRIE trial was a 19,185 patient, 304 center, international, randomized, double-blind, parallel-group study comparing clopidogrel (75 mg daily) to aspirin (325 mg daily). The patients randomized had: 1) recent histories of myocardial infarction (within 35 days); 2) recent histories of ischemic stroke (within 6 months) with at least a week of residual neurological signs; or 3) established peripheral arterial disease. Patients received randomized treatment for an average of 1.6 years (maximum of 3 years).
The trial's primary outcome was the time to first occurrence of new ischemic stroke (fatal or not), new myocardial infarction (fatal or not), or other vascular death. Deaths not easily attributable to nonvascular causes were all classified as vascular.

[[File:Clopidogrel_pharmacology_09.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

As shown in Table 6, clopidogrel was associated with a lower incidence of outcome events, primarily MI. The overall relative risk reduction (9.8% vs. 10.6%) was 8.7%, p = 0.045. Similar results were obtained when all-cause mortality and all-cause strokes were counted instead of vascular mortality and ischemic strokes (risk reduction 6.9%). In patients who survived an on-study stroke or myocardial infarction, the incidence of subsequent events was lower in the clopidogrel group.
The curves showing the overall event rate are shown in Figure 8. The event curves separated early and continued to diverge over the 3 year follow-up period.

[[File:Clopidogrel_pharmacology_10.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

The statistical significance favoring clopidogrel over aspirin was marginal (p = 0.045). However, because aspirin is itself effective in reducing cardiovascular events in patients with recent myocardial infarction or stroke, the effect of clopidogrel is substantial.
The CAPRIE trial included a population that was randomized on the basis of 3 entry criteria. The efficacy of clopidogrel relative to aspirin was heterogeneous across these randomized subgroups (p = 0.043). It is not clear whether this difference is real or a chance occurrence. Although the CAPRIE trial was not designed to evaluate the relative benefit of clopidogrel over aspirin in the individual patient subgroups, the benefit appeared to be strongest in patients who were enrolled because of peripheral vascular disease (especially those who also had a history of myocardial infarction) and weaker in stroke patients. In patients who were enrolled in the trial on the sole basis of a recent myocardial infarction, clopidogrel was not numerically superior to aspirin.

=====Lack of Established Benefit of Clopidogrel Plus Aspirin in Patients With Multiple Risk Factors or Established Vascular Disease=====

''CHARISMA''

The CHARISMA trial was a 15,603 subject, randomized, double-blind, parallel group study comparing clopidogrel (75 mg daily) to placebo for prevention of ischemic events in patients with vascular disease or multiple risk factors for atherosclerosis. All subjects were treated with aspirin 75 to 162 mg daily. The mean duration of treatment was 23 months. The study failed to demonstrate a reduction in the occurrence of the primary endpoint, a composite of CV death, MI, or stroke. A total of 534 (6.9%) patients in the clopidogrel group versus 573 (7.4%) patients in the placebo group experienced a primary outcome event (p = 0.22). Bleeding of all severities was more common in the subjects randomized to clopidogrel.
|howSupplied=Clopidogrel tablets USP are available as follows:
75 mg – light-pink to pink, film-coated, capsule shaped tablets debossed with “TV” on one side and “7314” on the other side, in bottles of 30, 90, and 500.
|storage=Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).
|fdaPatientInfo=For patient information about clopidogrel, click [[Clopidogrel (patient information)|here]].
|alcohol=Alcohol-Clopidogrel interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|nlmPatientInfo=For patient information about clopidogrel from NLM, click [[Clopidogrel (patient information)|here]].
}}
{{PillImage
|fileName=Clopidogrel 75 mg NDC 0093-7314.JPG
|drugName=Clopidogrel 75 MG (as clopidogrel bisulfate 97.875 MG) Oral Tablet
|NDC=0093-7314
|drugAuthor=Teva Pharmaceuticals USA Inc
|ingredients=crospovidone, hydrogenated cottonseed oil, hydroxypropyl cellulose (type h), hypromellose 2910 (15 mpa.s), indigotindisulfonate sodium, aluminum oxide, fd&c blue no. 2, ferric oxide red, ferric oxide yellow, lactose, lactose monohydrate, cellulose, microcrystalline, polyethylene glycol 4000, sodium lauryl sulfate, titanium dioxide
|pillImprint=TV;7314
|dosageValue=75
|dosageUnit=mg
|pillColor=Pink
|pillShape=Oval
|pillSize=13.00
|pillScore=1
}}
{{LabelImage
|fileName=Clopidogrel_label_01.jpg
}}
{{LabelImage
|fileName=Clopidogrel_panel_01.jpg
}}
[[Category:ADP receptor inhibitors]]
[[Category:Antiplatelet drugs]]
[[Category:Cardiovascular Drugs]]
[[Category:Drug]]
[[Category:Thienopyridines]]

Clopidogrel

2015-03-19T18:40:25Z

Sree Teja Yelamanchili:

{{DrugProjectFormSinglePage
|authorTag={{SS}}; {{STY}}
|genericName=Clopidogrel
|aOrAn=a
|drugClass=[[P2Y12]] platelet inhibitor, [[platelet aggregation inhibitor]]
|indicationType=treatment
|indication=[[acute coronary syndrome]] ([[ACS]]), recent [[MI]], recent [[stroke]], or established [[peripheral arterial disease]]
|hasBlackBoxWarning=Yes
|adverseReactions=non-major [[bleeding]]
|blackBoxWarningTitle=<span style="color:#FF0000;">WARNING: DIMINISHED EFFECTIVENESS IN POOR METABOLIZERS</span>
|blackBoxWarningBody=* Effectiveness of clopidogrel depends on activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19.
* Poor metabolizers treated with clopidogrel at recommended doses exhibit higher cardiovascular event rates following acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) than patients with normal CYP2C19 function.
* Tests are available to identify a patient's CYP2C19 genotype and can be used as an aid in determining therapeutic strategy.
* Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers.
|fdaLIADAdult=<h4>Acute Coronary Syndrome</h4>

* For patients with [[NSTEMI|non-ST-elevation]] [[ACS]]

:* Initial loading dosage: '''300 mg PO '''
:* Maitaining dosage: '''75 mg PO qd'''
:* In combination with: '''Aspirin 75-300 mg PO qd'''

* For patients with [[STEMI]]

:* Recommended dosage: '''75 mg PO qd''' (With or without the loading dosage)
:* In combination with: '''Aspirin 75-300 mg PO qd'''

<h4>Recent MI, Recent Stroke, or Established Peripheral Arterial Disease</h4>

* Dosing information

:* '''75 mg PO qd'''
|offLabelAdultGuideSupport=There is limited information about the guideline-supported use.
|offLabelAdultNoGuideSupport=<b>Prophylaxis of [[Thrombosis]] in patient with [[Atrial Fibrillation]]</b>

* Dosing Information

:* '''75 mg/day''' incombination with '''[[aspirin]] 75-100 mg'''<ref name="pmid19336502">ACTIVE Investigators. Connolly SJ, Pogue J, Hart RG, Hohnloser SH, Pfeffer M et al. (2009) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=19336502 Effect of clopidogrel added to aspirin in patients with atrial fibrillation.] ''N Engl J Med'' 360 (20):2066-78. [http://dx.doi.org/10.1056/NEJMoa0901301 DOI:10.1056/NEJMoa0901301] PMID: [http://pubmed.gov/19336502 19336502]</ref>

<b>Prophylaxis of [[Thrombosis]] in patient with [[Chronic Heart failure]]</b>

* Dosing information

:* '''75 mg/day'''<ref name="pmid19289640">Massie BM, Collins JF, Ammon SE, Armstrong PW, Cleland JG, Ezekowitz M et al. (2009) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=19289640 Randomized trial of warfarin, aspirin, and clopidogrel in patients with chronic heart failure: the Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial.] ''Circulation'' 119 (12):1616-24. [http://dx.doi.org/10.1161/CIRCULATIONAHA.108.801753 DOI:10.1161/CIRCULATIONAHA.108.801753] PMID: [http://pubmed.gov/19289640 19289640]</ref>

<b>[[Stasis ulcer]]</b>

* Dosing information

:* Recommended dosage: '''75 mg/day for 2-4 weeks'''<ref name="pmid11190899">Bick RL, Scott RG (2001) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=11190899 Stasis ulcers refractory to therapy--accelerated healing by treatment with clopidogrel +/- dalteparin: a preliminary report.] ''Clin Appl Thromb Hemost'' 7 (1):21-4. PMID: [http://pubmed.gov/11190899 11190899]</ref>
|offLabelPedGuideSupport=There is limited information about the guideline-supported use.

|offLabelPedNoGuideSupport=<b>Prophylaxis of Arterial thrombosis</b>

* Dosing Information

:* Recommended dosage: '''0.2 mg/kg/day'''<ref name="pmid18195173">Li JS, Yow E, Berezny KY, Bokesch PM, Takahashi M, Graham TP et al. (2008) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=18195173 Dosing of clopidogrel for platelet inhibition in infants and young children: primary results of the Platelet Inhibition in Children On Clopidogrel (PICOLO) trial.] ''Circulation'' 117 (4):553-9. [http://dx.doi.org/10.1161/CIRCULATIONAHA.107.715821 DOI:10.1161/CIRCULATIONAHA.107.715821] PMID: [http://pubmed.gov/18195173 18195173]</ref>
|contraindications=* Active [[Bleeding]]

:* Clopidogrel is contraindicated in patients with active pathological bleeding such as [[peptic ulcer]] or [[intracranial hemorrhage]].

* [[Hypersensitivity]]

:* Clopidogrel tablets are contraindicated in patients with [[hypersensitivity]] (e.g., [[anaphylaxis]]) to clopidogrel or any component of the product.
|warnings=*'''Diminished Antiplatelet Activity Due to Impaired CYP2C19 Function'''

:* Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is achieved through an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by genetic variations in CYP2C19 and by concomitant medications that interfere with CYP2C19.

* '''Proton Pump Inhibitors'''

:* Avoid concomitant use of clopidogrel with [[omeprazole]] or [[esomeprazole]] because both significantly reduce the antiplatelet activity of clopidogrel.

* '''General Risk of Bleeding'''

:* [[Thienopyridines]], including clopidogrel, increase the risk of bleeding. If a patient is to undergo surgery and an antiplatelet effect is not desired, discontinue clopidogrel five days prior to surgery. In patients who stopped therapy more than five days prior to [[CABG]] the rates of major bleeding were similar (event rate 4.4% clopidogrel + [[aspirin]]; 5.3% placebo + [[aspirin]]). In patients who remained on therapy within five days of CABG, the major bleeding rate was 9.6% for clopidogrel + [[aspirin]], and 6.3% for placebo + [[aspirin]].
:* [[Thienopyridines]] inhibit platelet aggregation for the lifetime of the platelet (7 to 10 days), so withholding a dose will not be useful in managing a bleeding event or the risk of bleeding associated with an invasive procedure. Because the half-life of clopidogrel's active metabolite is short, it may be possible to restore hemostasis by administering exogenous platelets; however, platelet transfusions within 4 hours of the loading dose or 2 hours of the maintenance dose may be less effective.

* '''Discontinuation of Clopidogrel'''

:* Avoid lapses in therapy, and if clopidogrel must be temporarily discontinued, restart as soon as possible. Premature discontinuation of clopidogrel may increase the risk of cardiovascular events.

* '''Patients With Recent [[Transient Ischemic Attack]] ([[TIA]]) or [[Stroke]]'''

:* In patients with recent [[TIA]] or stroke who are at high risk for recurrent ischemic events, the combination of [[aspirin]] and clopidogrel has not been shown to be more effective than clopidogrel alone, but the combination has been shown to increase major bleeding.

* '''Thrombotic Thrombocytopenic Purpura (TTP)'''

:* [[Thrombotic Thrombocytopenic Purpura|TTP]], sometimes fatal, has been reported following use of clopidogrel, sometimes after a short exposure (< 2 weeks). TTP is a serious condition that requires urgent treatment including [[plasmapheresis]] (plasma exchange). It is characterized by [[thrombocytopenia]], [[microangiopathic hemolytic anemia]] ([[schistocytes]] [fragmented RBCs] seen on peripheral smear), neurological findings, renal dysfunction, and fever.

* '''Cross-Reactivity Among Thienopyridines'''

:* [[Hypersensitivity]] including [[rash]], [[angioedema]] or hematologic reaction have been reported in patients receiving clopidogrel, including patients with a history of [[hypersensitivity]] or hematologic reaction to other [[thienopyridines]].
|clinicalTrials=Because clinical trials are conducted under widely varying conditions and durations of follow up, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Clopidogrel bisulfate has been evaluated for safety in more than 54,000 patients, including over 21,000 patients treated for 1 year or more. The clinically important adverse reactions observed in trials comparing clopidogrel plus aspirin to placebo plus aspirin and trials comparing clopidogrel bisulfate alone to aspirin alone are discussed below.

'''''Bleeding'''''

* '''CURE'''

:* In CURE, clopidogrel bisulfate use with aspirin was associated with an increase in major bleeding (primarily [[gastrointestinal bleeding]] and at puncture sites) compared to placebo with aspirin. The incidence of [[intracranial hemorrhage]] (0.1%) and fatal bleeding (0.2%) were the same in both groups. Other bleeding events that were reported more frequently in the clopidogrel group were [[epistaxis]], [[hematuria]], and bruise.
The overall incidence of bleeding is described in Table 1.
:* Ninety-two percent (92%) of the patients in the CURE study received [[heparin]] or [[low molecular weight heparin]] (LMWH), and the rate of bleeding in these patients was similar to the overall results.

* '''COMMIT'''
:* In COMMIT, similar rates of major bleeding were observed in the clopidogrel bisulfate and placebo groups, both of which also received aspirin.

[[File:Clopidogrel_adverse_01.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

:* Ninety-two percent (92%) of the patients in the CURE study received heparin or low molecular weight heparin (LMWH), and the rate of bleeding in these patients was similar to the overall results.

'''''COMMIT'''''

:* In COMMIT, similar rates of major bleeding were observed in the clopidogrel bisulfate and placebo groups, both of which also received aspirin.

[[File:Clopidogrel_adverse_02.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

* '''CAPRIE (Clopidogrel bisulfate vs. Aspirin)'''

:* In CAPRIE, gastrointestinal hemorrhage occurred at a rate of 2.0% in those taking clopidogrel bisulfate vs. 2.7% in those taking aspirin; bleeding requiring hospitalization occurred in 0.7% and 1.1%, respectively. The incidence of intracranial hemorrhage was 0.4% for clopidogrel bisulfate compared to 0.5% for aspirin.
:* Other bleeding events that were reported more frequently in the clopidogrel bisulfate group were epistaxis and hematoma.

* <sub>Other Adverse Events</sub>

:* In CURE and CHARISMA, which compared clopidogrel bisulfate plus aspirin to aspirin alone, there was no difference in the rate of adverse events (other than bleeding) between clopidogrel bisulfate and placebo.
:* In CAPRIE, which compared clopidogrel bisulfate to aspirin, pruritus was more frequently reported in those taking clopidogrel bisulfate. No other difference in the rate of adverse events (other than bleeding) was reported.
|postmarketing=The following adverse reactions have been identified during post-approval use of clopidogrel. Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Blood and lymphatic system disorders: [[Agranulocytosis]], [[aplastic anemia]]/[[pancytopenia]], [[thrombotic thrombocytopenic purpura]] ([[TTP]]), acquired [[hemophilia A]]
* Eye disorders: Eye (conjunctival, ocular, retinal) bleeding
* Gastrointestinal disorders: Gastrointestinal and [[retroperitoneal hemorrhage]] with fatal outcome, [[colitis]] (including ulcerative or [[lymphocytic colitis]]), [[pancreatitis]], [[stomatitis]], gastric/duodenal ulcer, [[diarrhea]]
* General disorders and administration site condition: [[Fever]], [[hemorrhage]] of operative wound
* Hepato-biliary disorders: [[Acute liver failure]], [[hepatitis]] (non-infectious), abnormal liver function test
* Immune system disorders: [[Hypersensitivity reactions]], [[anaphylactoid reactions]], [[serum sickness]]
* Musculoskeletal, connective tissue and bone disorders: Musculoskeletal bleeding, [[myalgia]], [[arthralgia]], [[arthritis]]
* Nervous system disorders: Taste disorders, fatal [[intracranial bleeding]], [[headache]]
* Psychiatric disorders: [[Confusion]], [[hallucinations]]
* Respiratory, thoracic and mediastinal disorders: [[Bronchospasm]], [[interstitial pneumonitis]], [[respiratory tract bleeding]], [[eosinophilic pneumonia]]
* Renal and urinary disorders: Increased creatinine levels
* Skin and subcutaneous tissue disorders: [[Maculopapular]], [[erythematous]] or exfoliative rash, [[urticaria]], [[bullous dermatitis]], [[eczema]], toxic [[epidermal necrolysis]], [[Stevens-Johnson syndrome]], [[angioedema]], drug-induced hypersensitivity syndrome, [[drug rash]] with [[eosinophilia]] and systemic symptoms (DRESS), [[erythema multiforme]], skin bleeding, [[lichen planus]], [[generalized pruritus]]
* Vascular disorders: [[Vasculitis]], [[hypotension]]
|drugInteractions======CYP2C19 Inhibitors=====
:* Clopidogrel is metabolized to its active metabolite in part by [[CYP2C19]]. Concomitant use of certain drugs that inhibit the activity of this enzyme results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition.

=====Proton Pump Inhibitors (PPI)=====

::* Avoid concomitant use of clopidogrel with [[omeprazole]] or [[esomeprazole]]. In clinical studies, [[omeprazole]] was shown to reduce the antiplatelet activity of clopidogrel when given concomitantly or 12 hours apart. A higher dose regimen of clopidogrel concomitantly administered with [[omeprazole]] increases antiplatelet response; an appropriate dose regimen has not been established. A similar reduction in antiplatelet activity was observed with [[esomeprazole]] when given concomitantly with clopidogrel. Consider using another acid-reducing agent with minimal or no CYP2C19 inhibitory effect on the formation of clopidogrel active metabolite. [[Dexlansoprazole]], [[lansoprazole]] and [[pantoprazole]] had less effect on the antiplatelet activity of clopidogrel than did [[omeprazole]] or [[esomeprazole]].

=====Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)=====
:* Coadministration of clopidogrel and [[NSAIDs]] increases the risk of [[gastrointestinal bleeding]].

=====Warfarin (CYP2C9 Substrates)=====
:* Although the administration of clopidogrel 75 mg per day did not modify the pharmacokinetics of S-warfarin (a [[CYP2C9]] substrate) or INR in patients receiving long-term [[warfarin]] therapy, coadministration of clopidogrel with warfarin increases the risk of bleeding because of independent effects on [[hemostasis]].
:* However, at high concentrations in vitro, clopidogrel inhibits [[CYP2C9]].

=====SSRIs and SNRIs=====
:* Since [[selective serotonin reuptake inhibitors]] ([[SSRIs]]) and [[serotonin norepinephrine reuptake inhibitors]] ([[SNRIs]]) affect platelet activation, the concomitant administration of SSRIs and SNRIs with clopidogrel may increase the risk of bleeding.
|FDAPregCat=B
|useInPregnancyFDA=Reproduction studies performed in rats and rabbits at doses up to 500 and 300 mg/kg/day, respectively (65 and 78 times the recommended daily human dose, respectively, on a mg/m2 basis), revealed no evidence of impaired fertility or fetotoxicity due to clopidogrel. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of a human response, clopidogrel should be used during pregnancy only if clearly needed.
|useInNursing=Studies in rats have shown that clopidogrel and/or its metabolites are excreted in the milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from clopidogrel, 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.
|useInPed=Safety and effectiveness in pediatric populations have not been established.
Additional information describing a clinical study in which efficacy was not demonstrated in neonates and infants is approved in the package insert for Bristol-Myers Squibb’s clopidogrel tablets. However, due to Bristol-Myers Squibb’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.
|useInGeri=Of the total number of subjects in the CAPRIE and CURE controlled clinical studies, approximately 50% of patients treated with clopidogrel were 65 years of age and older, and 15% were 75 years and older. In COMMIT, approximately 58% of the patients treated with clopidogrel were 60 years and older, 26% of whom were 70 years and older.
The observed risk of bleeding events with clopidogrel plus aspirin versus placebo plus aspirin by age category is provided in Table 1 and Table 2 for the CURE and COMMIT trials, respectively. No dosage adjustment is necessary in elderly patients.
|useInRenalImpair=Experience is limited in patients with severe and moderate [[renal impairment]].
|useInHepaticImpair=No dosage adjustment is necessary in patients with [[hepatic impairment]].
|administration======Acute Coronary Syndrome=====

Clopidogrel tablets USP can be administered with or without food.
For patients with [[NSTEMI|non-ST-elevation]] ACS (UA/[[NSTEMI]]), initiate clopidogrel tablets USP with a single 300 mg oral loading dose and then continue at 75 mg once daily. Initiate [[aspirin]] (75 to 325 mg once daily) and continue in combination with clopidogrel tablets USP.
For patients with STEMI, the recommended dose of clopidogrel tablets USP is 75 mg once daily orally, administered in combination with [[aspirin]] (75 to 325 mg once daily), with or without thrombolytics. Clopidogrel tablets USP may be initiated with or without a loading dose.

=====Recent MI, Recent Stroke, or Established Peripheral Arterial Disease=====

The recommended daily dose of clopidogrel tablets USP is 75 mg once daily orally, with or without food.

=====CYP2C19 Poor Metabolizers=====

CYP2C19 poor metabolizer status is associated with diminished antiplatelet response to clopidogrel. Although a higher dose regimen in poor metabolizers increases antiplatelet response, an appropriate dose regimen for this patient population has not been established.

=====Use With Proton Pump Inhibitors (PPI)=====

Avoid using [[omeprazole]] or [[esomeprazole]] with clopidogrel tablets USP. [[Omeprazole]] and [[esomeprazole]] significantly reduce the antiplatelet activity of clopidogrel tablets USP. When concomitant administration of a PPI is required, consider using another acid-reducing agent with minimal or no CYP2C19 inhibitory effect on the formation of clopidogrel active metabolite.
|overdose=Platelet inhibition by clopidogrel is irreversible and will last for the life of the platelet. Overdose following clopidogrel administration may result in bleeding complications. A single oral dose of clopidogrel at 1500 or 2000 mg/kg was lethal to mice and to rats and at 3000 mg/kg to baboons. Symptoms of acute toxicity were [[vomiting]], [[prostration]], difficult breathing, and [[gastrointestinal hemorrhage]] in animals.
Based on biological plausibility, platelet transfusion may restore clotting ability.
|drugBox={{drugbox2 | verifiedrevid = 460044539
| IUPAC_name = (+)-(''S'')-methyl 2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-''c'']pyridin-5(4''H'')-yl)acetate
| image = S-Clopidogrel structure.svg
| width = 200
| image2 = Clopidogrel 3D.png
| width2 = 200


| tradename = Plavix
| Drugs.com = {{drugs.com|monograph|plavix}}
| MedlinePlus = a601040
| pregnancy_AU = B1
| pregnancy_US = B
| pregnancy_category =
| legal_AU = S4
| legal_UK = POM
| legal_US = Rx-only
| legal_status =
| routes_of_administration = Oral
| licence_US = Plavix


| bioavailability = >50%
| protein_bound = 94–98%
| metabolism = [[Liver|Hepatic]]
| elimination_half-life = 7–8 hours (inactive metabolite)
| excretion = 50% [[renal]]<br />46% [[biliary]]


| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 113665-84-2
| ATC_prefix = B01
| ATC_suffix = AC04
| PubChem = 60606
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00758
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 54632
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = A74586SNO7
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D07729
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 37941
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1771


| C=16 | H=16 | Cl=1 | N=1 | O=2 | S=1
| molecular_weight = 321.82 g/mol
| smiles = COC(=O)[C@H](c1ccccc1Cl)N2CCc3c(ccs3)C2
| InChI = 1/C16H16ClNO2S/c1-20-16(19)15(12-4-2-3-5-13(12)17)18-8-6-14-11(10-18)7-9-21-14/h2-5,7,9,15H,6,8,10H2,1H3/t15-/m0/s1
| InChIKey = GKTWGGQPFAXNFI-HNNXBMFYBE
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C16H16ClNO2S/c1-20-16(19)15(12-4-2-3-5-13(12)17)18-8-6-14-11(10-18)7-9-21-14/h2-5,7,9,15H,6,8,10H2,1H3/t15-/m0/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = GKTWGGQPFAXNFI-HNNXBMFYSA-N
}}
|mechAction=Clopidogrel is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Y12 class of ADP receptors on platelets.
|structure=Clopidogrel bisulfate, USP is a thienopyridine class inhibitor of P2Y12 ADP platelet receptors. Chemically it is methyl (+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate sulfate (1:1).
The structural formula is as follows:

[[File:Clopidogrel_pharmacology_01.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

C16H16ClNO2S•H2SO4 M.W. 419.9
Clopidogrel bisulfate, USP is a white to off-white powder. It is practically insoluble in water at neutral pH but freely soluble at pH 1. It also dissolves freely in methanol, dissolves sparingly in methylene chloride, and is practically insoluble in ethyl ether. It has a specific optical rotation of about +56°.
Clopidogrel bisulfate, USP for oral administration is provided as light-pink to pink, debossed, film-coated, capsule shaped tablets containing 97.875 mg of clopidogrel bisulfate, USP which is the molar equivalent of 75 mg of clopidogrel base.
Each tablet contains the following inactive ingredients: crospovidone, hydrogenated vegetable oil, hydroxypropyl cellulose, hypromellose, indigo carmine aluminum lake FD&C blue #2, iron oxide red, iron oxide yellow, lactose, lactose monohydrate, microcrystalline cellulose, polyethylene glycol, sodium lauryl sulfate, and titanium dioxide.
|PD=Clopidogrel must be metabolized by CYP450 enzymes to produce the active metabolite that inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y12 receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. This action is irreversible. Consequently, platelets exposed to clopidogrel’s active metabolite are affected for the remainder of their lifespan (about 7 to 10 days). Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of platelet activation by released ADP.
Dose-dependent inhibition of platelet aggregation can be seen 2 hours after single oral doses of clopidogrel. Repeated doses of 75 mg clopidogrel per day inhibit ADP-induced platelet aggregation on the first day, and inhibition reaches steady state between Day 3 and Day 7. At steady state, the average inhibition level observed with a dose of 75 mg clopidogrel per day was between 40% and 60%. Platelet aggregation and bleeding time gradually return to baseline values after treatment is discontinued, generally in about 5 days.

'''''Geriatric Patients'''''

Elderly (≥ 75 years) and young healthy subjects had similar effects on platelet aggregation.

'''''Renally-Impaired Patients'''''

After repeated doses of 75 mg clopidogrel per day, patients with severe renal impairment (creatinine clearance from 5 to 15 mL/min) and moderate renal impairment (creatinine clearance from 30 to 60 mL/min) showed low (25%) inhibition of ADP-induced platelet aggregation.

'''''Hepatically-Impaired Patients'''''

After repeated doses of 75 mg clopidogrel per day for 10 days in patients with severe hepatic impairment, inhibition of ADP-induced platelet aggregation was similar to that observed in healthy subjects.

'''''Gender'''''

In a small study comparing men and women, less inhibition of ADP-induced platelet aggregation was observed in women.
|PK=Clopidogrel is a prodrug and is metabolized to a pharmacologically active metabolite and inactive metabolites.

'''''Absorption'''''
* After single and repeated oral doses of 75 mg per day, clopidogrel is rapidly absorbed. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites.

'''''Effect of Food'''''
* Clopidogrel can be administered with or without food. In a study in healthy male subjects when clopidogrel 75 mg per day was given with a standard breakfast, mean inhibition of ADP-induced platelet aggregation was reduced by less than 9%. The active metabolite AUC0-24 was unchanged in the presence of food, while there was a 57% decrease in active metabolite Cmax. Similar results were observed when a clopidogrel 300 mg loading dose was administered with a high-fat breakfast.

'''''Metabolism'''''
* Clopidogrel is extensively metabolized by two main metabolic pathways: one mediated by esterases and leading to hydrolysis into an inactive carboxylic acid derivative (85% of circulating metabolites) and one mediated by multiple cytochrome P450 enzymes. Cytochromes first oxidize clopidogrel to a 2-oxo-clopidogrel intermediate metabolite. Subsequent metabolism of the 2-oxo-clopidogrel intermediate metabolite results in formation of the active metabolite, a thiol derivative of clopidogrel. This metabolic pathway is mediated by CYP2C19, CYP3A, CYP2B6 and CYP1A2. The active thiol metabolite binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation for the lifespan of the platelet.

* The Cmax of the active metabolite is twice as high following a single 300 mg clopidogrel loading dose as it is after four days of 75 mg maintenance dose. Cmax occurs approximately 30 to 60 minutes after dosing. In the 75 to 300 mg dose range, the pharmacokinetics of the active metabolite deviates from dose proportionality: increasing the dose by a factor of four results in 2.0 and 2.7 fold increases in Cmax and AUC, respectively.

'''''Elimination'''''

* Following an oral dose of 14C-labeled clopidogrel in humans, approximately 50% of total radioactivity was excreted in urine and approximately 46% in feces over the 5 days post-dosing. After a single, oral dose of 75 mg, clopidogrel has a half-life of approximately 6 hours. The half-life of the active metabolite is about 30 minutes.

'''''Drug Interactions'''''

* Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of certain inhibitors of this enzyme results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition.

'''''Proton Pump Inhibitors (PPI)'''''

* The effect of proton pump inhibitors (PPI) on the systemic exposure to the clopidogrel active metabolite following multiple doses of clopidogrel 75 mg evaluated in dedicated drug interaction studies is presented in Figure 1.
|nonClinToxic=There was no evidence of tumorigenicity when clopidogrel was administered for 78 weeks to mice and 104 weeks to rats at dosages up to 77 mg/kg per day, which afforded plasma exposures > 25 times that in humans at the recommended daily dose of 75 mg.
Clopidogrel was not genotoxic in four in vitro tests (Ames test, DNA-repair test in rat hepatocytes, gene mutation assay in Chinese hamster fibroblasts, and metaphase chromosome analysis of human lymphocytes) and in one in vivo test (micronucleus test by oral route in mice).
Clopidogrel was found to have no effect on fertility of male and female rats at oral doses up to 400 mg/kg per day (52 times the recommended human dose on a mg/m2 basis).
|clinicalStudies======Acute Coronary Syndrome=====

''CURE''

The CURE study included 12,562 patients with ACS without ST-elevation (UA or NSTEMI) and presenting within 24 hours of onset of the most recent episode of chest pain or symptoms consistent with ischemia. Patients were required to have either ECG changes compatible with new ischemia (without ST-elevation) or elevated cardiac enzymes or troponin I or T to at least twice the upper limit of normal. The patient population was largely Caucasian (82%) and included 38% women, and 52% patients ≥ 65 years of age.
Patients were randomized to receive clopidogrel (300 mg loading dose followed by 75 mg once daily) or placebo, and were treated for up to one year. Patients also received aspirin (75 to 325 mg once daily) and other standard therapies such as heparin. The use of GPIIb/IIIa inhibitors was not permitted for three days prior to randomization.
The number of patients experiencing the primary outcome (CV death, MI, or stroke) was 582 (9.3%) in the clopidogrel-treated group and 719 (11.4%) in the placebo-treated group, a 20% relative risk reduction (95% CI of 10% to 28%; p < 0.001) for the clopidogrel-treated group.

[[File:Clopidogrel_pharmacology_01.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

Most of the benefit of clopidogrel occurred in the first two months, but the difference from placebo was maintained throughout the course of the trial (up to 12 months).

[[File:Clopidogrel_pharmacology_02.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

In CURE, the use of clopidogrel was associated with a lower incidence of CV death, MI or stroke in patient populations with different characteristics, as shown in Figure 3. The benefits associated with clopidogrel were independent of the use of other acute and long-term cardiovascular therapies, including heparin/LMWH, intravenous glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors, lipid-lowering drugs, beta-blockers, and ACE-inhibitors. The efficacy of clopidogrel was observed independently of the dose of aspirin (75 to 325 mg once daily). The use of oral anticoagulants, non-study antiplatelet drugs, and chronic NSAIDs was not allowed in CURE.

[[File:Clopidogrel_pharmacology_03.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

The use of clopidogrel in CURE was associated with a decrease in the use of thrombolytic therapy (71 patients [1.1%] in the clopidogrel group, 126 patients [2.0%] in the placebo group; relative risk reduction of 43%), and GPIIb/IIIa inhibitors (369 patients [5.9%] in the clopidogrel group, 454 patients [7.2%] in the placebo group, relative risk reduction of 18%). The use of clopidogrel in CURE did not affect the number of patients treated with CABG or PCI (with or without stenting), (2253 patients [36.0%] in the clopidogrel group, 2324 patients [36.9%] in the placebo group; relative risk reduction of 4.0%).

''COMMIT''

In patients with STEMI, the safety and efficacy of clopidogrel were evaluated in the randomized, placebo-controlled, double-blind study, COMMIT. COMMIT included 45,852 patients presenting within 24 hours of the onset of the symptoms of myocardial infarction with supporting ECG abnormalities (i.e., ST-elevation, ST-depression or left bundle-branch block). Patients were randomized to receive clopidogrel (75 mg once daily) or placebo, in combination with aspirin (162 mg per day), for 28 days or until hospital discharge, whichever came first.
The primary endpoints were death from any cause and the first occurrence of re-infarction, stroke or death.
The patient population included 28% women, 58% age ≥ 60 years (26% age ≥ 70 years), 55% patients who received thrombolytics, 68% who received ACE-inhibitors, and only 3% who underwent PCI.
As shown in Table 5 and Figures 4 and 5 below, clopidogrel significantly reduced the relative risk of death from any cause by 7% (p = 0.029), and the relative risk of the combination of re-infarction, stroke or death by 9% (p = 0.002).

[[File:Clopidogrel_pharmacology_04.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

[[File:Clopidogrel_pharmacology_05.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

[[File:Clopidogrel_pharmacology_06.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

* All treated patients received aspirin.

The effect of clopidogrel did not differ significantly in various pre-specified subgroups as shown in Figure 6. The effect was also similar in non-prespecified subgroups including those based on infarct location, Killip class or prior MI history. Such subgroup analyses should be interpreted cautiously.

[[File:Clopidogrel_pharmacology_07.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

* Three similar-sized prognostic index groups were based on absolute risk of primary composite outcome for each patient calculated from baseline prognostic variables (excluding allocated treatments) with a Cox regression model.

[[File:Clopidogrel_pharmacology_08.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

=====Recent Myocardial Infarction, Recent Stroke, or Established Peripheral Arterial Disease=====

''CAPRIE''

The CAPRIE trial was a 19,185 patient, 304 center, international, randomized, double-blind, parallel-group study comparing clopidogrel (75 mg daily) to aspirin (325 mg daily). The patients randomized had: 1) recent histories of myocardial infarction (within 35 days); 2) recent histories of ischemic stroke (within 6 months) with at least a week of residual neurological signs; or 3) established peripheral arterial disease. Patients received randomized treatment for an average of 1.6 years (maximum of 3 years).
The trial's primary outcome was the time to first occurrence of new ischemic stroke (fatal or not), new myocardial infarction (fatal or not), or other vascular death. Deaths not easily attributable to nonvascular causes were all classified as vascular.

[[File:Clopidogrel_pharmacology_09.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

As shown in Table 6, clopidogrel was associated with a lower incidence of outcome events, primarily MI. The overall relative risk reduction (9.8% vs. 10.6%) was 8.7%, p = 0.045. Similar results were obtained when all-cause mortality and all-cause strokes were counted instead of vascular mortality and ischemic strokes (risk reduction 6.9%). In patients who survived an on-study stroke or myocardial infarction, the incidence of subsequent events was lower in the clopidogrel group.
The curves showing the overall event rate are shown in Figure 8. The event curves separated early and continued to diverge over the 3 year follow-up period.

[[File:Clopidogrel_pharmacology_10.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

The statistical significance favoring clopidogrel over aspirin was marginal (p = 0.045). However, because aspirin is itself effective in reducing cardiovascular events in patients with recent myocardial infarction or stroke, the effect of clopidogrel is substantial.
The CAPRIE trial included a population that was randomized on the basis of 3 entry criteria. The efficacy of clopidogrel relative to aspirin was heterogeneous across these randomized subgroups (p = 0.043). It is not clear whether this difference is real or a chance occurrence. Although the CAPRIE trial was not designed to evaluate the relative benefit of clopidogrel over aspirin in the individual patient subgroups, the benefit appeared to be strongest in patients who were enrolled because of peripheral vascular disease (especially those who also had a history of myocardial infarction) and weaker in stroke patients. In patients who were enrolled in the trial on the sole basis of a recent myocardial infarction, clopidogrel was not numerically superior to aspirin.

=====Lack of Established Benefit of Clopidogrel Plus Aspirin in Patients With Multiple Risk Factors or Established Vascular Disease=====

''CHARISMA''

The CHARISMA trial was a 15,603 subject, randomized, double-blind, parallel group study comparing clopidogrel (75 mg daily) to placebo for prevention of ischemic events in patients with vascular disease or multiple risk factors for atherosclerosis. All subjects were treated with aspirin 75 to 162 mg daily. The mean duration of treatment was 23 months. The study failed to demonstrate a reduction in the occurrence of the primary endpoint, a composite of CV death, MI, or stroke. A total of 534 (6.9%) patients in the clopidogrel group versus 573 (7.4%) patients in the placebo group experienced a primary outcome event (p = 0.22). Bleeding of all severities was more common in the subjects randomized to clopidogrel.
|howSupplied=Clopidogrel tablets USP are available as follows:
75 mg – light-pink to pink, film-coated, capsule shaped tablets debossed with “TV” on one side and “7314” on the other side, in bottles of 30, 90, and 500.
|storage=Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).
|fdaPatientInfo=For patient information about clopidogrel, click [[Clopidogrel (patient information)|here]].
|alcohol=Alcohol-Clopidogrel interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|nlmPatientInfo=For patient information about clopidogrel from NLM, click [[Clopidogrel (patient information)|here]].
}}
{{PillImage
|fileName=Clopidogrel 75 mg NDC 0093-7314.JPG
|drugName=Clopidogrel 75 MG (as clopidogrel bisulfate 97.875 MG) Oral Tablet
|NDC=0093-7314
|drugAuthor=Teva Pharmaceuticals USA Inc
|ingredients=crospovidone, hydrogenated cottonseed oil, hydroxypropyl cellulose (type h), hypromellose 2910 (15 mpa.s), indigotindisulfonate sodium, aluminum oxide, fd&c blue no. 2, ferric oxide red, ferric oxide yellow, lactose, lactose monohydrate, cellulose, microcrystalline, polyethylene glycol 4000, sodium lauryl sulfate, titanium dioxide
|pillImprint=TV;7314
|dosageValue=75
|dosageUnit=mg
|pillColor=Pink
|pillShape=Oval
|pillSize=13.00
|pillScore=1
}}
{{LabelImage
|fileName=Clopidogrel_label_01.jpg
}}
{{LabelImage
|fileName=Clopidogrel_panel_01.jpg
}}
[[Category:ADP receptor inhibitors]]
[[Category:Antiplatelet drugs]]
[[Category:Cardiovascular Drugs]]
[[Category:Drug]]
[[Category:Thienopyridines]]

Clopidogrel

2015-03-19T18:25:22Z

Sree Teja Yelamanchili:

{{DrugProjectFormSinglePage
|authorTag={{SS}}; {{STY}}
|genericName=Clopidogrel
|aOrAn=a
|drugClass=[[P2Y12]] platelet inhibitor, [[platelet aggregation inhibitor]]
|indicationType=treatment
|indication=[[acute coronary syndrome]] ([[ACS]]), recent [[MI]], recent [[stroke]], or established [[peripheral arterial disease]]
|hasBlackBoxWarning=Yes
|adverseReactions=non-major [[bleeding]]
|blackBoxWarningTitle=<span style="color:#FF0000;">WARNING: DIMINISHED EFFECTIVENESS IN POOR METABOLIZERS</span>
|blackBoxWarningBody=
* Effectiveness of clopidogrel depends on activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19.
* Poor metabolizers treated with clopidogrel at recommended doses exhibit higher cardiovascular event rates following acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) than patients with normal CYP2C19 function.
* Tests are available to identify a patient's CYP2C19 genotype and can be used as an aid in determining therapeutic strategy.
* Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers.
|fdaLIADAdult=<h4>Acute Coronary Syndrome</h4>

* For patients with [[NSTEMI|non-ST-elevation]] [[ACS]]

:* Initial loading dosage: '''300 mg PO '''
:* Maitaining dosage: '''75 mg PO qd'''
:* In combination with: '''Aspirin 75-300 mg PO qd'''

* For patients with [[STEMI]]

:* Recommended dosage: '''75 mg PO qd''' (With or without the loading dosage)
:* In combination with: '''Aspirin 75-300 mg PO qd'''

<h4>Recent MI, Recent Stroke, or Established Peripheral Arterial Disease</h4>

* Dosing information

:* '''75 mg PO qd'''
|offLabelAdultGuideSupport=There is limited information about the guideline-supported use.
|offLabelAdultNoGuideSupport=<b>Prophylaxis of [[Thrombosis]] in patient with [[Atrial Fibrillation]]</b>

* Dosing Information

:* '''75 mg/day''' incombination with '''[[aspirin]] 75-100 mg'''<ref name="pmid19336502">ACTIVE Investigators. Connolly SJ, Pogue J, Hart RG, Hohnloser SH, Pfeffer M et al. (2009) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=19336502 Effect of clopidogrel added to aspirin in patients with atrial fibrillation.] ''N Engl J Med'' 360 (20):2066-78. [http://dx.doi.org/10.1056/NEJMoa0901301 DOI:10.1056/NEJMoa0901301] PMID: [http://pubmed.gov/19336502 19336502]</ref>

<b>Prophylaxis of [[Thrombosis]] in patient with [[Chronic Heart failure]]</b>

* Dosing information

:* '''75 mg/day'''<ref name="pmid19289640">Massie BM, Collins JF, Ammon SE, Armstrong PW, Cleland JG, Ezekowitz M et al. (2009) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=19289640 Randomized trial of warfarin, aspirin, and clopidogrel in patients with chronic heart failure: the Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial.] ''Circulation'' 119 (12):1616-24. [http://dx.doi.org/10.1161/CIRCULATIONAHA.108.801753 DOI:10.1161/CIRCULATIONAHA.108.801753] PMID: [http://pubmed.gov/19289640 19289640]</ref>

<b>[[Stasis ulcer]]<b>

* Dosing information

:* Recommended dosage: '''75 mg/day for 2-4 weeks'''<ref name="pmid11190899">Bick RL, Scott RG (2001) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=11190899 Stasis ulcers refractory to therapy--accelerated healing by treatment with clopidogrel +/- dalteparin: a preliminary report.] ''Clin Appl Thromb Hemost'' 7 (1):21-4. PMID: [http://pubmed.gov/11190899 11190899]</ref>
|offLabelPedGuideSupport=There is limited information about the guideline-supported use.

:* (Dosage)
|offLabelPedNoGuideSupport=<b>Prophylaxis of Arterial thrombosis</b>

* Dosing Information

:* Recommended dosage: '''0.2 mg/kg/day'''<ref name="pmid18195173">Li JS, Yow E, Berezny KY, Bokesch PM, Takahashi M, Graham TP et al. (2008) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=18195173 Dosing of clopidogrel for platelet inhibition in infants and young children: primary results of the Platelet Inhibition in Children On Clopidogrel (PICOLO) trial.] ''Circulation'' 117 (4):553-9. [http://dx.doi.org/10.1161/CIRCULATIONAHA.107.715821 DOI:10.1161/CIRCULATIONAHA.107.715821] PMID: [http://pubmed.gov/18195173 18195173]</ref>
|contraindications=* Active [[Bleeding]]

:* Clopidogrel is contraindicated in patients with active pathological bleeding such as [[peptic ulcer]] or [[intracranial hemorrhage]].

* [[Hypersensitivity]]

:* Clopidogrel tablets are contraindicated in patients with [[hypersensitivity]] (e.g., [[anaphylaxis]]) to clopidogrel or any component of the product.
|warnings=*'''Diminished Antiplatelet Activity Due to Impaired CYP2C19 Function'''

:* Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is achieved through an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by genetic variations in CYP2C19 and by concomitant medications that interfere with CYP2C19.

* '''Proton Pump Inhibitors'''

:* Avoid concomitant use of clopidogrel with [[omeprazole]] or [[esomeprazole]] because both significantly reduce the antiplatelet activity of clopidogrel.

* '''General Risk of Bleeding'''

:* [[Thienopyridines]], including clopidogrel, increase the risk of bleeding. If a patient is to undergo surgery and an antiplatelet effect is not desired, discontinue clopidogrel five days prior to surgery. In patients who stopped therapy more than five days prior to [[CABG]] the rates of major bleeding were similar (event rate 4.4% clopidogrel + [[aspirin]]; 5.3% placebo + [[aspirin]]). In patients who remained on therapy within five days of CABG, the major bleeding rate was 9.6% for clopidogrel + [[aspirin]], and 6.3% for placebo + [[aspirin]].
:* [[Thienopyridines]] inhibit platelet aggregation for the lifetime of the platelet (7 to 10 days), so withholding a dose will not be useful in managing a bleeding event or the risk of bleeding associated with an invasive procedure. Because the half-life of clopidogrel's active metabolite is short, it may be possible to restore hemostasis by administering exogenous platelets; however, platelet transfusions within 4 hours of the loading dose or 2 hours of the maintenance dose may be less effective.

* '''Discontinuation of Clopidogrel'''

:* Avoid lapses in therapy, and if clopidogrel must be temporarily discontinued, restart as soon as possible. Premature discontinuation of clopidogrel may increase the risk of cardiovascular events.

* '''Patients With Recent [[Transient Ischemic Attack]] ([[TIA]]) or [[Stroke]]'''

:* In patients with recent [[TIA]] or stroke who are at high risk for recurrent ischemic events, the combination of [[aspirin]] and clopidogrel has not been shown to be more effective than clopidogrel alone, but the combination has been shown to increase major bleeding.

* '''Thrombotic Thrombocytopenic Purpura (TTP)'''

:* [[Thrombotic Thrombocytopenic Purpura|TTP]], sometimes fatal, has been reported following use of clopidogrel, sometimes after a short exposure (< 2 weeks). TTP is a serious condition that requires urgent treatment including [[plasmapheresis]] (plasma exchange). It is characterized by [[thrombocytopenia]], [[microangiopathic hemolytic anemia]] ([[schistocytes]] [fragmented RBCs] seen on peripheral smear), neurological findings, renal dysfunction, and fever.

* '''Cross-Reactivity Among Thienopyridines'''

:* [[Hypersensitivity]] including [[rash]], [[angioedema]] or hematologic reaction have been reported in patients receiving clopidogrel, including patients with a history of [[hypersensitivity]] or hematologic reaction to other [[thienopyridines]].
|clinicalTrials=Because clinical trials are conducted under widely varying conditions and durations of follow up, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Clopidogrel bisulfate has been evaluated for safety in more than 54,000 patients, including over 21,000 patients treated for 1 year or more. The clinically important adverse reactions observed in trials comparing clopidogrel plus aspirin to placebo plus aspirin and trials comparing clopidogrel bisulfate alone to aspirin alone are discussed below.

'''''Bleeding'''''

* '''CURE'''

:* In CURE, clopidogrel bisulfate use with aspirin was associated with an increase in major bleeding (primarily [[gastrointestinal bleeding]] and at puncture sites) compared to placebo with aspirin. The incidence of [[intracranial hemorrhage]] (0.1%) and fatal bleeding (0.2%) were the same in both groups. Other bleeding events that were reported more frequently in the clopidogrel group were [[epistaxis]], [[hematuria]], and bruise.
The overall incidence of bleeding is described in Table 1.
:* Ninety-two percent (92%) of the patients in the CURE study received [[heparin]] or [[low molecular weight heparin]] (LMWH), and the rate of bleeding in these patients was similar to the overall results.

* '''COMMIT'''
:* In COMMIT, similar rates of major bleeding were observed in the clopidogrel bisulfate and placebo groups, both of which also received aspirin.

[[File:Clopidogrel_adverse_01.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

:* Ninety-two percent (92%) of the patients in the CURE study received heparin or low molecular weight heparin (LMWH), and the rate of bleeding in these patients was similar to the overall results.

'''''COMMIT'''''

:* In COMMIT, similar rates of major bleeding were observed in the clopidogrel bisulfate and placebo groups, both of which also received aspirin.

[[File:Clopidogrel_adverse_02.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

* '''CAPRIE (Clopidogrel bisulfate vs. Aspirin)'''

:* In CAPRIE, gastrointestinal hemorrhage occurred at a rate of 2.0% in those taking clopidogrel bisulfate vs. 2.7% in those taking aspirin; bleeding requiring hospitalization occurred in 0.7% and 1.1%, respectively. The incidence of intracranial hemorrhage was 0.4% for clopidogrel bisulfate compared to 0.5% for aspirin.
:* Other bleeding events that were reported more frequently in the clopidogrel bisulfate group were epistaxis and hematoma.

* <sub>Other Adverse Events</sub>

:* In CURE and CHARISMA, which compared clopidogrel bisulfate plus aspirin to aspirin alone, there was no difference in the rate of adverse events (other than bleeding) between clopidogrel bisulfate and placebo.
:* In CAPRIE, which compared clopidogrel bisulfate to aspirin, pruritus was more frequently reported in those taking clopidogrel bisulfate. No other difference in the rate of adverse events (other than bleeding) was reported.
|postmarketing=The following adverse reactions have been identified during post-approval use of clopidogrel. Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Blood and lymphatic system disorders: [[Agranulocytosis]], [[aplastic anemia]]/[[pancytopenia]], [[thrombotic thrombocytopenic purpura]] ([[TTP]]), acquired [[hemophilia A]]
* Eye disorders: Eye (conjunctival, ocular, retinal) bleeding
* Gastrointestinal disorders: Gastrointestinal and [[retroperitoneal hemorrhage]] with fatal outcome, [[colitis]] (including ulcerative or [[lymphocytic colitis]]), [[pancreatitis]], [[stomatitis]], gastric/duodenal ulcer, [[diarrhea]]
* General disorders and administration site condition: [[Fever]], [[hemorrhage]] of operative wound
* Hepato-biliary disorders: [[Acute liver failure]], [[hepatitis]] (non-infectious), abnormal liver function test
* Immune system disorders: [[Hypersensitivity reactions]], [[anaphylactoid reactions]], [[serum sickness]]
* Musculoskeletal, connective tissue and bone disorders: Musculoskeletal bleeding, [[myalgia]], [[arthralgia]], [[arthritis]]
* Nervous system disorders: Taste disorders, fatal [[intracranial bleeding]], [[headache]]
* Psychiatric disorders: [[Confusion]], [[hallucinations]]
* Respiratory, thoracic and mediastinal disorders: [[Bronchospasm]], [[interstitial pneumonitis]], [[respiratory tract bleeding]], [[eosinophilic pneumonia]]
* Renal and urinary disorders: Increased creatinine levels
* Skin and subcutaneous tissue disorders: [[Maculopapular]], [[erythematous]] or exfoliative rash, [[urticaria]], [[bullous dermatitis]], [[eczema]], toxic [[epidermal necrolysis]], [[Stevens-Johnson syndrome]], [[angioedema]], drug-induced hypersensitivity syndrome, [[drug rash]] with [[eosinophilia]] and systemic symptoms (DRESS), [[erythema multiforme]], skin bleeding, [[lichen planus]], [[generalized pruritus]]
* Vascular disorders: [[Vasculitis]], [[hypotension]]
|drugInteractions======CYP2C19 Inhibitors=====
:* Clopidogrel is metabolized to its active metabolite in part by [[CYP2C19]]. Concomitant use of certain drugs that inhibit the activity of this enzyme results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition.

=====Proton Pump Inhibitors (PPI)=====

::* Avoid concomitant use of clopidogrel with [[omeprazole]] or [[esomeprazole]]. In clinical studies, [[omeprazole]] was shown to reduce the antiplatelet activity of clopidogrel when given concomitantly or 12 hours apart. A higher dose regimen of clopidogrel concomitantly administered with [[omeprazole]] increases antiplatelet response; an appropriate dose regimen has not been established. A similar reduction in antiplatelet activity was observed with [[esomeprazole]] when given concomitantly with clopidogrel. Consider using another acid-reducing agent with minimal or no CYP2C19 inhibitory effect on the formation of clopidogrel active metabolite. [[Dexlansoprazole]], [[lansoprazole]] and [[pantoprazole]] had less effect on the antiplatelet activity of clopidogrel than did [[omeprazole]] or [[esomeprazole]].

=====Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)=====
:* Coadministration of clopidogrel and [[NSAIDs]] increases the risk of [[gastrointestinal bleeding]].

=====Warfarin (CYP2C9 Substrates)=====
:* Although the administration of clopidogrel 75 mg per day did not modify the pharmacokinetics of S-warfarin (a [[CYP2C9]] substrate) or INR in patients receiving long-term [[warfarin]] therapy, coadministration of clopidogrel with warfarin increases the risk of bleeding because of independent effects on [[hemostasis]].
:* However, at high concentrations in vitro, clopidogrel inhibits [[CYP2C9]].

=====SSRIs and SNRIs=====
:* Since [[selective serotonin reuptake inhibitors]] ([[SSRIs]]) and [[serotonin norepinephrine reuptake inhibitors]] ([[SNRIs]]) affect platelet activation, the concomitant administration of SSRIs and SNRIs with clopidogrel may increase the risk of bleeding.
|FDAPregCat=B
|useInPregnancyFDA=Reproduction studies performed in rats and rabbits at doses up to 500 and 300 mg/kg/day, respectively (65 and 78 times the recommended daily human dose, respectively, on a mg/m2 basis), revealed no evidence of impaired fertility or fetotoxicity due to clopidogrel. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of a human response, clopidogrel should be used during pregnancy only if clearly needed.
|useInNursing=Studies in rats have shown that clopidogrel and/or its metabolites are excreted in the milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from clopidogrel, 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.
|useInPed=Safety and effectiveness in pediatric populations have not been established.
Additional information describing a clinical study in which efficacy was not demonstrated in neonates and infants is approved in the package insert for Bristol-Myers Squibb’s clopidogrel tablets. However, due to Bristol-Myers Squibb’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.
|useInGeri=Of the total number of subjects in the CAPRIE and CURE controlled clinical studies, approximately 50% of patients treated with clopidogrel were 65 years of age and older, and 15% were 75 years and older. In COMMIT, approximately 58% of the patients treated with clopidogrel were 60 years and older, 26% of whom were 70 years and older.
The observed risk of bleeding events with clopidogrel plus aspirin versus placebo plus aspirin by age category is provided in Table 1 and Table 2 for the CURE and COMMIT trials, respectively. No dosage adjustment is necessary in elderly patients.
|useInRenalImpair=Experience is limited in patients with severe and moderate [[renal impairment]].
|useInHepaticImpair=No dosage adjustment is necessary in patients with [[hepatic impairment]].
|administration======Acute Coronary Syndrome=====

Clopidogrel tablets USP can be administered with or without food.
For patients with [[NSTEMI|non-ST-elevation]] ACS (UA/[[NSTEMI]]), initiate clopidogrel tablets USP with a single 300 mg oral loading dose and then continue at 75 mg once daily. Initiate [[aspirin]] (75 to 325 mg once daily) and continue in combination with clopidogrel tablets USP.
For patients with STEMI, the recommended dose of clopidogrel tablets USP is 75 mg once daily orally, administered in combination with [[aspirin]] (75 to 325 mg once daily), with or without thrombolytics. Clopidogrel tablets USP may be initiated with or without a loading dose.

=====Recent MI, Recent Stroke, or Established Peripheral Arterial Disease=====

The recommended daily dose of clopidogrel tablets USP is 75 mg once daily orally, with or without food.

=====CYP2C19 Poor Metabolizers=====

CYP2C19 poor metabolizer status is associated with diminished antiplatelet response to clopidogrel. Although a higher dose regimen in poor metabolizers increases antiplatelet response, an appropriate dose regimen for this patient population has not been established.

=====Use With Proton Pump Inhibitors (PPI)=====

Avoid using [[omeprazole]] or [[esomeprazole]] with clopidogrel tablets USP. [[Omeprazole]] and [[esomeprazole]] significantly reduce the antiplatelet activity of clopidogrel tablets USP. When concomitant administration of a PPI is required, consider using another acid-reducing agent with minimal or no CYP2C19 inhibitory effect on the formation of clopidogrel active metabolite.
|overdose=Platelet inhibition by clopidogrel is irreversible and will last for the life of the platelet. Overdose following clopidogrel administration may result in bleeding complications. A single oral dose of clopidogrel at 1500 or 2000 mg/kg was lethal to mice and to rats and at 3000 mg/kg to baboons. Symptoms of acute toxicity were [[vomiting]], [[prostration]], difficult breathing, and [[gastrointestinal hemorrhage]] in animals.
Based on biological plausibility, platelet transfusion may restore clotting ability.
|drugBox={{drugbox2 | verifiedrevid = 460044539
| IUPAC_name = (+)-(''S'')-methyl 2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-''c'']pyridin-5(4''H'')-yl)acetate
| image = S-Clopidogrel structure.svg
| width = 200
| image2 = Clopidogrel 3D.png
| width2 = 200


| tradename = Plavix
| Drugs.com = {{drugs.com|monograph|plavix}}
| MedlinePlus = a601040
| pregnancy_AU = B1
| pregnancy_US = B
| pregnancy_category =
| legal_AU = S4
| legal_UK = POM
| legal_US = Rx-only
| legal_status =
| routes_of_administration = Oral
| licence_US = Plavix


| bioavailability = >50%
| protein_bound = 94–98%
| metabolism = [[Liver|Hepatic]]
| elimination_half-life = 7–8 hours (inactive metabolite)
| excretion = 50% [[renal]]<br />46% [[biliary]]


| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 113665-84-2
| ATC_prefix = B01
| ATC_suffix = AC04
| PubChem = 60606
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00758
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 54632
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = A74586SNO7
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D07729
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 37941
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1771


| C=16 | H=16 | Cl=1 | N=1 | O=2 | S=1
| molecular_weight = 321.82 g/mol
| smiles = COC(=O)[C@H](c1ccccc1Cl)N2CCc3c(ccs3)C2
| InChI = 1/C16H16ClNO2S/c1-20-16(19)15(12-4-2-3-5-13(12)17)18-8-6-14-11(10-18)7-9-21-14/h2-5,7,9,15H,6,8,10H2,1H3/t15-/m0/s1
| InChIKey = GKTWGGQPFAXNFI-HNNXBMFYBE
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C16H16ClNO2S/c1-20-16(19)15(12-4-2-3-5-13(12)17)18-8-6-14-11(10-18)7-9-21-14/h2-5,7,9,15H,6,8,10H2,1H3/t15-/m0/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = GKTWGGQPFAXNFI-HNNXBMFYSA-N
}}
|mechAction=Clopidogrel is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Y12 class of ADP receptors on platelets.
|structure=Clopidogrel bisulfate, USP is a thienopyridine class inhibitor of P2Y12 ADP platelet receptors. Chemically it is methyl (+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate sulfate (1:1).
The structural formula is as follows:

[[File:Clopidogrel_pharmacology_01.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

C16H16ClNO2S•H2SO4 M.W. 419.9
Clopidogrel bisulfate, USP is a white to off-white powder. It is practically insoluble in water at neutral pH but freely soluble at pH 1. It also dissolves freely in methanol, dissolves sparingly in methylene chloride, and is practically insoluble in ethyl ether. It has a specific optical rotation of about +56°.
Clopidogrel bisulfate, USP for oral administration is provided as light-pink to pink, debossed, film-coated, capsule shaped tablets containing 97.875 mg of clopidogrel bisulfate, USP which is the molar equivalent of 75 mg of clopidogrel base.
Each tablet contains the following inactive ingredients: crospovidone, hydrogenated vegetable oil, hydroxypropyl cellulose, hypromellose, indigo carmine aluminum lake FD&C blue #2, iron oxide red, iron oxide yellow, lactose, lactose monohydrate, microcrystalline cellulose, polyethylene glycol, sodium lauryl sulfate, and titanium dioxide.
|PD=Clopidogrel must be metabolized by CYP450 enzymes to produce the active metabolite that inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y12 receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. This action is irreversible. Consequently, platelets exposed to clopidogrel’s active metabolite are affected for the remainder of their lifespan (about 7 to 10 days). Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of platelet activation by released ADP.
Dose-dependent inhibition of platelet aggregation can be seen 2 hours after single oral doses of clopidogrel. Repeated doses of 75 mg clopidogrel per day inhibit ADP-induced platelet aggregation on the first day, and inhibition reaches steady state between Day 3 and Day 7. At steady state, the average inhibition level observed with a dose of 75 mg clopidogrel per day was between 40% and 60%. Platelet aggregation and bleeding time gradually return to baseline values after treatment is discontinued, generally in about 5 days.

'''''Geriatric Patients'''''

Elderly (≥ 75 years) and young healthy subjects had similar effects on platelet aggregation.

'''''Renally-Impaired Patients'''''

After repeated doses of 75 mg clopidogrel per day, patients with severe renal impairment (creatinine clearance from 5 to 15 mL/min) and moderate renal impairment (creatinine clearance from 30 to 60 mL/min) showed low (25%) inhibition of ADP-induced platelet aggregation.

'''''Hepatically-Impaired Patients'''''

After repeated doses of 75 mg clopidogrel per day for 10 days in patients with severe hepatic impairment, inhibition of ADP-induced platelet aggregation was similar to that observed in healthy subjects.

'''''Gender'''''

In a small study comparing men and women, less inhibition of ADP-induced platelet aggregation was observed in women.
|PK=Clopidogrel is a prodrug and is metabolized to a pharmacologically active metabolite and inactive metabolites.

'''''Absorption'''''
* After single and repeated oral doses of 75 mg per day, clopidogrel is rapidly absorbed. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites.

'''''Effect of Food'''''
* Clopidogrel can be administered with or without food. In a study in healthy male subjects when clopidogrel 75 mg per day was given with a standard breakfast, mean inhibition of ADP-induced platelet aggregation was reduced by less than 9%. The active metabolite AUC0-24 was unchanged in the presence of food, while there was a 57% decrease in active metabolite Cmax. Similar results were observed when a clopidogrel 300 mg loading dose was administered with a high-fat breakfast.

'''''Metabolism'''''
* Clopidogrel is extensively metabolized by two main metabolic pathways: one mediated by esterases and leading to hydrolysis into an inactive carboxylic acid derivative (85% of circulating metabolites) and one mediated by multiple cytochrome P450 enzymes. Cytochromes first oxidize clopidogrel to a 2-oxo-clopidogrel intermediate metabolite. Subsequent metabolism of the 2-oxo-clopidogrel intermediate metabolite results in formation of the active metabolite, a thiol derivative of clopidogrel. This metabolic pathway is mediated by CYP2C19, CYP3A, CYP2B6 and CYP1A2. The active thiol metabolite binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation for the lifespan of the platelet.

* The Cmax of the active metabolite is twice as high following a single 300 mg clopidogrel loading dose as it is after four days of 75 mg maintenance dose. Cmax occurs approximately 30 to 60 minutes after dosing. In the 75 to 300 mg dose range, the pharmacokinetics of the active metabolite deviates from dose proportionality: increasing the dose by a factor of four results in 2.0 and 2.7 fold increases in Cmax and AUC, respectively.

'''''Elimination'''''

* Following an oral dose of 14C-labeled clopidogrel in humans, approximately 50% of total radioactivity was excreted in urine and approximately 46% in feces over the 5 days post-dosing. After a single, oral dose of 75 mg, clopidogrel has a half-life of approximately 6 hours. The half-life of the active metabolite is about 30 minutes.

'''''Drug Interactions'''''

* Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of certain inhibitors of this enzyme results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition.

'''''Proton Pump Inhibitors (PPI)'''''

* The effect of proton pump inhibitors (PPI) on the systemic exposure to the clopidogrel active metabolite following multiple doses of clopidogrel 75 mg evaluated in dedicated drug interaction studies is presented in Figure 1.
|nonClinToxic=There was no evidence of tumorigenicity when clopidogrel was administered for 78 weeks to mice and 104 weeks to rats at dosages up to 77 mg/kg per day, which afforded plasma exposures > 25 times that in humans at the recommended daily dose of 75 mg.
Clopidogrel was not genotoxic in four in vitro tests (Ames test, DNA-repair test in rat hepatocytes, gene mutation assay in Chinese hamster fibroblasts, and metaphase chromosome analysis of human lymphocytes) and in one in vivo test (micronucleus test by oral route in mice).
Clopidogrel was found to have no effect on fertility of male and female rats at oral doses up to 400 mg/kg per day (52 times the recommended human dose on a mg/m2 basis).
|clinicalStudies======Acute Coronary Syndrome=====

''CURE''

The CURE study included 12,562 patients with ACS without ST-elevation (UA or NSTEMI) and presenting within 24 hours of onset of the most recent episode of chest pain or symptoms consistent with ischemia. Patients were required to have either ECG changes compatible with new ischemia (without ST-elevation) or elevated cardiac enzymes or troponin I or T to at least twice the upper limit of normal. The patient population was largely Caucasian (82%) and included 38% women, and 52% patients ≥ 65 years of age.
Patients were randomized to receive clopidogrel (300 mg loading dose followed by 75 mg once daily) or placebo, and were treated for up to one year. Patients also received aspirin (75 to 325 mg once daily) and other standard therapies such as heparin. The use of GPIIb/IIIa inhibitors was not permitted for three days prior to randomization.
The number of patients experiencing the primary outcome (CV death, MI, or stroke) was 582 (9.3%) in the clopidogrel-treated group and 719 (11.4%) in the placebo-treated group, a 20% relative risk reduction (95% CI of 10% to 28%; p < 0.001) for the clopidogrel-treated group.

[[File:Clopidogrel_pharmacology_01.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

Most of the benefit of clopidogrel occurred in the first two months, but the difference from placebo was maintained throughout the course of the trial (up to 12 months).

[[File:Clopidogrel_pharmacology_02.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

In CURE, the use of clopidogrel was associated with a lower incidence of CV death, MI or stroke in patient populations with different characteristics, as shown in Figure 3. The benefits associated with clopidogrel were independent of the use of other acute and long-term cardiovascular therapies, including heparin/LMWH, intravenous glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors, lipid-lowering drugs, beta-blockers, and ACE-inhibitors. The efficacy of clopidogrel was observed independently of the dose of aspirin (75 to 325 mg once daily). The use of oral anticoagulants, non-study antiplatelet drugs, and chronic NSAIDs was not allowed in CURE.

[[File:Clopidogrel_pharmacology_03.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

The use of clopidogrel in CURE was associated with a decrease in the use of thrombolytic therapy (71 patients [1.1%] in the clopidogrel group, 126 patients [2.0%] in the placebo group; relative risk reduction of 43%), and GPIIb/IIIa inhibitors (369 patients [5.9%] in the clopidogrel group, 454 patients [7.2%] in the placebo group, relative risk reduction of 18%). The use of clopidogrel in CURE did not affect the number of patients treated with CABG or PCI (with or without stenting), (2253 patients [36.0%] in the clopidogrel group, 2324 patients [36.9%] in the placebo group; relative risk reduction of 4.0%).

''COMMIT''

In patients with STEMI, the safety and efficacy of clopidogrel were evaluated in the randomized, placebo-controlled, double-blind study, COMMIT. COMMIT included 45,852 patients presenting within 24 hours of the onset of the symptoms of myocardial infarction with supporting ECG abnormalities (i.e., ST-elevation, ST-depression or left bundle-branch block). Patients were randomized to receive clopidogrel (75 mg once daily) or placebo, in combination with aspirin (162 mg per day), for 28 days or until hospital discharge, whichever came first.
The primary endpoints were death from any cause and the first occurrence of re-infarction, stroke or death.
The patient population included 28% women, 58% age ≥ 60 years (26% age ≥ 70 years), 55% patients who received thrombolytics, 68% who received ACE-inhibitors, and only 3% who underwent PCI.
As shown in Table 5 and Figures 4 and 5 below, clopidogrel significantly reduced the relative risk of death from any cause by 7% (p = 0.029), and the relative risk of the combination of re-infarction, stroke or death by 9% (p = 0.002).

[[File:Clopidogrel_pharmacology_04.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

[[File:Clopidogrel_pharmacology_05.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

[[File:Clopidogrel_pharmacology_06.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

* All treated patients received aspirin.

The effect of clopidogrel did not differ significantly in various pre-specified subgroups as shown in Figure 6. The effect was also similar in non-prespecified subgroups including those based on infarct location, Killip class or prior MI history. Such subgroup analyses should be interpreted cautiously.

[[File:Clopidogrel_pharmacology_07.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

* Three similar-sized prognostic index groups were based on absolute risk of primary composite outcome for each patient calculated from baseline prognostic variables (excluding allocated treatments) with a Cox regression model.

[[File:Clopidogrel_pharmacology_08.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

=====Recent Myocardial Infarction, Recent Stroke, or Established Peripheral Arterial Disease=====

''CAPRIE''

The CAPRIE trial was a 19,185 patient, 304 center, international, randomized, double-blind, parallel-group study comparing clopidogrel (75 mg daily) to aspirin (325 mg daily). The patients randomized had: 1) recent histories of myocardial infarction (within 35 days); 2) recent histories of ischemic stroke (within 6 months) with at least a week of residual neurological signs; or 3) established peripheral arterial disease. Patients received randomized treatment for an average of 1.6 years (maximum of 3 years).
The trial's primary outcome was the time to first occurrence of new ischemic stroke (fatal or not), new myocardial infarction (fatal or not), or other vascular death. Deaths not easily attributable to nonvascular causes were all classified as vascular.

[[File:Clopidogrel_pharmacology_09.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

As shown in Table 6, clopidogrel was associated with a lower incidence of outcome events, primarily MI. The overall relative risk reduction (9.8% vs. 10.6%) was 8.7%, p = 0.045. Similar results were obtained when all-cause mortality and all-cause strokes were counted instead of vascular mortality and ischemic strokes (risk reduction 6.9%). In patients who survived an on-study stroke or myocardial infarction, the incidence of subsequent events was lower in the clopidogrel group.
The curves showing the overall event rate are shown in Figure 8. The event curves separated early and continued to diverge over the 3 year follow-up period.

[[File:Clopidogrel_pharmacology_10.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

The statistical significance favoring clopidogrel over aspirin was marginal (p = 0.045). However, because aspirin is itself effective in reducing cardiovascular events in patients with recent myocardial infarction or stroke, the effect of clopidogrel is substantial.
The CAPRIE trial included a population that was randomized on the basis of 3 entry criteria. The efficacy of clopidogrel relative to aspirin was heterogeneous across these randomized subgroups (p = 0.043). It is not clear whether this difference is real or a chance occurrence. Although the CAPRIE trial was not designed to evaluate the relative benefit of clopidogrel over aspirin in the individual patient subgroups, the benefit appeared to be strongest in patients who were enrolled because of peripheral vascular disease (especially those who also had a history of myocardial infarction) and weaker in stroke patients. In patients who were enrolled in the trial on the sole basis of a recent myocardial infarction, clopidogrel was not numerically superior to aspirin.

=====Lack of Established Benefit of Clopidogrel Plus Aspirin in Patients With Multiple Risk Factors or Established Vascular Disease=====

''CHARISMA''

The CHARISMA trial was a 15,603 subject, randomized, double-blind, parallel group study comparing clopidogrel (75 mg daily) to placebo for prevention of ischemic events in patients with vascular disease or multiple risk factors for atherosclerosis. All subjects were treated with aspirin 75 to 162 mg daily. The mean duration of treatment was 23 months. The study failed to demonstrate a reduction in the occurrence of the primary endpoint, a composite of CV death, MI, or stroke. A total of 534 (6.9%) patients in the clopidogrel group versus 573 (7.4%) patients in the placebo group experienced a primary outcome event (p = 0.22). Bleeding of all severities was more common in the subjects randomized to clopidogrel.
|howSupplied=Clopidogrel tablets USP are available as follows:
75 mg – light-pink to pink, film-coated, capsule shaped tablets debossed with “TV” on one side and “7314” on the other side, in bottles of 30, 90, and 500.
|storage=Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).
|fdaPatientInfo=For patient information about clopidogrel, click [[Clopidogrel (patient information)|here]].
|alcohol=Alcohol-Clopidogrel interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|nlmPatientInfo=For patient information about clopidogrel from NLM, click [[Clopidogrel (patient information)|here]].
}}
{{PillImage
|fileName=Clopidogrel 75 mg NDC 0093-7314.JPG
|drugName=Clopidogrel 75 MG (as clopidogrel bisulfate 97.875 MG) Oral Tablet
|NDC=0093-7314
|drugAuthor=Teva Pharmaceuticals USA Inc
|ingredients=crospovidone, hydrogenated cottonseed oil, hydroxypropyl cellulose (type h), hypromellose 2910 (15 mpa.s), indigotindisulfonate sodium, aluminum oxide, fd&c blue no. 2, ferric oxide red, ferric oxide yellow, lactose, lactose monohydrate, cellulose, microcrystalline, polyethylene glycol 4000, sodium lauryl sulfate, titanium dioxide
|pillImprint=TV;7314
|dosageValue=75
|dosageUnit=mg
|pillColor=Pink
|pillShape=Oval
|pillSize=13.00
|pillScore=1
}}
{{LabelImage
|fileName=Clopidogrel_label_01.jpg
}}
{{LabelImage
|fileName=Clopidogrel_panel_01.jpg
}}
[[Category:ADP receptor inhibitors]]
[[Category:Antiplatelet drugs]]
[[Category:Cardiovascular Drugs]]
[[Category:Drug]]
[[Category:Thienopyridines]]

Clopidogrel

2015-03-19T18:06:52Z

Sree Teja Yelamanchili:

{{DrugProjectFormSinglePage
|authorTag={{SS}}; {{STY}}
|genericName=Clopidogrel
|aOrAn=a
|drugClass=[[P2Y12]] platelet inhibitor, [[platelet aggregation inhibitor]]
|indicationType=treatment
|indication=[[acute coronary syndrome]] ([[ACS]]), recent [[MI]], recent [[stroke]], or established [[peripheral arterial disease]]
|hasBlackBoxWarning=Yes
|adverseReactions=non-major [[bleeding]]
|blackBoxWarningTitle=<span style="color:#FF0000;">WARNING: DIMINISHED EFFECTIVENESS IN POOR METABOLIZERS</span>
|blackBoxWarningBody=* Effectiveness of clopidogrel depends on activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19.
* Poor metabolizers treated with clopidogrel at recommended doses exhibit higher cardiovascular event rates following acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) than patients with normal CYP2C19 function.
* Tests are available to identify a patient's CYP2C19 genotype and can be used as an aid in determining therapeutic strategy.
* Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers.
|fdaLIADAdult=<h4>[[Acute Coronary Syndrome]]</h4>

* For patients with non-ST-elevation ACS

:* Initial loading dosage: '''300 mg PO '''
:* Maitaining dosage: '''75 mg PO qd'''
:* In combination with: '''Aspirin 75-300 mg PO qd'''

* For patients with STEMI

:* Recommended dosage: '''75 mg PO qd''' (With or without the loading dosage)
:* In combination with: '''Aspirin 75-300 mg PO qd'''

<h4>Recent [[MI]], Recent [[Stroke]], or Established [[Peripheral Arterial Disease]]</h4>

* Dosing information

:* '''75 mg PO qd'''
|offLabelAdultGuideSupport=There is limited information about the guideline-supported use.
|offLabelAdultNoGuideSupport=<b>Prophylaxis of ThrombosisAtrial in patient with Atrial Fibrillation</b>

* Dosing Information

:* '''75 mg/day''' incombination with '''[[aspirin]] 75-100 mg'''<ref name="pmid19336502">ACTIVE Investigators. Connolly SJ, Pogue J, Hart RG, Hohnloser SH, Pfeffer M et al. (2009) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=19336502 Effect of clopidogrel added to aspirin in patients with atrial fibrillation.] ''N Engl J Med'' 360 (20):2066-78. [http://dx.doi.org/10.1056/NEJMoa0901301 DOI:10.1056/NEJMoa0901301] PMID: [http://pubmed.gov/19336502 19336502]</ref>

<b>Prophylaxis of Thrombosis in patient with Chronical Heart failure</b>

* Dosing information

:* '''75 mg/day'''<ref name="pmid19289640">Massie BM, Collins JF, Ammon SE, Armstrong PW, Cleland JG, Ezekowitz M et al. (2009) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=19289640 Randomized trial of warfarin, aspirin, and clopidogrel in patients with chronic heart failure: the Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial.] ''Circulation'' 119 (12):1616-24. [http://dx.doi.org/10.1161/CIRCULATIONAHA.108.801753 DOI:10.1161/CIRCULATIONAHA.108.801753] PMID: [http://pubmed.gov/19289640 19289640]</ref>

<h4>Stasis ulcer</h4>

* Dosing information

:* Recommended dosage: '''75 mg/day for 2-4 weeks'''<ref name="pmid11190899">Bick RL, Scott RG (2001) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=11190899 Stasis ulcers refractory to therapy--accelerated healing by treatment with clopidogrel +/- dalteparin: a preliminary report.] ''Clin Appl Thromb Hemost'' 7 (1):21-4. PMID: [http://pubmed.gov/11190899 11190899]</ref>
|fdaLIADPed=<b>Condition 1</b>

* Dosing Information

:: (Dosage)
|offLabelPedGuideSupport=There is limited information about the guideline-supported use.

:* (Dosage)
|offLabelPedNoGuideSupport=<b>Prophylaxis of Arterial thrombosis</b>

* Dosing Information

:* Recommended dosage: '''0.2 mg/kg/day'''<ref name="pmid18195173">Li JS, Yow E, Berezny KY, Bokesch PM, Takahashi M, Graham TP et al. (2008) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=18195173 Dosing of clopidogrel for platelet inhibition in infants and young children: primary results of the Platelet Inhibition in Children On Clopidogrel (PICOLO) trial.] ''Circulation'' 117 (4):553-9. [http://dx.doi.org/10.1161/CIRCULATIONAHA.107.715821 DOI:10.1161/CIRCULATIONAHA.107.715821] PMID: [http://pubmed.gov/18195173 18195173]</ref>
|contraindications=* Active [[Bleeding]]

:* Clopidogrel is contraindicated in patients with active pathological bleeding such as [[peptic ulcer]] or [[intracranial hemorrhage]].

* [[Hypersensitivity]]

:* Clopidogrel tablets are contraindicated in patients with [[hypersensitivity]] (e.g., [[anaphylaxis]]) to clopidogrel or any component of the product.
|warnings=* '''Diminished Antiplatelet Activity Due to Impaired CYP2C19 Function'''

:* Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is achieved through an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by genetic variations in CYP2C19 and by concomitant medications that interfere with CYP2C19.

* ''[[Proton Pump Inhibitors]]''

:* Avoid concomitant use of clopidogrel with [[omeprazole]] or [[esomeprazole]] because both significantly reduce the antiplatelet activity of clopidogrel.

* '''General Risk of Bleeding'''

:* [[Thienopyridines]], including clopidogrel, increase the risk of bleeding. If a patient is to undergo surgery and an antiplatelet effect is not desired, discontinue clopidogrel five days prior to surgery. In patients who stopped therapy more than five days prior to [[CABG]] the rates of major bleeding were similar (event rate 4.4% clopidogrel + [[aspirin]]; 5.3% placebo + [[aspirin]]). In patients who remained on therapy within five days of CABG, the major bleeding rate was 9.6% for clopidogrel + [[aspirin]], and 6.3% for placebo + [[aspirin]].
:* [[Thienopyridines]] inhibit platelet aggregation for the lifetime of the platelet (7 to 10 days), so withholding a dose will not be useful in managing a bleeding event or the risk of bleeding associated with an invasive procedure. Because the half-life of clopidogrel's active metabolite is short, it may be possible to restore hemostasis by administering exogenous platelets; however, platelet transfusions within 4 hours of the loading dose or 2 hours of the maintenance dose may be less effective.

* '''Discontinuation of Clopidogrel'''

:* Avoid lapses in therapy, and if clopidogrel must be temporarily discontinued, restart as soon as possible. Premature discontinuation of clopidogrel may increase the risk of cardiovascular events.

* '''Patients With Recent [[Transient Ischemic Attack]] ([[TIA]]) or [[Stroke]]'''

:* In patients with recent [[TIA]] or stroke who are at high risk for recurrent ischemic events, the combination of [[aspirin]] and clopidogrel has not been shown to be more effective than clopidogrel alone, but the combination has been shown to increase major bleeding.

* '''[[Thrombotic Thrombocytopenic Purpura]] ([[TTP]])'''

:* [[TTP]], sometimes fatal, has been reported following use of clopidogrel, sometimes after a short exposure (< 2 weeks). TTP is a serious condition that requires urgent treatment including [[plasmapheresis]] (plasma exchange). It is characterized by [[thrombocytopenia]], microangiopathic hemolytic [[anemia]] (schistocytes [fragmented RBCs] seen on peripheral smear), neurological findings, renal dysfunction, and fever.

* '''Cross-Reactivity Among [[Thienopyridines]]'''

:* [[Hypersensitivity]] including [[rash]], [[angioedema]] or hematologic reaction have been reported in patients receiving clopidogrel, including patients with a history of [[hypersensitivity]] or hematologic reaction to other [[thienopyridines]].
|clinicalTrials=Because clinical trials are conducted under widely varying conditions and durations of follow up, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Clopidogrel bisulfate has been evaluated for safety in more than 54,000 patients, including over 21,000 patients treated for 1 year or more. The clinically important adverse reactions observed in trials comparing clopidogrel plus aspirin to placebo plus aspirin and trials comparing clopidogrel bisulfate alone to aspirin alone are discussed below.

'''''Bleeding'''''

* '''CURE'''

:* In CURE, clopidogrel bisulfate use with aspirin was associated with an increase in major bleeding (primarily [[gastrointestinal bleeding]] and at puncture sites) compared to placebo with aspirin. The incidence of [[intracranial hemorrhage]] (0.1%) and fatal bleeding (0.2%) were the same in both groups. Other bleeding events that were reported more frequently in the clopidogrel group were [[epistaxis]], [[hematuria]], and bruise.
The overall incidence of bleeding is described in Table 1.
:* Ninety-two percent (92%) of the patients in the CURE study received [[heparin]] or [[low molecular weight heparin]] (LMWH), and the rate of bleeding in these patients was similar to the overall results.

* '''COMMIT'''
:* In COMMIT, similar rates of major bleeding were observed in the clopidogrel bisulfate and placebo groups, both of which also received aspirin.

[[File:Clopidogrel_adverse_01.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

:* Ninety-two percent (92%) of the patients in the CURE study received heparin or low molecular weight heparin (LMWH), and the rate of bleeding in these patients was similar to the overall results.

'''''COMMIT'''''

:* In COMMIT, similar rates of major bleeding were observed in the clopidogrel bisulfate and placebo groups, both of which also received aspirin.

[[File:Clopidogrel_adverse_02.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

* '''CAPRIE (Clopidogrel bisulfate vs. Aspirin)'''

:* In CAPRIE, gastrointestinal hemorrhage occurred at a rate of 2.0% in those taking clopidogrel bisulfate vs. 2.7% in those taking aspirin; bleeding requiring hospitalization occurred in 0.7% and 1.1%, respectively. The incidence of intracranial hemorrhage was 0.4% for clopidogrel bisulfate compared to 0.5% for aspirin.
:* Other bleeding events that were reported more frequently in the clopidogrel bisulfate group were epistaxis and hematoma.

* <sub>Other Adverse Events</sub>

:* In CURE and CHARISMA, which compared clopidogrel bisulfate plus aspirin to aspirin alone, there was no difference in the rate of adverse events (other than bleeding) between clopidogrel bisulfate and placebo.
:* In CAPRIE, which compared clopidogrel bisulfate to aspirin, pruritus was more frequently reported in those taking clopidogrel bisulfate. No other difference in the rate of adverse events (other than bleeding) was reported.
|postmarketing=The following adverse reactions have been identified during post-approval use of clopidogrel. Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Blood and lymphatic system disorders: [[Agranulocytosis]], [[aplastic anemia]]/[[pancytopenia]], [[thrombotic thrombocytopenic purpura]] ([[TTP]]), acquired [[hemophilia A]]
* Eye disorders: Eye (conjunctival, ocular, retinal) bleeding
* Gastrointestinal disorders: Gastrointestinal and [[retroperitoneal hemorrhage]] with fatal outcome, [[colitis]] (including ulcerative or [[lymphocytic colitis]]), [[pancreatitis]], [[stomatitis]], gastric/duodenal ulcer, [[diarrhea]]
* General disorders and administration site condition: [[Fever]], [[hemorrhage]] of operative wound
* Hepato-biliary disorders: [[Acute liver failure]], [[hepatitis]] (non-infectious), abnormal liver function test
* Immune system disorders: [[Hypersensitivity reactions]], [[anaphylactoid reactions]], [[serum sickness]]
* Musculoskeletal, connective tissue and bone disorders: Musculoskeletal bleeding, [[myalgia]], [[arthralgia]], [[arthritis]]
* Nervous system disorders: Taste disorders, fatal [[intracranial bleeding]], [[headache]]
* Psychiatric disorders: [[Confusion]], [[hallucinations]]
* Respiratory, thoracic and mediastinal disorders: [[Bronchospasm]], [[interstitial pneumonitis]], [[respiratory tract bleeding]], [[eosinophilic pneumonia]]
* Renal and urinary disorders: Increased creatinine levels
* Skin and subcutaneous tissue disorders: [[Maculopapular]], [[erythematous]] or exfoliative rash, [[urticaria]], [[bullous dermatitis]], [[eczema]], toxic [[epidermal necrolysis]], [[Stevens-Johnson syndrome]], [[angioedema]], drug-induced hypersensitivity syndrome, [[drug rash]] with [[eosinophilia]] and systemic symptoms (DRESS), [[erythema multiforme]], skin bleeding, [[lichen planus]], [[generalized pruritus]]
* Vascular disorders: [[Vasculitis]], [[hypotension]]
|drugInteractions======CYP2C19 Inhibitors=====
:* Clopidogrel is metabolized to its active metabolite in part by [[CYP2C19]]. Concomitant use of certain drugs that inhibit the activity of this enzyme results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition.

=====Proton Pump Inhibitors (PPI)=====

::* Avoid concomitant use of clopidogrel with [[omeprazole]] or [[esomeprazole]]. In clinical studies, [[omeprazole]] was shown to reduce the antiplatelet activity of clopidogrel when given concomitantly or 12 hours apart. A higher dose regimen of clopidogrel concomitantly administered with [[omeprazole]] increases antiplatelet response; an appropriate dose regimen has not been established. A similar reduction in antiplatelet activity was observed with [[esomeprazole]] when given concomitantly with clopidogrel. Consider using another acid-reducing agent with minimal or no CYP2C19 inhibitory effect on the formation of clopidogrel active metabolite. [[Dexlansoprazole]], [[lansoprazole]] and [[pantoprazole]] had less effect on the antiplatelet activity of clopidogrel than did [[omeprazole]] or [[esomeprazole]].

=====Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)=====
:* Coadministration of clopidogrel and [[NSAIDs]] increases the risk of [[gastrointestinal bleeding]].

=====Warfarin (CYP2C9 Substrates)=====
:* Although the administration of clopidogrel 75 mg per day did not modify the pharmacokinetics of S-warfarin (a [[CYP2C9]] substrate) or INR in patients receiving long-term [[warfarin]] therapy, coadministration of clopidogrel with warfarin increases the risk of bleeding because of independent effects on [[hemostasis]].
:* However, at high concentrations in vitro, clopidogrel inhibits [[CYP2C9]].

=====SSRIs and SNRIs=====
:* Since [[selective serotonin reuptake inhibitors]] ([[SSRIs]]) and [[serotonin norepinephrine reuptake inhibitors]] ([[SNRIs]]) affect platelet activation, the concomitant administration of SSRIs and SNRIs with clopidogrel may increase the risk of bleeding.
|FDAPregCat=B
|useInPregnancyFDA=Reproduction studies performed in rats and rabbits at doses up to 500 and 300 mg/kg/day, respectively (65 and 78 times the recommended daily human dose, respectively, on a mg/m2 basis), revealed no evidence of impaired fertility or fetotoxicity due to clopidogrel. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of a human response, clopidogrel should be used during pregnancy only if clearly needed.
|useInNursing=Studies in rats have shown that clopidogrel and/or its metabolites are excreted in the milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from clopidogrel, 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.
|useInPed=Safety and effectiveness in pediatric populations have not been established.
Additional information describing a clinical study in which efficacy was not demonstrated in neonates and infants is approved in the package insert for Bristol-Myers Squibb’s clopidogrel tablets. However, due to Bristol-Myers Squibb’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.
|useInGeri=Of the total number of subjects in the CAPRIE and CURE controlled clinical studies, approximately 50% of patients treated with clopidogrel were 65 years of age and older, and 15% were 75 years and older. In COMMIT, approximately 58% of the patients treated with clopidogrel were 60 years and older, 26% of whom were 70 years and older.
The observed risk of bleeding events with clopidogrel plus aspirin versus placebo plus aspirin by age category is provided in Table 1 and Table 2 for the CURE and COMMIT trials, respectively. No dosage adjustment is necessary in elderly patients.
|useInRenalImpair=Experience is limited in patients with severe and moderate [[renal impairment]].
|useInHepaticImpair=No dosage adjustment is necessary in patients with [[hepatic impairment]].
|administration======Acute Coronary Syndrome=====

Clopidogrel tablets USP can be administered with or without food.
For patients with [[NSTEMI|non-ST-elevation]] ACS (UA/[[NSTEMI]]), initiate clopidogrel tablets USP with a single 300 mg oral loading dose and then continue at 75 mg once daily. Initiate [[aspirin]] (75 to 325 mg once daily) and continue in combination with clopidogrel tablets USP.
For patients with STEMI, the recommended dose of clopidogrel tablets USP is 75 mg once daily orally, administered in combination with [[aspirin]] (75 to 325 mg once daily), with or without thrombolytics. Clopidogrel tablets USP may be initiated with or without a loading dose.

=====Recent MI, Recent Stroke, or Established Peripheral Arterial Disease=====

The recommended daily dose of clopidogrel tablets USP is 75 mg once daily orally, with or without food.

=====CYP2C19 Poor Metabolizers=====

CYP2C19 poor metabolizer status is associated with diminished antiplatelet response to clopidogrel. Although a higher dose regimen in poor metabolizers increases antiplatelet response, an appropriate dose regimen for this patient population has not been established.

=====Use With Proton Pump Inhibitors (PPI)=====

Avoid using [[omeprazole]] or [[esomeprazole]] with clopidogrel tablets USP. [[Omeprazole]] and [[esomeprazole]] significantly reduce the antiplatelet activity of clopidogrel tablets USP. When concomitant administration of a PPI is required, consider using another acid-reducing agent with minimal or no CYP2C19 inhibitory effect on the formation of clopidogrel active metabolite.
|overdose=Platelet inhibition by clopidogrel is irreversible and will last for the life of the platelet. Overdose following clopidogrel administration may result in bleeding complications. A single oral dose of clopidogrel at 1500 or 2000 mg/kg was lethal to mice and to rats and at 3000 mg/kg to baboons. Symptoms of acute toxicity were [[vomiting]], [[prostration]], difficult breathing, and [[gastrointestinal hemorrhage]] in animals.
Based on biological plausibility, platelet transfusion may restore clotting ability.
|drugBox={{drugbox2 | verifiedrevid = 460044539
| IUPAC_name = (+)-(''S'')-methyl 2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-''c'']pyridin-5(4''H'')-yl)acetate
| image = S-Clopidogrel structure.svg
| width = 200
| image2 = Clopidogrel 3D.png
| width2 = 200


| tradename = Plavix
| Drugs.com = {{drugs.com|monograph|plavix}}
| MedlinePlus = a601040
| pregnancy_AU = B1
| pregnancy_US = B
| pregnancy_category =
| legal_AU = S4
| legal_UK = POM
| legal_US = Rx-only
| legal_status =
| routes_of_administration = Oral
| licence_US = Plavix


| bioavailability = >50%
| protein_bound = 94–98%
| metabolism = [[Liver|Hepatic]]
| elimination_half-life = 7–8 hours (inactive metabolite)
| excretion = 50% [[renal]]<br />46% [[biliary]]


| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 113665-84-2
| ATC_prefix = B01
| ATC_suffix = AC04
| PubChem = 60606
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00758
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 54632
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = A74586SNO7
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D07729
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 37941
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1771


| C=16 | H=16 | Cl=1 | N=1 | O=2 | S=1
| molecular_weight = 321.82 g/mol
| smiles = COC(=O)[C@H](c1ccccc1Cl)N2CCc3c(ccs3)C2
| InChI = 1/C16H16ClNO2S/c1-20-16(19)15(12-4-2-3-5-13(12)17)18-8-6-14-11(10-18)7-9-21-14/h2-5,7,9,15H,6,8,10H2,1H3/t15-/m0/s1
| InChIKey = GKTWGGQPFAXNFI-HNNXBMFYBE
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C16H16ClNO2S/c1-20-16(19)15(12-4-2-3-5-13(12)17)18-8-6-14-11(10-18)7-9-21-14/h2-5,7,9,15H,6,8,10H2,1H3/t15-/m0/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = GKTWGGQPFAXNFI-HNNXBMFYSA-N
}}
|mechAction=Clopidogrel is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Y12 class of ADP receptors on platelets.
|structure=Clopidogrel bisulfate, USP is a thienopyridine class inhibitor of P2Y12 ADP platelet receptors. Chemically it is methyl (+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate sulfate (1:1).
The structural formula is as follows:

[[File:Clopidogrel_pharmacology_01.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

C16H16ClNO2S•H2SO4 M.W. 419.9
Clopidogrel bisulfate, USP is a white to off-white powder. It is practically insoluble in water at neutral pH but freely soluble at pH 1. It also dissolves freely in methanol, dissolves sparingly in methylene chloride, and is practically insoluble in ethyl ether. It has a specific optical rotation of about +56°.
Clopidogrel bisulfate, USP for oral administration is provided as light-pink to pink, debossed, film-coated, capsule shaped tablets containing 97.875 mg of clopidogrel bisulfate, USP which is the molar equivalent of 75 mg of clopidogrel base.
Each tablet contains the following inactive ingredients: crospovidone, hydrogenated vegetable oil, hydroxypropyl cellulose, hypromellose, indigo carmine aluminum lake FD&C blue #2, iron oxide red, iron oxide yellow, lactose, lactose monohydrate, microcrystalline cellulose, polyethylene glycol, sodium lauryl sulfate, and titanium dioxide.
|PD=Clopidogrel must be metabolized by CYP450 enzymes to produce the active metabolite that inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y12 receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. This action is irreversible. Consequently, platelets exposed to clopidogrel’s active metabolite are affected for the remainder of their lifespan (about 7 to 10 days). Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of platelet activation by released ADP.
Dose-dependent inhibition of platelet aggregation can be seen 2 hours after single oral doses of clopidogrel. Repeated doses of 75 mg clopidogrel per day inhibit ADP-induced platelet aggregation on the first day, and inhibition reaches steady state between Day 3 and Day 7. At steady state, the average inhibition level observed with a dose of 75 mg clopidogrel per day was between 40% and 60%. Platelet aggregation and bleeding time gradually return to baseline values after treatment is discontinued, generally in about 5 days.

'''''Geriatric Patients'''''

Elderly (≥ 75 years) and young healthy subjects had similar effects on platelet aggregation.

'''''Renally-Impaired Patients'''''

After repeated doses of 75 mg clopidogrel per day, patients with severe renal impairment (creatinine clearance from 5 to 15 mL/min) and moderate renal impairment (creatinine clearance from 30 to 60 mL/min) showed low (25%) inhibition of ADP-induced platelet aggregation.

'''''Hepatically-Impaired Patients'''''

After repeated doses of 75 mg clopidogrel per day for 10 days in patients with severe hepatic impairment, inhibition of ADP-induced platelet aggregation was similar to that observed in healthy subjects.

'''''Gender'''''

In a small study comparing men and women, less inhibition of ADP-induced platelet aggregation was observed in women.
|PK=Clopidogrel is a prodrug and is metabolized to a pharmacologically active metabolite and inactive metabolites.

'''''Absorption'''''
* After single and repeated oral doses of 75 mg per day, clopidogrel is rapidly absorbed. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites.

'''''Effect of Food'''''
* Clopidogrel can be administered with or without food. In a study in healthy male subjects when clopidogrel 75 mg per day was given with a standard breakfast, mean inhibition of ADP-induced platelet aggregation was reduced by less than 9%. The active metabolite AUC0-24 was unchanged in the presence of food, while there was a 57% decrease in active metabolite Cmax. Similar results were observed when a clopidogrel 300 mg loading dose was administered with a high-fat breakfast.

'''''Metabolism'''''
* Clopidogrel is extensively metabolized by two main metabolic pathways: one mediated by esterases and leading to hydrolysis into an inactive carboxylic acid derivative (85% of circulating metabolites) and one mediated by multiple cytochrome P450 enzymes. Cytochromes first oxidize clopidogrel to a 2-oxo-clopidogrel intermediate metabolite. Subsequent metabolism of the 2-oxo-clopidogrel intermediate metabolite results in formation of the active metabolite, a thiol derivative of clopidogrel. This metabolic pathway is mediated by CYP2C19, CYP3A, CYP2B6 and CYP1A2. The active thiol metabolite binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation for the lifespan of the platelet.

* The Cmax of the active metabolite is twice as high following a single 300 mg clopidogrel loading dose as it is after four days of 75 mg maintenance dose. Cmax occurs approximately 30 to 60 minutes after dosing. In the 75 to 300 mg dose range, the pharmacokinetics of the active metabolite deviates from dose proportionality: increasing the dose by a factor of four results in 2.0 and 2.7 fold increases in Cmax and AUC, respectively.

'''''Elimination'''''

* Following an oral dose of 14C-labeled clopidogrel in humans, approximately 50% of total radioactivity was excreted in urine and approximately 46% in feces over the 5 days post-dosing. After a single, oral dose of 75 mg, clopidogrel has a half-life of approximately 6 hours. The half-life of the active metabolite is about 30 minutes.

'''''Drug Interactions'''''

* Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of certain inhibitors of this enzyme results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition.

'''''Proton Pump Inhibitors (PPI)'''''

* The effect of proton pump inhibitors (PPI) on the systemic exposure to the clopidogrel active metabolite following multiple doses of clopidogrel 75 mg evaluated in dedicated drug interaction studies is presented in Figure 1.
|nonClinToxic=There was no evidence of tumorigenicity when clopidogrel was administered for 78 weeks to mice and 104 weeks to rats at dosages up to 77 mg/kg per day, which afforded plasma exposures > 25 times that in humans at the recommended daily dose of 75 mg.
Clopidogrel was not genotoxic in four in vitro tests (Ames test, DNA-repair test in rat hepatocytes, gene mutation assay in Chinese hamster fibroblasts, and metaphase chromosome analysis of human lymphocytes) and in one in vivo test (micronucleus test by oral route in mice).
Clopidogrel was found to have no effect on fertility of male and female rats at oral doses up to 400 mg/kg per day (52 times the recommended human dose on a mg/m2 basis).
|clinicalStudies======Acute Coronary Syndrome=====

''CURE''

The CURE study included 12,562 patients with ACS without ST-elevation (UA or NSTEMI) and presenting within 24 hours of onset of the most recent episode of chest pain or symptoms consistent with ischemia. Patients were required to have either ECG changes compatible with new ischemia (without ST-elevation) or elevated cardiac enzymes or troponin I or T to at least twice the upper limit of normal. The patient population was largely Caucasian (82%) and included 38% women, and 52% patients ≥ 65 years of age.
Patients were randomized to receive clopidogrel (300 mg loading dose followed by 75 mg once daily) or placebo, and were treated for up to one year. Patients also received aspirin (75 to 325 mg once daily) and other standard therapies such as heparin. The use of GPIIb/IIIa inhibitors was not permitted for three days prior to randomization.
The number of patients experiencing the primary outcome (CV death, MI, or stroke) was 582 (9.3%) in the clopidogrel-treated group and 719 (11.4%) in the placebo-treated group, a 20% relative risk reduction (95% CI of 10% to 28%; p < 0.001) for the clopidogrel-treated group.

[[File:Clopidogrel_pharmacology_01.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

Most of the benefit of clopidogrel occurred in the first two months, but the difference from placebo was maintained throughout the course of the trial (up to 12 months).

[[File:Clopidogrel_pharmacology_02.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

In CURE, the use of clopidogrel was associated with a lower incidence of CV death, MI or stroke in patient populations with different characteristics, as shown in Figure 3. The benefits associated with clopidogrel were independent of the use of other acute and long-term cardiovascular therapies, including heparin/LMWH, intravenous glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors, lipid-lowering drugs, beta-blockers, and ACE-inhibitors. The efficacy of clopidogrel was observed independently of the dose of aspirin (75 to 325 mg once daily). The use of oral anticoagulants, non-study antiplatelet drugs, and chronic NSAIDs was not allowed in CURE.

[[File:Clopidogrel_pharmacology_03.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

The use of clopidogrel in CURE was associated with a decrease in the use of thrombolytic therapy (71 patients [1.1%] in the clopidogrel group, 126 patients [2.0%] in the placebo group; relative risk reduction of 43%), and GPIIb/IIIa inhibitors (369 patients [5.9%] in the clopidogrel group, 454 patients [7.2%] in the placebo group, relative risk reduction of 18%). The use of clopidogrel in CURE did not affect the number of patients treated with CABG or PCI (with or without stenting), (2253 patients [36.0%] in the clopidogrel group, 2324 patients [36.9%] in the placebo group; relative risk reduction of 4.0%).

''COMMIT''

In patients with STEMI, the safety and efficacy of clopidogrel were evaluated in the randomized, placebo-controlled, double-blind study, COMMIT. COMMIT included 45,852 patients presenting within 24 hours of the onset of the symptoms of myocardial infarction with supporting ECG abnormalities (i.e., ST-elevation, ST-depression or left bundle-branch block). Patients were randomized to receive clopidogrel (75 mg once daily) or placebo, in combination with aspirin (162 mg per day), for 28 days or until hospital discharge, whichever came first.
The primary endpoints were death from any cause and the first occurrence of re-infarction, stroke or death.
The patient population included 28% women, 58% age ≥ 60 years (26% age ≥ 70 years), 55% patients who received thrombolytics, 68% who received ACE-inhibitors, and only 3% who underwent PCI.
As shown in Table 5 and Figures 4 and 5 below, clopidogrel significantly reduced the relative risk of death from any cause by 7% (p = 0.029), and the relative risk of the combination of re-infarction, stroke or death by 9% (p = 0.002).

[[File:Clopidogrel_pharmacology_04.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

[[File:Clopidogrel_pharmacology_05.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

[[File:Clopidogrel_pharmacology_06.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

* All treated patients received aspirin.

The effect of clopidogrel did not differ significantly in various pre-specified subgroups as shown in Figure 6. The effect was also similar in non-prespecified subgroups including those based on infarct location, Killip class or prior MI history. Such subgroup analyses should be interpreted cautiously.

[[File:Clopidogrel_pharmacology_07.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

* Three similar-sized prognostic index groups were based on absolute risk of primary composite outcome for each patient calculated from baseline prognostic variables (excluding allocated treatments) with a Cox regression model.

[[File:Clopidogrel_pharmacology_08.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

=====Recent Myocardial Infarction, Recent Stroke, or Established Peripheral Arterial Disease=====

''CAPRIE''

The CAPRIE trial was a 19,185 patient, 304 center, international, randomized, double-blind, parallel-group study comparing clopidogrel (75 mg daily) to aspirin (325 mg daily). The patients randomized had: 1) recent histories of myocardial infarction (within 35 days); 2) recent histories of ischemic stroke (within 6 months) with at least a week of residual neurological signs; or 3) established peripheral arterial disease. Patients received randomized treatment for an average of 1.6 years (maximum of 3 years).
The trial's primary outcome was the time to first occurrence of new ischemic stroke (fatal or not), new myocardial infarction (fatal or not), or other vascular death. Deaths not easily attributable to nonvascular causes were all classified as vascular.

[[File:Clopidogrel_pharmacology_09.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

As shown in Table 6, clopidogrel was associated with a lower incidence of outcome events, primarily MI. The overall relative risk reduction (9.8% vs. 10.6%) was 8.7%, p = 0.045. Similar results were obtained when all-cause mortality and all-cause strokes were counted instead of vascular mortality and ischemic strokes (risk reduction 6.9%). In patients who survived an on-study stroke or myocardial infarction, the incidence of subsequent events was lower in the clopidogrel group.
The curves showing the overall event rate are shown in Figure 8. The event curves separated early and continued to diverge over the 3 year follow-up period.

[[File:Clopidogrel_pharmacology_10.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

The statistical significance favoring clopidogrel over aspirin was marginal (p = 0.045). However, because aspirin is itself effective in reducing cardiovascular events in patients with recent myocardial infarction or stroke, the effect of clopidogrel is substantial.
The CAPRIE trial included a population that was randomized on the basis of 3 entry criteria. The efficacy of clopidogrel relative to aspirin was heterogeneous across these randomized subgroups (p = 0.043). It is not clear whether this difference is real or a chance occurrence. Although the CAPRIE trial was not designed to evaluate the relative benefit of clopidogrel over aspirin in the individual patient subgroups, the benefit appeared to be strongest in patients who were enrolled because of peripheral vascular disease (especially those who also had a history of myocardial infarction) and weaker in stroke patients. In patients who were enrolled in the trial on the sole basis of a recent myocardial infarction, clopidogrel was not numerically superior to aspirin.

=====Lack of Established Benefit of Clopidogrel Plus Aspirin in Patients With Multiple Risk Factors or Established Vascular Disease=====

''CHARISMA''

The CHARISMA trial was a 15,603 subject, randomized, double-blind, parallel group study comparing clopidogrel (75 mg daily) to placebo for prevention of ischemic events in patients with vascular disease or multiple risk factors for atherosclerosis. All subjects were treated with aspirin 75 to 162 mg daily. The mean duration of treatment was 23 months. The study failed to demonstrate a reduction in the occurrence of the primary endpoint, a composite of CV death, MI, or stroke. A total of 534 (6.9%) patients in the clopidogrel group versus 573 (7.4%) patients in the placebo group experienced a primary outcome event (p = 0.22). Bleeding of all severities was more common in the subjects randomized to clopidogrel.
|howSupplied=Clopidogrel tablets USP are available as follows:
75 mg – light-pink to pink, film-coated, capsule shaped tablets debossed with “TV” on one side and “7314” on the other side, in bottles of 30, 90, and 500.
|storage=Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).
|fdaPatientInfo=For patient information about clopidogrel, click [[Clopidogrel (patient information)|here]].
|alcohol=Alcohol-Clopidogrel interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|nlmPatientInfo=For patient information about clopidogrel from NLM, click [[Clopidogrel (patient information)|here]].
}}
{{PillImage
|fileName=Clopidogrel 75 mg NDC 0093-7314.JPG
|drugName=Clopidogrel 75 MG (as clopidogrel bisulfate 97.875 MG) Oral Tablet
|NDC=0093-7314
|drugAuthor=Teva Pharmaceuticals USA Inc
|ingredients=crospovidone, hydrogenated cottonseed oil, hydroxypropyl cellulose (type h), hypromellose 2910 (15 mpa.s), indigotindisulfonate sodium, aluminum oxide, fd&c blue no. 2, ferric oxide red, ferric oxide yellow, lactose, lactose monohydrate, cellulose, microcrystalline, polyethylene glycol 4000, sodium lauryl sulfate, titanium dioxide
|pillImprint=TV;7314
|dosageValue=75
|dosageUnit=mg
|pillColor=Pink
|pillShape=Oval
|pillSize=13.00
|pillScore=1
}}
{{LabelImage
|fileName=Clopidogrel_label_01.jpg
}}
{{LabelImage
|fileName=Clopidogrel_panel_01.jpg
}}
[[Category:ADP receptor inhibitors]]
[[Category:Antiplatelet drugs]]
[[Category:Cardiovascular Drugs]]
[[Category:Drug]]
[[Category:Thienopyridines]]

Clopidogrel

2015-03-19T18:04:09Z

Sree Teja Yelamanchili:

{{DrugProjectFormSinglePage
|authorTag={{SS}}
|genericName=Clopidogrel
|aOrAn=a
|drugClass=[[P2Y12]] platelet inhibitor, [[platelet aggregation inhibitor]]
|indicationType=treatment
|indication=[[acute coronary syndrome]] ([[ACS]]), recent [[MI]], recent [[stroke]], or established [[peripheral arterial disease]]
|hasBlackBoxWarning=Yes
|adverseReactions=non-major [[bleeding]]
|blackBoxWarningTitle=<span style="color:#FF0000;">WARNING: DIMINISHED EFFECTIVENESS IN POOR METABOLIZERS</span>
|blackBoxWarningBody=* Effectiveness of clopidogrel depends on activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19.
* Poor metabolizers treated with clopidogrel at recommended doses exhibit higher cardiovascular event rates following acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) than patients with normal CYP2C19 function.
* Tests are available to identify a patient's CYP2C19 genotype and can be used as an aid in determining therapeutic strategy.
* Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers.
|fdaLIADAdult=<h4>[[Acute Coronary Syndrome]]</h4>

* For patients with non-ST-elevation ACS

:* Initial loading dosage: '''300 mg PO '''
:* Maitaining dosage: '''75 mg PO qd'''
:* In combination with: '''Aspirin 75-300 mg PO qd'''

* For patients with STEMI

:* Recommended dosage: '''75 mg PO qd''' (With or without the loading dosage)
:* In combination with: '''Aspirin 75-300 mg PO qd'''

<h4>Recent [[MI]], Recent [[Stroke]], or Established [[Peripheral Arterial Disease]]</h4>

* Dosing information

:* '''75 mg PO qd'''
|offLabelAdultGuideSupport=There is limited information about the guideline-supported use.
|offLabelAdultNoGuideSupport=<b>Prophylaxis of ThrombosisAtrial in patient with Atrial Fibrillation</b>

* Dosing Information

:* '''75 mg/day''' incombination with '''[[aspirin]] 75-100 mg'''<ref name="pmid19336502">ACTIVE Investigators. Connolly SJ, Pogue J, Hart RG, Hohnloser SH, Pfeffer M et al. (2009) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=19336502 Effect of clopidogrel added to aspirin in patients with atrial fibrillation.] ''N Engl J Med'' 360 (20):2066-78. [http://dx.doi.org/10.1056/NEJMoa0901301 DOI:10.1056/NEJMoa0901301] PMID: [http://pubmed.gov/19336502 19336502]</ref>

<b>Prophylaxis of Thrombosis in patient with Chronical Heart failure</b>

* Dosing information

:* '''75 mg/day'''<ref name="pmid19289640">Massie BM, Collins JF, Ammon SE, Armstrong PW, Cleland JG, Ezekowitz M et al. (2009) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=19289640 Randomized trial of warfarin, aspirin, and clopidogrel in patients with chronic heart failure: the Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial.] ''Circulation'' 119 (12):1616-24. [http://dx.doi.org/10.1161/CIRCULATIONAHA.108.801753 DOI:10.1161/CIRCULATIONAHA.108.801753] PMID: [http://pubmed.gov/19289640 19289640]</ref>

<h4>Stasis ulcer</h4>

* Dosing information

:* Recommended dosage: '''75 mg/day for 2-4 weeks'''<ref name="pmid11190899">Bick RL, Scott RG (2001) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=11190899 Stasis ulcers refractory to therapy--accelerated healing by treatment with clopidogrel +/- dalteparin: a preliminary report.] ''Clin Appl Thromb Hemost'' 7 (1):21-4. PMID: [http://pubmed.gov/11190899 11190899]</ref>
|fdaLIADPed=<b>Condition 1</b>

* Dosing Information

:: (Dosage)
|offLabelPedGuideSupport=There is limited information about the guideline-supported use.

:* (Dosage)
|offLabelPedNoGuideSupport=<b>Prophylaxis of Arterial thrombosis</b>

* Dosing Information

:* Recommended dosage: '''0.2 mg/kg/day'''<ref name="pmid18195173">Li JS, Yow E, Berezny KY, Bokesch PM, Takahashi M, Graham TP et al. (2008) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=18195173 Dosing of clopidogrel for platelet inhibition in infants and young children: primary results of the Platelet Inhibition in Children On Clopidogrel (PICOLO) trial.] ''Circulation'' 117 (4):553-9. [http://dx.doi.org/10.1161/CIRCULATIONAHA.107.715821 DOI:10.1161/CIRCULATIONAHA.107.715821] PMID: [http://pubmed.gov/18195173 18195173]</ref>
|contraindications=* Active [[Bleeding]]

:* Clopidogrel is contraindicated in patients with active pathological bleeding such as [[peptic ulcer]] or [[intracranial hemorrhage]].

* [[Hypersensitivity]]

:* Clopidogrel tablets are contraindicated in patients with [[hypersensitivity]] (e.g., [[anaphylaxis]]) to clopidogrel or any component of the product.
|warnings=* '''Diminished Antiplatelet Activity Due to Impaired CYP2C19 Function'''

:* Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is achieved through an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by genetic variations in CYP2C19 and by concomitant medications that interfere with CYP2C19.

* ''[[Proton Pump Inhibitors]]''

:* Avoid concomitant use of clopidogrel with [[omeprazole]] or [[esomeprazole]] because both significantly reduce the antiplatelet activity of clopidogrel.

* '''General Risk of Bleeding'''

:* [[Thienopyridines]], including clopidogrel, increase the risk of bleeding. If a patient is to undergo surgery and an antiplatelet effect is not desired, discontinue clopidogrel five days prior to surgery. In patients who stopped therapy more than five days prior to [[CABG]] the rates of major bleeding were similar (event rate 4.4% clopidogrel + [[aspirin]]; 5.3% placebo + [[aspirin]]). In patients who remained on therapy within five days of CABG, the major bleeding rate was 9.6% for clopidogrel + [[aspirin]], and 6.3% for placebo + [[aspirin]].
:* [[Thienopyridines]] inhibit platelet aggregation for the lifetime of the platelet (7 to 10 days), so withholding a dose will not be useful in managing a bleeding event or the risk of bleeding associated with an invasive procedure. Because the half-life of clopidogrel's active metabolite is short, it may be possible to restore hemostasis by administering exogenous platelets; however, platelet transfusions within 4 hours of the loading dose or 2 hours of the maintenance dose may be less effective.

* '''Discontinuation of Clopidogrel'''

:* Avoid lapses in therapy, and if clopidogrel must be temporarily discontinued, restart as soon as possible. Premature discontinuation of clopidogrel may increase the risk of cardiovascular events.

* '''Patients With Recent [[Transient Ischemic Attack]] ([[TIA]]) or [[Stroke]]'''

:* In patients with recent [[TIA]] or stroke who are at high risk for recurrent ischemic events, the combination of [[aspirin]] and clopidogrel has not been shown to be more effective than clopidogrel alone, but the combination has been shown to increase major bleeding.

* '''[[Thrombotic Thrombocytopenic Purpura]] ([[TTP]])'''

:* [[TTP]], sometimes fatal, has been reported following use of clopidogrel, sometimes after a short exposure (< 2 weeks). TTP is a serious condition that requires urgent treatment including [[plasmapheresis]] (plasma exchange). It is characterized by [[thrombocytopenia]], microangiopathic hemolytic [[anemia]] (schistocytes [fragmented RBCs] seen on peripheral smear), neurological findings, renal dysfunction, and fever.

* '''Cross-Reactivity Among [[Thienopyridines]]'''

:* [[Hypersensitivity]] including [[rash]], [[angioedema]] or hematologic reaction have been reported in patients receiving clopidogrel, including patients with a history of [[hypersensitivity]] or hematologic reaction to other [[thienopyridines]].
|clinicalTrials=Because clinical trials are conducted under widely varying conditions and durations of follow up, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Clopidogrel bisulfate has been evaluated for safety in more than 54,000 patients, including over 21,000 patients treated for 1 year or more. The clinically important adverse reactions observed in trials comparing clopidogrel plus aspirin to placebo plus aspirin and trials comparing clopidogrel bisulfate alone to aspirin alone are discussed below.

'''''Bleeding'''''

* '''CURE'''

:* In CURE, clopidogrel bisulfate use with aspirin was associated with an increase in major bleeding (primarily [[gastrointestinal bleeding]] and at puncture sites) compared to placebo with aspirin. The incidence of [[intracranial hemorrhage]] (0.1%) and fatal bleeding (0.2%) were the same in both groups. Other bleeding events that were reported more frequently in the clopidogrel group were [[epistaxis]], [[hematuria]], and bruise.
The overall incidence of bleeding is described in Table 1.
:* Ninety-two percent (92%) of the patients in the CURE study received [[heparin]] or [[low molecular weight heparin]] (LMWH), and the rate of bleeding in these patients was similar to the overall results.

* '''COMMIT'''
:* In COMMIT, similar rates of major bleeding were observed in the clopidogrel bisulfate and placebo groups, both of which also received aspirin.

[[File:Clopidogrel_adverse_01.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

:* Ninety-two percent (92%) of the patients in the CURE study received heparin or low molecular weight heparin (LMWH), and the rate of bleeding in these patients was similar to the overall results.

'''''COMMIT'''''

:* In COMMIT, similar rates of major bleeding were observed in the clopidogrel bisulfate and placebo groups, both of which also received aspirin.

[[File:Clopidogrel_adverse_02.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

* '''CAPRIE (Clopidogrel bisulfate vs. Aspirin)'''

:* In CAPRIE, gastrointestinal hemorrhage occurred at a rate of 2.0% in those taking clopidogrel bisulfate vs. 2.7% in those taking aspirin; bleeding requiring hospitalization occurred in 0.7% and 1.1%, respectively. The incidence of intracranial hemorrhage was 0.4% for clopidogrel bisulfate compared to 0.5% for aspirin.
:* Other bleeding events that were reported more frequently in the clopidogrel bisulfate group were epistaxis and hematoma.

* <sub>Other Adverse Events</sub>

:* In CURE and CHARISMA, which compared clopidogrel bisulfate plus aspirin to aspirin alone, there was no difference in the rate of adverse events (other than bleeding) between clopidogrel bisulfate and placebo.
:* In CAPRIE, which compared clopidogrel bisulfate to aspirin, pruritus was more frequently reported in those taking clopidogrel bisulfate. No other difference in the rate of adverse events (other than bleeding) was reported.
|postmarketing=The following adverse reactions have been identified during post-approval use of clopidogrel. Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Blood and lymphatic system disorders: [[Agranulocytosis]], [[aplastic anemia]]/[[pancytopenia]], [[thrombotic thrombocytopenic purpura]] ([[TTP]]), acquired [[hemophilia A]]
* Eye disorders: Eye (conjunctival, ocular, retinal) bleeding
* Gastrointestinal disorders: Gastrointestinal and [[retroperitoneal hemorrhage]] with fatal outcome, [[colitis]] (including ulcerative or [[lymphocytic colitis]]), [[pancreatitis]], [[stomatitis]], gastric/duodenal ulcer, [[diarrhea]]
* General disorders and administration site condition: [[Fever]], [[hemorrhage]] of operative wound
* Hepato-biliary disorders: [[Acute liver failure]], [[hepatitis]] (non-infectious), abnormal liver function test
* Immune system disorders: [[Hypersensitivity reactions]], [[anaphylactoid reactions]], [[serum sickness]]
* Musculoskeletal, connective tissue and bone disorders: Musculoskeletal bleeding, [[myalgia]], [[arthralgia]], [[arthritis]]
* Nervous system disorders: Taste disorders, fatal [[intracranial bleeding]], [[headache]]
* Psychiatric disorders: [[Confusion]], [[hallucinations]]
* Respiratory, thoracic and mediastinal disorders: [[Bronchospasm]], [[interstitial pneumonitis]], [[respiratory tract bleeding]], [[eosinophilic pneumonia]]
* Renal and urinary disorders: Increased creatinine levels
* Skin and subcutaneous tissue disorders: [[Maculopapular]], [[erythematous]] or exfoliative rash, [[urticaria]], [[bullous dermatitis]], [[eczema]], toxic [[epidermal necrolysis]], [[Stevens-Johnson syndrome]], [[angioedema]], drug-induced hypersensitivity syndrome, [[drug rash]] with [[eosinophilia]] and systemic symptoms (DRESS), [[erythema multiforme]], skin bleeding, [[lichen planus]], [[generalized pruritus]]
* Vascular disorders: [[Vasculitis]], [[hypotension]]
|drugInteractions======CYP2C19 Inhibitors=====
:* Clopidogrel is metabolized to its active metabolite in part by [[CYP2C19]]. Concomitant use of certain drugs that inhibit the activity of this enzyme results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition.

=====Proton Pump Inhibitors (PPI)=====

::* Avoid concomitant use of clopidogrel with [[omeprazole]] or [[esomeprazole]]. In clinical studies, [[omeprazole]] was shown to reduce the antiplatelet activity of clopidogrel when given concomitantly or 12 hours apart. A higher dose regimen of clopidogrel concomitantly administered with [[omeprazole]] increases antiplatelet response; an appropriate dose regimen has not been established. A similar reduction in antiplatelet activity was observed with [[esomeprazole]] when given concomitantly with clopidogrel. Consider using another acid-reducing agent with minimal or no CYP2C19 inhibitory effect on the formation of clopidogrel active metabolite. [[Dexlansoprazole]], [[lansoprazole]] and [[pantoprazole]] had less effect on the antiplatelet activity of clopidogrel than did [[omeprazole]] or [[esomeprazole]].

=====Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)=====
:* Coadministration of clopidogrel and [[NSAIDs]] increases the risk of [[gastrointestinal bleeding]].

=====Warfarin (CYP2C9 Substrates)=====
:* Although the administration of clopidogrel 75 mg per day did not modify the pharmacokinetics of S-warfarin (a [[CYP2C9]] substrate) or INR in patients receiving long-term [[warfarin]] therapy, coadministration of clopidogrel with warfarin increases the risk of bleeding because of independent effects on [[hemostasis]].
:* However, at high concentrations in vitro, clopidogrel inhibits [[CYP2C9]].

=====SSRIs and SNRIs=====
:* Since [[selective serotonin reuptake inhibitors]] ([[SSRIs]]) and [[serotonin norepinephrine reuptake inhibitors]] ([[SNRIs]]) affect platelet activation, the concomitant administration of SSRIs and SNRIs with clopidogrel may increase the risk of bleeding.
|FDAPregCat=B
|useInPregnancyFDA=Reproduction studies performed in rats and rabbits at doses up to 500 and 300 mg/kg/day, respectively (65 and 78 times the recommended daily human dose, respectively, on a mg/m2 basis), revealed no evidence of impaired fertility or fetotoxicity due to clopidogrel. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of a human response, clopidogrel should be used during pregnancy only if clearly needed.
|useInNursing=Studies in rats have shown that clopidogrel and/or its metabolites are excreted in the milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from clopidogrel, 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.
|useInPed=Safety and effectiveness in pediatric populations have not been established.
Additional information describing a clinical study in which efficacy was not demonstrated in neonates and infants is approved in the package insert for Bristol-Myers Squibb’s clopidogrel tablets. However, due to Bristol-Myers Squibb’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.
|useInGeri=Of the total number of subjects in the CAPRIE and CURE controlled clinical studies, approximately 50% of patients treated with clopidogrel were 65 years of age and older, and 15% were 75 years and older. In COMMIT, approximately 58% of the patients treated with clopidogrel were 60 years and older, 26% of whom were 70 years and older.
The observed risk of bleeding events with clopidogrel plus aspirin versus placebo plus aspirin by age category is provided in Table 1 and Table 2 for the CURE and COMMIT trials, respectively. No dosage adjustment is necessary in elderly patients.
|useInRenalImpair=Experience is limited in patients with severe and moderate [[renal impairment]].
|useInHepaticImpair=No dosage adjustment is necessary in patients with [[hepatic impairment]].
|administration======Acute Coronary Syndrome=====

Clopidogrel tablets USP can be administered with or without food.
For patients with [[NSTEMI|non-ST-elevation]] ACS (UA/[[NSTEMI]]), initiate clopidogrel tablets USP with a single 300 mg oral loading dose and then continue at 75 mg once daily. Initiate [[aspirin]] (75 to 325 mg once daily) and continue in combination with clopidogrel tablets USP.
For patients with STEMI, the recommended dose of clopidogrel tablets USP is 75 mg once daily orally, administered in combination with [[aspirin]] (75 to 325 mg once daily), with or without thrombolytics. Clopidogrel tablets USP may be initiated with or without a loading dose.

=====Recent MI, Recent Stroke, or Established Peripheral Arterial Disease=====

The recommended daily dose of clopidogrel tablets USP is 75 mg once daily orally, with or without food.

=====CYP2C19 Poor Metabolizers=====

CYP2C19 poor metabolizer status is associated with diminished antiplatelet response to clopidogrel. Although a higher dose regimen in poor metabolizers increases antiplatelet response, an appropriate dose regimen for this patient population has not been established.

=====Use With Proton Pump Inhibitors (PPI)=====

Avoid using [[omeprazole]] or [[esomeprazole]] with clopidogrel tablets USP. [[Omeprazole]] and [[esomeprazole]] significantly reduce the antiplatelet activity of clopidogrel tablets USP. When concomitant administration of a PPI is required, consider using another acid-reducing agent with minimal or no CYP2C19 inhibitory effect on the formation of clopidogrel active metabolite.
|overdose=Platelet inhibition by clopidogrel is irreversible and will last for the life of the platelet. Overdose following clopidogrel administration may result in bleeding complications. A single oral dose of clopidogrel at 1500 or 2000 mg/kg was lethal to mice and to rats and at 3000 mg/kg to baboons. Symptoms of acute toxicity were [[vomiting]], [[prostration]], difficult breathing, and [[gastrointestinal hemorrhage]] in animals.
Based on biological plausibility, platelet transfusion may restore clotting ability.
|drugBox={{drugbox2 | verifiedrevid = 460044539
| IUPAC_name = (+)-(''S'')-methyl 2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-''c'']pyridin-5(4''H'')-yl)acetate
| image = S-Clopidogrel structure.svg
| width = 200
| image2 = Clopidogrel 3D.png
| width2 = 200


| tradename = Plavix
| Drugs.com = {{drugs.com|monograph|plavix}}
| MedlinePlus = a601040
| pregnancy_AU = B1
| pregnancy_US = B
| pregnancy_category =
| legal_AU = S4
| legal_UK = POM
| legal_US = Rx-only
| legal_status =
| routes_of_administration = Oral
| licence_US = Plavix


| bioavailability = >50%
| protein_bound = 94–98%
| metabolism = [[Liver|Hepatic]]
| elimination_half-life = 7–8 hours (inactive metabolite)
| excretion = 50% [[renal]]<br />46% [[biliary]]


| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 113665-84-2
| ATC_prefix = B01
| ATC_suffix = AC04
| PubChem = 60606
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00758
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 54632
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = A74586SNO7
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D07729
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 37941
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1771


| C=16 | H=16 | Cl=1 | N=1 | O=2 | S=1
| molecular_weight = 321.82 g/mol
| smiles = COC(=O)[C@H](c1ccccc1Cl)N2CCc3c(ccs3)C2
| InChI = 1/C16H16ClNO2S/c1-20-16(19)15(12-4-2-3-5-13(12)17)18-8-6-14-11(10-18)7-9-21-14/h2-5,7,9,15H,6,8,10H2,1H3/t15-/m0/s1
| InChIKey = GKTWGGQPFAXNFI-HNNXBMFYBE
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C16H16ClNO2S/c1-20-16(19)15(12-4-2-3-5-13(12)17)18-8-6-14-11(10-18)7-9-21-14/h2-5,7,9,15H,6,8,10H2,1H3/t15-/m0/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = GKTWGGQPFAXNFI-HNNXBMFYSA-N
}}
|mechAction=Clopidogrel is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Y12 class of ADP receptors on platelets.
|structure=Clopidogrel bisulfate, USP is a thienopyridine class inhibitor of P2Y12 ADP platelet receptors. Chemically it is methyl (+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate sulfate (1:1).
The structural formula is as follows:

[[File:Clopidogrel_pharmacology_01.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

C16H16ClNO2S•H2SO4 M.W. 419.9
Clopidogrel bisulfate, USP is a white to off-white powder. It is practically insoluble in water at neutral pH but freely soluble at pH 1. It also dissolves freely in methanol, dissolves sparingly in methylene chloride, and is practically insoluble in ethyl ether. It has a specific optical rotation of about +56°.
Clopidogrel bisulfate, USP for oral administration is provided as light-pink to pink, debossed, film-coated, capsule shaped tablets containing 97.875 mg of clopidogrel bisulfate, USP which is the molar equivalent of 75 mg of clopidogrel base.
Each tablet contains the following inactive ingredients: crospovidone, hydrogenated vegetable oil, hydroxypropyl cellulose, hypromellose, indigo carmine aluminum lake FD&C blue #2, iron oxide red, iron oxide yellow, lactose, lactose monohydrate, microcrystalline cellulose, polyethylene glycol, sodium lauryl sulfate, and titanium dioxide.
|PD=Clopidogrel must be metabolized by CYP450 enzymes to produce the active metabolite that inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y12 receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. This action is irreversible. Consequently, platelets exposed to clopidogrel’s active metabolite are affected for the remainder of their lifespan (about 7 to 10 days). Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of platelet activation by released ADP.
Dose-dependent inhibition of platelet aggregation can be seen 2 hours after single oral doses of clopidogrel. Repeated doses of 75 mg clopidogrel per day inhibit ADP-induced platelet aggregation on the first day, and inhibition reaches steady state between Day 3 and Day 7. At steady state, the average inhibition level observed with a dose of 75 mg clopidogrel per day was between 40% and 60%. Platelet aggregation and bleeding time gradually return to baseline values after treatment is discontinued, generally in about 5 days.

'''''Geriatric Patients'''''

Elderly (≥ 75 years) and young healthy subjects had similar effects on platelet aggregation.

'''''Renally-Impaired Patients'''''

After repeated doses of 75 mg clopidogrel per day, patients with severe renal impairment (creatinine clearance from 5 to 15 mL/min) and moderate renal impairment (creatinine clearance from 30 to 60 mL/min) showed low (25%) inhibition of ADP-induced platelet aggregation.

'''''Hepatically-Impaired Patients'''''

After repeated doses of 75 mg clopidogrel per day for 10 days in patients with severe hepatic impairment, inhibition of ADP-induced platelet aggregation was similar to that observed in healthy subjects.

'''''Gender'''''

In a small study comparing men and women, less inhibition of ADP-induced platelet aggregation was observed in women.
|PK=Clopidogrel is a prodrug and is metabolized to a pharmacologically active metabolite and inactive metabolites.

'''''Absorption'''''
* After single and repeated oral doses of 75 mg per day, clopidogrel is rapidly absorbed. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites.

'''''Effect of Food'''''
* Clopidogrel can be administered with or without food. In a study in healthy male subjects when clopidogrel 75 mg per day was given with a standard breakfast, mean inhibition of ADP-induced platelet aggregation was reduced by less than 9%. The active metabolite AUC0-24 was unchanged in the presence of food, while there was a 57% decrease in active metabolite Cmax. Similar results were observed when a clopidogrel 300 mg loading dose was administered with a high-fat breakfast.

'''''Metabolism'''''
* Clopidogrel is extensively metabolized by two main metabolic pathways: one mediated by esterases and leading to hydrolysis into an inactive carboxylic acid derivative (85% of circulating metabolites) and one mediated by multiple cytochrome P450 enzymes. Cytochromes first oxidize clopidogrel to a 2-oxo-clopidogrel intermediate metabolite. Subsequent metabolism of the 2-oxo-clopidogrel intermediate metabolite results in formation of the active metabolite, a thiol derivative of clopidogrel. This metabolic pathway is mediated by CYP2C19, CYP3A, CYP2B6 and CYP1A2. The active thiol metabolite binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation for the lifespan of the platelet.

* The Cmax of the active metabolite is twice as high following a single 300 mg clopidogrel loading dose as it is after four days of 75 mg maintenance dose. Cmax occurs approximately 30 to 60 minutes after dosing. In the 75 to 300 mg dose range, the pharmacokinetics of the active metabolite deviates from dose proportionality: increasing the dose by a factor of four results in 2.0 and 2.7 fold increases in Cmax and AUC, respectively.

'''''Elimination'''''

* Following an oral dose of 14C-labeled clopidogrel in humans, approximately 50% of total radioactivity was excreted in urine and approximately 46% in feces over the 5 days post-dosing. After a single, oral dose of 75 mg, clopidogrel has a half-life of approximately 6 hours. The half-life of the active metabolite is about 30 minutes.

'''''Drug Interactions'''''

* Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of certain inhibitors of this enzyme results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition.

'''''Proton Pump Inhibitors (PPI)'''''

* The effect of proton pump inhibitors (PPI) on the systemic exposure to the clopidogrel active metabolite following multiple doses of clopidogrel 75 mg evaluated in dedicated drug interaction studies is presented in Figure 1.
|nonClinToxic=There was no evidence of tumorigenicity when clopidogrel was administered for 78 weeks to mice and 104 weeks to rats at dosages up to 77 mg/kg per day, which afforded plasma exposures > 25 times that in humans at the recommended daily dose of 75 mg.
Clopidogrel was not genotoxic in four in vitro tests (Ames test, DNA-repair test in rat hepatocytes, gene mutation assay in Chinese hamster fibroblasts, and metaphase chromosome analysis of human lymphocytes) and in one in vivo test (micronucleus test by oral route in mice).
Clopidogrel was found to have no effect on fertility of male and female rats at oral doses up to 400 mg/kg per day (52 times the recommended human dose on a mg/m2 basis).
|clinicalStudies======Acute Coronary Syndrome=====

''CURE''

The CURE study included 12,562 patients with ACS without ST-elevation (UA or NSTEMI) and presenting within 24 hours of onset of the most recent episode of chest pain or symptoms consistent with ischemia. Patients were required to have either ECG changes compatible with new ischemia (without ST-elevation) or elevated cardiac enzymes or troponin I or T to at least twice the upper limit of normal. The patient population was largely Caucasian (82%) and included 38% women, and 52% patients ≥ 65 years of age.
Patients were randomized to receive clopidogrel (300 mg loading dose followed by 75 mg once daily) or placebo, and were treated for up to one year. Patients also received aspirin (75 to 325 mg once daily) and other standard therapies such as heparin. The use of GPIIb/IIIa inhibitors was not permitted for three days prior to randomization.
The number of patients experiencing the primary outcome (CV death, MI, or stroke) was 582 (9.3%) in the clopidogrel-treated group and 719 (11.4%) in the placebo-treated group, a 20% relative risk reduction (95% CI of 10% to 28%; p < 0.001) for the clopidogrel-treated group.

[[File:Clopidogrel_pharmacology_01.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

Most of the benefit of clopidogrel occurred in the first two months, but the difference from placebo was maintained throughout the course of the trial (up to 12 months).

[[File:Clopidogrel_pharmacology_02.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

In CURE, the use of clopidogrel was associated with a lower incidence of CV death, MI or stroke in patient populations with different characteristics, as shown in Figure 3. The benefits associated with clopidogrel were independent of the use of other acute and long-term cardiovascular therapies, including heparin/LMWH, intravenous glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors, lipid-lowering drugs, beta-blockers, and ACE-inhibitors. The efficacy of clopidogrel was observed independently of the dose of aspirin (75 to 325 mg once daily). The use of oral anticoagulants, non-study antiplatelet drugs, and chronic NSAIDs was not allowed in CURE.

[[File:Clopidogrel_pharmacology_03.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

The use of clopidogrel in CURE was associated with a decrease in the use of thrombolytic therapy (71 patients [1.1%] in the clopidogrel group, 126 patients [2.0%] in the placebo group; relative risk reduction of 43%), and GPIIb/IIIa inhibitors (369 patients [5.9%] in the clopidogrel group, 454 patients [7.2%] in the placebo group, relative risk reduction of 18%). The use of clopidogrel in CURE did not affect the number of patients treated with CABG or PCI (with or without stenting), (2253 patients [36.0%] in the clopidogrel group, 2324 patients [36.9%] in the placebo group; relative risk reduction of 4.0%).

''COMMIT''

In patients with STEMI, the safety and efficacy of clopidogrel were evaluated in the randomized, placebo-controlled, double-blind study, COMMIT. COMMIT included 45,852 patients presenting within 24 hours of the onset of the symptoms of myocardial infarction with supporting ECG abnormalities (i.e., ST-elevation, ST-depression or left bundle-branch block). Patients were randomized to receive clopidogrel (75 mg once daily) or placebo, in combination with aspirin (162 mg per day), for 28 days or until hospital discharge, whichever came first.
The primary endpoints were death from any cause and the first occurrence of re-infarction, stroke or death.
The patient population included 28% women, 58% age ≥ 60 years (26% age ≥ 70 years), 55% patients who received thrombolytics, 68% who received ACE-inhibitors, and only 3% who underwent PCI.
As shown in Table 5 and Figures 4 and 5 below, clopidogrel significantly reduced the relative risk of death from any cause by 7% (p = 0.029), and the relative risk of the combination of re-infarction, stroke or death by 9% (p = 0.002).

[[File:Clopidogrel_pharmacology_04.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

[[File:Clopidogrel_pharmacology_05.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

[[File:Clopidogrel_pharmacology_06.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

* All treated patients received aspirin.

The effect of clopidogrel did not differ significantly in various pre-specified subgroups as shown in Figure 6. The effect was also similar in non-prespecified subgroups including those based on infarct location, Killip class or prior MI history. Such subgroup analyses should be interpreted cautiously.

[[File:Clopidogrel_pharmacology_07.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

* Three similar-sized prognostic index groups were based on absolute risk of primary composite outcome for each patient calculated from baseline prognostic variables (excluding allocated treatments) with a Cox regression model.

[[File:Clopidogrel_pharmacology_08.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

=====Recent Myocardial Infarction, Recent Stroke, or Established Peripheral Arterial Disease=====

''CAPRIE''

The CAPRIE trial was a 19,185 patient, 304 center, international, randomized, double-blind, parallel-group study comparing clopidogrel (75 mg daily) to aspirin (325 mg daily). The patients randomized had: 1) recent histories of myocardial infarction (within 35 days); 2) recent histories of ischemic stroke (within 6 months) with at least a week of residual neurological signs; or 3) established peripheral arterial disease. Patients received randomized treatment for an average of 1.6 years (maximum of 3 years).
The trial's primary outcome was the time to first occurrence of new ischemic stroke (fatal or not), new myocardial infarction (fatal or not), or other vascular death. Deaths not easily attributable to nonvascular causes were all classified as vascular.

[[File:Clopidogrel_pharmacology_09.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

As shown in Table 6, clopidogrel was associated with a lower incidence of outcome events, primarily MI. The overall relative risk reduction (9.8% vs. 10.6%) was 8.7%, p = 0.045. Similar results were obtained when all-cause mortality and all-cause strokes were counted instead of vascular mortality and ischemic strokes (risk reduction 6.9%). In patients who survived an on-study stroke or myocardial infarction, the incidence of subsequent events was lower in the clopidogrel group.
The curves showing the overall event rate are shown in Figure 8. The event curves separated early and continued to diverge over the 3 year follow-up period.

[[File:Clopidogrel_pharmacology_10.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

The statistical significance favoring clopidogrel over aspirin was marginal (p = 0.045). However, because aspirin is itself effective in reducing cardiovascular events in patients with recent myocardial infarction or stroke, the effect of clopidogrel is substantial.
The CAPRIE trial included a population that was randomized on the basis of 3 entry criteria. The efficacy of clopidogrel relative to aspirin was heterogeneous across these randomized subgroups (p = 0.043). It is not clear whether this difference is real or a chance occurrence. Although the CAPRIE trial was not designed to evaluate the relative benefit of clopidogrel over aspirin in the individual patient subgroups, the benefit appeared to be strongest in patients who were enrolled because of peripheral vascular disease (especially those who also had a history of myocardial infarction) and weaker in stroke patients. In patients who were enrolled in the trial on the sole basis of a recent myocardial infarction, clopidogrel was not numerically superior to aspirin.

=====Lack of Established Benefit of Clopidogrel Plus Aspirin in Patients With Multiple Risk Factors or Established Vascular Disease=====

''CHARISMA''

The CHARISMA trial was a 15,603 subject, randomized, double-blind, parallel group study comparing clopidogrel (75 mg daily) to placebo for prevention of ischemic events in patients with vascular disease or multiple risk factors for atherosclerosis. All subjects were treated with aspirin 75 to 162 mg daily. The mean duration of treatment was 23 months. The study failed to demonstrate a reduction in the occurrence of the primary endpoint, a composite of CV death, MI, or stroke. A total of 534 (6.9%) patients in the clopidogrel group versus 573 (7.4%) patients in the placebo group experienced a primary outcome event (p = 0.22). Bleeding of all severities was more common in the subjects randomized to clopidogrel.
|howSupplied=Clopidogrel tablets USP are available as follows:
75 mg – light-pink to pink, film-coated, capsule shaped tablets debossed with “TV” on one side and “7314” on the other side, in bottles of 30, 90, and 500.
|storage=Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).
|fdaPatientInfo=For patient information about clopidogrel, click [[Clopidogrel (patient information)|here]].
|alcohol=Alcohol-Clopidogrel interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|nlmPatientInfo=For patient information about clopidogrel from NLM, click [[Clopidogrel (patient information)|here]].
}}
{{PillImage
|fileName=Clopidogrel 75 mg NDC 0093-7314.JPG
|drugName=Clopidogrel 75 MG (as clopidogrel bisulfate 97.875 MG) Oral Tablet
|NDC=0093-7314
|drugAuthor=Teva Pharmaceuticals USA Inc
|ingredients=crospovidone, hydrogenated cottonseed oil, hydroxypropyl cellulose (type h), hypromellose 2910 (15 mpa.s), indigotindisulfonate sodium, aluminum oxide, fd&c blue no. 2, ferric oxide red, ferric oxide yellow, lactose, lactose monohydrate, cellulose, microcrystalline, polyethylene glycol 4000, sodium lauryl sulfate, titanium dioxide
|pillImprint=TV;7314
|dosageValue=75
|dosageUnit=mg
|pillColor=Pink
|pillShape=Oval
|pillSize=13.00
|pillScore=1
}}
{{LabelImage
|fileName=Clopidogrel_label_01.jpg
}}
{{LabelImage
|fileName=Clopidogrel_panel_01.jpg
}}
[[Category:ADP receptor inhibitors]]
[[Category:Antiplatelet drugs]]
[[Category:Cardiovascular Drugs]]
[[Category:Drug]]
[[Category:Thienopyridines]]

Antihemophilic factor

2015-03-19T16:00:57Z

Sree Teja Yelamanchili:

{{DrugProjectFormSinglePage
|authorTag={{SS}}; {{STY}}
|genericName=antihemophilic factor
|aOrAn=a
|drugClass=human antihemophilic factor
|indicationType=treatment
|indication=[[hemophilia A]]
|adverseReactions=[[nausea]], [[headache]], [[blurred vision]]
|blackBoxWarningTitle=<b><span style="color:#FF0000;">TITLE</span></b>
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)
|fdaLIADAdult=<H4>Hemophilia A</H4>

* Indication

:* Antihemophilic factor is a recombinant antihemophilic factor indicated for:

::* Control and prevention of bleeding episodes in adults and children with [[hemophilia A]].

::* Surgical prophylaxis in adults and children with [[hemophilia A]].

::* Routine prophylactic treatment to prevent or reduce the frequency of [[bleeding]] episodes in children with [[hemophilia A]] and to reduce the risk of joint damage in children without pre-existing joint damage.

::* Routine prophylactic treatment to prevent or reduce the frequency of bleeding episodes in adults with [[hemophilia A]].

*Antihemophilic factor is not indicated for the treatment of [[von Willebrand disease]].

* Dosing Information

:* Dosage and duration of treatment depend on the severity of the [[factor VIII deficiency]], the location and extent of bleeding, and the patient's clinical condition.1 Careful control of replacement therapy is especially important in cases of major surgery or life-threatening bleeding episodes.
:* Each vial of Antihemophilic factor has the recombinant [[factor VIII]] (rFVIII) potency in international units (IU, unit) stated on the label. One IU (unit), as defined by the World Health Organization standard for blood [[coagulation factor VIII]], human, is approximately equal to the level of [[factor VIII]] activity found in 1 mL of fresh pooled human plasma.

:* The expected in vivo peak increase in [[factor VIII]] level expressed as IU/dL (or % normal) can be estimated using the following formulas:

'''Dosage (units) = body weight (kg) × desired [[factor VIII]] rise (IU/dL or % of normal) × 0.5 (IU/kg per IU/dL)'''
or
'''IU/dL (or % normal) = Total Dose (IU)/body weight (kg) × 2 [IU/dL]/[IU/kg]'''

:* Titrate dose to the patient's clinical response. Patients may vary in their pharmacokinetic (e.g., half-life, in vivo recovery) and clinical responses to Antihemophilic factor.2,3,4 Although the dose can be estimated by the calculations above, it is highly recommended that appropriate laboratory tests, including serial [[factor VIII]] activity assays, are performed.
* Control and Prevention of Bleeding Episodes

A guide for dosing Antihemophilic factor for the control and prevention of bleeding episodes is provided in Table 1. The goal of treatment is to maintain a plasma [[factor VIII]] activity level at or above the plasma levels (in % of normal or in IU/dL) outlined in Table 1.

[[File:Antihemophilic factor_administration_01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]

* Peri-operative Management

A guide for dosing Antihemophilic factor during surgery (perioperative management) is provided in Table 2. The goal of treatment is to maintain a plasma [[factor VIII]] activity level at or above the plasma level (in % of normal or in IU/dL) outlined in Table 2.

[[File:Antihemophilic factor_administration_02.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]

* Routine Prophylaxis in Adults

:* Recommended dosage: ''' 25 units/kg body weight IV three times per week'''.

* Routine Prophylaxis in Children

:* Recommended dosage: '''25 IU/kg body IV weight qod'''

<H4>Preparation and Reconstitution</H4>

* Antihemophilic factor is administered by intravenous injection after reconstitution. Patients should follow the specific reconstitution and administration procedures provided by their physicians.
* Reconstitute and administer Antihemophilic factor with the components provided with each package. If any component of the package is opened or damaged, do not use this component.
* Product reconstitution, administration, and handling of the administration set and needles must be done with caution because percutaneous puncture with a needle contaminated with blood can transmit infectious viruses, including [[HIV]] ([[AIDS]]) and [[hepatitis]]. Place needles in a sharps container after single use. Discard all equipment, including any reconstituted Antihemophilic factor product, in an appropriate container. Obtain immediate medical attention if injury occurs.
* For instructions, patients should follow the recommendations in the FDA-Approved Patient Labeling.
* The procedures below are provided as general guidelines for the reconstitution of Antihemophilic factor.

:* Work on a clean flat surface and wash hands thoroughly using soap and warm water before performing the procedures.

:* Reconstitute the product with the components provided with each package. If any component of the package is opened or damaged, do not use this component.

:* Filter the reconstituted product prior to administration to remove potential particulate matter in the solution. Filtering can be achieved by using the Mix2Vial™ vial adapter.

[[File:Antihemophilic factor_administration_03.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
|offLabelAdultGuideSupport=There is limited information regarding Off-Label Guideline-Supported Use of Amiodarone in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding Off-Label Non–Guideline-Supported Use of Amiodarone in adult patients
|fdaLIADPed=FDA Package Insert for Antihemophilic factor contains no information regarding FDA-labeled indications and dosage information for children.
|offLabelPedGuideSupport=There is limited information regarding Off-Label Guideline-Supported Use of Amiodarone in pediatric patients
|offLabelPedNoGuideSupport=There is limited information regarding Off-Label Non–Guideline-Supported Use of Amiodarone in pediatric patients
|contraindications=Antihemophilic factor is contraindicated in patients who have life-threatening [[hypersensitivity]] reactions, including [[anaphylaxis]] to mouse or hamster protein or other constituents of the product ([[sucrose]], [[glycine]], [[histidine]], [[sodium]], [[calcium chloride]], [[polysorbate 80]], [[sucrose]], [[imidazole]], tri-n-butyl phosphate, and copper).
|warnings====Hypersensitivity Reactions===

*Hypersensitivity reactions, including [[anaphylaxis]] have been reported with Antihemophilic factor. Reported symptoms included [[facial swelling]], [[flushing]], [[hives]], [[hypotension|decrease in blood pressure]], [[nausea]], [[rash]], [[restlessness]], [[shortness of breath]], [[tachycardia]], tightness of the chest, [[tingling]], [[urticaria]], and [[vomiting]].
*Antihemophilic factor contains trace amounts of mouse immunoglobulin G (MuIgG) and hamster (BHK) proteins. Patients treated with this product may develop hypersensitivity to these non-human mammalian proteins.
*Discontinue Antihemophilic factor if symptoms occur and seek immediate emergency treatment.

===Neutralizing Antibodies===

Neutralizing antibodies (inhibitors) have been reported following administration of Antihemophilic factor predominantly in previously untreated patients. Carefully monitor patients for the development of factor VIII inhibitors, using appropriate clinical observations and laboratory tests. If expected plasma [[factor VIII]] activity levels are not attained, or if bleeding is not controlled with an expected dose, perform an assay that measures factor VIII inhibitor concentration.

===Cardiovascular Risk Factors===

Hemophilic patients with cardiovascular risk factors or diseases may be at the same risk to develop cardiovascular events as non-hemophilic patients when clotting has been normalized by treatment with factor VIII.

===Monitoring Laboratory Tests===

* Monitor plasma [[factor VIII]] activity levels by the one-stage clotting assay to confirm the adequate factor VIII levels have been achieved and maintained, when clinically indicated.

* Monitor for development of factor VIII inhibitors. Perform assay to determine if [[factor VIII]] inhibitor is present. If expected factor VIII activity plasma levels are not attained or if bleeding is not controlled with the expected dose of Antihemophilic factor, use Bethesda Units (BU) to titer inhibitors.

:* If the inhibitor is less than 10 BU per mL, the administration of additional Antihemophilic factor concentrate may neutralize the inhibitor and may permit an appropriate hemostatic response.

:* If inhibitor titers are above 10 BU per mL, adequate hemostasis may not be achieved. The inhibitor titer may rise following Antihemophilic factor infusion as a result of an anamnestic response to [[factor VIII]]. The treatment or prevention of bleeding in such patients requires the use of alternative therapeutic approaches and agents.
|clinicalTrials=*Serious adverse reactions seen with Antihemophilic factor are systemic [[hypersensitivity]] reactions, including bronchospastic reactions and/or [[hypotension]] and [[anaphylaxis]], and the development of high-titer inhibitors necessitating alternative treatments to factor VIII.
*The most common adverse reactions (≥ 4%) observed in clinical trials were inhibitor formation in previously untreated patients (PUPs) and minimally treated patients (MTPs), skin-related hypersensitivity reactions (e.g., [[rash]], [[pruritus]]), infusion site reactions (e.g., inflammation, pain), and [[Central venous catheter|central venous access device]] (CVAD) associated infections.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in clinical practice.

===Previously Treated Patients (PTPs)===

During the open-label clinical studies conducted in 73 PTPs, there were 24 adverse reactions reported in the course of 24,936 infusions.
Adverse reactions reported by ≥ 4% of the patients are listed in Table 3 below.

[[File:Antihemophilic factor_adverse_01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]

===Previously Untreated Patients (PUPs) and Minimally Treated Patients (MTPs)===

In clinical studies with pediatric PUPs and MTPs, there were 29 adverse reactions reported in the course of 9,389 infusions.
Adverse reactions reported by ≥ 4% of the patients are listed in Table 4 below.

[[File:Antihemophilic factor_adverse_02.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]

===Minimally Treated Patients (MTPs) in the Joint Outcome Study===

In the Joint Outcome Study with pediatric MTPs treated with routine prophylaxis or episodic enhanced treatment for 5.5 years, 46 of the 65 randomized patients experienced adverse events over the study duration.

[[File:Antihemophilic factor_adverse_03.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]

<u>Immunogenicity</u>

*In clinical studies with 73 PTPs (defined as having more than 100 exposure days), one patient had a pre-existing inhibitor.
*In the other 72 patients, followed over 4 years, no de novo inhibitors were observed.
*In clinical studies with pediatric PUPs and MTPs, inhibitor development was observed in 9 out of 60 patients (15%), 6 were high titer1 (> 5 BU) and 3 were low-titer inhibitors.
*Inhibitors were detected at a median number of 7 exposure days (range 2 to 16 exposure days).
*In the Joint Outcome Study with Antihemophilic factor,5 de novo inhibitor development was observed in 8 of 64 patients with negative baseline values (12.5%), 2 patients developed high titer1 (> 5 BU) and were withdrawn from the study. Six patients developed low-titer inhibitors.
*Inhibitors were detected at a median number of 44 exposure days (range 5 to 151 exposure days).
*The detection of antibody formation is dependent on the sensitivity and specificity of the assay.
*Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease.
*For these reasons, comparison of the incidence of antibodies to Antihemophilic factor with the incidence of antibodies to other products may be misleading.
|postmarketing=The following adverse reaction has been identified during post approval use of Antihemophilic factor. Because adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

===Sensory System – Dysgeusia===

Additionally, available registries have reported inhibitor rates for PUPs with severe hemophilia A in the range of 28% to 38% for [[factor VIII]] products.
|drugInteractions=FDA Package Insert for Antihemophilic factor contains no information regarding drug interactions.
|FDAPregCat=C
|useInPregnancyFDA=Animal reproduction studies have not been conducted with Antihemophilic factor. It is also not known whether Antihemophilic factor can cause fetal harm when administered to a pregnant woman or affect reproductive capacity. Antihemophilic factor should be given to a pregnant woman only if clearly needed.
|useInLaborDelivery=There is no information available on the effect of factor VIII replacement therapy on labor and delivery. Antihemophilic factor should be used only if clinically needed.
|useInNursing=It is not known whether this drug is excreted into human milk. Because many drugs are excreted into human milk, caution should be exercised if Antihemophilic factor is administered to a nursing woman.
|useInPed=There is no FDA guidance on the use of Tranexamic Acid in pediatric patients.
|useInGeri=Clinical studies with Antihemophilic factor did not include patients aged 65 and over. Dose selection for an elderly patient should be individualized.
|useInGender=Safety and efficacy studies have been performed in previously untreated and minimally treated pediatric patients. Children, in comparison to adults, present higher factor VIII clearance values and, thus, lower half-life and recovery of factor VIII. This may be due to differences in body composition.7 Account for this difference in clearance when dosing or following factor VIII levels in the pediatric population.
Routine prophylactic treatment in children ages 0–2.5 years with no pre-existing joint damage has been shown to reduce spontaneous joint bleeding and the risk of joint damage. This data can be extrapolated to ages >2.5–16 years for children who have no existing joint damage.
|useInRace=There is no FDA guidance on the use of Antihemophilic factor with respect to specific racial populations.
|useInRenalImpair=There is no FDA guidance on the use of Antihemophilic factor in patients with renal impairment.
|useInHepaticImpair=There is no FDA guidance on the use of Antihemophilic factor in patients with hepatic impairment.
|useInReproPotential=here is no FDA guidance on the use of Antihemophilic factor in women of reproductive potentials and males
|useInImmunocomp=There is no FDA guidance one the use of Antihemophilic factor in patients who are immunocompromised.
|othersTitle=Others
|useInOthers=(Description)
|administration=For intravenous use after reconstitution only.

:* Inspect Antihemophilic factor visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Turbid or discolored solution should be discarded.

:* Store the reconstituted Antihemophilic factor at room temperature prior to administration, but administer it within 3 hours.

:* Administer Antihemophilic factor over a period of 1 to 15 minutes. Adapt the rate of administration to the response of each individual patient. Determine the pulse rate before and during administration of Antihemophilic factor. If there is a significant increase in pulse rate, reduce the rate of administration or temporarily halt the infusion allowing the symptoms to disappear promptly.
|monitoring=* Monitor plasma factor VIII activity levels by the one-stage clotting assay to confirm the adequate factor VIII levels have been achieved and maintained, when clinically indicated.

* Monitor for development of factor VIII inhibitors. Perform assay to determine if [[factor VIII]] inhibitor is present. If expected factor VIII activity plasma levels are not attained or if bleeding is not controlled with the expected dose of Antihemophilic factor, use Bethesda Units (BU) to titer inhibitors.

:* If the inhibitor is less than 10 BU per mL, the administration of additional Antihemophilic factor concentrate may neutralize the inhibitor and may permit an appropriate hemostatic response.

:* If inhibitor titers are above 10 BU per mL, adequate [[hemostasis]] may not be achieved. The inhibitor titer may rise following Antihemophilic factor infusion as a result of an anamnestic response to [[factor VIII]]. The treatment or prevention of bleeding in such patients requires the use of alternative therapeutic approaches and agents.
|IVCompat=There is limited information about the IV Compatibilty.
|overdose=FDA Package Insert for Antihemophilic factor contains no information regarding Adverse Reactions.
|drugBox={{PBB|geneid=2157}}
|mechAction=Antihemophilic factor temporarily replaces the missing clotting factor VIII that is needed for effective hemostasis.
|structure=(Description with picture)
|PD=The activated partial thromboplastin time (aPTT) is prolonged in patients with [[hemophilia]]. Determination of aPTT is a conventional in vitro assay for biological activity of [[factor VIII]]. Treatment with Antihemophilic factor normalizes the aPTT over the effective dosing period.
|PK=The pharmacokinetic properties of Antihemophilic factor were investigated in two separate studies in adult and pediatric previously treated patients (PTPs).
Pharmacokinetic studies with Antihemophilic factor were conducted in 20 PTPs (ages 12 to 33 years) with severe hemophilia A. The pharmacokinetic parameters for Antihemophilic factor were measured in a randomized, crossover clinical trial with the predecessor HELIXATE product using a single dose administration of 50 IU per kg. After 24 weeks, the same dose of Antihemophilic factor was administered to the same patients. The recovery and half-life data for Antihemophilic factor were unchanged after 24 weeks of continued treatment with sustained efficacy and no evidence of factor VIII inhibition.

[[File:Antihemophilic factor_administration_01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]

The pharmacokinetics of Antihemophilic factor were investigated in pediatric PTPs (4.4–18.1 years of age, average age 12).7 The pharmacokinetic parameters in children compared to adults show differences in higher clearance, lower incremental in vivo factor VIII recovery and a shorter factor VIII half-life. The pharmacokinetic parameters are depicted in Table 9.

[[File:Antihemophilic factor_administration_02.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
|nonClinToxic====Carcinogenesis, Mutagenesis, Impairment of Fertility===

No studies have been conducted with Antihemophilic factor to assess its mutagenic or carcinogenic potential and impairment of fertility. By inference, the predecessor product HELIXATE and Antihemophilic factor would be expected to have equivalent mutagenic and carcinogenic potential.
The predecessor product did not demonstrate reverse mutation or chromosomal aberrations at doses substantially greater than the maximum expected clinical dose. In vivo evaluation with the predecessor product in animals using doses ranging between 10 and 40 times the expected clinical maximum also indicated that the predecessor product did not possess a mutagenic potential. Long-term investigations of carcinogenic potential in animals have not been performed due to the immune response to heterologous proteins in all non-human mammalian species.

===Animal Toxicology and/or Pharmacology===

Preclinical studies evaluating Antihemophilic factor in [[hemophilia A]] with mice, rats, rabbits, and dogs demonstrated safe and effective restoration of [[hemostasis]]. Doses several fold higher than the recommended clinical dose (related to body weight) did not demonstrate any acute or subacute toxic effect for Antihemophilic factor in laboratory animals.
Antihemophilic factor has been shown to be comparable to the predecessor product HELIXATE with respect to its biochemical and physiochemical properties, as well as its non-clinical in vivo pharmacology and toxicology.
|clinicalStudies====Previously Treated Patients (PTPs) Clinical Studies===

A total of 73 patients with severe (≤ 2% FVIII) hemophilia A, ages 12–59, who had been previously treated with other recombinant or with plasma-derived AHF products, were treated up to 54 months in open label studies with Antihemophilic factor. A total of 5,684 bleeding episodes were treated during the studies; 92.7% of the bleeds were treated with one (79.7%) or two (13.0%) infusions. Patients could be treated with on-demand or prophylaxis. Regularly scheduled prophylaxis treatment represented 76% of all infusions (treatment regimens of 2–3 infusions per week).
A total of 30 patients received Antihemophilic factor for 41 surgical procedures during the PTP studies. There were both minor and major surgery types, 16 and 25 respectively. Efficacy was measured by the attending surgeon based on a comparison of estimated blood loss from experience with non-hemophilic patients undergoing similar procedures. The surgeon or treating physician assigned a rating to the hemostatic outcome according to 4 categories: "excellent (blood loss less than expected)," "good (blood loss as expected)," "moderate (blood loss more than expected)," or "none (uncontrolled bleeding)." Hemostasis was rated as satisfactory ("excellent" or "good") in all cases.

===Previously Untreated Patients (PUPs) and Minimally Treated Patients (MTPs) Clinical Study===

Antihemophilic factor has been used in the treatment of bleeding episodes in pediatric PUPs and MTPs with severe (<2% FVIII) hemophilia A. There were 37 PUPs and 24 MTPs (defined as having equal to or less than 4 exposure days) treated with a total of 9,419 infusions of Antihemophilic factor for a follow up duration up to 3.1 years. A total of 1047 bleeding episodes were treated; the bleeds were treated with one (73%) or two (15%) infusions.
A total of 27 surgical procedures were performed in 22 patients during the PUPs and MTPs study. There were both minor and major surgery types, 21 and 6 respectively. The attending surgeon measured efficacy and assigned a rating to the hemostatic outcome according to 4 categories as described above for PTPs. Hemostasis was rated as satisfactory ("excellent" or "good") in all cases.

===Adult Prophylaxis for Bleeding Frequency Reduction===

An ongoing, 3-year, multicenter, open-label, parallel-group, prospective, randomized, controlled clinical study of the effect of routine prophylaxis with Antihemophilic factor versus on-demand use on bleeding frequency in adults and adolescents included 84 PTPs with severe Hemophilia A (FVIII level < 1 IU/dL), age 15 to 50 years. Patients were matched at baseline on demographic and disease characteristics. The median number of bleeds in the year before enrollment was 18.
Patients were randomized 1:1 to prophylaxis (25 units per kg three times a week) or on-demand use of Antihemophilic factor. Escalation of the prophylaxis dose by 5 units per kg/infusion after years 1 and 2, up to a maximum of 35 units per kg/infusion, was allowed.
Bleeding frequency was analyzed in the intent-to-treat population after a median follow-up period of 1.4 years. Patients who received prophylaxis experienced statistically significantly fewer bleeds (p<0.0001) compared to patients treated on-demand regardless of baseline subgroups examined including age, bleeding history, and presence or absence of target joints. The ratio of the mean bleeding frequency was 15.2 (95% CI: 8.5, 27.2; p<0.0001) for on-demand versus prophylaxis, indicating that patients who received on-demand treatment experienced on average 15.2 times as many bleeds compared to patients treated with prophylaxis. The mean annualized bleed rates (bleeds/subject/year) were 37 in the on-demand group versus 2 in the prophylaxis group. The median annualized bleed rate (bleeds/subject/year) in the on-demand group was 33 versus zero in the prophylaxis group. Most of the bleeding occurred in joints: the median joint bleed rate (joint bleeds/subject/year) was 24 in the on-demand group versus zero in the prophylaxis group. The mean annualized joint bleed rate was 29 in the on-demand group versus 2 in the prophylaxis group.
Twenty-two of 42 (52%) prophylaxis subjects experienced no bleeding, and 12 of 42 (29%) prophylaxis subjects experienced only 1–2 bleeds during the follow-up period. Among prophylaxis patients the mean number of infusions/week was 2.8, and the median dose per prophylaxis infusion was 26 units per kg.

===Pediatric Prophylaxis for Joint Damage Risk Reduction===

A total of 65 boys less than 30 months of age with severe hemophilia A (FVIII level ≤ 2 IU/dL) and with ≤ 2 bleeds into each index joint and normal baseline joint imaging, were observed for up to 5.5 years in a multicenter, open-label, prospective, randomized, controlled clinical study.5 Patients received either 25 IU per kg every other day (primary prophylaxis; n = 32) or at least 3 doses totaling a minimum of 80 IU per kg at the time of a bleeding episode (enhanced episodic; n = 33). Joint damage was evaluated by magnetic resonance imaging (MRI) or radiography, as well as the frequency of bleeding episodes. Joint damage detected by MRI or radiography in the ankles, knees, and elbows (i.e., index joints) was statistically significantly lower (p = 0.002) for subjects receiving prophylactic therapy (7%) than for subjects receiving episodic therapy (42%). This corresponds to a 6.29-fold relative risk of joint damage for subjects treated with enhanced episodic therapy compared to prophylaxis. The mean rate of index joint hemorrhages for subjects on episodic therapy was 4.89 bleeds per year, versus 0.63 bleeds per year observed in the prophylaxis arm. Three of 33 (9.1%) subjects in the episodic arm experienced recurrent life threatening bleeds (intracranial, gastrointestinal) compared to no subjects in the prophylaxis arm. On a per joint basis, joints in the regular prophylaxis arm were 8-fold more likely to remain damage-free than those in the episodic arm. Joint damage was most frequently observed in ankle joints and was detected at higher rates by MRI than by radiography. Ankles were also the index joint that demonstrated the highest frequency of bleeding events in this study (left ankle, mean 2.7 hemorrhages; right ankle, mean 2.6 hemorrhages).
As shown in Table 10 below, the incidence of joint damage was statistically significantly lower in the prophylactic group as compared to the episodic treatment group when assessed by MRI, or either MRI or radiography, using predefined criteria (described below) for establishing joint damage. However, there was no statistically significant difference between the two groups when joint damage was assessed by radiography alone.
To evaluate joint damage, MRIs were scored using a scale developed by Nuss et al.,14 and X-rays were scored using the method of Pettersson et al.15 Both scales have been validated in various clinical trials and are routinely used for joint damage evaluation in hemophiliacs. Joint damage was defined as bone and/or cartilage damage including subchondral cysts, erosions and cartilage loss with narrowing of joint space. This corresponded to a total MRI score of ≥ 7 or an X-ray score of ≥1 in any of the following categories: subchondral cysts, erosions of joint surfaces or narrowing of joint spaces. Images were read separately by two independent radiologists centrally. Any discrepant reading was read by an independent third radiologist who was not aware of the initial reading results. The concordant reading of two out of three readers was used for analysis purposes.

[[File:Antihemophilic factor_clinical studies_01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]
|howSupplied=Antihemophilic factor is available as a kit in the following single-use glass vial sizes. A suitable volume of Sterile Water for Injection, USP and Mix2Vial™ filter transfer device are provided in the kit.

[[File:Antihemophilic factor_how supplied_01.png|thumb|none|600px|This image is provided by the National Library of Medicine.]]

Actual factor VIII activity in IU is stated on the label of each Antihemophilic factor vial.
|storage=The product vial and diluent vial are not made with natural rubber latex.

<u>Product as Packaged for Sale</u>

Store Antihemophilic factor at +2°C to +8°C (36°F to 46°F) for up to 30 months from the date of manufacture. Within this period, Antihemophilic factor may be stored for a period of up to 12 months at temperatures up to +25°C or 77°F.

Record the starting date of room temperature storage on the unopened product carton. Once stored at room temperature, do not return the product to the refrigerator. The shelf-life then expires after storage at room temperature, or after the expiration date on the product vial, whichever is earlier.

Do not use Antihemophilic factor after the expiration date indicated on the vial.

Do not freeze.

Protect from extreme exposure to light and store the lyophilized powder in the carton prior to use.

<u>Product After Reconstitution</u>

After reconstitution, store the Antihemophilic factor solution at room temperature and administer within 3 hours.
|fdaPatientInfo=* Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

* Advise patients to report any adverse reactions or problems following Antihemophilic factor administration to their physician or healthcare provider.

* Allergic-type [[hypersensitivity]] reactions have been reported with Antihemophilic factor. Warn patients of the early signs of [[hypersensitivity]] reactions [including hives ([[rash]] with itching), generalized [[urticaria]], tightness of the chest, wheezing, hypotension] and anaphylaxis. Advise patients to discontinue use of the product if these symptoms occur and seek immediate emergency treatment with resuscitative measures such as the administration of [[epinephrine]] and oxygen.

* Inhibitor formation may occur at any time in the treatment of a patient with [[hemophilia A]]. Advise patients to contact their physician or treatment center for further treatment and/or assessment, if they experience a lack of clinical response to factor VIII replacement therapy, as this may be a manifestation of an inhibitor.

* Advise patients to consult with their healthcare provider prior to travel. While traveling advise patients to bring an adequate supply of Antihemophilic factor based on their current regimen of treatment.
|alcohol=Alcohol-Antihemophilic factor interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=* Koate DVI
* Monoclate-P
* antihemophilic factor
|lookAlike=FDA Package Insert for Antihemophilic factor contains no information regarding Adverse Reactions.
|nlmPatientInfo=(Link to patient information page)
|drugShortage=Drug Shortage
}}
{{LabelImage
|fileName=Antihemophilic factor_label_01.jpg
}}
{{LabelImage
|fileName=Antihemophilic factor_label_02.jpg
}}
{{LabelImage
|fileName=Antihemophilic factor_label_03.jpg
}}
{{LabelImage
|fileName=Antihemophilic factor_label_04.jpg
}}
{{LabelImage
|fileName=Antihemophilic factor_label_05.jpg
}}

[[Category: Cardiovascular Drugs]]
[[Category: Drug]]

Antihemophilic factor

2015-03-19T15:56:59Z

Sree Teja Yelamanchili:

{{DrugProjectFormSinglePage
|authorTag={{SS}}; {{STY}}
|genericName=antihemophilic factor
|aOrAn=a
|drugClass=human antihemophilic factor
|indicationType=treatment
|indication=[[hemophilia A]]
|adverseReactions=[[nausea]], [[headache]], [[blurred vision]]
|blackBoxWarningTitle=<b><span style="color:#FF0000;">TITLE</span></b>
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)
|fdaLIADAdult=<H4>Hemophilia A</H4>

* Indication

:* Antihemophilic factor is a recombinant antihemophilic factor indicated for:

::* Control and prevention of bleeding episodes in adults and children with [[hemophilia A]].

::* Surgical prophylaxis in adults and children with [[hemophilia A]].

::* Routine prophylactic treatment to prevent or reduce the frequency of [[bleeding]] episodes in children with [[hemophilia A]] and to reduce the risk of joint damage in children without pre-existing joint damage.

::* Routine prophylactic treatment to prevent or reduce the frequency of bleeding episodes in adults with [[hemophilia A]].

*Antihemophilic factor is not indicated for the treatment of [[von Willebrand disease]].

* Dosing Information

:* Dosage and duration of treatment depend on the severity of the [[factor VIII deficiency]], the location and extent of bleeding, and the patient's clinical condition.1 Careful control of replacement therapy is especially important in cases of major surgery or life-threatening bleeding episodes.
:* Each vial of Antihemophilic factor has the recombinant [[factor VIII]] (rFVIII) potency in international units (IU, unit) stated on the label. One IU (unit), as defined by the World Health Organization standard for blood [[coagulation factor VIII]], human, is approximately equal to the level of [[factor VIII]] activity found in 1 mL of fresh pooled human plasma.

:* The expected in vivo peak increase in [[factor VIII]] level expressed as IU/dL (or % normal) can be estimated using the following formulas:

'''Dosage (units) = body weight (kg) × desired [[factor VIII]] rise (IU/dL or % of normal) × 0.5 (IU/kg per IU/dL)'''
or
'''IU/dL (or % normal) = Total Dose (IU)/body weight (kg) × 2 [IU/dL]/[IU/kg]'''

:* Titrate dose to the patient's clinical response. Patients may vary in their pharmacokinetic (e.g., half-life, in vivo recovery) and clinical responses to Antihemophilic factor.2,3,4 Although the dose can be estimated by the calculations above, it is highly recommended that appropriate laboratory tests, including serial [[factor VIII]] activity assays, are performed.
* Control and Prevention of Bleeding Episodes

A guide for dosing Antihemophilic factor for the control and prevention of bleeding episodes is provided in Table 1. The goal of treatment is to maintain a plasma [[factor VIII]] activity level at or above the plasma levels (in % of normal or in IU/dL) outlined in Table 1.

[[File:Antihemophilic factor_administration_01.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

* Peri-operative Management

A guide for dosing Antihemophilic factor during surgery (perioperative management) is provided in Table 2. The goal of treatment is to maintain a plasma [[factor VIII]] activity level at or above the plasma level (in % of normal or in IU/dL) outlined in Table 2.

[[File:Antihemophilic factor_administration_02.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

* Routine Prophylaxis in Adults

:* Recommended dosage: ''' 25 units/kg body weight IV three times per week'''.

* Routine Prophylaxis in Children

:* Recommended dosage: '''25 IU/kg body IV weight qod'''

<H4>Preparation and Reconstitution</H4>

* Antihemophilic factor is administered by intravenous injection after reconstitution. Patients should follow the specific reconstitution and administration procedures provided by their physicians.
* Reconstitute and administer Antihemophilic factor with the components provided with each package. If any component of the package is opened or damaged, do not use this component.
* Product reconstitution, administration, and handling of the administration set and needles must be done with caution because percutaneous puncture with a needle contaminated with blood can transmit infectious viruses, including [[HIV]] ([[AIDS]]) and [[hepatitis]]. Place needles in a sharps container after single use. Discard all equipment, including any reconstituted Antihemophilic factor product, in an appropriate container. Obtain immediate medical attention if injury occurs.
* For instructions, patients should follow the recommendations in the FDA-Approved Patient Labeling.
* The procedures below are provided as general guidelines for the reconstitution of Antihemophilic factor.

:* Work on a clean flat surface and wash hands thoroughly using soap and warm water before performing the procedures.

:* Reconstitute the product with the components provided with each package. If any component of the package is opened or damaged, do not use this component.

:* Filter the reconstituted product prior to administration to remove potential particulate matter in the solution. Filtering can be achieved by using the Mix2Vial™ vial adapter.

[[File:Antihemophilic factor_administration_03.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|offLabelAdultGuideSupport=There is limited information regarding Off-Label Guideline-Supported Use of Amiodarone in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding Off-Label Non–Guideline-Supported Use of Amiodarone in adult patients
|fdaLIADPed=FDA Package Insert for Antihemophilic factor contains no information regarding FDA-labeled indications and dosage information for children.
|offLabelPedGuideSupport=There is limited information regarding Off-Label Guideline-Supported Use of Amiodarone in pediatric patients
|offLabelPedNoGuideSupport=There is limited information regarding Off-Label Non–Guideline-Supported Use of Amiodarone in pediatric patients
|contraindications=Antihemophilic factor is contraindicated in patients who have life-threatening [[hypersensitivity]] reactions, including [[anaphylaxis]] to mouse or hamster protein or other constituents of the product ([[sucrose]], [[glycine]], [[histidine]], [[sodium]], [[calcium chloride]], [[polysorbate 80]], [[sucrose]], [[imidazole]], tri-n-butyl phosphate, and copper).
|warnings====Hypersensitivity Reactions===

*Hypersensitivity reactions, including [[anaphylaxis]] have been reported with Antihemophilic factor. Reported symptoms included [[facial swelling]], [[flushing]], [[hives]], [[hypotension|decrease in blood pressure]], [[nausea]], [[rash]], [[restlessness]], [[shortness of breath]], [[tachycardia]], tightness of the chest, [[tingling]], [[urticaria]], and [[vomiting]].
*Antihemophilic factor contains trace amounts of mouse immunoglobulin G (MuIgG) and hamster (BHK) proteins. Patients treated with this product may develop hypersensitivity to these non-human mammalian proteins.
*Discontinue Antihemophilic factor if symptoms occur and seek immediate emergency treatment.

===Neutralizing Antibodies===

Neutralizing antibodies (inhibitors) have been reported following administration of Antihemophilic factor predominantly in previously untreated patients. Carefully monitor patients for the development of factor VIII inhibitors, using appropriate clinical observations and laboratory tests. If expected plasma [[factor VIII]] activity levels are not attained, or if bleeding is not controlled with an expected dose, perform an assay that measures factor VIII inhibitor concentration.

===Cardiovascular Risk Factors===

Hemophilic patients with cardiovascular risk factors or diseases may be at the same risk to develop cardiovascular events as non-hemophilic patients when clotting has been normalized by treatment with factor VIII.

===Monitoring Laboratory Tests===

* Monitor plasma [[factor VIII]] activity levels by the one-stage clotting assay to confirm the adequate factor VIII levels have been achieved and maintained, when clinically indicated.

* Monitor for development of factor VIII inhibitors. Perform assay to determine if [[factor VIII]] inhibitor is present. If expected factor VIII activity plasma levels are not attained or if bleeding is not controlled with the expected dose of Antihemophilic factor, use Bethesda Units (BU) to titer inhibitors.

:* If the inhibitor is less than 10 BU per mL, the administration of additional Antihemophilic factor concentrate may neutralize the inhibitor and may permit an appropriate hemostatic response.

:* If inhibitor titers are above 10 BU per mL, adequate hemostasis may not be achieved. The inhibitor titer may rise following Antihemophilic factor infusion as a result of an anamnestic response to [[factor VIII]]. The treatment or prevention of bleeding in such patients requires the use of alternative therapeutic approaches and agents.
|clinicalTrials=*Serious adverse reactions seen with Antihemophilic factor are systemic [[hypersensitivity]] reactions, including bronchospastic reactions and/or [[hypotension]] and [[anaphylaxis]], and the development of high-titer inhibitors necessitating alternative treatments to factor VIII.
*The most common adverse reactions (≥ 4%) observed in clinical trials were inhibitor formation in previously untreated patients (PUPs) and minimally treated patients (MTPs), skin-related hypersensitivity reactions (e.g., [[rash]], [[pruritus]]), infusion site reactions (e.g., inflammation, pain), and [[Central venous catheter|central venous access device]] (CVAD) associated infections.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in clinical practice.

===Previously Treated Patients (PTPs)===

During the open-label clinical studies conducted in 73 PTPs, there were 24 adverse reactions reported in the course of 24,936 infusions.
Adverse reactions reported by ≥ 4% of the patients are listed in Table 3 below.

[[File:Antihemophilic factor_adverse_01.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

===Previously Untreated Patients (PUPs) and Minimally Treated Patients (MTPs)===

In clinical studies with pediatric PUPs and MTPs, there were 29 adverse reactions reported in the course of 9,389 infusions.
Adverse reactions reported by ≥ 4% of the patients are listed in Table 4 below.

[[File:Antihemophilic factor_adverse_02.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

===Minimally Treated Patients (MTPs) in the Joint Outcome Study===

In the Joint Outcome Study with pediatric MTPs treated with routine prophylaxis or episodic enhanced treatment for 5.5 years, 46 of the 65 randomized patients experienced adverse events over the study duration.

[[File:Antihemophilic factor_adverse_03.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

<u>Immunogenicity</u>

*In clinical studies with 73 PTPs (defined as having more than 100 exposure days), one patient had a pre-existing inhibitor.
*In the other 72 patients, followed over 4 years, no de novo inhibitors were observed.
*In clinical studies with pediatric PUPs and MTPs, inhibitor development was observed in 9 out of 60 patients (15%), 6 were high titer1 (> 5 BU) and 3 were low-titer inhibitors.
*Inhibitors were detected at a median number of 7 exposure days (range 2 to 16 exposure days).
*In the Joint Outcome Study with Antihemophilic factor,5 de novo inhibitor development was observed in 8 of 64 patients with negative baseline values (12.5%), 2 patients developed high titer1 (> 5 BU) and were withdrawn from the study. Six patients developed low-titer inhibitors.
*Inhibitors were detected at a median number of 44 exposure days (range 5 to 151 exposure days).
*The detection of antibody formation is dependent on the sensitivity and specificity of the assay.
*Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease.
*For these reasons, comparison of the incidence of antibodies to Antihemophilic factor with the incidence of antibodies to other products may be misleading.
|postmarketing=The following adverse reaction has been identified during post approval use of Antihemophilic factor. Because adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

===Sensory System – Dysgeusia===

Additionally, available registries have reported inhibitor rates for PUPs with severe hemophilia A in the range of 28% to 38% for [[factor VIII]] products.
|drugInteractions=FDA Package Insert for Antihemophilic factor contains no information regarding drug interactions.
|FDAPregCat=C
|useInPregnancyFDA=Animal reproduction studies have not been conducted with Antihemophilic factor. It is also not known whether Antihemophilic factor can cause fetal harm when administered to a pregnant woman or affect reproductive capacity. Antihemophilic factor should be given to a pregnant woman only if clearly needed.
|useInLaborDelivery=There is no information available on the effect of factor VIII replacement therapy on labor and delivery. Antihemophilic factor should be used only if clinically needed.
|useInNursing=It is not known whether this drug is excreted into human milk. Because many drugs are excreted into human milk, caution should be exercised if Antihemophilic factor is administered to a nursing woman.
|useInPed=There is no FDA guidance on the use of Tranexamic Acid in pediatric patients.
|useInGeri=Clinical studies with Antihemophilic factor did not include patients aged 65 and over. Dose selection for an elderly patient should be individualized.
|useInGender=Safety and efficacy studies have been performed in previously untreated and minimally treated pediatric patients. Children, in comparison to adults, present higher factor VIII clearance values and, thus, lower half-life and recovery of factor VIII. This may be due to differences in body composition.7 Account for this difference in clearance when dosing or following factor VIII levels in the pediatric population.
Routine prophylactic treatment in children ages 0–2.5 years with no pre-existing joint damage has been shown to reduce spontaneous joint bleeding and the risk of joint damage. This data can be extrapolated to ages >2.5–16 years for children who have no existing joint damage.
|useInRace=There is no FDA guidance on the use of Antihemophilic factor with respect to specific racial populations.
|useInRenalImpair=There is no FDA guidance on the use of Antihemophilic factor in patients with renal impairment.
|useInHepaticImpair=There is no FDA guidance on the use of Antihemophilic factor in patients with hepatic impairment.
|useInReproPotential=here is no FDA guidance on the use of Antihemophilic factor in women of reproductive potentials and males
|useInImmunocomp=There is no FDA guidance one the use of Antihemophilic factor in patients who are immunocompromised.
|othersTitle=Others
|useInOthers=(Description)
|administration=For intravenous use after reconstitution only.

:* Inspect Antihemophilic factor visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Turbid or discolored solution should be discarded.

:* Store the reconstituted Antihemophilic factor at room temperature prior to administration, but administer it within 3 hours.

:* Administer Antihemophilic factor over a period of 1 to 15 minutes. Adapt the rate of administration to the response of each individual patient. Determine the pulse rate before and during administration of Antihemophilic factor. If there is a significant increase in pulse rate, reduce the rate of administration or temporarily halt the infusion allowing the symptoms to disappear promptly.
|monitoring=* Monitor plasma factor VIII activity levels by the one-stage clotting assay to confirm the adequate factor VIII levels have been achieved and maintained, when clinically indicated.

* Monitor for development of factor VIII inhibitors. Perform assay to determine if [[factor VIII]] inhibitor is present. If expected factor VIII activity plasma levels are not attained or if bleeding is not controlled with the expected dose of Antihemophilic factor, use Bethesda Units (BU) to titer inhibitors.

:* If the inhibitor is less than 10 BU per mL, the administration of additional Antihemophilic factor concentrate may neutralize the inhibitor and may permit an appropriate hemostatic response.

:* If inhibitor titers are above 10 BU per mL, adequate [[hemostasis]] may not be achieved. The inhibitor titer may rise following Antihemophilic factor infusion as a result of an anamnestic response to [[factor VIII]]. The treatment or prevention of bleeding in such patients requires the use of alternative therapeutic approaches and agents.
|IVCompat=There is limited information about the IV Compatibilty.
|overdose=FDA Package Insert for Antihemophilic factor contains no information regarding Adverse Reactions.
|drugBox={{PBB|geneid=2157}}
|mechAction=Antihemophilic factor temporarily replaces the missing clotting factor VIII that is needed for effective hemostasis.
|structure=(Description with picture)
|PD=The activated partial thromboplastin time (aPTT) is prolonged in patients with [[hemophilia]]. Determination of aPTT is a conventional in vitro assay for biological activity of [[factor VIII]]. Treatment with Antihemophilic factor normalizes the aPTT over the effective dosing period.
|PK=The pharmacokinetic properties of Antihemophilic factor were investigated in two separate studies in adult and pediatric previously treated patients (PTPs).
Pharmacokinetic studies with Antihemophilic factor were conducted in 20 PTPs (ages 12 to 33 years) with severe hemophilia A. The pharmacokinetic parameters for Antihemophilic factor were measured in a randomized, crossover clinical trial with the predecessor HELIXATE product using a single dose administration of 50 IU per kg. After 24 weeks, the same dose of Antihemophilic factor was administered to the same patients. The recovery and half-life data for Antihemophilic factor were unchanged after 24 weeks of continued treatment with sustained efficacy and no evidence of factor VIII inhibition.

[[File:Antihemophilic factor_administration_01.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

The pharmacokinetics of Antihemophilic factor were investigated in pediatric PTPs (4.4–18.1 years of age, average age 12).7 The pharmacokinetic parameters in children compared to adults show differences in higher clearance, lower incremental in vivo factor VIII recovery and a shorter factor VIII half-life. The pharmacokinetic parameters are depicted in Table 9.

[[File:Antihemophilic factor_administration_02.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|nonClinToxic====Carcinogenesis, Mutagenesis, Impairment of Fertility===

No studies have been conducted with Antihemophilic factor to assess its mutagenic or carcinogenic potential and impairment of fertility. By inference, the predecessor product HELIXATE and Antihemophilic factor would be expected to have equivalent mutagenic and carcinogenic potential.
The predecessor product did not demonstrate reverse mutation or chromosomal aberrations at doses substantially greater than the maximum expected clinical dose. In vivo evaluation with the predecessor product in animals using doses ranging between 10 and 40 times the expected clinical maximum also indicated that the predecessor product did not possess a mutagenic potential. Long-term investigations of carcinogenic potential in animals have not been performed due to the immune response to heterologous proteins in all non-human mammalian species.

===Animal Toxicology and/or Pharmacology===

Preclinical studies evaluating Antihemophilic factor in [[hemophilia A]] with mice, rats, rabbits, and dogs demonstrated safe and effective restoration of [[hemostasis]]. Doses several fold higher than the recommended clinical dose (related to body weight) did not demonstrate any acute or subacute toxic effect for Antihemophilic factor in laboratory animals.
Antihemophilic factor has been shown to be comparable to the predecessor product HELIXATE with respect to its biochemical and physiochemical properties, as well as its non-clinical in vivo pharmacology and toxicology.
|clinicalStudies====Previously Treated Patients (PTPs) Clinical Studies===

A total of 73 patients with severe (≤ 2% FVIII) hemophilia A, ages 12–59, who had been previously treated with other recombinant or with plasma-derived AHF products, were treated up to 54 months in open label studies with Antihemophilic factor. A total of 5,684 bleeding episodes were treated during the studies; 92.7% of the bleeds were treated with one (79.7%) or two (13.0%) infusions. Patients could be treated with on-demand or prophylaxis. Regularly scheduled prophylaxis treatment represented 76% of all infusions (treatment regimens of 2–3 infusions per week).
A total of 30 patients received Antihemophilic factor for 41 surgical procedures during the PTP studies. There were both minor and major surgery types, 16 and 25 respectively. Efficacy was measured by the attending surgeon based on a comparison of estimated blood loss from experience with non-hemophilic patients undergoing similar procedures. The surgeon or treating physician assigned a rating to the hemostatic outcome according to 4 categories: "excellent (blood loss less than expected)," "good (blood loss as expected)," "moderate (blood loss more than expected)," or "none (uncontrolled bleeding)." Hemostasis was rated as satisfactory ("excellent" or "good") in all cases.

===Previously Untreated Patients (PUPs) and Minimally Treated Patients (MTPs) Clinical Study===

Antihemophilic factor has been used in the treatment of bleeding episodes in pediatric PUPs and MTPs with severe (<2% FVIII) hemophilia A. There were 37 PUPs and 24 MTPs (defined as having equal to or less than 4 exposure days) treated with a total of 9,419 infusions of Antihemophilic factor for a follow up duration up to 3.1 years. A total of 1047 bleeding episodes were treated; the bleeds were treated with one (73%) or two (15%) infusions.
A total of 27 surgical procedures were performed in 22 patients during the PUPs and MTPs study. There were both minor and major surgery types, 21 and 6 respectively. The attending surgeon measured efficacy and assigned a rating to the hemostatic outcome according to 4 categories as described above for PTPs. Hemostasis was rated as satisfactory ("excellent" or "good") in all cases.

===Adult Prophylaxis for Bleeding Frequency Reduction===

An ongoing, 3-year, multicenter, open-label, parallel-group, prospective, randomized, controlled clinical study of the effect of routine prophylaxis with Antihemophilic factor versus on-demand use on bleeding frequency in adults and adolescents included 84 PTPs with severe Hemophilia A (FVIII level < 1 IU/dL), age 15 to 50 years. Patients were matched at baseline on demographic and disease characteristics. The median number of bleeds in the year before enrollment was 18.
Patients were randomized 1:1 to prophylaxis (25 units per kg three times a week) or on-demand use of Antihemophilic factor. Escalation of the prophylaxis dose by 5 units per kg/infusion after years 1 and 2, up to a maximum of 35 units per kg/infusion, was allowed.
Bleeding frequency was analyzed in the intent-to-treat population after a median follow-up period of 1.4 years. Patients who received prophylaxis experienced statistically significantly fewer bleeds (p<0.0001) compared to patients treated on-demand regardless of baseline subgroups examined including age, bleeding history, and presence or absence of target joints. The ratio of the mean bleeding frequency was 15.2 (95% CI: 8.5, 27.2; p<0.0001) for on-demand versus prophylaxis, indicating that patients who received on-demand treatment experienced on average 15.2 times as many bleeds compared to patients treated with prophylaxis. The mean annualized bleed rates (bleeds/subject/year) were 37 in the on-demand group versus 2 in the prophylaxis group. The median annualized bleed rate (bleeds/subject/year) in the on-demand group was 33 versus zero in the prophylaxis group. Most of the bleeding occurred in joints: the median joint bleed rate (joint bleeds/subject/year) was 24 in the on-demand group versus zero in the prophylaxis group. The mean annualized joint bleed rate was 29 in the on-demand group versus 2 in the prophylaxis group.
Twenty-two of 42 (52%) prophylaxis subjects experienced no bleeding, and 12 of 42 (29%) prophylaxis subjects experienced only 1–2 bleeds during the follow-up period. Among prophylaxis patients the mean number of infusions/week was 2.8, and the median dose per prophylaxis infusion was 26 units per kg.

===Pediatric Prophylaxis for Joint Damage Risk Reduction===

A total of 65 boys less than 30 months of age with severe hemophilia A (FVIII level ≤ 2 IU/dL) and with ≤ 2 bleeds into each index joint and normal baseline joint imaging, were observed for up to 5.5 years in a multicenter, open-label, prospective, randomized, controlled clinical study.5 Patients received either 25 IU per kg every other day (primary prophylaxis; n = 32) or at least 3 doses totaling a minimum of 80 IU per kg at the time of a bleeding episode (enhanced episodic; n = 33). Joint damage was evaluated by magnetic resonance imaging (MRI) or radiography, as well as the frequency of bleeding episodes. Joint damage detected by MRI or radiography in the ankles, knees, and elbows (i.e., index joints) was statistically significantly lower (p = 0.002) for subjects receiving prophylactic therapy (7%) than for subjects receiving episodic therapy (42%). This corresponds to a 6.29-fold relative risk of joint damage for subjects treated with enhanced episodic therapy compared to prophylaxis. The mean rate of index joint hemorrhages for subjects on episodic therapy was 4.89 bleeds per year, versus 0.63 bleeds per year observed in the prophylaxis arm. Three of 33 (9.1%) subjects in the episodic arm experienced recurrent life threatening bleeds (intracranial, gastrointestinal) compared to no subjects in the prophylaxis arm. On a per joint basis, joints in the regular prophylaxis arm were 8-fold more likely to remain damage-free than those in the episodic arm. Joint damage was most frequently observed in ankle joints and was detected at higher rates by MRI than by radiography. Ankles were also the index joint that demonstrated the highest frequency of bleeding events in this study (left ankle, mean 2.7 hemorrhages; right ankle, mean 2.6 hemorrhages).
As shown in Table 10 below, the incidence of joint damage was statistically significantly lower in the prophylactic group as compared to the episodic treatment group when assessed by MRI, or either MRI or radiography, using predefined criteria (described below) for establishing joint damage. However, there was no statistically significant difference between the two groups when joint damage was assessed by radiography alone.
To evaluate joint damage, MRIs were scored using a scale developed by Nuss et al.,14 and X-rays were scored using the method of Pettersson et al.15 Both scales have been validated in various clinical trials and are routinely used for joint damage evaluation in hemophiliacs. Joint damage was defined as bone and/or cartilage damage including subchondral cysts, erosions and cartilage loss with narrowing of joint space. This corresponded to a total MRI score of ≥ 7 or an X-ray score of ≥1 in any of the following categories: subchondral cysts, erosions of joint surfaces or narrowing of joint spaces. Images were read separately by two independent radiologists centrally. Any discrepant reading was read by an independent third radiologist who was not aware of the initial reading results. The concordant reading of two out of three readers was used for analysis purposes.

[[File:Antihemophilic factor_clinical studies_01.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|howSupplied=Antihemophilic factor is available as a kit in the following single-use glass vial sizes. A suitable volume of Sterile Water for Injection, USP and Mix2Vial™ filter transfer device are provided in the kit.

[[File:Antihemophilic factor_how supplied_01.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

Actual factor VIII activity in IU is stated on the label of each Antihemophilic factor vial.
|storage=The product vial and diluent vial are not made with natural rubber latex.

<u>Product as Packaged for Sale</u>

Store Antihemophilic factor at +2°C to +8°C (36°F to 46°F) for up to 30 months from the date of manufacture. Within this period, Antihemophilic factor may be stored for a period of up to 12 months at temperatures up to +25°C or 77°F.

Record the starting date of room temperature storage on the unopened product carton. Once stored at room temperature, do not return the product to the refrigerator. The shelf-life then expires after storage at room temperature, or after the expiration date on the product vial, whichever is earlier.

Do not use Antihemophilic factor after the expiration date indicated on the vial.

Do not freeze.

Protect from extreme exposure to light and store the lyophilized powder in the carton prior to use.

<u>Product After Reconstitution</u>

After reconstitution, store the Antihemophilic factor solution at room temperature and administer within 3 hours.
|fdaPatientInfo=* Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

* Advise patients to report any adverse reactions or problems following Antihemophilic factor administration to their physician or healthcare provider.

* Allergic-type [[hypersensitivity]] reactions have been reported with Antihemophilic factor. Warn patients of the early signs of [[hypersensitivity]] reactions [including hives ([[rash]] with itching), generalized [[urticaria]], tightness of the chest, wheezing, hypotension] and anaphylaxis. Advise patients to discontinue use of the product if these symptoms occur and seek immediate emergency treatment with resuscitative measures such as the administration of [[epinephrine]] and oxygen.

* Inhibitor formation may occur at any time in the treatment of a patient with [[hemophilia A]]. Advise patients to contact their physician or treatment center for further treatment and/or assessment, if they experience a lack of clinical response to factor VIII replacement therapy, as this may be a manifestation of an inhibitor.

* Advise patients to consult with their healthcare provider prior to travel. While traveling advise patients to bring an adequate supply of Antihemophilic factor based on their current regimen of treatment.
|alcohol=Alcohol-Antihemophilic factor interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=* Koate DVI
* Monoclate-P
* antihemophilic factor
|lookAlike=FDA Package Insert for Antihemophilic factor contains no information regarding Adverse Reactions.
|nlmPatientInfo=(Link to patient information page)
|drugShortage=Drug Shortage
}}
{{LabelImage
|fileName=Antihemophilic factor_label_01.jpg
}}
{{LabelImage
|fileName=Antihemophilic factor_label_02.jpg
}}
{{LabelImage
|fileName=Antihemophilic factor_label_03.jpg
}}
{{LabelImage
|fileName=Antihemophilic factor_label_04.jpg
}}
{{LabelImage
|fileName=Antihemophilic factor_label_05.jpg
}}

[[Category: Cardiovascular Drugs]]
[[Category: Drug]]

Antihemophilic factor

2015-03-19T15:53:40Z

Sree Teja Yelamanchili:

{{DrugProjectFormSinglePage
|authorTag={{SS}}; {{STY}}
|genericName=antihemophilic factor
|aOrAn=a
|drugClass=human antihemophilic factor
|indicationType=treatment
|indication=[[hemophilia A]]
|adverseReactions=[[nausea]], [[headache]], [[blurred vision]]
|blackBoxWarningTitle=<b><span style="color:#FF0000;">TITLE</span></b>
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)
|fdaLIADAdult=<H4>Hemophilia A</H4>

* Indication

:* Helixate® FS is a recombinant antihemophilic factor indicated for:

::* Control and prevention of bleeding episodes in adults and children with [[hemophilia A]].

::* Surgical prophylaxis in adults and children with [[hemophilia A]].

::* Routine prophylactic treatment to prevent or reduce the frequency of [[bleeding]] episodes in children with [[hemophilia A]] and to reduce the risk of joint damage in children without pre-existing joint damage.

::* Routine prophylactic treatment to prevent or reduce the frequency of bleeding episodes in adults with [[hemophilia A]].

*Antihemophilic factor is not indicated for the treatment of [[von Willebrand disease]].

* Dosing Information

:* Dosage and duration of treatment depend on the severity of the [[factor VIII deficiency]], the location and extent of bleeding, and the patient's clinical condition.1 Careful control of replacement therapy is especially important in cases of major surgery or life-threatening bleeding episodes.
:* Each vial of Antihemophilic factor has the recombinant [[factor VIII]] (rFVIII) potency in international units (IU, unit) stated on the label. One IU (unit), as defined by the World Health Organization standard for blood [[coagulation factor VIII]], human, is approximately equal to the level of [[factor VIII]] activity found in 1 mL of fresh pooled human plasma.

:* The expected in vivo peak increase in [[factor VIII]] level expressed as IU/dL (or % normal) can be estimated using the following formulas:

'''Dosage (units) = body weight (kg) × desired [[factor VIII]] rise (IU/dL or % of normal) × 0.5 (IU/kg per IU/dL)'''
or
'''IU/dL (or % normal) = Total Dose (IU)/body weight (kg) × 2 [IU/dL]/[IU/kg]'''

:* Titrate dose to the patient's clinical response. Patients may vary in their pharmacokinetic (e.g., half-life, in vivo recovery) and clinical responses to Antihemophilic factor.2,3,4 Although the dose can be estimated by the calculations above, it is highly recommended that appropriate laboratory tests, including serial [[factor VIII]] activity assays, are performed.
* Control and Prevention of Bleeding Episodes

A guide for dosing Antihemophilic factor for the control and prevention of bleeding episodes is provided in Table 1. The goal of treatment is to maintain a plasma [[factor VIII]] activity level at or above the plasma levels (in % of normal or in IU/dL) outlined in Table 1.

[[File:Antihemophilic factor_administration_01.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

* Peri-operative Management

A guide for dosing Antihemophilic factor during surgery (perioperative management) is provided in Table 2. The goal of treatment is to maintain a plasma [[factor VIII]] activity level at or above the plasma level (in % of normal or in IU/dL) outlined in Table 2.

[[File:Antihemophilic factor_administration_02.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

* Routine Prophylaxis in Adults

:* Recommended dosage: ''' 25 units/kg body weight IV three times per week'''.

* Routine Prophylaxis in Children

:* Recommended dosage: '''25 IU/kg body IV weight qod'''

<H4>Preparation and Reconstitution</H4>

* Antihemophilic factor is administered by intravenous injection after reconstitution. Patients should follow the specific reconstitution and administration procedures provided by their physicians.
* Reconstitute and administer Antihemophilic factor with the components provided with each package. If any component of the package is opened or damaged, do not use this component.
* Product reconstitution, administration, and handling of the administration set and needles must be done with caution because percutaneous puncture with a needle contaminated with blood can transmit infectious viruses, including [[HIV]] ([[AIDS]]) and [[hepatitis]]. Place needles in a sharps container after single use. Discard all equipment, including any reconstituted Antihemophilic factor product, in an appropriate container. Obtain immediate medical attention if injury occurs.
* For instructions, patients should follow the recommendations in the FDA-Approved Patient Labeling.
* The procedures below are provided as general guidelines for the reconstitution of Antihemophilic factor.

:* Work on a clean flat surface and wash hands thoroughly using soap and warm water before performing the procedures.

:* Reconstitute the product with the components provided with each package. If any component of the package is opened or damaged, do not use this component.

:* Filter the reconstituted product prior to administration to remove potential particulate matter in the solution. Filtering can be achieved by using the Mix2Vial™ vial adapter.

[[File:Antihemophilic factor_administration_03.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|offLabelAdultGuideSupport=There is limited information regarding Off-Label Guideline-Supported Use of Amiodarone in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding Off-Label Non–Guideline-Supported Use of Amiodarone in adult patients
|fdaLIADPed=FDA Package Insert for Antihemophilic factor contains no information regarding FDA-labeled indications and dosage information for children.
|offLabelPedGuideSupport=There is limited information regarding Off-Label Guideline-Supported Use of Amiodarone in pediatric patients
|offLabelPedNoGuideSupport=There is limited information regarding Off-Label Non–Guideline-Supported Use of Amiodarone in pediatric patients
|contraindications=Antihemophilic factor is contraindicated in patients who have life-threatening [[hypersensitivity]] reactions, including [[anaphylaxis]] to mouse or hamster protein or other constituents of the product ([[sucrose]], [[glycine]], [[histidine]], [[sodium]], [[calcium chloride]], [[polysorbate 80]], [[sucrose]], [[imidazole]], tri-n-butyl phosphate, and copper).
|warnings====Hypersensitivity Reactions===

*Hypersensitivity reactions, including [[anaphylaxis]] have been reported with Antihemophilic factor. Reported symptoms included [[facial swelling]], [[flushing]], [[hives]], [[hypotension|decrease in blood pressure]], [[nausea]], [[rash]], [[restlessness]], [[shortness of breath]], [[tachycardia]], tightness of the chest, [[tingling]], [[urticaria]], and [[vomiting]].
*Antihemophilic factor contains trace amounts of mouse immunoglobulin G (MuIgG) and hamster (BHK) proteins. Patients treated with this product may develop hypersensitivity to these non-human mammalian proteins.
*Discontinue Antihemophilic factor if symptoms occur and seek immediate emergency treatment.

===Neutralizing Antibodies===

Neutralizing antibodies (inhibitors) have been reported following administration of Antihemophilic factor predominantly in previously untreated patients. Carefully monitor patients for the development of factor VIII inhibitors, using appropriate clinical observations and laboratory tests. If expected plasma [[factor VIII]] activity levels are not attained, or if bleeding is not controlled with an expected dose, perform an assay that measures factor VIII inhibitor concentration.

===Cardiovascular Risk Factors===

Hemophilic patients with cardiovascular risk factors or diseases may be at the same risk to develop cardiovascular events as non-hemophilic patients when clotting has been normalized by treatment with factor VIII.

===Monitoring Laboratory Tests===

* Monitor plasma [[factor VIII]] activity levels by the one-stage clotting assay to confirm the adequate factor VIII levels have been achieved and maintained, when clinically indicated.

* Monitor for development of factor VIII inhibitors. Perform assay to determine if [[factor VIII]] inhibitor is present. If expected factor VIII activity plasma levels are not attained or if bleeding is not controlled with the expected dose of Antihemophilic factor, use Bethesda Units (BU) to titer inhibitors.

:* If the inhibitor is less than 10 BU per mL, the administration of additional Antihemophilic factor concentrate may neutralize the inhibitor and may permit an appropriate hemostatic response.

:* If inhibitor titers are above 10 BU per mL, adequate hemostasis may not be achieved. The inhibitor titer may rise following Antihemophilic factor infusion as a result of an anamnestic response to [[factor VIII]]. The treatment or prevention of bleeding in such patients requires the use of alternative therapeutic approaches and agents.
|clinicalTrials=*Serious adverse reactions seen with Antihemophilic factor are systemic [[hypersensitivity]] reactions, including bronchospastic reactions and/or [[hypotension]] and [[anaphylaxis]], and the development of high-titer inhibitors necessitating alternative treatments to factor VIII.
*The most common adverse reactions (≥ 4%) observed in clinical trials were inhibitor formation in previously untreated patients (PUPs) and minimally treated patients (MTPs), skin-related hypersensitivity reactions (e.g., [[rash]], [[pruritus]]), infusion site reactions (e.g., inflammation, pain), and [[Central venous catheter|central venous access device]] (CVAD) associated infections.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in clinical practice.

===Previously Treated Patients (PTPs)===

During the open-label clinical studies conducted in 73 PTPs, there were 24 adverse reactions reported in the course of 24,936 infusions.
Adverse reactions reported by ≥ 4% of the patients are listed in Table 3 below.

[[File:Antihemophilic factor_adverse_01.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

===Previously Untreated Patients (PUPs) and Minimally Treated Patients (MTPs)===

In clinical studies with pediatric PUPs and MTPs, there were 29 adverse reactions reported in the course of 9,389 infusions.
Adverse reactions reported by ≥ 4% of the patients are listed in Table 4 below.

[[File:Antihemophilic factor_adverse_02.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

===Minimally Treated Patients (MTPs) in the Joint Outcome Study===

In the Joint Outcome Study with pediatric MTPs treated with routine prophylaxis or episodic enhanced treatment for 5.5 years, 46 of the 65 randomized patients experienced adverse events over the study duration.

[[File:Antihemophilic factor_adverse_03.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

<u>Immunogenicity</u>

*In clinical studies with 73 PTPs (defined as having more than 100 exposure days), one patient had a pre-existing inhibitor.
*In the other 72 patients, followed over 4 years, no de novo inhibitors were observed.
*In clinical studies with pediatric PUPs and MTPs, inhibitor development was observed in 9 out of 60 patients (15%), 6 were high titer1 (> 5 BU) and 3 were low-titer inhibitors.
*Inhibitors were detected at a median number of 7 exposure days (range 2 to 16 exposure days).
*In the Joint Outcome Study with Antihemophilic factor,5 de novo inhibitor development was observed in 8 of 64 patients with negative baseline values (12.5%), 2 patients developed high titer1 (> 5 BU) and were withdrawn from the study. Six patients developed low-titer inhibitors.
*Inhibitors were detected at a median number of 44 exposure days (range 5 to 151 exposure days).
*The detection of antibody formation is dependent on the sensitivity and specificity of the assay.
*Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease.
*For these reasons, comparison of the incidence of antibodies to Antihemophilic factor with the incidence of antibodies to other products may be misleading.
|postmarketing=The following adverse reaction has been identified during post approval use of Antihemophilic factor. Because adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

===Sensory System – Dysgeusia===

Additionally, available registries have reported inhibitor rates for PUPs with severe hemophilia A in the range of 28% to 38% for [[factor VIII]] products.
|drugInteractions=FDA Package Insert for Antihemophilic factor contains no information regarding drug interactions.
|FDAPregCat=C
|useInPregnancyFDA=Animal reproduction studies have not been conducted with Antihemophilic factor. It is also not known whether Antihemophilic factor can cause fetal harm when administered to a pregnant woman or affect reproductive capacity. Antihemophilic factor should be given to a pregnant woman only if clearly needed.
|useInLaborDelivery=There is no information available on the effect of factor VIII replacement therapy on labor and delivery. Antihemophilic factor should be used only if clinically needed.
|useInNursing=It is not known whether this drug is excreted into human milk. Because many drugs are excreted into human milk, caution should be exercised if Antihemophilic factor is administered to a nursing woman.
|useInPed=There is no FDA guidance on the use of Tranexamic Acid in pediatric patients.
|useInGeri=Clinical studies with Antihemophilic factor did not include patients aged 65 and over. Dose selection for an elderly patient should be individualized.
|useInGender=Safety and efficacy studies have been performed in previously untreated and minimally treated pediatric patients. Children, in comparison to adults, present higher factor VIII clearance values and, thus, lower half-life and recovery of factor VIII. This may be due to differences in body composition.7 Account for this difference in clearance when dosing or following factor VIII levels in the pediatric population.
Routine prophylactic treatment in children ages 0–2.5 years with no pre-existing joint damage has been shown to reduce spontaneous joint bleeding and the risk of joint damage. This data can be extrapolated to ages >2.5–16 years for children who have no existing joint damage.
|useInRace=There is no FDA guidance on the use of Antihemophilic factor with respect to specific racial populations.
|useInRenalImpair=There is no FDA guidance on the use of Antihemophilic factor in patients with renal impairment.
|useInHepaticImpair=There is no FDA guidance on the use of Antihemophilic factor in patients with hepatic impairment.
|useInReproPotential=here is no FDA guidance on the use of Antihemophilic factor in women of reproductive potentials and males
|useInImmunocomp=There is no FDA guidance one the use of Antihemophilic factor in patients who are immunocompromised.
|othersTitle=Others
|useInOthers=(Description)
|administration=For intravenous use after reconstitution only.

:* Inspect Antihemophilic factor visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Turbid or discolored solution should be discarded.

:* Store the reconstituted Antihemophilic factor at room temperature prior to administration, but administer it within 3 hours.

:* Administer Antihemophilic factor over a period of 1 to 15 minutes. Adapt the rate of administration to the response of each individual patient. Determine the pulse rate before and during administration of Antihemophilic factor. If there is a significant increase in pulse rate, reduce the rate of administration or temporarily halt the infusion allowing the symptoms to disappear promptly.
|monitoring=* Monitor plasma factor VIII activity levels by the one-stage clotting assay to confirm the adequate factor VIII levels have been achieved and maintained, when clinically indicated.

* Monitor for development of factor VIII inhibitors. Perform assay to determine if [[factor VIII]] inhibitor is present. If expected factor VIII activity plasma levels are not attained or if bleeding is not controlled with the expected dose of Antihemophilic factor, use Bethesda Units (BU) to titer inhibitors.

:* If the inhibitor is less than 10 BU per mL, the administration of additional Antihemophilic factor concentrate may neutralize the inhibitor and may permit an appropriate hemostatic response.

:* If inhibitor titers are above 10 BU per mL, adequate [[hemostasis]] may not be achieved. The inhibitor titer may rise following Antihemophilic factor infusion as a result of an anamnestic response to [[factor VIII]]. The treatment or prevention of bleeding in such patients requires the use of alternative therapeutic approaches and agents.
|IVCompat=There is limited information about the IV Compatibilty.
|overdose=FDA Package Insert for Antihemophilic factor contains no information regarding Adverse Reactions.
|drugBox={{PBB|geneid=2157}}
|mechAction=Antihemophilic factor temporarily replaces the missing clotting factor VIII that is needed for effective hemostasis.
|structure=(Description with picture)
|PD=The activated partial thromboplastin time (aPTT) is prolonged in patients with [[hemophilia]]. Determination of aPTT is a conventional in vitro assay for biological activity of [[factor VIII]]. Treatment with Antihemophilic factor normalizes the aPTT over the effective dosing period.
|PK=The pharmacokinetic properties of Antihemophilic factor were investigated in two separate studies in adult and pediatric previously treated patients (PTPs).
Pharmacokinetic studies with Antihemophilic factor were conducted in 20 PTPs (ages 12 to 33 years) with severe hemophilia A. The pharmacokinetic parameters for Antihemophilic factor were measured in a randomized, crossover clinical trial with the predecessor HELIXATE product using a single dose administration of 50 IU per kg. After 24 weeks, the same dose of Antihemophilic factor was administered to the same patients. The recovery and half-life data for Antihemophilic factor were unchanged after 24 weeks of continued treatment with sustained efficacy and no evidence of factor VIII inhibition.

[[File:Antihemophilic factor_administration_01.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

The pharmacokinetics of Antihemophilic factor were investigated in pediatric PTPs (4.4–18.1 years of age, average age 12).7 The pharmacokinetic parameters in children compared to adults show differences in higher clearance, lower incremental in vivo factor VIII recovery and a shorter factor VIII half-life. The pharmacokinetic parameters are depicted in Table 9.

[[File:Antihemophilic factor_administration_02.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|nonClinToxic====Carcinogenesis, Mutagenesis, Impairment of Fertility===

No studies have been conducted with Antihemophilic factor to assess its mutagenic or carcinogenic potential and impairment of fertility. By inference, the predecessor product HELIXATE and Antihemophilic factor would be expected to have equivalent mutagenic and carcinogenic potential.
The predecessor product did not demonstrate reverse mutation or chromosomal aberrations at doses substantially greater than the maximum expected clinical dose. In vivo evaluation with the predecessor product in animals using doses ranging between 10 and 40 times the expected clinical maximum also indicated that the predecessor product did not possess a mutagenic potential. Long-term investigations of carcinogenic potential in animals have not been performed due to the immune response to heterologous proteins in all non-human mammalian species.

===Animal Toxicology and/or Pharmacology===

Preclinical studies evaluating Antihemophilic factor in [[hemophilia A]] with mice, rats, rabbits, and dogs demonstrated safe and effective restoration of [[hemostasis]]. Doses several fold higher than the recommended clinical dose (related to body weight) did not demonstrate any acute or subacute toxic effect for Antihemophilic factor in laboratory animals.
Antihemophilic factor has been shown to be comparable to the predecessor product HELIXATE with respect to its biochemical and physiochemical properties, as well as its non-clinical in vivo pharmacology and toxicology.
|clinicalStudies====Previously Treated Patients (PTPs) Clinical Studies===

A total of 73 patients with severe (≤ 2% FVIII) hemophilia A, ages 12–59, who had been previously treated with other recombinant or with plasma-derived AHF products, were treated up to 54 months in open label studies with Antihemophilic factor. A total of 5,684 bleeding episodes were treated during the studies; 92.7% of the bleeds were treated with one (79.7%) or two (13.0%) infusions. Patients could be treated with on-demand or prophylaxis. Regularly scheduled prophylaxis treatment represented 76% of all infusions (treatment regimens of 2–3 infusions per week).
A total of 30 patients received Antihemophilic factor for 41 surgical procedures during the PTP studies. There were both minor and major surgery types, 16 and 25 respectively. Efficacy was measured by the attending surgeon based on a comparison of estimated blood loss from experience with non-hemophilic patients undergoing similar procedures. The surgeon or treating physician assigned a rating to the hemostatic outcome according to 4 categories: "excellent (blood loss less than expected)," "good (blood loss as expected)," "moderate (blood loss more than expected)," or "none (uncontrolled bleeding)." Hemostasis was rated as satisfactory ("excellent" or "good") in all cases.

===Previously Untreated Patients (PUPs) and Minimally Treated Patients (MTPs) Clinical Study===

Antihemophilic factor has been used in the treatment of bleeding episodes in pediatric PUPs and MTPs with severe (<2% FVIII) hemophilia A. There were 37 PUPs and 24 MTPs (defined as having equal to or less than 4 exposure days) treated with a total of 9,419 infusions of Antihemophilic factor for a follow up duration up to 3.1 years. A total of 1047 bleeding episodes were treated; the bleeds were treated with one (73%) or two (15%) infusions.
A total of 27 surgical procedures were performed in 22 patients during the PUPs and MTPs study. There were both minor and major surgery types, 21 and 6 respectively. The attending surgeon measured efficacy and assigned a rating to the hemostatic outcome according to 4 categories as described above for PTPs. Hemostasis was rated as satisfactory ("excellent" or "good") in all cases.

===Adult Prophylaxis for Bleeding Frequency Reduction===

An ongoing, 3-year, multicenter, open-label, parallel-group, prospective, randomized, controlled clinical study of the effect of routine prophylaxis with Antihemophilic factor versus on-demand use on bleeding frequency in adults and adolescents included 84 PTPs with severe Hemophilia A (FVIII level < 1 IU/dL), age 15 to 50 years. Patients were matched at baseline on demographic and disease characteristics. The median number of bleeds in the year before enrollment was 18.
Patients were randomized 1:1 to prophylaxis (25 units per kg three times a week) or on-demand use of Antihemophilic factor. Escalation of the prophylaxis dose by 5 units per kg/infusion after years 1 and 2, up to a maximum of 35 units per kg/infusion, was allowed.
Bleeding frequency was analyzed in the intent-to-treat population after a median follow-up period of 1.4 years. Patients who received prophylaxis experienced statistically significantly fewer bleeds (p<0.0001) compared to patients treated on-demand regardless of baseline subgroups examined including age, bleeding history, and presence or absence of target joints. The ratio of the mean bleeding frequency was 15.2 (95% CI: 8.5, 27.2; p<0.0001) for on-demand versus prophylaxis, indicating that patients who received on-demand treatment experienced on average 15.2 times as many bleeds compared to patients treated with prophylaxis. The mean annualized bleed rates (bleeds/subject/year) were 37 in the on-demand group versus 2 in the prophylaxis group. The median annualized bleed rate (bleeds/subject/year) in the on-demand group was 33 versus zero in the prophylaxis group. Most of the bleeding occurred in joints: the median joint bleed rate (joint bleeds/subject/year) was 24 in the on-demand group versus zero in the prophylaxis group. The mean annualized joint bleed rate was 29 in the on-demand group versus 2 in the prophylaxis group.
Twenty-two of 42 (52%) prophylaxis subjects experienced no bleeding, and 12 of 42 (29%) prophylaxis subjects experienced only 1–2 bleeds during the follow-up period. Among prophylaxis patients the mean number of infusions/week was 2.8, and the median dose per prophylaxis infusion was 26 units per kg.

===Pediatric Prophylaxis for Joint Damage Risk Reduction===

A total of 65 boys less than 30 months of age with severe hemophilia A (FVIII level ≤ 2 IU/dL) and with ≤ 2 bleeds into each index joint and normal baseline joint imaging, were observed for up to 5.5 years in a multicenter, open-label, prospective, randomized, controlled clinical study.5 Patients received either 25 IU per kg every other day (primary prophylaxis; n = 32) or at least 3 doses totaling a minimum of 80 IU per kg at the time of a bleeding episode (enhanced episodic; n = 33). Joint damage was evaluated by magnetic resonance imaging (MRI) or radiography, as well as the frequency of bleeding episodes. Joint damage detected by MRI or radiography in the ankles, knees, and elbows (i.e., index joints) was statistically significantly lower (p = 0.002) for subjects receiving prophylactic therapy (7%) than for subjects receiving episodic therapy (42%). This corresponds to a 6.29-fold relative risk of joint damage for subjects treated with enhanced episodic therapy compared to prophylaxis. The mean rate of index joint hemorrhages for subjects on episodic therapy was 4.89 bleeds per year, versus 0.63 bleeds per year observed in the prophylaxis arm. Three of 33 (9.1%) subjects in the episodic arm experienced recurrent life threatening bleeds (intracranial, gastrointestinal) compared to no subjects in the prophylaxis arm. On a per joint basis, joints in the regular prophylaxis arm were 8-fold more likely to remain damage-free than those in the episodic arm. Joint damage was most frequently observed in ankle joints and was detected at higher rates by MRI than by radiography. Ankles were also the index joint that demonstrated the highest frequency of bleeding events in this study (left ankle, mean 2.7 hemorrhages; right ankle, mean 2.6 hemorrhages).
As shown in Table 10 below, the incidence of joint damage was statistically significantly lower in the prophylactic group as compared to the episodic treatment group when assessed by MRI, or either MRI or radiography, using predefined criteria (described below) for establishing joint damage. However, there was no statistically significant difference between the two groups when joint damage was assessed by radiography alone.
To evaluate joint damage, MRIs were scored using a scale developed by Nuss et al.,14 and X-rays were scored using the method of Pettersson et al.15 Both scales have been validated in various clinical trials and are routinely used for joint damage evaluation in hemophiliacs. Joint damage was defined as bone and/or cartilage damage including subchondral cysts, erosions and cartilage loss with narrowing of joint space. This corresponded to a total MRI score of ≥ 7 or an X-ray score of ≥1 in any of the following categories: subchondral cysts, erosions of joint surfaces or narrowing of joint spaces. Images were read separately by two independent radiologists centrally. Any discrepant reading was read by an independent third radiologist who was not aware of the initial reading results. The concordant reading of two out of three readers was used for analysis purposes.

[[File:Antihemophilic factor_clinical studies_01.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|howSupplied=Antihemophilic factor is available as a kit in the following single-use glass vial sizes. A suitable volume of Sterile Water for Injection, USP and Mix2Vial™ filter transfer device are provided in the kit.

[[File:Antihemophilic factor_how supplied_01.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

Actual factor VIII activity in IU is stated on the label of each Antihemophilic factor vial.
|storage=The product vial and diluent vial are not made with natural rubber latex.

<u>Product as Packaged for Sale</u>

Store Antihemophilic factor at +2°C to +8°C (36°F to 46°F) for up to 30 months from the date of manufacture. Within this period, Antihemophilic factor may be stored for a period of up to 12 months at temperatures up to +25°C or 77°F.

Record the starting date of room temperature storage on the unopened product carton. Once stored at room temperature, do not return the product to the refrigerator. The shelf-life then expires after storage at room temperature, or after the expiration date on the product vial, whichever is earlier.

Do not use Antihemophilic factor after the expiration date indicated on the vial.

Do not freeze.

Protect from extreme exposure to light and store the lyophilized powder in the carton prior to use.

<u>Product After Reconstitution</u>

After reconstitution, store the Antihemophilic factor solution at room temperature and administer within 3 hours.
|fdaPatientInfo=* Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

* Advise patients to report any adverse reactions or problems following Antihemophilic factor administration to their physician or healthcare provider.

* Allergic-type [[hypersensitivity]] reactions have been reported with Antihemophilic factor. Warn patients of the early signs of [[hypersensitivity]] reactions [including hives ([[rash]] with itching), generalized [[urticaria]], tightness of the chest, wheezing, hypotension] and anaphylaxis. Advise patients to discontinue use of the product if these symptoms occur and seek immediate emergency treatment with resuscitative measures such as the administration of [[epinephrine]] and oxygen.

* Inhibitor formation may occur at any time in the treatment of a patient with [[hemophilia A]]. Advise patients to contact their physician or treatment center for further treatment and/or assessment, if they experience a lack of clinical response to factor VIII replacement therapy, as this may be a manifestation of an inhibitor.

* Advise patients to consult with their healthcare provider prior to travel. While traveling advise patients to bring an adequate supply of Antihemophilic factor based on their current regimen of treatment.
|alcohol=Alcohol-Antihemophilic factor interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=* Koate DVI
* Monoclate-P
* Helixate® FS
|lookAlike=FDA Package Insert for Antihemophilic factor contains no information regarding Adverse Reactions.
|nlmPatientInfo=(Link to patient information page)
|drugShortage=Drug Shortage
}}
{{LabelImage
|fileName=Antihemophilic factor_label_01.jpg
}}
{{LabelImage
|fileName=Antihemophilic factor_label_02.jpg
}}
{{LabelImage
|fileName=Antihemophilic factor_label_03.jpg
}}
{{LabelImage
|fileName=Antihemophilic factor_label_04.jpg
}}
{{LabelImage
|fileName=Antihemophilic factor_label_05.jpg
}}

[[Category: Cardiovascular Drugs]]
[[Category: Drug]]

Allopurinol (oral)

2015-03-19T15:29:49Z

Sree Teja Yelamanchili:

{{DrugProjectFormSinglePage
|authorTag={{SS}}; {{STY}}
|genericName=allopurinol
|aOrAn=a
|drugClass=[[xanthine oxidase]] inhibitor
|indicationType=treatment
|indication=primary or secondary [[gout]] (acute attacks, [[tophus|tophi]], joint destruction, [[uric acid nephrolithiasis]], and/or [[nephropathy]]), [[leukemia]], [[lymphoma]] and [[malignancies]], recurrent [[calcium oxalate]] calculi
|adverseReactions=[[Maculopapular rash|maculopapular eruption]], [[pruritus]]
|blackBoxWarningTitle=<b><span style="color:#FF0000;">TITLE</span></b>
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)
|fdaLIADAdult=<h4>Gout</h4>

* Dosing information (The dosage of allopurinol tablets to accomplish full control of [[gout]] and to lower [[serum uric acid]] to normal or near-normal levels varies with the severity of the disease.)
:* Dosing information in patients with mild [[gout]]: '''200 to 300 mg/day'''
:* Dosing information in patients with moderately severe tophaceous [[gout]]: '''400 to 600 mg/day'''

:* The appropriate dosage may be administered in divided doses or as a single equivalent dose with the 300 mg tablet. Dosage requirements in excess of 300 mg should be administered in divided doses. The minimal effective dosage is 100 to 200 mg daily and the maximal recommended dosage is 800 mg daily.
:* To reduce the possibility of flare-up of acute gouty attacks
::* Recommended dosage: '''100 mg PO qd''' and increase at weekly intervals by '''100 mg''' until a serum uric acid level of '''6 mg/dL''' or less is attained but without exceeding the maximal recommended dosage.

:* Normal serum urate levels are usually achieved in 1 to 3 weeks. The upper limit of normal is about '''7 mg/dL''' for men and postmenopausal women and '''6 mg/dL''' for premenopausal women. Too much reliance should not be placed on a single serum uric acid determination since, for technical reasons, estimation of uric acid may be difficult. By selecting the appropriate dosage and, in certain patients, using [[uricosuric]] agents concurrently, it is possible to reduce serum uric acid to normal or, if desired, to as low as '''2 to 3''' mg/dL and keep it there indefinitely.

:* While adjusting the dosage of allopurinol tablets in patients who are being treated with [[colchicine]] and/or anti-inflammatory agents, it is wise to continue the latter therapy until serum uric acid has been normalized and there has been freedom from acute gouty attacks for several months.

:* In transferring a patient from a [[uricosuric|uricosuric agent]] to allopurinol tablets, the dose of the uricosuric agent should be gradually reduced over a period of several weeks and the dose of allopurinol tablets gradually increased to the required dose needed to maintain a normal serum [[uric acid]] level.

:* It should also be noted that allopurinol tablets are generally better tolerated if taken following meals. A fluid intake sufficient to yield a daily urinary output of at least 2 liters and the maintenance of a neutral or, preferably, slightly alkaline urine are desirable.

:* Since allopurinol tablets and its metabolites are primarily eliminated only by the kidney, accumulation of the drug can occur in renal failure, and the dose of allopurinol tablets should consequently be reduced. With a creatinine clearance of '''10 to 20 mL/min''', a daily dosage of '''200 mg''' of allopurinol tablets is suitable. When the creatinine clearance is less than 10 mL/min, the daily dosage should not exceed 100 mg. With extreme renal impairment ([[creatinine clearance]] less than 3 mL/min) the interval between doses may also need to be lengthened.

:* The correct size and frequency of dosage for maintaining the serum uric acid just within the normal range is best determined by using the serum uric acid level as an index.

:* For the prevention of uric acid [[nephropathy]] during the vigorous therapy of neoplastic disease, treatment with '''600 to 800 mg daily''' for 2 or 3 days is advisable together with a high fluid intake. Otherwise similar considerations to the above recommendations for treating patients with gout govern the regulation of dosage for maintenance purposes in secondary [[hyperuricemia]].

:* The dose of allopurinol tablets recommended for management of recurrent [[calcium oxalate]] stones in hyperuricosuric patients is '''200 to 300 mg/day''' in divided doses or as the single equivalent.
*This dose may be adjusted up or down depending upon the resultant control of the [[hyperuricosuria]] based upon subsequent 24 hour urinary urate determinations.
*Clinical experience suggests that patients with recurrent calcium oxalate stones may also benefit from dietary changes such as the reduction of animal protein, sodium, refined sugars, oxalate-rich foods, and excessive calcium intake, as well as an increase in oral fluids and dietary fiber.
|offLabelAdultGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Allopurinol in adult patients.
|offLabelAdultNoGuideSupport=<h4>Leishmaniasis</h4>

* Dosing information
:* '''10 to 36 milligrams/kilogram/day'''<ref name="pmid9114142">{{cite journal| author=Martinez S, Gonzalez M, Vernaza ME| title=Treatment of cutaneous leishmaniasis with allopurinol and stibogluconate. | journal=Clin Infect Dis | year= 1997 | volume= 24 | issue= 2 | pages= 165-9 | pmid=9114142 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9114142 }} </ref>
:* '''0.6 to 20 micrograms/milliliter''' <ref name="pmid2029827">{{cite journal| author=Shapiro TA, Were JB, Danso K, Nelson DJ, Desjardins RE, Pamplin CL| title=Pharmacokinetics and metabolism of allopurinol riboside. | journal=Clin Pharmacol Ther | year= 1991 | volume= 49 | issue= 5 | pages= 506-14 | pmid=2029827 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2029827 }} </ref>

<h4>Malaria</h4>

* Dosing information
:* '''200 to 400 milligrams daily''' <ref name="pmid9574791">{{cite journal| author=Sarma PS, Mandal AK, Khamis HJ| title=Allopurinol as an additive to quinine in the treatment of acute complicated falciparum malaria. | journal=Am J Trop Med Hyg | year= 1998 | volume= 58 | issue= 4 | pages= 454-7 | pmid=9574791 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9574791 }} </ref>

<h4>Schizophrenia</h4>

* Dosing information
:* '''300 milligrams (mg) PO qd or bid''' <ref name="pmid17119103">{{cite journal| author=Buie LW, Oertel MD, Cala SO| title=Allopurinol as adjuvant therapy in poorly responsive or treatment refractory schizophrenia. | journal=Ann Pharmacother | year= 2006 | volume= 40 | issue= 12 | pages= 2200-4 | pmid=17119103 | doi=10.1345/aph.1H222 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17119103 }} </ref>
|fdaLIADPed=<h4>Dosing in pediatric patients</h4>

* Children, 6 to 10 years of age, with secondary [[hyperuricemia]] associated with malignancies may be given '''300 mg''' allopurinol tablets daily while those under 6 years are generally given '''150 mg daily'''. The response is evaluated after approximately 48 hours of therapy and a dosage adjustment is made if necessary.
|offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Allopurinol in pediatric patients.
|offLabelPedNoGuideSupport=<h4>Leishmaniasis</h4>

* Dosing information
:* '''10 to 36 milligrams/kilogram/day'''<ref name="pmid9027276">{{cite journal| author=Velez I, Agudelo S, Hendrickx E, Puerta J, Grogl M, Modabber F et al.| title=Inefficacy of allopurinol as monotherapy for Colombian cutaneous leishmaniasis. A randomized, controlled trial. | journal=Ann Intern Med | year= 1997 | volume= 126 | issue= 3 | pages= 232-6 | pmid=9027276 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9027276 }} </ref>
|contraindications=Patients who have developed a severe reaction to allopurinol tablets should not be restarted on the drug.
|warnings=*ALLOPURINOL TABLETS SHOULD BE DISCONTINUED AT THE FIRST APPEARANCE OF SKIN RASH OR OTHER SIGNS WHICH MAY INDICATE AN ALLERGIC REACTION.
*In some instances a skin rash may be followed by more severe hypersensitivity reactions such as [[Exfoliative skin disorder|exfoliative]], [[urticaria|urticarial]], and purpuric lesions, as well as [[Stevens-Johnson syndrome]] (erythema multiforme exudativum), and/or generalized [[vasculitis]], irreversible [[hepatotoxicity]], and, on rare occasions, death.
*In patients receiving [[mercaptopurine]] or [[azathioprine]], the concomitant administration of 300 to 600 mg of allopurinol tablets per day will require a reduction in dose to approximately one-third to one-fourth of the usual dose of mercaptopurine or azathioprine.
*Subsequent adjustment of doses of mercaptopurine or azathioprine should be made on the basis of therapeutic response and the appearance of toxic effects.
*A few cases of reversible clinical [[hepatotoxicity]] have been noted in patients taking allopurinol tablets, and in some patients, asymptomatic rises in [[ALP|serum alkaline phosphatase]] or [[transaminases|serum transaminase]] have been observed.
*If [[anorexia]], weight loss, or [[pruritus]] develop in patients on allopurinol tablets, evaluation of liver function should be part of their diagnostic workup.
*In patients with pre-existing liver disease, periodic [[liver function tests]] are recommended during the early stages of therapy.
*Due to the occasional occurrence of [[drowsiness]], patients should be alerted to the need for due precaution when engaging in activities where alertness is mandatory.
*The occurrence of hypersensitivity reactions to allopurinol tablets may be increased in patients with decreased renal function receiving [[thiazides]] and allopurinol tablets concurrently.
*For this reason, in this clinical setting, such combinations should be administered with caution and patients should be observed closely.

===General===

*An increase in acute attacks of [[gout]] has been reported during the early stages of administration of allopurinol tablets, even when normal or subnormal [[serum uric acid]] levels have been attained.
*Accordingly, maintenance doses of [[colchicine]] generally should be given prophylactically when allopurinol tablets are begun.
*In addition, it is recommended that the patient start with a low dose of allopurinol tablets (100 mg daily) and increase at weekly intervals by 100 mg until a serum uric acid level of 6 mg/dL or less is attained but without exceeding the maximum recommended dose (800 mg per day).
*The use of colchicine or anti-inflammatory agents may be required to suppress gouty attacks in some cases.
*The attacks usually become shorter and less severe after several months of therapy.
*The mobilization of urates from tissue deposits which cause fluctuations in the serum uric acid levels may be a possible explanation for these episodes. *Even with adequate therapy with allopurinol tablets, it may require several months to deplete the uric acid pool sufficiently to achieve control of the acute attacks.

A fluid intake sufficient to yield a daily urinary output of at least 2 liters and the maintenance of a neutral or, preferably, slightly alkaline urine are desirable to (1) avoid the theoretical possibility of formation of [[xanthine]] [[calculi]] under the influence of therapy with allopurinol tablets and (2) help prevent renal precipitation of urates in patients receiving concomitant [[uricosuric agents]].

*Some patients with pre-existing renal disease or poor urate clearance have shown a rise in BUN during administration of allopurinol tablets. Although the mechanism responsible for this has not been established, patients with impaired renal function should be carefully observed during the early stages of administration of allopurinol tablets and the dosage decreased or the drug withdrawn if increased abnormalities in renal function appear and persist.

*[[Renal failure]] in association with administration of allopurinol tablets has been observed among patients with [[hyperuricemia]] secondary to neoplastic diseases. Concurrent conditions such as [[multiple myeloma]] and [[CHF|congestive myocardial disease]] were present among those patients whose renal dysfunction increased after allopurinol tablets were begun.
*Renal failure is also frequently associated with gouty nephropathy and rarely with hypersensitivity reactions associated with allopurinol tablets.
*[[Albuminuria]] has been observed among patients who developed clinical [[gout]] following chronic [[glomerulonephritis]] and chronic [[pyelonephritis]].

*Patients with decreased renal function require lower doses of allopurinol tablets than those with normal renal function. Lower than recommended doses should be used to initiate therapy in any patients with decreased renal function and they should be observed closely during the early stages of administration of allopurinol tablets.
*In patients with severely impaired renal function or decreased urate clearance, the half-life of oxipurinol in the plasma is greatly prolonged. Therefore, a dose of 100 mg per day or 300 mg twice a week, or perhaps less, may be sufficient to maintain adequate [[xanthine oxidase]] inhibition to reduce serum urate levels.

*Bone marrow depression has been reported in patients receiving allopurinol tablets, most of whom received concomitant drugs with the potential for causing this reaction. This has occurred as early as 6 weeks to as long as 6 years after the initiation of therapy of allopurinol tablets. Rarely, a patient may develop varying degrees of bone marrow depression, affecting one or more cell lines, while receiving allopurinol tablets alone.
|clinicalTrials=Data upon which the following estimates of incidence of adverse reactions are made are derived from experiences reported in the literature, unpublished clinical trials and voluntary reports since marketing of allopurinol tablets began. Past experience suggested that the most frequent event following the initiation of allopurinol treatment was an increase in acute attacks of [[gout]] (average 6% in early studies). An analysis of current usage suggests that the incidence of acute [[gout]]y attacks has diminished to less than 1%. The explanation for this decrease has not been determined but may be due in part to initiating therapy more gradually .

The most frequent adverse reaction to allopurinol tablets is skin rash. Skin reactions can be severe and sometimes fatal. Therefore, treatment with allopurinol tablets should be discontinued immediately if a [[rash]] develops . Some patients with the most severe reaction also had fever, [[chills]], [[arthralgias]], [[cholestatic jaundice]], [[eosinophilia]] and mild [[leukocytosis]] or [[leukopenia]]. Among 55 patients with [[gout]] treated with allopurinol tablets for 3 to 34 months (average greater than 1 year) and followed prospectively, Rundles observed that 3% of patients developed a type of drug reaction which was predominantly a [[pruritic]] maculopapular skin eruption, sometimes scaly or [[exfoliative]]. However, with current usage, skin reactions have been observed less frequently than 1%. The explanation for this decrease is not obvious. The incidence of skin [[rash]] may be increased in the presence of renal insufficiency. The frequency of skin rash among patients receiving [[ampicillin]] or [[amoxicillin]] concurrently with allopurinol tablets has been reported to be increased

Most Common Reactions

* Probably Causally Related:

<i>Gastrointestinal</i>: [[Diarrhea]], [[nausea]], alkaline phosphatase increase, SGOT/SGPT increase.

<i>Metabolic and Nutritional</i>: Acute attacks of [[gout]].

<i>Skin and Appendages</i>: [[Rash]], [[maculopapular rash]].

*Early clinical studies and incidence rates from early clinical experience with allopurinol tablets suggested that these adverse reactions were found to occur at a rate of greater than 1%. The most frequent event observed was acute attacks of [[gout]] following the initiation of therapy. Analyses of current usage suggest that the incidence of these adverse reactions is now less than 1%. The explanation for this decrease has not been determined, but it may be due to following recommended usage .

Incidence Less Than 1% Probably Causally Related:

<i>Body As a Whole</i>: [[Ecchymosis]], [[fever]], [[headache]].

<i>Cardiovascular</i>: [[Necrotizing angiitis]], [[vasculitis]].

<i>Gastrointestinal</i>: [[Hepatic necrosis]], [[granulomatous hepatitis]], [[hepatomegaly]], [[hyperbilirubinemia]], [[cholestatic jaundice]], [[vomiting]], intermittent [[abdominal pain]], [[gastritis]], [[dyspepsia]].

<i>Hemic and Lymphatic</i>: [[Thrombocytopenia]], [[eosinophilia]], [[leukocytosis]], [[leukopenia]].

<i>Musculoskeletal</i>: [[Myopathy]], [[arthralgias]].

<i>Nervous</i>: [[Peripheral neuropathy]], [[neuritis]], [[paresthesia]], [[somnolence]].

<i>Respiratory</i>: [[Epistaxis]].

<i>Skin and Appendages</i>: Erythema multiforme exudativum ([[Stevens-Johnson syndrome]]), [[toxic epidermal necrolysis]] ([[Lyell's syndrome]]), [[hypersensitivity vasculitis]], [[purpura]], [[vesicular bullous dermatitis]], [[exfoliative]] dermatitis, [[eczematoid dermatitis]], [[pruritus]], [[urticaria]], [[alopecia]], [[onycholysis]], [[lichen planus]].

<i>Special Senses</i>: Taste loss/perversion.

<i>Urogenital</i>: [[Renal failure]], [[uremia]] .

Incidence Less Than 1% Causal Relationship Unknown:

<i>Body As a Whole</i>: [[Malaise]].

<i>Cardiovascular</i>: [[Pericarditis]], [[peripheral vascular disease]], [[thrombophlebitis]], [[bradycardia]], [[vasodilation]].

<i>Endocrine</i>: Infertility (male), [[hypercalcemia]], [[gynecomastia]] (male).

<i>Gastrointestinal</i>: [[Hemorrhagic pancreatitis]], gastrointestinal bleeding, [[stomatitis]], salivary gland swelling, [[hyperlipidemia]], [[tongue edema]], [[anorexia]].

<i>Hemic and Lymphatic</i>: [[Aplastic anemia]], [[agranulocytosis]], [[eosinophilic fibrohistiocytic]] lesion of bone marrow, [[pancytopenia]], prothrombin decrease, [[anemia]], [[hemolytic anemia]], [[reticulocytosis]], [[lymphadenopathy]], [[lymphocytosis]].

<i>Musculoskeletal</i>: [[Myalgia]].

<i>Nervous</i>: [[Optic neuritis]], [[confusion]], [[dizziness]], [[vertigo]], foot drop, decrease in libido, [[depression]], [[amnesia]], [[tinnitus]], [[asthenia]], [[insomnia]].

<i>Respiratory</i>: [[Bronchospasm]], [[asthma]], [[pharyngitis]], [[rhinitis]].

<i>Skin and Appendages</i>: [[Furunculosis]], [[facial edema]], [[sweating]], skin [[edema]].

<i>Special Senses</i>: [[Cataracts]], [[macular retinitis]], [[iritis]], [[conjunctivitis]], [[amblyopia]].

<i>Urogenital</i>: [[Nephritis]], [[impotence]], primary [[hematuria]], [[albuminuria]].
|postmarketing=FDA Package Insert for Allopurinol contains no information regarding Postmarketing experience.
|drugInteractions=*In patients receiving [[mercaptopurine]] or [[azathioprine]], the concomitant administration of 300 to 600 mg of allopurinol tablets per day will require a reduction in dose to approximately one third to one fourth of the usual dose of [[mercaptopurine]] or [[azathioprine]]. Subsequent adjustment of doses of [[mercaptopurine]] or [[azathioprine]] should be made on the basis of therapeutic response and the appearance of toxic effects .

*It has been reported that allopurinol tablets prolong the half-life of the anticoagulant, [[dicumarol]]. The clinical basis of this drug interaction has not been established but should be noted when allopurinol tablets are given to patients already on dicumarol therapy.

*Since the excretion of oxipurinol is similar to that of urate, uricosuric agents, which increase the excretion of urate, are also likely to increase the excretion of oxipurinol and thus lower the degree of inhibition of [[xanthine oxidase]]. The concomitant administration of [[uricosuric agents]] and allopurinol tablets has been associated with a decrease in the excretion of oxypurines ([[hypoxanthine]] and [[xanthine]]) and an increase in urinary [[uric acid]] excretion compared with that observed with allopurinol tablets alone. Although clinical evidence to date has not demonstrated renal precipitation of oxypurines in patients either on allopurinol tablets alone or in combination with uricosuric agents, the possibility should be kept in mind.

*The reports that the concomitant use of allopurinol tablets and [[thiazide diuretics]] may contribute to the enhancement of allopurinol toxicity in some patients have been reviewed in an attempt to establish a cause-and-effect relationship and a mechanism of causation. Review of these case reports indicates that the patients were mainly receiving thiazide diuretics for hypertension and that tests to rule out decreased renal function secondary to hypertensive nephropathy were not often performed. In those patients in whom [[renal insufficiency]] was documented, however, the recommendation to lower the dose of allopurinol tablets was not followed. Although a causal mechanism and a cause-and-effect relationship have not been established, current evidence suggests that renal function should be monitored in patients on [[thiazide diuretics]] and allopurinol tablets even in the absence of renal failure, and dosage levels should be even more conservatively adjusted in those patients on such combined therapy if diminished renal function is detected.

*An increase in the frequency of skin [[rash]] has been reported among patients receiving [[ampicillin]] or [[amoxicillin]] concurrently with allopurinol tablets compared to patients who are not receiving both drugs. The cause of the reported association has not been established.

*Enhanced [[bone marrow suppression]] by cyclophosphamide and other [[cytotoxic agents]] has been reported among patients with neoplastic disease, except [[leukemia]], in the presence of allopurinol tablets. However, in a well-controlled study of patients with [[lymphoma]] on combination therapy, allopurinol tablets did not increase the marrow toxicity of patients treated with [[cyclophosphamide]], [[doxorubicin]], [[bleomycin]], [[procarbazine]], and/or mechlorethamine.

*[[Tolbutamide|Tolbutamide's]] conversion to inactive metabolites has been shown to be catalyzed by [[xanthine oxidase]] from rat liver. The clinical significance, if any, of these observations is unknown.

*[[Chlorpropamide|Chlorpropamide's]] plasma half-life may be prolonged by allopurinol tablets, since allopurinol and [[chlorpropamide]] may compete for excretion in the renal tubule. The risk of hypoglycemia secondary to this mechanism may be increased if allopurinol tablets and chlorpropamide are given concomitantly in the presence of renal insufficiency.

*Rare reports indicate that [[cyclosporine]] levels may be increased during concomitant treatment with allopurinol tablets. Monitoring of cyclosporine levels and possible adjustment of cyclosporine dosage should be considered when these drugs are coadministered.

=====Drug/Laboratory Test Interactions=====

Allopurinol tablets are not known to alter the accuracy of laboratory tests.
|FDAPregCat=C
|useInPregnancyFDA=Teratogenic Effects: Pregnancy Category C. Reproductive studies have been performed in rats and rabbits at doses up to twenty times the usual human dose (5 mg/kg per day), and it was concluded that there was no impaired fertility or harm to the fetus due to allopurinol. There is a published report of a study in pregnant mice given 50 or 100 mg/kg allopurinol intraperitoneally on gestation days 10 or 13. There were increased numbers of dead fetuses in dams given 100 mg/kg allopurinol but not in those given 50 mg/kg. There were increased numbers of external malformations in fetuses at both doses of allopurinol on gestation day 10 and increased numbers of skeletal malformations in fetuses at both doses on gestation day 13. It cannot be determined whether this represented a fetal effect or an effect secondary to maternal toxicity. There are, however, no adequate or well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Experience with allopurinol tablets during human pregnancy has been limited partly because women of reproductive age rarely require treatment with allopurinol tablets. There are two unpublished reports and one published paper of women giving birth to normal offspring after receiving allopurinol tablets during pregnancy.
|useInNursing=Allopurinol and [[oxipurinol]] have been found in the milk of a mother who was receiving allopurinol tablets. Since the effect of allopurinol on the nursing infant is unknown, caution should be exercised when allopurinol tablets are administered to a nursing woman.
|useInPed=Allopurinol tablets are rarely indicated for use in children with the exception of those with [[hyperuricemia]] secondary to malignancy or to certain rare inborn errors of purine metabolism.
|administration=Oral
|monitoring=FDA Package Insert for Allopurinol contains no information regarding Drug Monitoring.
|IVCompat=There is limited information about the IV Compatibility.
|overdose=Massive overdosing or acute poisoning by allopurinol tablets has not been reported.

In mice, the 50% lethal dose (LD50) is 160 mg/kg given intraperitoneally (IP) with deaths delayed up to 5 days and 700 mg/kg orally (PO) (approximately 140 times the usual human dose) with deaths delayed up to 3 days. In rats, the acute LD50 is 750 mg/kg IP and 6000 mg/kg PO (approximately 1200 times the human dose).

In the management of overdosage there is no specific antidote for allopurinol tablets. There has been no clinical experience in the management of a patient who has taken massive amounts of allopurinol tablets.

Both allopurinol and [[oxipurinol]] are dialyzable; however, the usefulness of hemodialysis or peritoneal dialysis in the management of an overdose of allopurinol tablets is unknown.
|drugBox={{drugbox2
| Watchedfields = changed
| verifiedrevid = 477318043
| IUPAC_name = 1''H''-pyrazolo[3,4-d]pyrimidin-4(2H)-one
| image = Allopurinol V.1.png
| width = 150
| image2 = Allopurinol_3d_structure.png


| tradename = Zyloprim
| Drugs.com = {{drugs.com|monograph|allopurinol}}
| MedlinePlus = a682673
| pregnancy_category = C(USA)
| legal_US = Rx-only
| routes_of_administration = tablet (100, 300 mg)


| bioavailability = 78±20%
| protein_bound = Negligible
| metabolism = hepatic (80% oxypurinol, 10% allopurinol ribosides)
| elimination_half-life = 2 h (oxypurinol 18-30 h)


| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 315-30-0
| ATC_prefix = M04
| ATC_suffix = AA01
| ATC_supplemental =
| PubChem = 2094
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00437
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 2010
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 63CZ7GJN5I
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00224
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 40279
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1467


| C=5 | H=4 | N=4 | O=1
| molecular_weight = 136.112 g/mol
| smiles = c1c2c([nH]n1)ncnc2O
| InChI = 1/C5H4N4O/c10-5-3-1-8-9-4(3)6-2-7-5/h1-2H,(H2,6,7,8,9,10)
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C5H4N4O/c10-5-3-1-8-9-4(3)6-2-7-5/h1-2H,(H2,6,7,8,9,10)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = OFCNXPDARWKPPY-UHFFFAOYSA-N
}}
|mechAction=Allopurinol is a purine analog; it is a structural [[isomer]] of [[hypoxanthine]] (a naturally occurring [[purine]] in the body) and is an [[enzyme inhibitor|inhibitor]] of the enzyme [[xanthine oxidase]].<ref name="pmid16507884"/> Xanthine oxidase is responsible for the successive oxidation of hypoxanthine and [[xanthine]], resulting in the production of [[uric acid]], the product of human purine metabolism.<ref name="pmid16507884"/> In addition to blocking uric acid production, inhibition of xanthine oxidase causes an increase in hypoxanthine and xanthine. While xanthine cannot be converted to purine ribotides, hypoxanthine can be salvaged to the purine [[ribotide]]s [[adenosine monophosphate|adenosine]] and [[guanosine monophosphate]]s. Increased levels of these ribotides may cause feedback inhibition of [[amidophosphoribosyl transferase]], the first and rate-limiting enzyme of purine biosynthesis. Allopurinol, therefore, decreases uric acid formation and may also inhibit purine synthesis.
|structure=Allopurinol has the following structural formula:

[[File:Allopurinol_structure_01.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

Allopurinol is known chemically as 1, 5-dihydro-4H-pyrazolo [3, 4-d] pyrimidin-4-one. It is a xanthine oxidase inhibitor which is administered orally. Its solubility in water at 37°C is 80.0 mg/dL and is greater in an alkaline solution. Each scored white to off-white tablet contains 100 mg allopurinol and the inactive ingredients lactose monohydrate, corn starch, sodium starch glycolate, povidone and stearic acid. Each scored peach tablet contains 300 mg allopurinol and the inactive ingredients lactose monohydrate, corn starch, sodium starch glycolate , FD & C yellow no. 6, povidone and stearic acid.
|clinicalStudies=FDA Package Insert for Allopurinol contains no information regarding Clinical Studies.
|howSupplied=100 mg white to off-white colored, round, beveled edged uncoated tablets with "RG10" embossed on one side and breakline on the other side.

The tablets are supplied in the following package sizes:

Bottles of 100 tablets NDC 63304-539-01

Bottles of 1000 tablets NDC 63304-539-10

300 mg peach colored, round, beveled edged uncoated tablets with "RG11" embossed on one side and breakline on the other side.

The tablets are supplied in the following package sizes:

Bottles of 100 tablets NDC 63304-540-01

Bottles of 500 tablets NDC 63304-540-05
|storage=Store at 20° - 25°C (68° - 77°F)
|fdaPatientInfo=Patients should be informed of the following:

(1) They should be cautioned to discontinue allopurinol tablets and to consult their physician immediately at the first sign of a skin rash, painful urination, blood in the urine, irritation of the eyes, or swelling of the lips or mouth. (2) They should be reminded to continue drug therapy prescribed for [[gout]]y attacks since optimal benefit of allopurinol tablets may be delayed for 2 to 6 weeks. (3) They should be encouraged to increase fluid intake during therapy to prevent renal stones. (4) If a single dose of allopurinol tablets is occasionally forgotten, there is no need to double the dose at the next scheduled time. (5) There may be certain risks associated with the concomitant use of allopurinol tablets and dicumarol, sulfinpyrazone, mercaptopurine, azathioprine, ampicillin, amoxicillin, and thiazide diuretics, and they should follow the instructions of their physician. (6) Due to the occasional occurrence of drowsiness, patients should take precautions when engaging in activities where alertness is mandatory. (7) Patients may wish to take allopurinol tablets after meals to minimize gastric irritation.
|alcohol=Alcohol-Allopurinol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=* Zyloprim
|lookAlike=There is limited information about the look-like drug names.
}}
{{PillImage
|fileName=No_image.jpg
|drugName=Allopurinol 100 MG Oral Tablet
|NDC=63304-539
|drugAuthor=Ranbaxy Pharmaceuticals Inc.
|ingredients=lactose monohydrate, povidone, sodium starch glycolate type a potato, starch, corn, stearic acid, fd&c yellow no. 6
|pillImprint=RG10
|dosageValue=100
|dosageUnit=mg
|pillColor=White
|pillShape=Round
|pillSize=8.00
|pillScore=2
}}
{{PillImage
|fileName=No_image.jpg
|drugName=Allopurinol 300 MG Oral Tablet
|NDC=63304-540
|drugAuthor=Ranbaxy Pharmaceuticals Inc.
|ingredients=fd&c yellow no. 6, lactose monohydrate, povidone, sodium starch glycolate type a potato, starch, corn, stearic acid
|pillImprint=RG11
|dosageValue=300
|dosageUnit=mg
|pillColor=Orange
|pillShape=Round
|pillSize=12.00
|pillScore=2
}}
{{LabelImage
|fileName=Allopurinol_label_01.jpg
}}
{{LabelImage
|fileName=Allopurinol_label_02.jpg
}}
{{LabelImage
|fileName=Allopurinol_panel_01.png
}}
{{LabelImage
|fileName=Allopurinol_panel_02.png
}}

Allopurinol (oral)

2015-03-18T20:36:46Z

Sree Teja Yelamanchili:

{{DrugProjectFormSinglePage
|authorTag={{SS}}; {{STY}}
|genericName=allopurinol
|aOrAn=a
|drugClass=[[xanthine oxidase]] inhibitor
|indicationType=treatment
|indication=primary or secondary [[gout]] (acute attacks, [[tophus|tophi]], joint destruction, uric acid lithiasis, and/or [[nephropathy]]), [[leukemia]], [[lymphoma]] and [[malignancies]], recurrent [[calcium oxalate]] calculi
|adverseReactions=[[Maculopapular rash|maculopapular eruption]], [[pruritus]]
|blackBoxWarningTitle=<b><span style="color:#FF0000;">TITLE</span></b>
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)
|fdaLIADAdult=<h4>Gout</h4>

* Dosing information (The dosage of allopurinol tablets to accomplish full control of [[gout]] and to lower [[serum uric acid]] to normal or near-normal levels varies with the severity of the disease.)
:* Dosing information in patients with mild [[gout]]: '''200 to 300 mg/day'''
:* Dosing information in patients with moderately severe tophaceous [[gout]]: '''400 to 600 mg/day'''

:* The appropriate dosage may be administered in divided doses or as a single equivalent dose with the 300 mg tablet. Dosage requirements in excess of 300 mg should be administered in divided doses. The minimal effective dosage is 100 to 200 mg daily and the maximal recommended dosage is 800 mg daily.
:* To reduce the possibility of flare-up of acute gouty attacks
::* Recommended dosage: '''100 mg PO qd''' and increase at weekly intervals by '''100 mg''' until a serum uric acid level of '''6 mg/dL''' or less is attained but without exceeding the maximal recommended dosage.

:* Normal serum urate levels are usually achieved in 1 to 3 weeks. The upper limit of normal is about '''7 mg/dL''' for men and postmenopausal women and '''6 mg/dL''' for premenopausal women. Too much reliance should not be placed on a single serum uric acid determination since, for technical reasons, estimation of uric acid may be difficult. By selecting the appropriate dosage and, in certain patients, using [[uricosuric]] agents concurrently, it is possible to reduce serum uric acid to normal or, if desired, to as low as '''2 to 3''' mg/dL and keep it there indefinitely.

:* While adjusting the dosage of allopurinol tablets in patients who are being treated with [[colchicine]] and/or anti-inflammatory agents, it is wise to continue the latter therapy until serum uric acid has been normalized and there has been freedom from acute gouty attacks for several months.

:* In transferring a patient from a [[uricosuric|uricosuric agent]] to allopurinol tablets, the dose of the uricosuric agent should be gradually reduced over a period of several weeks and the dose of allopurinol tablets gradually increased to the required dose needed to maintain a normal serum [[uric acid]] level.

:* It should also be noted that allopurinol tablets are generally better tolerated if taken following meals. A fluid intake sufficient to yield a daily urinary output of at least 2 liters and the maintenance of a neutral or, preferably, slightly alkaline urine are desirable.

:* Since allopurinol tablets and its metabolites are primarily eliminated only by the kidney, accumulation of the drug can occur in renal failure, and the dose of allopurinol tablets should consequently be reduced. With a creatinine clearance of '''10 to 20 mL/min''', a daily dosage of '''200 mg''' of allopurinol tablets is suitable. When the creatinine clearance is less than 10 mL/min, the daily dosage should not exceed 100 mg. With extreme renal impairment ([[creatinine clearance]] less than 3 mL/min) the interval between doses may also need to be lengthened.

:* The correct size and frequency of dosage for maintaining the serum uric acid just within the normal range is best determined by using the serum uric acid level as an index.

:* For the prevention of uric acid [[nephropathy]] during the vigorous therapy of neoplastic disease, treatment with '''600 to 800 mg daily''' for 2 or 3 days is advisable together with a high fluid intake. Otherwise similar considerations to the above recommendations for treating patients with gout govern the regulation of dosage for maintenance purposes in secondary [[hyperuricemia]].

:* The dose of allopurinol tablets recommended for management of recurrent [[calcium oxalate]] stones in hyperuricosuric patients is '''200 to 300 mg/day''' in divided doses or as the single equivalent.
*This dose may be adjusted up or down depending upon the resultant control of the [[hyperuricosuria]] based upon subsequent 24 hour urinary urate determinations.
*Clinical experience suggests that patients with recurrent calcium oxalate stones may also benefit from dietary changes such as the reduction of animal protein, sodium, refined sugars, oxalate-rich foods, and excessive calcium intake, as well as an increase in oral fluids and dietary fiber.
|offLabelAdultGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Allopurinol in adult patients.
|offLabelAdultNoGuideSupport=<h4>Leishmaniasis</h4>

* Dosing information
:* '''10 to 36 milligrams/kilogram/day'''<ref name="pmid9114142">{{cite journal| author=Martinez S, Gonzalez M, Vernaza ME| title=Treatment of cutaneous leishmaniasis with allopurinol and stibogluconate. | journal=Clin Infect Dis | year= 1997 | volume= 24 | issue= 2 | pages= 165-9 | pmid=9114142 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9114142 }} </ref>
:* '''0.6 to 20 micrograms/milliliter''' <ref name="pmid2029827">{{cite journal| author=Shapiro TA, Were JB, Danso K, Nelson DJ, Desjardins RE, Pamplin CL| title=Pharmacokinetics and metabolism of allopurinol riboside. | journal=Clin Pharmacol Ther | year= 1991 | volume= 49 | issue= 5 | pages= 506-14 | pmid=2029827 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2029827 }} </ref>

<h4>Malaria</h4>

* Dosing information
:* '''200 to 400 milligrams daily''' <ref name="pmid9574791">{{cite journal| author=Sarma PS, Mandal AK, Khamis HJ| title=Allopurinol as an additive to quinine in the treatment of acute complicated falciparum malaria. | journal=Am J Trop Med Hyg | year= 1998 | volume= 58 | issue= 4 | pages= 454-7 | pmid=9574791 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9574791 }} </ref>

<h4>Schizophrenia</h4>

* Dosing information
:* '''300 milligrams (mg) PO qd or bid''' <ref name="pmid17119103">{{cite journal| author=Buie LW, Oertel MD, Cala SO| title=Allopurinol as adjuvant therapy in poorly responsive or treatment refractory schizophrenia. | journal=Ann Pharmacother | year= 2006 | volume= 40 | issue= 12 | pages= 2200-4 | pmid=17119103 | doi=10.1345/aph.1H222 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17119103 }} </ref>
|fdaLIADPed=<h4>Dosing in pediatric patients</h4>

* Children, 6 to 10 years of age, with secondary [[hyperuricemia]] associated with malignancies may be given '''300 mg''' allopurinol tablets daily while those under 6 years are generally given '''150 mg daily'''. The response is evaluated after approximately 48 hours of therapy and a dosage adjustment is made if necessary.
|offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Allopurinol in pediatric patients.
|offLabelPedNoGuideSupport=<h4>Leishmaniasis</h4>

* Dosing information
:* '''10 to 36 milligrams/kilogram/day'''<ref name="pmid9027276">{{cite journal| author=Velez I, Agudelo S, Hendrickx E, Puerta J, Grogl M, Modabber F et al.| title=Inefficacy of allopurinol as monotherapy for Colombian cutaneous leishmaniasis. A randomized, controlled trial. | journal=Ann Intern Med | year= 1997 | volume= 126 | issue= 3 | pages= 232-6 | pmid=9027276 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9027276 }} </ref>
|contraindications=Patients who have developed a severe reaction to allopurinol tablets should not be restarted on the drug.
|warnings=*ALLOPURINOL TABLETS SHOULD BE DISCONTINUED AT THE FIRST APPEARANCE OF SKIN RASH OR OTHER SIGNS WHICH MAY INDICATE AN ALLERGIC REACTION.
*In some instances a skin rash may be followed by more severe hypersensitivity reactions such as [[Exfoliative skin disorder|exfoliative]], [[urticaria|urticarial]], and purpuric lesions, as well as [[Stevens-Johnson syndrome]] (erythema multiforme exudativum), and/or generalized [[vasculitis]], irreversible [[hepatotoxicity]], and, on rare occasions, death.
*In patients receiving [[mercaptopurine]] or [[azathioprine]], the concomitant administration of 300 to 600 mg of allopurinol tablets per day will require a reduction in dose to approximately one-third to one-fourth of the usual dose of mercaptopurine or azathioprine.
*Subsequent adjustment of doses of mercaptopurine or azathioprine should be made on the basis of therapeutic response and the appearance of toxic effects.
*A few cases of reversible clinical hepatotoxicity have been noted in patients taking allopurinol tablets, and in some patients, asymptomatic rises in serum alkaline phosphatase or serum transaminase have been observed.
*If [[anorexia]], weight loss, or [[pruritus]] develop in patients on allopurinol tablets, evaluation of liver function should be part of their diagnostic workup.
*In patients with pre-existing liver disease, periodic liver function tests are recommended during the early stages of therapy.
*Due to the occasional occurrence of [[drowsiness]], patients should be alerted to the need for due precaution when engaging in activities where alertness is mandatory.
*The occurrence of hypersensitivity reactions to allopurinol tablets may be increased in patients with decreased renal function receiving thiazides and allopurinol tablets concurrently.
*For this reason, in this clinical setting, such combinations should be administered with caution and patients should be observed closely.

===General===

*An increase in acute attacks of [[gout]] has been reported during the early stages of administration of allopurinol tablets, even when normal or subnormal serum uric acid levels have been attained.
*Accordingly, maintenance doses of colchicine generally should be given prophylactically when allopurinol tablets are begun.
*In addition, it is recommended that the patient start with a low dose of allopurinol tablets (100 mg daily) and increase at weekly intervals by 100 mg until a serum uric acid level of 6 mg/dL or less is attained but without exceeding the maximum recommended dose (800 mg per day).
*The use of colchicine or anti-inflammatory agents may be required to suppress gouty attacks in some cases.
*The attacks usually become shorter and less severe after several months of therapy.
*The mobilization of urates from tissue deposits which cause fluctuations in the serum uric acid levels may be a possible explanation for these episodes. *Even with adequate therapy with allopurinol tablets, it may require several months to deplete the uric acid pool sufficiently to achieve control of the acute attacks.

A fluid intake sufficient to yield a daily urinary output of at least 2 liters and the maintenance of a neutral or, preferably, slightly alkaline urine are desirable to (1) avoid the theoretical possibility of formation of [[xanthine calculi]] under the influence of therapy with allopurinol tablets and (2) help prevent renal precipitation of urates in patients receiving concomitant uricosuric agents.

Some patients with pre-existing renal disease or poor urate clearance have shown a rise in BUN during administration of allopurinol tablets. Although the mechanism responsible for this has not been established, patients with impaired renal function should be carefully observed during the early stages of administration of allopurinol tablets and the dosage decreased or the drug withdrawn if increased abnormalities in renal function appear and persist.

Renal failure in association with administration of allopurinol tablets has been observed among patients with [[hyperuricemia]] secondary to neoplastic diseases. Concurrent conditions such as [[multiple myeloma]] and congestive myocardial disease were present among those patients whose renal dysfunction increased after allopurinol tablets were begun. Renal failure is also frequently associated with [[gout]]y nephropathy and rarely with hypersensitivity reactions associated with allopurinol tablets. Albuminuria has been observed among patients who developed clinical [[gout]] following chronic [[glomerulonephritis]] and [[chronic pyelonephritis]].

Patients with decreased renal function require lower doses of allopurinol tablets than those with normal renal function. Lower than recommended doses should be used to initiate therapy in any patients with decreased renal function and they should be observed closely during the early stages of administration of allopurinol tablets. In patients with severely impaired renal function or decreased urate clearance, the half-life of [[oxipurinol]] in the plasma is greatly prolonged. Therefore, a dose of 100 mg per day or 300 mg twice a week, or perhaps less, may be sufficient to maintain adequate xanthine oxidase inhibition to reduce serum urate levels.

Bone marrow depression has been reported in patients receiving allopurinol tablets, most of whom received concomitant drugs with the potential for causing this reaction. This has occurred as early as 6 weeks to as long as 6 years after the initiation of therapy of allopurinol tablets. Rarely, a patient may develop varying degrees of bone marrow depression, affecting one or more cell lines, while receiving allopurinol tablets alone.
|clinicalTrials=Data upon which the following estimates of incidence of adverse reactions are made are derived from experiences reported in the literature, unpublished clinical trials and voluntary reports since marketing of allopurinol tablets began. Past experience suggested that the most frequent event following the initiation of allopurinol treatment was an increase in acute attacks of [[gout]] (average 6% in early studies). An analysis of current usage suggests that the incidence of acute [[gout]]y attacks has diminished to less than 1%. The explanation for this decrease has not been determined but may be due in part to initiating therapy more gradually .

The most frequent adverse reaction to allopurinol tablets is skin rash. Skin reactions can be severe and sometimes fatal. Therefore, treatment with allopurinol tablets should be discontinued immediately if a [[rash]] develops . Some patients with the most severe reaction also had fever, [[chills]], [[arthralgias]], [[cholestatic jaundice]], [[eosinophilia]] and mild [[leukocytosis]] or [[leukopenia]]. Among 55 patients with [[gout]] treated with allopurinol tablets for 3 to 34 months (average greater than 1 year) and followed prospectively, Rundles observed that 3% of patients developed a type of drug reaction which was predominantly a [[pruritic]] maculopapular skin eruption, sometimes scaly or [[exfoliative]]. However, with current usage, skin reactions have been observed less frequently than 1%. The explanation for this decrease is not obvious. The incidence of skin [[rash]] may be increased in the presence of renal insufficiency. The frequency of skin rash among patients receiving [[ampicillin]] or [[amoxicillin]] concurrently with allopurinol tablets has been reported to be increased

Most Common Reactions

* Probably Causally Related:

<i>Gastrointestinal</i>: [[Diarrhea]], [[nausea]], alkaline phosphatase increase, SGOT/SGPT increase.

<i>Metabolic and Nutritional</i>: Acute attacks of [[gout]].

<i>Skin and Appendages</i>: [[Rash]], [[maculopapular rash]].

*Early clinical studies and incidence rates from early clinical experience with allopurinol tablets suggested that these adverse reactions were found to occur at a rate of greater than 1%. The most frequent event observed was acute attacks of [[gout]] following the initiation of therapy. Analyses of current usage suggest that the incidence of these adverse reactions is now less than 1%. The explanation for this decrease has not been determined, but it may be due to following recommended usage .

Incidence Less Than 1% Probably Causally Related:

<i>Body As a Whole</i>: [[Ecchymosis]], [[fever]], [[headache]].

<i>Cardiovascular</i>: [[Necrotizing angiitis]], [[vasculitis]].

<i>Gastrointestinal</i>: [[Hepatic necrosis]], [[granulomatous hepatitis]], [[hepatomegaly]], [[hyperbilirubinemia]], [[cholestatic jaundice]], [[vomiting]], intermittent [[abdominal pain]], [[gastritis]], [[dyspepsia]].

<i>Hemic and Lymphatic</i>: [[Thrombocytopenia]], [[eosinophilia]], [[leukocytosis]], [[leukopenia]].

<i>Musculoskeletal</i>: [[Myopathy]], [[arthralgias]].

<i>Nervous</i>: [[Peripheral neuropathy]], [[neuritis]], [[paresthesia]], [[somnolence]].

<i>Respiratory</i>: [[Epistaxis]].

<i>Skin and Appendages</i>: Erythema multiforme exudativum ([[Stevens-Johnson syndrome]]), [[toxic epidermal necrolysis]] ([[Lyell's syndrome]]), [[hypersensitivity vasculitis]], [[purpura]], [[vesicular bullous dermatitis]], [[exfoliative]] dermatitis, [[eczematoid dermatitis]], [[pruritus]], [[urticaria]], [[alopecia]], [[onycholysis]], [[lichen planus]].

<i>Special Senses</i>: Taste loss/perversion.

<i>Urogenital</i>: [[Renal failure]], [[uremia]] .

Incidence Less Than 1% Causal Relationship Unknown:

<i>Body As a Whole</i>: [[Malaise]].

<i>Cardiovascular</i>: [[Pericarditis]], [[peripheral vascular disease]], [[thrombophlebitis]], [[bradycardia]], [[vasodilation]].

<i>Endocrine</i>: Infertility (male), [[hypercalcemia]], [[gynecomastia]] (male).

<i>Gastrointestinal</i>: [[Hemorrhagic pancreatitis]], gastrointestinal bleeding, [[stomatitis]], salivary gland swelling, [[hyperlipidemia]], [[tongue edema]], [[anorexia]].

<i>Hemic and Lymphatic</i>: [[Aplastic anemia]], [[agranulocytosis]], [[eosinophilic fibrohistiocytic]] lesion of bone marrow, [[pancytopenia]], prothrombin decrease, [[anemia]], [[hemolytic anemia]], [[reticulocytosis]], [[lymphadenopathy]], [[lymphocytosis]].

<i>Musculoskeletal</i>: [[Myalgia]].

<i>Nervous</i>: [[Optic neuritis]], [[confusion]], [[dizziness]], [[vertigo]], foot drop, decrease in libido, [[depression]], [[amnesia]], [[tinnitus]], [[asthenia]], [[insomnia]].

<i>Respiratory</i>: [[Bronchospasm]], [[asthma]], [[pharyngitis]], [[rhinitis]].

<i>Skin and Appendages</i>: [[Furunculosis]], [[facial edema]], [[sweating]], skin [[edema]].

<i>Special Senses</i>: [[Cataracts]], [[macular retinitis]], [[iritis]], [[conjunctivitis]], [[amblyopia]].

<i>Urogenital</i>: [[Nephritis]], [[impotence]], primary [[hematuria]], [[albuminuria]].
|postmarketing=FDA Package Insert for Allopurinol contains no information regarding Postmarketing experience.
|drugInteractions=In patients receiving [[mercaptopurine]] or [[azathioprine]], the concomitant administration of 300 to 600 mg of allopurinol tablets per day will require a reduction in dose to approximately one third to one fourth of the usual dose of [[mercaptopurine]] or [[azathioprine]]. Subsequent adjustment of doses of [[mercaptopurine]] or [[azathioprine]] should be made on the basis of therapeutic response and the appearance of toxic effects .

It has been reported that allopurinol tablets prolong the half-life of the anticoagulant, [[dicumarol]]. The clinical basis of this drug interaction has not been established but should be noted when allopurinol tablets are given to patients already on dicumarol therapy.

Since the excretion of [[oxipurinol]] is similar to that of urate, uricosuric agents, which increase the excretion of urate, are also likely to increase the excretion of [[oxipurinol]] and thus lower the degree of inhibition of xanthine oxidase. The concomitant administration of uricosuric agents and allopurinol tablets has been associated with a decrease in the excretion of oxypurines (hypoxanthine and xanthine) and an increase in urinary uric acid excretion compared with that observed with allopurinol tablets alone. Although clinical evidence to date has not demonstrated renal precipitation of oxypurines in patients either on allopurinol tablets alone or in combination with uricosuric agents, the possibility should be kept in mind.

The reports that the concomitant use of allopurinol tablets and thiazide diuretics may contribute to the enhancement of allopurinol toxicity in some patients have been reviewed in an attempt to establish a cause-and-effect relationship and a mechanism of causation. Review of these case reports indicates that the patients were mainly receiving thiazide diuretics for hypertension and that tests to rule out decreased renal function secondary to hypertensive nephropathy were not often performed. In those patients in whom renal insufficiency was documented, however, the recommendation to lower the dose of allopurinol tablets was not followed. Although a causal mechanism and a cause-and-effect relationship have not been established, current evidence suggests that renal function should be monitored in patients on thiazide diuretics and allopurinol tablets even in the absence of renal failure, and dosage levels should be even more conservatively adjusted in those patients on such combined therapy if diminished renal function is detected.

An increase in the frequency of skin [[rash]] has been reported among patients receiving ampicillin or amoxicillin concurrently with allopurinol tablets compared to patients who are not receiving both drugs. The cause of the reported association has not been established.

Enhanced bone marrow suppression by cyclophosphamide and other cytotoxic agents has been reported among patients with neoplastic disease, except [[leukemia]], in the presence of allopurinol tablets. However, in a well-controlled study of patients with lymphoma on combination therapy, allopurinol tablets did not increase the marrow toxicity of patients treated with cyclophosphamide, doxorubicin, bleomycin, procarbazine, and/or mechlorethamine.

Tolbutamide's conversion to inactive metabolites has been shown to be catalyzed by xanthine oxidase from rat liver. The clinical significance, if any, of these observations is unknown.

Chlorpropamide's plasma half-life may be prolonged by allopurinol tablets, since allopurinol and chlorpropamide may compete for excretion in the renal tubule. The risk of hypoglycemia secondary to this mechanism may be increased if allopurinol tablets and chlorpropamide are given concomitantly in the presence of renal insufficiency.

Rare reports indicate that cyclosporine levels may be increased during concomitant treatment with allopurinol tablets. Monitoring of cyclosporine levels and possible adjustment of cyclosporine dosage should be considered when these drugs are coadministered.

Drug/Laboratory Test Interactions

Allopurinol tablets are not known to alter the accuracy of laboratory tests.
|FDAPregCat=C
|useInPregnancyFDA=Teratogenic Effects: Pregnancy Category C. Reproductive studies have been performed in rats and rabbits at doses up to twenty times the usual human dose (5 mg/kg per day), and it was concluded that there was no impaired fertility or harm to the fetus due to allopurinol. There is a published report of a study in pregnant mice given 50 or 100 mg/kg allopurinol intraperitoneally on gestation days 10 or 13. There were increased numbers of dead fetuses in dams given 100 mg/kg allopurinol but not in those given 50 mg/kg. There were increased numbers of external malformations in fetuses at both doses of allopurinol on gestation day 10 and increased numbers of skeletal malformations in fetuses at both doses on gestation day 13. It cannot be determined whether this represented a fetal effect or an effect secondary to maternal toxicity. There are, however, no adequate or well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Experience with allopurinol tablets during human pregnancy has been limited partly because women of reproductive age rarely require treatment with allopurinol tablets. There are two unpublished reports and one published paper of women giving birth to normal offspring after receiving allopurinol tablets during pregnancy.
|useInNursing=Allopurinol and [[oxipurinol]] have been found in the milk of a mother who was receiving allopurinol tablets. Since the effect of allopurinol on the nursing infant is unknown, caution should be exercised when allopurinol tablets are administered to a nursing woman.
|useInPed=Allopurinol tablets are rarely indicated for use in children with the exception of those with [[hyperuricemia]] secondary to malignancy or to certain rare inborn errors of purine metabolism.
|administration=Oral
|monitoring=FDA Package Insert for Allopurinol contains no information regarding Drug Monitoring.
|IVCompat=There is limited information about the IV Compatibility.
|overdose=Massive overdosing or acute poisoning by allopurinol tablets has not been reported.

In mice, the 50% lethal dose (LD50) is 160 mg/kg given intraperitoneally (IP) with deaths delayed up to 5 days and 700 mg/kg orally (PO) (approximately 140 times the usual human dose) with deaths delayed up to 3 days. In rats, the acute LD50 is 750 mg/kg IP and 6000 mg/kg PO (approximately 1200 times the human dose).

In the management of overdosage there is no specific antidote for allopurinol tablets. There has been no clinical experience in the management of a patient who has taken massive amounts of allopurinol tablets.

Both allopurinol and [[oxipurinol]] are dialyzable; however, the usefulness of hemodialysis or peritoneal dialysis in the management of an overdose of allopurinol tablets is unknown.
|drugBox={{drugbox2
| Watchedfields = changed
| verifiedrevid = 477318043
| IUPAC_name = 1''H''-pyrazolo[3,4-d]pyrimidin-4(2H)-one
| image = Allopurinol V.1.png
| width = 150
| image2 = Allopurinol_3d_structure.png


| tradename = Zyloprim
| Drugs.com = {{drugs.com|monograph|allopurinol}}
| MedlinePlus = a682673
| pregnancy_category = C(USA)
| legal_US = Rx-only
| routes_of_administration = tablet (100, 300 mg)


| bioavailability = 78±20%
| protein_bound = Negligible
| metabolism = hepatic (80% oxypurinol, 10% allopurinol ribosides)
| elimination_half-life = 2 h (oxypurinol 18-30 h)


| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 315-30-0
| ATC_prefix = M04
| ATC_suffix = AA01
| ATC_supplemental =
| PubChem = 2094
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00437
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 2010
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 63CZ7GJN5I
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00224
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 40279
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1467


| C=5 | H=4 | N=4 | O=1
| molecular_weight = 136.112 g/mol
| smiles = c1c2c([nH]n1)ncnc2O
| InChI = 1/C5H4N4O/c10-5-3-1-8-9-4(3)6-2-7-5/h1-2H,(H2,6,7,8,9,10)
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C5H4N4O/c10-5-3-1-8-9-4(3)6-2-7-5/h1-2H,(H2,6,7,8,9,10)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = OFCNXPDARWKPPY-UHFFFAOYSA-N
}}
|mechAction=Allopurinol is a purine analog; it is a structural [[isomer]] of [[hypoxanthine]] (a naturally occurring [[purine]] in the body) and is an [[enzyme inhibitor|inhibitor]] of the enzyme [[xanthine oxidase]].<ref name="pmid16507884"/> Xanthine oxidase is responsible for the successive oxidation of hypoxanthine and [[xanthine]], resulting in the production of [[uric acid]], the product of human purine metabolism.<ref name="pmid16507884"/> In addition to blocking uric acid production, inhibition of xanthine oxidase causes an increase in hypoxanthine and xanthine. While xanthine cannot be converted to purine ribotides, hypoxanthine can be salvaged to the purine [[ribotide]]s [[adenosine monophosphate|adenosine]] and [[guanosine monophosphate]]s. Increased levels of these ribotides may cause feedback inhibition of [[amidophosphoribosyl transferase]], the first and rate-limiting enzyme of purine biosynthesis. Allopurinol, therefore, decreases uric acid formation and may also inhibit purine synthesis.
|structure=Allopurinol has the following structural formula:

[[File:Allopurinol_structure_01.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

Allopurinol is known chemically as 1, 5-dihydro-4H-pyrazolo [3, 4-d] pyrimidin-4-one. It is a xanthine oxidase inhibitor which is administered orally. Its solubility in water at 37°C is 80.0 mg/dL and is greater in an alkaline solution. Each scored white to off-white tablet contains 100 mg allopurinol and the inactive ingredients lactose monohydrate, corn starch, sodium starch glycolate, povidone and stearic acid. Each scored peach tablet contains 300 mg allopurinol and the inactive ingredients lactose monohydrate, corn starch, sodium starch glycolate , FD & C yellow no. 6, povidone and stearic acid.
|clinicalStudies=FDA Package Insert for Allopurinol contains no information regarding Clinical Studies.
|howSupplied=100 mg white to off-white colored, round, beveled edged uncoated tablets with "RG10" embossed on one side and breakline on the other side.

The tablets are supplied in the following package sizes:

Bottles of 100 tablets NDC 63304-539-01

Bottles of 1000 tablets NDC 63304-539-10

300 mg peach colored, round, beveled edged uncoated tablets with "RG11" embossed on one side and breakline on the other side.

The tablets are supplied in the following package sizes:

Bottles of 100 tablets NDC 63304-540-01

Bottles of 500 tablets NDC 63304-540-05
|storage=Store at 20° - 25°C (68° - 77°F)
|fdaPatientInfo=Patients should be informed of the following:

(1) They should be cautioned to discontinue allopurinol tablets and to consult their physician immediately at the first sign of a skin rash, painful urination, blood in the urine, irritation of the eyes, or swelling of the lips or mouth. (2) They should be reminded to continue drug therapy prescribed for [[gout]]y attacks since optimal benefit of allopurinol tablets may be delayed for 2 to 6 weeks. (3) They should be encouraged to increase fluid intake during therapy to prevent renal stones. (4) If a single dose of allopurinol tablets is occasionally forgotten, there is no need to double the dose at the next scheduled time. (5) There may be certain risks associated with the concomitant use of allopurinol tablets and dicumarol, sulfinpyrazone, mercaptopurine, azathioprine, ampicillin, amoxicillin, and thiazide diuretics, and they should follow the instructions of their physician. (6) Due to the occasional occurrence of drowsiness, patients should take precautions when engaging in activities where alertness is mandatory. (7) Patients may wish to take allopurinol tablets after meals to minimize gastric irritation.
|alcohol=Alcohol-Allopurinol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=* Zyloprim
|lookAlike=There is limited information about the look-like drug names.
}}
{{PillImage
|fileName=No_image.jpg
|drugName=Allopurinol 100 MG Oral Tablet
|NDC=63304-539
|drugAuthor=Ranbaxy Pharmaceuticals Inc.
|ingredients=lactose monohydrate, povidone, sodium starch glycolate type a potato, starch, corn, stearic acid, fd&c yellow no. 6
|pillImprint=RG10
|dosageValue=100
|dosageUnit=mg
|pillColor=White
|pillShape=Round
|pillSize=8.00
|pillScore=2
}}
{{PillImage
|fileName=No_image.jpg
|drugName=Allopurinol 300 MG Oral Tablet
|NDC=63304-540
|drugAuthor=Ranbaxy Pharmaceuticals Inc.
|ingredients=fd&c yellow no. 6, lactose monohydrate, povidone, sodium starch glycolate type a potato, starch, corn, stearic acid
|pillImprint=RG11
|dosageValue=300
|dosageUnit=mg
|pillColor=Orange
|pillShape=Round
|pillSize=12.00
|pillScore=2
}}
{{LabelImage
|fileName=Allopurinol_label_01.jpg
}}
{{LabelImage
|fileName=Allopurinol_label_02.jpg
}}
{{LabelImage
|fileName=Allopurinol_panel_01.png
}}
{{LabelImage
|fileName=Allopurinol_panel_02.png
}}

Allopurinol (oral)

2015-03-18T17:24:52Z

Sree Teja Yelamanchili:

{{DrugProjectFormSinglePage
|authorTag={{SS}}; {{STY}}
|genericName=allopurinol
|aOrAn=a
|drugClass=[[xanthine oxidase]] inhibitor
|indicationType=treatment
|indication=primary or secondary [[gout]] (acute attacks, [[tophus|tophi]], joint destruction, uric acid lithiasis, and/or [[nephropathy]]), [[leukemia]], [[lymphoma]] and [[malignancies]], recurrent [[calcium oxalate]] calculi
|adverseReactions=[[Maculopapular rash|maculopapular eruption]], [[pruritus]]
|blackBoxWarningTitle=<b><span style="color:#FF0000;">TITLE</span></b>
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)
|fdaLIADAdult=<h4>Gout</h4>

* Dosing information (The dosage of allopurinol tablets to accomplish full control of [[gout]] and to lower serum uric acid to normal or near-normal levels varies with the severity of the disease.)
:* Dosing information in patients with mild [[gout]]: '''200 to 300 mg/day'''
:* Dosing information in patients with moderately severe tophaceous [[gout]]: '''400 to 600 mg/day'''

:* The appropriate dosage may be administered in divided doses or as a single equivalent dose with the 300 mg tablet. Dosage requirements in excess of 300 mg should be administered in divided doses. The minimal effective dosage is 100 to 200 mg daily and the maximal recommended dosage is 800 mg daily.
:* To reduce the possibility of flare-up of acute gouty attacks
::* Recommended dosage: '''100 mg PO qd''' and increase at weekly intervals by '''100 mg''' until a serum uric acid level of '''6 mg/dL''' or less is attained but without exceeding the maximal recommended dosage.

:* Normal serum urate levels are usually achieved in 1 to 3 weeks. The upper limit of normal is about '''7 mg/dL''' for men and postmenopausal women and '''6 mg/dL''' for premenopausal women. Too much reliance should not be placed on a single serum uric acid determination since, for technical reasons, estimation of uric acid may be difficult. By selecting the appropriate dosage and, in certain patients, using uricosuric agents concurrently, it is possible to reduce serum uric acid to normal or, if desired, to as low as '''2 to 3''' mg/dL and keep it there indefinitely.

:* While adjusting the dosage of allopurinol tablets in patients who are being treated with [[colchicine]] and/or anti-inflammatory agents, it is wise to continue the latter therapy until serum uric acid has been normalized and there has been freedom from acute [[gout]]y attacks for several months.

:* In transferring a patient from a [[uricosuric|uricosuric agent]] to allopurinol tablets, the dose of the uricosuric agent should be gradually reduced over a period of several weeks and the dose of allopurinol tablets gradually increased to the required dose needed to maintain a normal serum uric acid level.

:* It should also be noted that allopurinol tablets are generally better tolerated if taken following meals. A fluid intake sufficient to yield a daily urinary output of at least 2 liters and the maintenance of a neutral or, preferably, slightly alkaline urine are desirable.

:* Since allopurinol tablets and its metabolites are primarily eliminated only by the kidney, accumulation of the drug can occur in renal failure, and the dose of allopurinol tablets should consequently be reduced. With a creatinine clearance of '''10 to 20 mL/min''', a daily dosage of '''200 mg''' of allopurinol tablets is suitable. When the creatinine clearance is less than 10 mL/min, the daily dosage should not exceed 100 mg. With extreme renal impairment (creatinine clearance less than 3 mL/min) the interval between doses may also need to be lengthened.

:* The correct size and frequency of dosage for maintaining the serum uric acid just within the normal range is best determined by using the serum uric acid level as an index.

:* For the prevention of uric acid nephropathy during the vigorous therapy of neoplastic disease, treatment with '''600 to 800 mg daily''' for 2 or 3 days is advisable together with a high fluid intake. Otherwise similar considerations to the above recommendations for treating patients with [[gout]] govern the regulation of dosage for maintenance purposes in secondary [[hyperuricemia]].

:* The dose of allopurinol tablets recommended for management of recurrent calcium oxalate stones in hyperuricosuric patients is '''200 to 300 mg/day''' in divided doses or as the single equivalent. This dose may be adjusted up or down depending upon the resultant control of the [[hyperuricosuria]] based upon subsequent 24 hour urinary urate determinations. Clinical experience suggests that patients with recurrent calcium oxalate stones may also benefit from dietary changes such as the reduction of animal protein, sodium, refined sugars, oxalate-rich foods, and excessive calcium intake, as well as an increase in oral fluids and dietary fiber.
|offLabelAdultGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Allopurinol in adult patients.
|offLabelAdultNoGuideSupport=<h4>Leishmaniasis</h4>

* Dosing information
:* '''10 to 36 milligrams/kilogram/day'''<ref name="pmid9114142">{{cite journal| author=Martinez S, Gonzalez M, Vernaza ME| title=Treatment of cutaneous leishmaniasis with allopurinol and stibogluconate. | journal=Clin Infect Dis | year= 1997 | volume= 24 | issue= 2 | pages= 165-9 | pmid=9114142 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9114142 }} </ref>
:* '''0.6 to 20 micrograms/milliliter''' <ref name="pmid2029827">{{cite journal| author=Shapiro TA, Were JB, Danso K, Nelson DJ, Desjardins RE, Pamplin CL| title=Pharmacokinetics and metabolism of allopurinol riboside. | journal=Clin Pharmacol Ther | year= 1991 | volume= 49 | issue= 5 | pages= 506-14 | pmid=2029827 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2029827 }} </ref>

<h4>Malaria</h4>

* Dosing information
:* '''200 to 400 milligrams daily''' <ref name="pmid9574791">{{cite journal| author=Sarma PS, Mandal AK, Khamis HJ| title=Allopurinol as an additive to quinine in the treatment of acute complicated falciparum malaria. | journal=Am J Trop Med Hyg | year= 1998 | volume= 58 | issue= 4 | pages= 454-7 | pmid=9574791 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9574791 }} </ref>

<h4>Schizophrenia</h4>

* Dosing information
:* '''300 milligrams (mg) PO qd or bid''' <ref name="pmid17119103">{{cite journal| author=Buie LW, Oertel MD, Cala SO| title=Allopurinol as adjuvant therapy in poorly responsive or treatment refractory schizophrenia. | journal=Ann Pharmacother | year= 2006 | volume= 40 | issue= 12 | pages= 2200-4 | pmid=17119103 | doi=10.1345/aph.1H222 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17119103 }} </ref>
|fdaLIADPed=<h4>Dosing in pediatric patients</h4>

* Children, 6 to 10 years of age, with secondary [[hyperuricemia]] associated with malignancies may be given '''300 mg''' allopurinol tablets daily while those under 6 years are generally given '''150 mg daily'''. The response is evaluated after approximately 48 hours of therapy and a dosage adjustment is made if necessary.
|offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Allopurinol in pediatric patients.
|offLabelPedNoGuideSupport=<h4>Leishmaniasis</h4>

* Dosing information
:* '''10 to 36 milligrams/kilogram/day'''<ref name="pmid9027276">{{cite journal| author=Velez I, Agudelo S, Hendrickx E, Puerta J, Grogl M, Modabber F et al.| title=Inefficacy of allopurinol as monotherapy for Colombian cutaneous leishmaniasis. A randomized, controlled trial. | journal=Ann Intern Med | year= 1997 | volume= 126 | issue= 3 | pages= 232-6 | pmid=9027276 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9027276 }} </ref>
|contraindications=Patients who have developed a severe reaction to allopurinol tablets should not be restarted on the drug.
|warnings=ALLOPURINOL TABLETS SHOULD BE DISCONTINUED AT THE FIRST APPEARANCE OF SKIN RASH OR OTHER SIGNS WHICH MAY INDICATE AN ALLERGIC REACTION. In some instances a skin rash may be followed by more severe hypersensitivity reactions such as [[exfoliative]], urticarial, and purpuric lesions, as well as [[Stevens-Johnson syndrome]] ([[erythema multiforme exudativum]]), and/or generalized vasculitis, irreversible hepatotoxicity, and, on rare occasions, death.

In patients receiving mercaptopurine or [[azathioprine]], the concomitant administration of 300 to 600 mg of allopurinol tablets per day will require a reduction in dose to approximately one-third to one-fourth of the usual dose of [[mercaptopurine]] or [[azathioprine]]. Subsequent adjustment of doses of [[mercaptopurine]] or [[azathioprine]] should be made on the basis of therapeutic response and the appearance of toxic effects .

A few cases of reversible clinical hepatotoxicity have been noted in patients taking allopurinol tablets, and in some patients, asymptomatic rises in serum alkaline phosphatase or serum transaminase have been observed. If [[anorexia]], weight loss, or [[pruritus]] develop in patients on allopurinol tablets, evaluation of liver function should be part of their diagnostic workup. In patients with pre-existing liver disease, periodic liver function tests are recommended during the early stages of therapy.

Due to the occasional occurrence of [[drowsiness]], patients should be alerted to the need for due precaution when engaging in activities where alertness is mandatory.

The occurrence of hypersensitivity reactions to allopurinol tablets may be increased in patients with decreased renal function receiving thiazides and allopurinol tablets concurrently. For this reason, in this clinical setting, such combinations should be administered with caution and patients should be observed closely.

==General==

An increase in acute attacks of [[gout]] has been reported during the early stages of administration of allopurinol tablets, even when normal or subnormal serum uric acid levels have been attained. Accordingly, maintenance doses of colchicine generally should be given prophylactically when allopurinol tablets are begun. In addition, it is recommended that the patient start with a low dose of allopurinol tablets (100 mg daily) and increase at weekly intervals by 100 mg until a serum uric acid level of 6 mg/dL or less is attained but without exceeding the maximum recommended dose (800 mg per day). The use of colchicine or anti-inflammatory agents may be required to suppress [[gout]]y attacks in some cases. The attacks usually become shorter and less severe after several months of therapy. The mobilization of urates from tissue deposits which cause fluctuations in the serum uric acid levels may be a possible explanation for these episodes. Even with adequate therapy with allopurinol tablets, it may require several months to deplete the uric acid pool sufficiently to achieve control of the acute attacks.

A fluid intake sufficient to yield a daily urinary output of at least 2 liters and the maintenance of a neutral or, preferably, slightly alkaline urine are desirable to (1) avoid the theoretical possibility of formation of [[xanthine calculi]] under the influence of therapy with allopurinol tablets and (2) help prevent renal precipitation of urates in patients receiving concomitant uricosuric agents.

Some patients with pre-existing renal disease or poor urate clearance have shown a rise in BUN during administration of allopurinol tablets. Although the mechanism responsible for this has not been established, patients with impaired renal function should be carefully observed during the early stages of administration of allopurinol tablets and the dosage decreased or the drug withdrawn if increased abnormalities in renal function appear and persist.

Renal failure in association with administration of allopurinol tablets has been observed among patients with [[hyperuricemia]] secondary to neoplastic diseases. Concurrent conditions such as [[multiple myeloma]] and congestive myocardial disease were present among those patients whose renal dysfunction increased after allopurinol tablets were begun. Renal failure is also frequently associated with [[gout]]y nephropathy and rarely with hypersensitivity reactions associated with allopurinol tablets. Albuminuria has been observed among patients who developed clinical [[gout]] following chronic [[glomerulonephritis]] and [[chronic pyelonephritis]].

Patients with decreased renal function require lower doses of allopurinol tablets than those with normal renal function. Lower than recommended doses should be used to initiate therapy in any patients with decreased renal function and they should be observed closely during the early stages of administration of allopurinol tablets. In patients with severely impaired renal function or decreased urate clearance, the half-life of [[oxipurinol]] in the plasma is greatly prolonged. Therefore, a dose of 100 mg per day or 300 mg twice a week, or perhaps less, may be sufficient to maintain adequate xanthine oxidase inhibition to reduce serum urate levels.

Bone marrow depression has been reported in patients receiving allopurinol tablets, most of whom received concomitant drugs with the potential for causing this reaction. This has occurred as early as 6 weeks to as long as 6 years after the initiation of therapy of allopurinol tablets. Rarely, a patient may develop varying degrees of bone marrow depression, affecting one or more cell lines, while receiving allopurinol tablets alone.
|clinicalTrials=Data upon which the following estimates of incidence of adverse reactions are made are derived from experiences reported in the literature, unpublished clinical trials and voluntary reports since marketing of allopurinol tablets began. Past experience suggested that the most frequent event following the initiation of allopurinol treatment was an increase in acute attacks of [[gout]] (average 6% in early studies). An analysis of current usage suggests that the incidence of acute [[gout]]y attacks has diminished to less than 1%. The explanation for this decrease has not been determined but may be due in part to initiating therapy more gradually .

The most frequent adverse reaction to allopurinol tablets is skin rash. Skin reactions can be severe and sometimes fatal. Therefore, treatment with allopurinol tablets should be discontinued immediately if a [[rash]] develops . Some patients with the most severe reaction also had fever, [[chills]], [[arthralgias]], [[cholestatic jaundice]], [[eosinophilia]] and mild [[leukocytosis]] or [[leukopenia]]. Among 55 patients with [[gout]] treated with allopurinol tablets for 3 to 34 months (average greater than 1 year) and followed prospectively, Rundles observed that 3% of patients developed a type of drug reaction which was predominantly a [[pruritic]] maculopapular skin eruption, sometimes scaly or [[exfoliative]]. However, with current usage, skin reactions have been observed less frequently than 1%. The explanation for this decrease is not obvious. The incidence of skin [[rash]] may be increased in the presence of renal insufficiency. The frequency of skin rash among patients receiving [[ampicillin]] or [[amoxicillin]] concurrently with allopurinol tablets has been reported to be increased

Most Common Reactions

* Probably Causally Related:

<i>Gastrointestinal</i>: [[Diarrhea]], [[nausea]], alkaline phosphatase increase, SGOT/SGPT increase.

<i>Metabolic and Nutritional</i>: Acute attacks of [[gout]].

<i>Skin and Appendages</i>: [[Rash]], [[maculopapular rash]].

*Early clinical studies and incidence rates from early clinical experience with allopurinol tablets suggested that these adverse reactions were found to occur at a rate of greater than 1%. The most frequent event observed was acute attacks of [[gout]] following the initiation of therapy. Analyses of current usage suggest that the incidence of these adverse reactions is now less than 1%. The explanation for this decrease has not been determined, but it may be due to following recommended usage .

Incidence Less Than 1% Probably Causally Related:

<i>Body As a Whole</i>: [[Ecchymosis]], [[fever]], [[headache]].

<i>Cardiovascular</i>: [[Necrotizing angiitis]], [[vasculitis]].

<i>Gastrointestinal</i>: [[Hepatic necrosis]], [[granulomatous hepatitis]], [[hepatomegaly]], [[hyperbilirubinemia]], [[cholestatic jaundice]], [[vomiting]], intermittent [[abdominal pain]], [[gastritis]], [[dyspepsia]].

<i>Hemic and Lymphatic</i>: [[Thrombocytopenia]], [[eosinophilia]], [[leukocytosis]], [[leukopenia]].

<i>Musculoskeletal</i>: [[Myopathy]], [[arthralgias]].

<i>Nervous</i>: [[Peripheral neuropathy]], [[neuritis]], [[paresthesia]], [[somnolence]].

<i>Respiratory</i>: [[Epistaxis]].

<i>Skin and Appendages</i>: Erythema multiforme exudativum ([[Stevens-Johnson syndrome]]), [[toxic epidermal necrolysis]] ([[Lyell's syndrome]]), [[hypersensitivity vasculitis]], [[purpura]], [[vesicular bullous dermatitis]], [[exfoliative]] dermatitis, [[eczematoid dermatitis]], [[pruritus]], [[urticaria]], [[alopecia]], [[onycholysis]], [[lichen planus]].

<i>Special Senses</i>: Taste loss/perversion.

<i>Urogenital</i>: [[Renal failure]], [[uremia]] .

Incidence Less Than 1% Causal Relationship Unknown:

<i>Body As a Whole</i>: [[Malaise]].

<i>Cardiovascular</i>: [[Pericarditis]], [[peripheral vascular disease]], [[thrombophlebitis]], [[bradycardia]], [[vasodilation]].

<i>Endocrine</i>: Infertility (male), [[hypercalcemia]], [[gynecomastia]] (male).

<i>Gastrointestinal</i>: [[Hemorrhagic pancreatitis]], gastrointestinal bleeding, [[stomatitis]], salivary gland swelling, [[hyperlipidemia]], [[tongue edema]], [[anorexia]].

<i>Hemic and Lymphatic</i>: [[Aplastic anemia]], [[agranulocytosis]], [[eosinophilic fibrohistiocytic]] lesion of bone marrow, [[pancytopenia]], prothrombin decrease, [[anemia]], [[hemolytic anemia]], [[reticulocytosis]], [[lymphadenopathy]], [[lymphocytosis]].

<i>Musculoskeletal</i>: [[Myalgia]].

<i>Nervous</i>: [[Optic neuritis]], [[confusion]], [[dizziness]], [[vertigo]], foot drop, decrease in libido, [[depression]], [[amnesia]], [[tinnitus]], [[asthenia]], [[insomnia]].

<i>Respiratory</i>: [[Bronchospasm]], [[asthma]], [[pharyngitis]], [[rhinitis]].

<i>Skin and Appendages</i>: [[Furunculosis]], [[facial edema]], [[sweating]], skin [[edema]].

<i>Special Senses</i>: [[Cataracts]], [[macular retinitis]], [[iritis]], [[conjunctivitis]], [[amblyopia]].

<i>Urogenital</i>: [[Nephritis]], [[impotence]], primary [[hematuria]], [[albuminuria]].
|postmarketing=FDA Package Insert for Allopurinol contains no information regarding Postmarketing experience.
|drugInteractions=In patients receiving [[mercaptopurine]] or [[azathioprine]], the concomitant administration of 300 to 600 mg of allopurinol tablets per day will require a reduction in dose to approximately one third to one fourth of the usual dose of [[mercaptopurine]] or [[azathioprine]]. Subsequent adjustment of doses of [[mercaptopurine]] or [[azathioprine]] should be made on the basis of therapeutic response and the appearance of toxic effects .

It has been reported that allopurinol tablets prolong the half-life of the anticoagulant, [[dicumarol]]. The clinical basis of this drug interaction has not been established but should be noted when allopurinol tablets are given to patients already on dicumarol therapy.

Since the excretion of [[oxipurinol]] is similar to that of urate, uricosuric agents, which increase the excretion of urate, are also likely to increase the excretion of [[oxipurinol]] and thus lower the degree of inhibition of xanthine oxidase. The concomitant administration of uricosuric agents and allopurinol tablets has been associated with a decrease in the excretion of oxypurines (hypoxanthine and xanthine) and an increase in urinary uric acid excretion compared with that observed with allopurinol tablets alone. Although clinical evidence to date has not demonstrated renal precipitation of oxypurines in patients either on allopurinol tablets alone or in combination with uricosuric agents, the possibility should be kept in mind.

The reports that the concomitant use of allopurinol tablets and thiazide diuretics may contribute to the enhancement of allopurinol toxicity in some patients have been reviewed in an attempt to establish a cause-and-effect relationship and a mechanism of causation. Review of these case reports indicates that the patients were mainly receiving thiazide diuretics for hypertension and that tests to rule out decreased renal function secondary to hypertensive nephropathy were not often performed. In those patients in whom renal insufficiency was documented, however, the recommendation to lower the dose of allopurinol tablets was not followed. Although a causal mechanism and a cause-and-effect relationship have not been established, current evidence suggests that renal function should be monitored in patients on thiazide diuretics and allopurinol tablets even in the absence of renal failure, and dosage levels should be even more conservatively adjusted in those patients on such combined therapy if diminished renal function is detected.

An increase in the frequency of skin [[rash]] has been reported among patients receiving ampicillin or amoxicillin concurrently with allopurinol tablets compared to patients who are not receiving both drugs. The cause of the reported association has not been established.

Enhanced bone marrow suppression by cyclophosphamide and other cytotoxic agents has been reported among patients with neoplastic disease, except [[leukemia]], in the presence of allopurinol tablets. However, in a well-controlled study of patients with lymphoma on combination therapy, allopurinol tablets did not increase the marrow toxicity of patients treated with cyclophosphamide, doxorubicin, bleomycin, procarbazine, and/or mechlorethamine.

Tolbutamide's conversion to inactive metabolites has been shown to be catalyzed by xanthine oxidase from rat liver. The clinical significance, if any, of these observations is unknown.

Chlorpropamide's plasma half-life may be prolonged by allopurinol tablets, since allopurinol and chlorpropamide may compete for excretion in the renal tubule. The risk of hypoglycemia secondary to this mechanism may be increased if allopurinol tablets and chlorpropamide are given concomitantly in the presence of renal insufficiency.

Rare reports indicate that cyclosporine levels may be increased during concomitant treatment with allopurinol tablets. Monitoring of cyclosporine levels and possible adjustment of cyclosporine dosage should be considered when these drugs are coadministered.

Drug/Laboratory Test Interactions

Allopurinol tablets are not known to alter the accuracy of laboratory tests.
|FDAPregCat=C
|useInPregnancyFDA=Teratogenic Effects: Pregnancy Category C. Reproductive studies have been performed in rats and rabbits at doses up to twenty times the usual human dose (5 mg/kg per day), and it was concluded that there was no impaired fertility or harm to the fetus due to allopurinol. There is a published report of a study in pregnant mice given 50 or 100 mg/kg allopurinol intraperitoneally on gestation days 10 or 13. There were increased numbers of dead fetuses in dams given 100 mg/kg allopurinol but not in those given 50 mg/kg. There were increased numbers of external malformations in fetuses at both doses of allopurinol on gestation day 10 and increased numbers of skeletal malformations in fetuses at both doses on gestation day 13. It cannot be determined whether this represented a fetal effect or an effect secondary to maternal toxicity. There are, however, no adequate or well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Experience with allopurinol tablets during human pregnancy has been limited partly because women of reproductive age rarely require treatment with allopurinol tablets. There are two unpublished reports and one published paper of women giving birth to normal offspring after receiving allopurinol tablets during pregnancy.
|useInNursing=Allopurinol and [[oxipurinol]] have been found in the milk of a mother who was receiving allopurinol tablets. Since the effect of allopurinol on the nursing infant is unknown, caution should be exercised when allopurinol tablets are administered to a nursing woman.
|useInPed=Allopurinol tablets are rarely indicated for use in children with the exception of those with [[hyperuricemia]] secondary to malignancy or to certain rare inborn errors of purine metabolism.
|administration=Oral
|monitoring=FDA Package Insert for Allopurinol contains no information regarding Drug Monitoring.
|IVCompat=There is limited information about the IV Compatibility.
|overdose=Massive overdosing or acute poisoning by allopurinol tablets has not been reported.

In mice, the 50% lethal dose (LD50) is 160 mg/kg given intraperitoneally (IP) with deaths delayed up to 5 days and 700 mg/kg orally (PO) (approximately 140 times the usual human dose) with deaths delayed up to 3 days. In rats, the acute LD50 is 750 mg/kg IP and 6000 mg/kg PO (approximately 1200 times the human dose).

In the management of overdosage there is no specific antidote for allopurinol tablets. There has been no clinical experience in the management of a patient who has taken massive amounts of allopurinol tablets.

Both allopurinol and [[oxipurinol]] are dialyzable; however, the usefulness of hemodialysis or peritoneal dialysis in the management of an overdose of allopurinol tablets is unknown.
|drugBox={{drugbox2
| Watchedfields = changed
| verifiedrevid = 477318043
| IUPAC_name = 1''H''-pyrazolo[3,4-d]pyrimidin-4(2H)-one
| image = Allopurinol V.1.png
| width = 150
| image2 = Allopurinol_3d_structure.png


| tradename = Zyloprim
| Drugs.com = {{drugs.com|monograph|allopurinol}}
| MedlinePlus = a682673
| pregnancy_category = C(USA)
| legal_US = Rx-only
| routes_of_administration = tablet (100, 300 mg)


| bioavailability = 78±20%
| protein_bound = Negligible
| metabolism = hepatic (80% oxypurinol, 10% allopurinol ribosides)
| elimination_half-life = 2 h (oxypurinol 18-30 h)


| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 315-30-0
| ATC_prefix = M04
| ATC_suffix = AA01
| ATC_supplemental =
| PubChem = 2094
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00437
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 2010
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 63CZ7GJN5I
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00224
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 40279
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1467


| C=5 | H=4 | N=4 | O=1
| molecular_weight = 136.112 g/mol
| smiles = c1c2c([nH]n1)ncnc2O
| InChI = 1/C5H4N4O/c10-5-3-1-8-9-4(3)6-2-7-5/h1-2H,(H2,6,7,8,9,10)
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C5H4N4O/c10-5-3-1-8-9-4(3)6-2-7-5/h1-2H,(H2,6,7,8,9,10)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = OFCNXPDARWKPPY-UHFFFAOYSA-N
}}
|mechAction=Allopurinol is a purine analog; it is a structural [[isomer]] of [[hypoxanthine]] (a naturally occurring [[purine]] in the body) and is an [[enzyme inhibitor|inhibitor]] of the enzyme [[xanthine oxidase]].<ref name="pmid16507884"/> Xanthine oxidase is responsible for the successive oxidation of hypoxanthine and [[xanthine]], resulting in the production of [[uric acid]], the product of human purine metabolism.<ref name="pmid16507884"/> In addition to blocking uric acid production, inhibition of xanthine oxidase causes an increase in hypoxanthine and xanthine. While xanthine cannot be converted to purine ribotides, hypoxanthine can be salvaged to the purine [[ribotide]]s [[adenosine monophosphate|adenosine]] and [[guanosine monophosphate]]s. Increased levels of these ribotides may cause feedback inhibition of [[amidophosphoribosyl transferase]], the first and rate-limiting enzyme of purine biosynthesis. Allopurinol, therefore, decreases uric acid formation and may also inhibit purine synthesis.
|structure=Allopurinol has the following structural formula:

[[File:Allopurinol_structure_01.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

Allopurinol is known chemically as 1, 5-dihydro-4H-pyrazolo [3, 4-d] pyrimidin-4-one. It is a xanthine oxidase inhibitor which is administered orally. Its solubility in water at 37°C is 80.0 mg/dL and is greater in an alkaline solution. Each scored white to off-white tablet contains 100 mg allopurinol and the inactive ingredients lactose monohydrate, corn starch, sodium starch glycolate, povidone and stearic acid. Each scored peach tablet contains 300 mg allopurinol and the inactive ingredients lactose monohydrate, corn starch, sodium starch glycolate , FD & C yellow no. 6, povidone and stearic acid.
|clinicalStudies=FDA Package Insert for Allopurinol contains no information regarding Clinical Studies.
|howSupplied=100 mg white to off-white colored, round, beveled edged uncoated tablets with "RG10" embossed on one side and breakline on the other side.

The tablets are supplied in the following package sizes:

Bottles of 100 tablets NDC 63304-539-01

Bottles of 1000 tablets NDC 63304-539-10

300 mg peach colored, round, beveled edged uncoated tablets with "RG11" embossed on one side and breakline on the other side.

The tablets are supplied in the following package sizes:

Bottles of 100 tablets NDC 63304-540-01

Bottles of 500 tablets NDC 63304-540-05
|storage=Store at 20° - 25°C (68° - 77°F)
|fdaPatientInfo=Patients should be informed of the following:

(1) They should be cautioned to discontinue allopurinol tablets and to consult their physician immediately at the first sign of a skin rash, painful urination, blood in the urine, irritation of the eyes, or swelling of the lips or mouth. (2) They should be reminded to continue drug therapy prescribed for [[gout]]y attacks since optimal benefit of allopurinol tablets may be delayed for 2 to 6 weeks. (3) They should be encouraged to increase fluid intake during therapy to prevent renal stones. (4) If a single dose of allopurinol tablets is occasionally forgotten, there is no need to double the dose at the next scheduled time. (5) There may be certain risks associated with the concomitant use of allopurinol tablets and dicumarol, sulfinpyrazone, mercaptopurine, azathioprine, ampicillin, amoxicillin, and thiazide diuretics, and they should follow the instructions of their physician. (6) Due to the occasional occurrence of drowsiness, patients should take precautions when engaging in activities where alertness is mandatory. (7) Patients may wish to take allopurinol tablets after meals to minimize gastric irritation.
|alcohol=Alcohol-Allopurinol interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=* Zyloprim
|lookAlike=There is limited information about the look-like drug names.
}}
{{PillImage
|fileName=No_image.jpg
|drugName=Allopurinol 100 MG Oral Tablet
|NDC=63304-539
|drugAuthor=Ranbaxy Pharmaceuticals Inc.
|ingredients=lactose monohydrate, povidone, sodium starch glycolate type a potato, starch, corn, stearic acid, fd&c yellow no. 6
|pillImprint=RG10
|dosageValue=100
|dosageUnit=mg
|pillColor=White
|pillShape=Round
|pillSize=8.00
|pillScore=2
}}
{{PillImage
|fileName=No_image.jpg
|drugName=Allopurinol 300 MG Oral Tablet
|NDC=63304-540
|drugAuthor=Ranbaxy Pharmaceuticals Inc.
|ingredients=fd&c yellow no. 6, lactose monohydrate, povidone, sodium starch glycolate type a potato, starch, corn, stearic acid
|pillImprint=RG11
|dosageValue=300
|dosageUnit=mg
|pillColor=Orange
|pillShape=Round
|pillSize=12.00
|pillScore=2
}}
{{LabelImage
|fileName=Allopurinol_label_01.jpg
}}
{{LabelImage
|fileName=Allopurinol_label_02.jpg
}}
{{LabelImage
|fileName=Allopurinol_panel_01.png
}}
{{LabelImage
|fileName=Allopurinol_panel_02.png
}}

Ezetimibe

2015-03-18T16:24:14Z

Sree Teja Yelamanchili:

{{DrugProjectFormSinglePage
|authorTag={{SS}}; {{STY}}
|genericName=ezetimibe
|aOrAn=a
|drugClass=dietary [[cholesterol absorption inhibitor]]
|indicationType=treatment
|indication=[[hyperlipidemia|primary hyperlipidemia]], [[homozygous familial hypercholesterolemia]] (HoFH), homozygous sitosterolemia.
|adverseReactions=[[diarrhea]], [[arthralgia]], [[myalgia]], [[nasopharyngitis]], [[sinusitis]], [[upper respiratory infection]].
|blackBoxWarningTitle=<b><span style="color:#FF0000;">TITLE</span></b>
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)
|fdaLIADAdult=<h4>General Dosing Information</h4>

* Recommended dosage: '''10 mg PO qd'''
:* Ezetimibe can be administered with or without food.

<h4>Concomitant Lipid-Lowering Therapy</h4>

* Dosing information
:* Ezetimibe may be administered with a [[statin]] (in patients with [[Hyperlipidemia|primary hyperlipidemia]]) or with [[fenofibrate]] (in patients with mixed hyperlipidemia) for incremental effect. For convenience, the daily dose of Ezetimibe may be taken at the same time as the statin or fenofibrate, according to the dosing recommendations for the respective medications.

<H4>Coadministration with Bile Acid Sequestrants</H4>

* Dosing information
:* Dosing of Ezetimibe should occur either ≥2 hours before or ≥4 hours after administration of a [[bile acid sequestrant]].

<H4>Patients with Hepatic Impairment</H4>

* Dosing information
:* No dosage adjustment is necessary in patients with mild hepatic impairment.

<H4>Patients with Renal Impairment</H4>

* Dosing information
:* No dosage adjustment is necessary in patients with renal impairment. When given with [[simvastatin]] in patients with moderate to severe renal impairment (estimated [[glomerular filtration rate]] <60 mL/min/1.73 m2), doses of simvastatin exceeding 20 mg should be used with caution and close monitoring.

<h4>Geriatric Patients</h4>

* Dosing information
:* No dosage adjustment is necessary in geriatric patients.
|offLabelAdultGuideSupport=There is limited information about <i>Off-Label Guideline-Supported Use</i> of Ezetimibe in adult patients.
|offLabelAdultNoGuideSupport=There is limited information about <i>Off-Label Non–Guideline-Supported Use</i> of Ezetimibe in adult patients.
|fdaLIADPed=FDA Package Insert for Ezetimibe contains no information regarding Pediatric Indications and Dosage.
|offLabelPedGuideSupport=There is limited information about <i>Off-Label Guideline-Supported Use</i> of Ezetimibe in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information about <i>Off-Label Non–Guideline-Supported Use</i> of Ezetimibe in pediatric patients.
|contraindications=Ezetimibe is contraindicated in the following conditions:

*The combination of Ezetimibe with a statin is contraindicated in patients with active liver disease or unexplained persistent elevations in hepatic [[transaminase]] levels.
*Women who are pregnant or may become pregnant because [[statins]] decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, Ezetimibe in combination with a statin may cause fetal harm when administered to pregnant women.
*Additionally, there is no apparent benefit to therapy during pregnancy, and safety in pregnant women has not been established.
*If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus and the lack of known clinical benefit with continued use during pregnancy.
*Nursing mothers-Because [[statins]] may pass into breast milk, and because [[statins]] have the potential to cause serious adverse reactions in nursing infants, women who require Ezetimibe treatment in combination with a statin should be advised not to nurse their infants.
*Patients with a known [[hypersensitivity]] to any component of this product. [[hypersensitivity]] reactions including [[anaphylaxis]], [[angioedema]], [[rash]] and [[urticaria]] have been reported with Ezetimibe.
|warnings=====Use with statins or fenofibrate====

Concurrent administration of Ezetimibe with a specific [[statin]] or [[fenofibrate]] should be in accordance with the product labeling for that medication.

====Liver Enzymes====

*In controlled clinical monotherapy studies, the incidence of consecutive elevations (≥3 × the upper limit of normal [ULN]) in hepatic transaminase levels was similar between Ezetimibe (0.5%) and placebo (0.3%).
*In controlled clinical combination studies of Ezetimibe initiated concurrently with a [[statin]], the incidence of consecutive elevations (≥3 × ULN) in hepatic transaminase levels was 1.3% for patients treated with Ezetimibe administered with [[statins]] and 0.4% for patients treated with [[statins]] alone.
*These elevations in [[transaminases]] were generally asymptomatic, not associated with [[cholestasis]], and returned to baseline after discontinuation of therapy or with continued treatment.
*When Ezetimibe is coadministered with a [[statin]], liver tests should be performed at initiation of therapy and according to the recommendations of the [[statin]].
*Should an increase in ALT or AST ≥3 × ULN persist, consider withdrawal of Ezetimibe and/or the [[statin]].

====Myopathy/Rhabdomyolysis====

*In clinical trials, there was no excess of [[myopathy]] or [[rhabdomyolysis]] associated with Ezetimibe compared with the relevant control arm (placebo or statin alone).
*However, myopathy and rhabdomyolysis are known adverse reactions to statins and other lipid-lowering drugs.
*In clinical trials, the incidence of [[creatine phosphokinase]] (CPK) >10 × ULN was 0.2% for Ezetimibe vs. 0.1% for placebo, and 0.1% for Ezetimibe coadministered with a [[statin]] vs. 0.4% for [[statins]] alone.
*Risk for skeletal muscle toxicity increases with higher doses of statin, advanced age (>65), [[hypothyroidism]], [[renal impairment]], and depending on the statin used, concomitant use of other drugs.
*In post-marketing experience with Ezetimibe, cases of [[myopathy]] and [[rhabdomyolysis]] have been reported.
*Most patients who developed [[rhabdomyolysis]] were taking a [[statin]] prior to initiating Ezetimibe.
*However, [[rhabdomyolysis]] has been reported with Ezetimibe monotherapy and with the addition of Ezetimibe to agents known to be associated with increased risk of [[rhabdomyolysis]], such as fibrates.
*Ezetimibe and any statin or fibrate that the patient is taking concomitantly should be immediately discontinued if [[myopathy]] is diagnosed or suspected.
*The presence of muscle symptoms and a CPK level >10 × the ULN indicates myopathy.

====Hepatic Impairment====

Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate to severe [[hepatic impairment]], Ezetimibe is not recommended in these patients.
|clinicalTrials=The following serious adverse reactions are discussed in greater detail in other sections of the label:

*[[Liver enzyme]] abnormalities
*[[Rhabdomyolysis]] and [[myopathy]]

'''Monotherapy Studies''': In the Ezetimibe controlled clinical trials database (placebo-controlled) of 2396 patients with a median treatment duration of 12 weeks (range 0 to 39 weeks), 3.3% of patients on Ezetimibe and 2.9% of patients on placebo discontinued due to adverse reactions. The most common adverse reactions in the group of patients treated with Ezetimibe that led to treatment discontinuation and occurred at a rate greater than placebo were:

*[[Arthralgia]] (0.3%)
*[[Dizziness]] (0.2%)
*[[Gamma-glutamyltransferase]] increased (0.2%)

The most commonly reported adverse reactions (incidence ≥2% and greater than placebo) in the Ezetimibe monotherapy controlled clinical trial database of 2396 patients were: [[upper respiratory tract infection]] (4.3%), [[diarrhea ]](4.1%), [[arthralgia]] (3.0%), [[sinusitis]] (2.8%), and pain in extremity (2.7%).

'''Statin Coadministration Studies''': In the Ezetimibe + statin controlled clinical trials database of 11,308 patients with a median treatment duration of 8 weeks (range 0 to 112 weeks), 4.0% of patients on Ezetimibe + statin and 3.3% of patients on [[statin]] alone discontinued due to adverse reactions. The most common adverse reactions in the group of patients treated with Ezetimibe + statin that led to treatment discontinuation and occurred at a rate greater than statin alone were:

*[[Alanine aminotransferase]] increased (0.6%)
*[[Myalgia]] (0.5%)
*[[Fatigue]], [[aspartate aminotransferase ]]increased, [[headache]], and pain in extremity (each at 0.2%)

The most commonly reported adverse reactions (incidence ≥2% and greater than statin alone) in the Ezetimibe + statin controlled clinical trial database of 11,308 patients were: [[nasopharyngitis]] (3.7%), [[myalgia]] (3.2%), [[upper respiratory tract infection]] (2.9%), [[arthralgia ]](2.6%) and [[diarrhea]] (2.5%).

===Clinical Trials Experience===

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.

====Monotherapy====

In 10 double-blind, placebo-controlled clinical trials, 2396 patients with primary [[hyperlipidemia]] (age range 9–86 years, 50% women, 90% Caucasians, 5% Blacks, 3% Hispanics, 2% Asians) and elevated LDL-C were treated with Ezetimibe 10 mg/day for a median treatment duration of 12 weeks (range 0 to 39 weeks).

Adverse reactions reported in ≥2% of patients treated with Ezetimibe and at an incidence greater than placebo in placebo-controlled studies of Ezetimibe, regardless of causality assessment, are shown in Table 1.
[[File:Zetia01.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

====Combination with a statin====

In 28 double-blind, controlled (placebo or active-controlled) clinical trials, 11,308 patients with primary [[hyperlipidemia]] (age range 10–93 years, 48% women, 85% Caucasians, 7% Blacks, 4% Hispanics, 3% Asians) and elevated LDL-C were treated with Ezetimibe 10 mg/day concurrently with or added to on-going [[statin]] therapy for a median treatment duration of 8 weeks (range 0 to 112 weeks).

The incidence of consecutive increased transaminases (≥3 × ULN) was higher in patients receiving Ezetimibe administered with [[statins]] (1.3%) than in patients treated with [[statins]] alone (0.4%).

Clinical adverse reactions reported in ≥2% of patients treated with Ezetimibe + statin and at an incidence greater than [[statin]], regardless of causality assessment, are shown in Table 2.
[[File:Zetia02.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

====Combination with Fenofibrate====

*This clinical study involving 625 patients with mixed dyslipidemia (age range 20–76 years, 44% women, 79% Caucasians, 0.1% Blacks, 11% Hispanics, 5% Asians) treated for up to 12 weeks and 576 patients treated for up to an additional 48 weeks evaluated coadministration of Ezetimibe and [[Fenofibrate]].
*This study was not designed to compare treatment groups for infrequent events.
*Incidence rates (95% CI) for clinically important elevations (≥3 × ULN, consecutive) in hepatic transaminase levels were 4.5% (1.9, 8.8) and 2.7% (1.2, 5.4) for [[Fenofibrate]] monotherapy (n=188) and Ezetimibe coadministered with [[Fenofibrate]] (n=183), respectively, adjusted for treatment exposure.
*Corresponding incidence rates for cholecystectomy were 0.6% (95% CI: 0.0%, 3.1%) and 1.7% (95% CI: 0.6%, 4.0%) for Fenofibrate monotherapy and Ezetimibe coadministered with [[Fenofibrate]], respectively.
*The numbers of patients exposed to coadministration therapy as well as [[Fenofibrate]] and ezetimibe monotherapy were inadequate to assess gallbladder disease risk.
*There were no CPK elevations >10 × ULN in any of the treatment groups.
|postmarketing=Because the reactions below are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following additional adverse reactions have been identified during post-approval use of Ezetimibe:

[[Hypersensitivity]] reactions, including [[anaphylaxis]], [[angioedema]], [[rash]], and [[urticaria]]; [[erythema multiforme]]; [[arthralgia]]; [[myalgia]]; elevated [[creatine phosphokinase]]; [[myopathy]]/[[Rhabdomyolysis]]; [[elevated liver transaminases|elevations in liver transaminases]]; [[hepatitis]]; [[abdominal pain]]; [[thrombocytopenia]]; [[pancreatitis]]; [[nausea]]; [[dizziness]]; [[paresthesia]]; [[depression]]; [[headache]]; [[cholelithiasis]]; [[cholecystitis]].
|drugInteractions=====Cyclosporine====

Caution should be exercised when using Ezetimibe and [[cyclosporine]] concomitantly due to increased exposure to both ezetimibe and [[cyclosporine]]. Cyclosporine concentrations should be monitored in patients receiving Ezetimibe and [[cyclosporine]].

The degree of increase in ezetimibe exposure may be greater in patients with severe [[renal insufficiency]]. In patients treated with [[cyclosporine]], the potential effects of the increased exposure to ezetimibe from concomitant use should be carefully weighed against the benefits of alterations in lipid levels provided by ezetimibe.

====Fibrates====

The efficacy and safety of coadministration of ezetimibe with [[fibrates]] other than [[fenofibrate]] have not been studied.

[[Fibrates]] may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Coadministration of Ezetimibe with [[Fibrates]] other than [[fenofibrate]] is not recommended until use in patients is adequately studied.

====Fenofibrate====

If cholelithiasis is suspected in a patient receiving Ezetimibe and [[fenofibrate]], gallbladder studies are indicated and alternative lipid-lowering therapy should be considered and the product labeling for [[fenofibrate]].

====Cholestyramine====

Concomitant [[cholestyramine ]]administration decreased the mean area under the curve (AUC) of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction.

====Coumarin Anticoagulants====

If ezetimibe is added to [[warfarin]], a coumarin [[anticoagulant]], the [[International Normalized Ratio ]]([[INR]]) should be appropriately monitored.
|FDAPregCat=C
|useInPregnancyFDA=There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus.

In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 × the human exposure at 10 mg daily based on AUC0–24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 × the human exposure at 10 mg daily based on AUC0–24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses.

Multiple-dose studies of ezetimibe given in combination with [[statins]] in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy.

All [[statins]] are contraindicated in pregnant and nursing women. When Ezetimibe is administered with a statin in a woman of childbearing potential, refer to the pregnancy category and product labeling for the statin.
|useInNursing=It is not known whether ezetimibe is excreted into human breast milk. In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. Because many drugs are excreted in human milk, caution should be exercised when Ezetimibe is administered to a nursing woman. Ezetimibe should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant.
|useInPed=The effects of Ezetimibe coadministered with [[simvastatin]] (n=126) compared to [[simvastatin]] monotherapy (n=122) have been evaluated in adolescent boys and girls with [[heterozygous familial hypercholesterolemia]] (HeFH). In a multicenter, double-blind, controlled study followed by an open-label phase, 142 boys and 106 postmenarchal girls, 10 to 17 years of age (mean age 14.2 years, 43% females, 82% Caucasians, 4% Asian, 2% Blacks, 13% multi-racial) with HeFH were randomized to receive either Ezetimibe coadministered with [[simvastatin]] or [[simvastatin]] monotherapy. Inclusion in the study required 1) a baseline LDL-C level between 160 and 400 mg/dL and 2) a medical history and clinical presentation consistent with HeFH. The mean baseline LDL-C value was 225 mg/dL (range: 161–351 mg/dL) in the Ezetimibe coadministered with [[simvastatin]] group compared to 219 mg/dL (range: 149–336 mg/dL) in the [[simvastatin]] monotherapy group. The patients received coadministered Ezetimibe and [[simvastatin]] (10 mg, 20 mg, or 40 mg) or [[simvastatin]] monotherapy (10 mg, 20 mg, or 40 mg) for 6 weeks, coadministered Ezetimibe and 40-mg [[simvastatin]] or 40-mg [[simvastatin]] monotherapy for the next 27 weeks, and open-label coadministered Ezetimibe and [[simvastatin]] (10 mg, 20 mg, or 40 mg) for 20 weeks thereafter.

The results of the study at Week 6 are summarized in Table 3. Results at Week 33 were consistent with those at Week 6.
[[File:Zetia03.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

From the start of the trial to the end of Week 33, discontinuations due to an adverse reaction occurred in 7 (6%) patients in the Ezetimibe coadministered with simvastatin group and in 2 (2%) patients in the [[simvastatin]] monotherapy group.

During the trial, hepatic transaminase elevations (two consecutive measurements for ALT and/or AST ≥3 × ULN) occurred in four (3%) individuals in the Ezetimibe coadministered with [[simvastatin]] group and in two (2%) individuals in the [[simvastatin]] monotherapy group. Elevations of CPK (≥10 × ULN) occurred in two (2%) individuals in the Ezetimibe coadministered with [[simvastatin]] group and in zero individuals in the [[simvastatin]] monotherapy group.

In this limited controlled study, there was no significant effect on growth or sexual maturation in the adolescent boys or girls, or on menstrual cycle length in girls.

Coadministration of Ezetimibe with [[simvastatin]] at doses greater than 40 mg/day has not been studied in adolescents. Also, Ezetimibe has not been studied in patients younger than 10 years of age or in pre-menarchal girls.

Based on total ezetimibe (ezetimibe + ezetimibe-glucuronide), there are no pharmacokinetic differences between adolescents and adults. Pharmacokinetic data in the pediatric population less than 10 years of age are not available.
|useInGeri=====Monotherapy Studies====

Of the 2396 patients who received Ezetimibe in clinical studies, 669 (28%) were 65 and older, and 111 (5%) were 75 and older.

====Statin Coadministration Studies====

Of the 11,308 patients who received Ezetimibe + [[statin]] in clinical studies, 3587 (32%) were 65 and older, and 924 (8%) were 75 and older.

No overall differences in safety and effectiveness were observed between these patients and younger patients, 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.
|useInRenalImpair=When used as monotherapy, no dosage adjustment of Ezetimibe is necessary.

In the Study of Heart and Renal Protection (SHARP) trial of 9270 patients with moderate to severe renal impairment (6247 non-dialysis patients with median serum creatinine 2.5 mg/dL and median estimated glomerular filtration rate 25.6 mL/min/1.73 m2, and 3023 dialysis patients), the incidence of serious adverse events, adverse events leading to discontinuation of study treatment, or adverse events of special interest (musculoskeletal adverse events, liver enzyme abnormalities, incident cancer) was similar between patients ever assigned to ezetimibe 10 mg plus [[simvastatin]] 20 mg (n=4650) or placebo (n=4620) during a median follow-up of 4.9 years. However, because renal impairment is a risk factor for statin-associated myopathy, doses of [[simvastatin]] exceeding 20 mg should be used with caution and close monitoring when administered concomitantly with Ezetimibe in patients with moderate to severe renal impairment.
|useInHepaticImpair=Ezetimibe is not recommended in patients with moderate to severe [[hepatic impairment]].

Ezetimibe given concomitantly with a statin is contraindicated in patients with active liver disease or unexplained persistent elevations of hepatic transaminase levels.
|administration=Oral
|monitoring=FDA Package Insert for ezetimibe contains no information regarding drug monitoring.
|IVCompat=FDA Package Insert for ezetimibe contains no information regarding IV Compatibility.
|overdose=In clinical studies, administration of ezetimibe, 50 mg/day to 15 healthy subjects for up to 14 days, 40 mg/day to 18 patients with primary [[hyperlipidemia]] for up to 56 days, and 40 mg/day to 27 patients with homozygous sitosterolemia for 26 weeks was generally well tolerated. One female patient with [[homozygous sitosterolemia ]]took an accidental overdose of ezetimibe 120 mg/day for 28 days with no reported clinical or laboratory adverse events.

In the event of an overdose, symptomatic and supportive measures should be employed.
|drugBox={{Drugbox2
| Watchedfields = changed
| verifiedrevid = 461098524
| IUPAC_name = (3''R'',4''S'')-1-(4-fluorophenyl)-3-[(3''S'')-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one
| image = Ezetimibe.png
| width = 200


| tradename = Ezetimibe
| Drugs.com = {{drugs.com|monograph|ezetimibe}}
| MedlinePlus = a603015
| pregnancy_AU = C
| pregnancy_US = C
| legal_AU = S4
| legal_CA = Rx-only
| legal_UK = POM
| legal_US = Rx-only
| routes_of_administration = Oral


| bioavailability = 35–65%
| protein_bound = >90%
| metabolism = Intestinal wall, hepatic
| elimination_half-life = 19–30 hours
| excretion = Renal 11%, faecal 78%


| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 163222-33-1
| ATC_prefix = C10
| ATC_suffix = AX09
| PubChem = 150311
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00973
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 132493
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = EOR26LQQ24
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D01966
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 49040
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1138


| C=24 | H=21 | F=2 | N=1 | O=3
| molecular_weight = 409.4 g·mol<sup>−1</sup>
| smiles = Fc1ccc(cc1)[C@@H](O)CC[C@H]4C(=O)N(c2ccc(F)cc2)[C@@H]4c3ccc(O)cc3
| InChI = 1/C24H21F2NO3/c25-17-5-1-15(2-6-17)22(29)14-13-21-23(16-3-11-20(28)12-4-16)27(24(21)30)19-9-7-18(26)8-10-19/h1-12,21-23,28-29H,13-14H2/t21-,22+,23-/m1/s1
| InChIKey = OLNTVTPDXPETLC-XPWALMASBY
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C24H21F2NO3/c25-17-5-1-15(2-6-17)22(29)14-13-21-23(16-3-11-20(28)12-4-16)27(24(21)30)19-9-7-18(26)8-10-19/h1-12,21-23,28-29H,13-14H2/t21-,22+,23-/m1/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = OLNTVTPDXPETLC-XPWALMASSA-N
| melting_point = 164
| melting_high = 166
}}
|mechAction=Ezetimibe reduces blood cholesterol by inhibiting the absorption of cholesterol by the small intestine. In a 2-week clinical study in 18 hypercholesterolemic patients, Ezetimibe inhibited intestinal cholesterol absorption by 54%, compared with placebo. Ezetimibe had no clinically meaningful effect on the plasma concentrations of the fat-soluble vitamins A, D, and E (in a study of 113 patients), and did not impair adrenocortical steroid hormone production (in a study of 118 patients).
The cholesterol content of the liver is derived predominantly from three sources. The liver can synthesize cholesterol, take up cholesterol from the blood from circulating lipoproteins, or take up cholesterol absorbed by the small intestine. Intestinal cholesterol is derived primarily from cholesterol secreted in the bile and from dietary cholesterol.
Ezetimibe has a mechanism of action that differs from those of other classes of cholesterol-reducing compounds (statins, bile acid sequestrants [resins], fibric acid derivatives, and plant stanols). The molecular target of ezetimibe has been shown to be the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is involved in the intestinal uptake of cholesterol and phytosterols.
Ezetimibe does not inhibit cholesterol synthesis in the liver, or increase bile acid excretion. Instead, ezetimibe localizes at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood; this distinct mechanism is complementary to that of statins and of fenofibrate.
|structure=Ezetimibe (ezetimibe) is in a class of lipid-lowering compounds that selectively inhibits the intestinal absorption of cholesterol and related phytosterols. The chemical name of ezetimibe is 1-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone. The empirical formula is C24H21F2NO3. Its molecular weight is 409.4 and its structural formula is:
[[File:Zetia04.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

Ezetimibe is a white, crystalline powder that is freely to very soluble in ethanol, methanol, and acetone and practically insoluble in water. Ezetimibe has a melting point of about 163°C and is stable at ambient temperature. Ezetimibe is available as a tablet for oral administration containing 10 mg of ezetimibe and the following inactive ingredients: croscarmellose sodium NF, lactose monohydrate NF, magnesium stearate NF, microcrystalline cellulose NF, povidone USP, and sodium lauryl sulfate NF.
|PD=Clinical studies have demonstrated that elevated levels of total-C, LDL-C and Apo B, the major protein constituent of LDL, promote human [[atherosclerosis]]. In addition, decreased levels of HDL-C are associated with the development of [[atherosclerosis]]. Epidemiologic studies have established that cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C and inversely with the level of HDL-C. Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and remnants, can also promote [[atherosclerosis]]. The independent effect of raising HDL-C or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.

Ezetimibe reduces total-C, LDL-C, Apo B, non-HDL-C, and TG, and increases HDL-C in patients with [[hyperlipidemia]]. Administration of Ezetimibe with a [[statin]] is effective in improving serum total-C, LDL-C, Apo B, non-HDL-C, TG, and HDL-C beyond either treatment alone. Administration of Ezetimibe with [[fenofibrate]] is effective in improving serum total-C, LDL-C, Apo B, and non-HDL-C in patients with mixed [[hyperlipidemia]] as compared to either treatment alone. The effects of ezetimibe given either alone or in addition to a [[statin]] or [[fenofibrate]] on cardiovascular morbidity and mortality have not been established.
|PK=====Absorption====
After oral administration, ezetimibe is absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). After a single 10-mg dose of Ezetimibe to fasted adults, mean ezetimibe peak plasma concentrations (Cmax) of 3.4 to 5.5 ng/mL were attained within 4 to 12 hours (Tmax). Ezetimibe-glucuronide mean Cmax values of 45 to 71 ng/mL were achieved between 1 and 2 hours (Tmax). There was no substantial deviation from dose proportionality between 5 and 20 mg. The absolute bioavailability of ezetimibe cannot be determined, as the compound is virtually insoluble in aqueous media suitable for injection.

====Effect of Food on Oral Absorption====

Concomitant food administration (high-fat or non-fat meals) had no effect on the extent of absorption of ezetimibe when administered as Ezetimibe 10-mg tablets. The Cmaxvalue of ezetimibe was increased by 38% with consumption of high-fat meals. Ezetimibe can be administered with or without food.

====Distribution====

Ezetimibe and ezetimibe-glucuronide are highly bound (>90%) to human plasma proteins.

====Metabolism and Excretion====

Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide conjugation (a phase II reaction) with subsequent biliary and renal excretion. Minimal oxidative metabolism (a phase I reaction) has been observed in all species evaluated.

In humans, ezetimibe is rapidly metabolized to ezetimibe-glucuronide. Ezetimibe and ezetimibe-glucuronide are the major drug-derived compounds detected in plasma, constituting approximately 10 to 20% and 80 to 90% of the total drug in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are eliminated from plasma with a half-life of approximately 22 hours for both ezetimibe and ezetimibe-glucuronide. Plasma concentration-time profiles exhibit multiple peaks, suggesting enterohepatic recycling.

Following oral administration of 14C-ezetimibe (20 mg) to human subjects, total ezetimibe (ezetimibe + ezetimibe-glucuronide) accounted for approximately 93% of the total radioactivity in plasma. After 48 hours, there were no detectable levels of radioactivity in the plasma.

Approximately 78% and 11% of the administered radioactivity were recovered in the feces and urine, respectively, over a 10-day collection period. Ezetimibe was the major component in feces and accounted for 69% of the administered dose, while ezetimibe-glucuronide was the major component in urine and accounted for 9% of the administered dose.

====Specific Populations====

'''Geriatric Patients''': In a multiple-dose study with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were about 2-fold higher in older (≥65 years) healthy subjects compared to younger subjects.

'''Pediatric Patients''':

'''Gender''': In a multiple-dose study with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were slightly higher (less than 20%) in women than in men.

'''Race''': Based on a meta-analysis of multiple-dose pharmacokinetic studies, there were no pharmacokinetic differences between Black and Caucasian subjects. Studies in Asian subjects indicated that the pharmacokinetics of ezetimibe were similar to those seen in Caucasian subjects.

'''Hepatic Impairment''': After a single 10-mg dose of ezetimibe, the mean AUC for total ezetimibe was increased approximately 1.7-fold in patients with mild [[hepatic impairment]] (Child-Pugh score 5 to 6), compared to healthy subjects. The mean AUC values for total ezetimibe and ezetimibe were increased approximately 3- to 4-fold and 5- to 6-fold, respectively, in patients with moderate (Child-Pugh score 7 to 9) or severe [[hepatic impairment]] (Child-Pugh score 10 to 15). In a 14-day, multiple-dose study (10 mg daily) in patients with moderate [[hepatic impairment]], the mean AUC values for total ezetimibe and ezetimibe were increased approximately 4-fold on Day 1 and Day 14 compared to healthy subjects. Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe [[hepatic impairment]], Ezetimibe is not recommended in these patients.

'''Renal Impairment''': After a single 10-mg dose of ezetimibe in patients with severe [[renal disease ]](n=8; mean CrCl ≤30 mL/min/1.73 m2), the mean AUC values for total ezetimibe, ezetimibe-glucuronide, and ezetimibe were increased approximately 1.5-fold, compared to healthy subjects (n=9).
|nonClinToxic=Clinical studies have demonstrated that elevated levels of total-C, LDL-C and Apo B, the major protein constituent of LDL, promote human [[atherosclerosis]]. In addition, decreased levels of HDL-C are associated with the development of [[atherosclerosis]]. Epidemiologic studies have established that cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C and inversely with the level of HDL-C. Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and remnants, can also promote [[atherosclerosis]]. The independent effect of raising HDL-C or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.

Ezetimibe reduces total-C, LDL-C, Apo B, non-HDL-C, and TG, and increases HDL-C in patients with [[hyperlipidemia]]. Administration of Ezetimibe with a [[statin]] is effective in improving serum total-C, LDL-C, Apo B, non-HDL-C, TG, and HDL-C beyond either treatment alone. Administration of Ezetimibe with [[fenofibrate]] is effective in improving serum total-C, LDL-C, Apo B, and non-HDL-C in patients with mixed [[hyperlipidemia]] as compared to either treatment alone. The effects of ezetimibe given either alone or in addition to a [[statin]] or [[fenofibrate]] on cardiovascular morbidity and mortality have not been established.
|clinicalStudies====Primary [[hyperlipidemia]]===

Ezetimibe reduces total-C, LDL-C, Apo B, non-HDL-C, and TG, and increases HDL-C in patients with [[hyperlipidemia]]. Maximal to near maximal response is generally achieved within 2 weeks and maintained during chronic therapy.

====Monotherapy====

In two multicenter, double-blind, placebo-controlled, 12-week studies in 1719 patients with primary [[hyperlipidemia]], Ezetimibe significantly lowered total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to placebo (Table 6). Reduction in LDL-C was consistent across age, sex, and baseline LDL-C.
[[File:Zetia07.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

====Combination with [[statins]]====

=====Ezetimibe Added to On-going Statin Therapy=====

In a multicenter, double-blind, placebo-controlled, 8-week study, 769 patients with primary [[hyperlipidemia]], known coronary heart disease or multiple cardiovascular risk factors who were already receiving statin monotherapy, but who had not met their NCEP ATP II target LDL-C goal were randomized to receive either Ezetimibe or placebo in addition to their on-going statin.

Ezetimibe, added to on-going statin therapy, significantly lowered total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared with a statin administered alone (see Table 7). LDL-C reductions induced by Ezetimibe were generally consistent across all [[statins]].
[[File:Zetia08.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

=====Ezetimibe Initiated Concurrently with a Statin=====

In four multicenter, double-blind, placebo-controlled, 12-week trials, in 2382 hyperlipidemic patients, Ezetimibe or placebo was administered alone or with various doses of [[atorvastatin]],[[simvastatin]], [[pravastatin]], or [[lovastatin]].

When all patients receiving Ezetimibe with a statin were compared to all those receiving the corresponding statin alone, Ezetimibe significantly lowered total-C, LDL-C, Apo B, non-HDL-C, and TG, and, with the exception of pravastatin, increased HDL-C compared to the [[statin]] administered alone. LDL-C reductions induced by Ezetimibe were generally consistent across all [[statins]].
[[File:Zetia09.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]
[[File:Zetia10.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]
[[File:Zetia11.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]
[[File:Zetia12.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

====Combination with [[fenofibrate]]====

In a multicenter, double-blind, placebo-controlled, clinical study in patients with mixed [[hyperlipidemia]], 625 patients were treated for up to 12 weeks and 576 for up to an additional 48 weeks. Patients were randomized to receive placebo, Ezetimibe alone, 160-mg [[fenofibrate]] alone, or Ezetimibe and 160-mg [[fenofibrate]] in the 12-week study. After completing the 12-week study, eligible patients were assigned to Ezetimibe coadministered with [[fenofibrate]] or [[fenofibrate]] monotherapy for an additional 48 weeks.

Ezetimibe coadministered with [[fenofibrate]] significantly lowered total-C, LDL-C, Apo B, and non-HDL-C compared to [[fenofibrate]] administered alone. The percent decrease in TG and percent increase in HDL-C for Ezetimibe coadministered with [[fenofibrate]] were comparable to those for [[fenofibrate]] administered alone (see Table 12).
[[File:Zetia13.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

The changes in lipid endpoints after an additional 48 weeks of treatment with Ezetimibe coadministered with [[fenofibrate]] or with [[fenofibrate]] alone were consistent with the 12-week data displayed above.

===Homozygous Familial Hypercholesterolemia (HoFH)===

A study was conducted to assess the efficacy of Ezetimibe in the treatment of HoFH. This double-blind, randomized, 12-week study enrolled 50 patients with a clinical and/or genotypic diagnosis of HoFH, with or without concomitant LDL apheresis, already receiving atorvastatin or simvastatin (40 mg). Patients were randomized to one of three treatment groups, atorvastatin or simvastatin (80 mg), Ezetimibe administered with atorvastatin or simvastatin (40 mg), or Ezetimibe administered with atorvastatin or simvastatin (80 mg). Due to decreased bioavailability of ezetimibe in patients concomitantly receiving cholestyramine, ezetimibe was dosed at least 4 hours before or after administration of resins. Mean baseline LDL-C was 341 mg/dL in those patients randomized to atorvastatin 80 mg or simvastatin 80 mg alone and 316 mg/dL in the group randomized to Ezetimibe plus atorvastatin 40 or 80 mg or simvastatin 40 or 80 mg. Ezetimibe, administered with atorvastatin or simvastatin (40- and 80-mg statin groups, pooled), significantly reduced LDL-C (21%) compared with increasing the dose of simvastatin or atorvastatin monotherapy from 40 to 80 mg (7%). In those treated with Ezetimibe plus 80-mg atorvastatin or with Ezetimibe plus 80-mg simvastatin, LDL-C was reduced by 27%.

===Homozygous Sitosterolemia (Phytosterolemia)===

A study was conducted to assess the efficacy of Ezetimibe in the treatment of homozygous sitosterolemia. In this multicenter, double-blind, placebo-controlled, 8-week trial, 37 patients with homozygous [[sitosterolemia]] with elevated plasma sitosterol levels (more than 5 mg/dL) on their current therapeutic regimen (diet, bile-acid-binding resins, [[statins]], ileal bypass surgery and/or LDL apheresis), were randomized to receive Ezetimibe (n=30) or placebo (n=7). Due to decreased bioavailability of ezetimibe in patients concomitantly receiving [[cholestyramine]], ezetimibe was dosed at least 2 hours before or 4 hours after resins were administered. Excluding the one subject receiving LDL apheresis, Ezetimibe significantly lowered plasma [[sitosterol]] and [[campesterol]], by 21% and 24% from baseline, respectively. In contrast, patients who received placebo had increases in [[sitosterol]] and [[campesterol ]]of 4% and 3% from baseline, respectively. For patients treated with Ezetimibe, mean plasma levels of plant sterols were reduced progressively over the course of the study. The effects of reducing plasma [[sitosterol]] and [[campesterol ]]on reducing the risks of cardiovascular morbidity and mortality have not been established.

Reductions in [[sitosterol ]]and [[campesterol]]were consistent between patients taking Ezetimibe concomitantly with bile acid sequestrants (n=8) and patients not on concomitant bile acid sequestrant therapy (n=21).

====Limitations of Use====

The effect of Ezetimibe on cardiovascular morbidity and mortality has not been determined.
|howSupplied=No. 3861 — Tablets Ezetimibe, 10 mg, are white to off-white, capsule-shaped tablets debossed with "414" on one side. They are supplied as follows:
NDC 66582-414-31 bottles of 30 NDC 66582-414-54 bottles of 90 NDC 66582-414-74 bottles of 500 NDC 66582-414-76 bottles of 5000 NDC 66582-414-28 unit dose packages of 100.
|storage=Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F). [USP Controlled Room Temperature.] Protect from moisture.
|fdaPatientInfo=See FDA-Approved Patient Labeling (Patient Information).

Patients should be advised to adhere to their National Cholesterol Education Program (NCEP)-recommended diet, a regular exercise program, and periodic testing of a fasting lipid panel.

===Muscle Pain===

All patients starting therapy with ezetimibe should be advised of the risk of [[myopathy ]]and told to report promptly any unexplained muscle pain, tenderness or weakness. The risk of this occurring is increased when taking certain types of medication. Patients should discuss all medication, both prescription and over-the-counter, with their physician.

===Liver Enzymes===

Liver tests should be performed when Ezetimibe is added to [[statin]] therapy and according to [[statin]] recommendations.

===Pregnancy===

Women of childbearing age should be advised to use an effective method of birth control to prevent pregnancy while using Ezetimibe added to [[statin]] therapy. Discuss future pregnancy plans with your patients, and discuss when to stop combination Ezetimibe and [[statin]] therapy if they are trying to conceive. Patients should be advised that if they become pregnant they should stop taking combination Ezetimibe and [[statin]] therapy and call their healthcare professional.

===Breastfeeding===

Women who are breastfeeding should be advised to not use Ezetimibe added to [[statin]] therapy. Patients who have a lipid disorder and are breastfeeding should be advised to discuss the options with their healthcare professionals.
|alcohol=Alcohol-Ezetimibe interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|lookAlike=Ezetimibe - Zebeta
Ezetimibe - Zestril<ref name="www.ismp.org">{{Cite web | last = | first = | title =https://www.ismp.org | url = https://www.ismp.org | publisher = | date = | accessdate = }}</ref>
}}
{{PillImage
|fileName=Ezetimibe_10 mg_NDC 66582-414.jpg
|drugName=Ezetimibe
|NDC=66582-414
|drugAuthor=Merck Sharp & Dohme Corp.
|ingredients=croscarmellose sodium, lactose monohydrate, magnesium stearate, cellulose, microcrystalline, povidones, sodium lauryl sulfate
|pillImprint=414
|dosageValue=10
|dosageUnit=mg
|pillColor=White
|pillShape=Oval
|pillSize=8.00
|pillScore=1
}}
{{LabelImage
|fileName=Ezetimibe label 01.jpg
}}
{{LabelImage
|fileName=Ezetimibe panel 01.png
}}
{{LabelImage
|fileName=Ezetimibe panel 02.png
}}

[[Category:Drug]]
[[Category:Cardiovascular Drugs]]
[[Category:Hypolipidemic agents]]

Ezetimibe

2015-03-18T16:20:03Z

Sree Teja Yelamanchili:

{{DrugProjectFormSinglePage
|authorTag={{SS}}; {{STY}}
|genericName=ezetimibe
|aOrAn=a
|drugClass=dietary [[cholesterol absorption inhibitor]]
|indicationType=treatment
|indication=[[hyperlipidemia|primary hyperlipidemia]], [[homozygous familial hypercholesterolemia]] (HoFH), homozygous sitosterolemia.
|adverseReactions=[[diarrhea]], [[arthralgia]], [[myalgia]], [[nasopharyngitis]], [[sinusitis]], [[upper respiratory infection]].
|blackBoxWarningTitle=<b><span style="color:#FF0000;">TITLE</span></b>
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)
|fdaLIADAdult=<h4>General Dosing Information</h4>

* Recommended dosage: '''10 mg PO qd'''
:* Ezetimibe can be administered with or without food.

<h4>Concomitant Lipid-Lowering Therapy</h4>

* Dosing information
:* Ezetimibe may be administered with a [[statin]] (in patients with [[Hyperlipidemia|primary hyperlipidemia]]) or with [[fenofibrate]] (in patients with mixed hyperlipidemia) for incremental effect. For convenience, the daily dose of Ezetimibe may be taken at the same time as the statin or fenofibrate, according to the dosing recommendations for the respective medications.

<H4>Coadministration with Bile Acid Sequestrants</H4>

* Dosing information
:* Dosing of Ezetimibe should occur either ≥2 hours before or ≥4 hours after administration of a [[bile acid sequestrant]].

<H4>Patients with Hepatic Impairment</H4>

* Dosing information
:* No dosage adjustment is necessary in patients with mild hepatic impairment.

<H4>Patients with Renal Impairment</H4>

* Dosing information
:* No dosage adjustment is necessary in patients with renal impairment. When given with [[simvastatin]] in patients with moderate to severe renal impairment (estimated [[glomerular filtration rate]] <60 mL/min/1.73 m2), doses of simvastatin exceeding 20 mg should be used with caution and close monitoring.

<h4>Geriatric Patients</h4>

* Dosing information
:* No dosage adjustment is necessary in geriatric patients.
|offLabelAdultGuideSupport=There is limited information about <i>Off-Label Guideline-Supported Use</i> of Ezetimibe in adult patients.
|offLabelAdultNoGuideSupport=There is limited information about <i>Off-Label Non–Guideline-Supported Use</i> of Ezetimibe in adult patients.
|fdaLIADPed=FDA Package Insert for Ezetimibe contains no information regarding Pediatric Indications and Dosage.
|offLabelPedGuideSupport=There is limited information about <i>Off-Label Guideline-Supported Use</i> of Ezetimibe in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information about <i>Off-Label Non–Guideline-Supported Use</i> of Ezetimibe in pediatric patients.
|contraindications=Ezetimibe is contraindicated in the following conditions:

*The combination of Ezetimibe with a statin is contraindicated in patients with active liver disease or unexplained persistent elevations in hepatic [[transaminase]] levels.
*Women who are pregnant or may become pregnant because [[statins]] decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, Ezetimibe in combination with a statin may cause fetal harm when administered to pregnant women.
*Additionally, there is no apparent benefit to therapy during pregnancy, and safety in pregnant women has not been established.
*If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus and the lack of known clinical benefit with continued use during pregnancy.
*Nursing mothers-Because [[statins]] may pass into breast milk, and because [[statins]] have the potential to cause serious adverse reactions in nursing infants, women who require Ezetimibe treatment in combination with a statin should be advised not to nurse their infants.
*Patients with a known [[hypersensitivity]] to any component of this product. [[hypersensitivity]] reactions including [[anaphylaxis]], [[angioedema]], [[rash]] and [[urticaria]] have been reported with Ezetimibe.
|warnings=====Use with statins or fenofibrate====

Concurrent administration of Ezetimibe with a specific [[statin]] or [[fenofibrate]] should be in accordance with the product labeling for that medication.

====Liver Enzymes====

*In controlled clinical monotherapy studies, the incidence of consecutive elevations (≥3 × the upper limit of normal [ULN]) in hepatic transaminase levels was similar between Ezetimibe (0.5%) and placebo (0.3%).
*In controlled clinical combination studies of Ezetimibe initiated concurrently with a [[statin]], the incidence of consecutive elevations (≥3 × ULN) in hepatic transaminase levels was 1.3% for patients treated with Ezetimibe administered with [[statins]] and 0.4% for patients treated with [[statins]] alone.
*These elevations in [[transaminases]] were generally asymptomatic, not associated with [[cholestasis]], and returned to baseline after discontinuation of therapy or with continued treatment.
*When Ezetimibe is coadministered with a [[statin]], liver tests should be performed at initiation of therapy and according to the recommendations of the [[statin]].
*Should an increase in ALT or AST ≥3 × ULN persist, consider withdrawal of Ezetimibe and/or the [[statin]].

===Myopathy/Rhabdomyolysis===

*In clinical trials, there was no excess of [[myopathy]] or [[rhabdomyolysis]] associated with Ezetimibe compared with the relevant control arm (placebo or statin alone).
*However, myopathy and rhabdomyolysis are known adverse reactions to statins and other lipid-lowering drugs.
*In clinical trials, the incidence of [[creatine phosphokinase]] (CPK) >10 × ULN was 0.2% for Ezetimibe vs. 0.1% for placebo, and 0.1% for Ezetimibe coadministered with a [[statin]] vs. 0.4% for [[statins]] alone.
*Risk for skeletal muscle toxicity increases with higher doses of statin, advanced age (>65), [[hypothyroidism]], [[renal impairment]], and depending on the statin used, concomitant use of other drugs.
*In post-marketing experience with Ezetimibe, cases of [[myopathy]] and [[rhabdomyolysis]] have been reported.
*Most patients who developed [[rhabdomyolysis]] were taking a [[statin]] prior to initiating Ezetimibe.
*However, [[rhabdomyolysis]] has been reported with Ezetimibe monotherapy and with the addition of Ezetimibe to agents known to be associated with increased risk of [[rhabdomyolysis]], such as fibrates.
*Ezetimibe and any statin or fibrate that the patient is taking concomitantly should be immediately discontinued if [[myopathy]] is diagnosed or suspected.
*The presence of muscle symptoms and a CPK level >10 × the ULN indicates myopathy.

===Hepatic Impairment===

Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate to severe [[hepatic impairment]], Ezetimibe is not recommended in these patients.
|clinicalTrials=The following serious adverse reactions are discussed in greater detail in other sections of the label:

*[[Liver enzyme]] abnormalities
*[[Rhabdomyolysis]] and [[myopathy]]

'''Monotherapy Studies''': In the Ezetimibe controlled clinical trials database (placebo-controlled) of 2396 patients with a median treatment duration of 12 weeks (range 0 to 39 weeks), 3.3% of patients on Ezetimibe and 2.9% of patients on placebo discontinued due to adverse reactions. The most common adverse reactions in the group of patients treated with Ezetimibe that led to treatment discontinuation and occurred at a rate greater than placebo were:

*[[Arthralgia]] (0.3%)
*[[Dizziness]] (0.2%)
*[[Gamma-glutamyltransferase]] increased (0.2%)

The most commonly reported adverse reactions (incidence ≥2% and greater than placebo) in the Ezetimibe monotherapy controlled clinical trial database of 2396 patients were: [[upper respiratory tract infection]] (4.3%), [[diarrhea ]](4.1%), [[arthralgia]] (3.0%), [[sinusitis]] (2.8%), and pain in extremity (2.7%).

'''Statin Coadministration Studies''': In the Ezetimibe + statin controlled clinical trials database of 11,308 patients with a median treatment duration of 8 weeks (range 0 to 112 weeks), 4.0% of patients on Ezetimibe + statin and 3.3% of patients on [[statin]] alone discontinued due to adverse reactions. The most common adverse reactions in the group of patients treated with Ezetimibe + statin that led to treatment discontinuation and occurred at a rate greater than statin alone were:

*[[Alanine aminotransferase]] increased (0.6%)
*[[Myalgia]] (0.5%)
*[[Fatigue]], [[aspartate aminotransferase ]]increased, [[headache]], and pain in extremity (each at 0.2%)

The most commonly reported adverse reactions (incidence ≥2% and greater than statin alone) in the Ezetimibe + statin controlled clinical trial database of 11,308 patients were: [[nasopharyngitis]] (3.7%), [[myalgia]] (3.2%), [[upper respiratory tract infection]] (2.9%), [[arthralgia ]](2.6%) and [[diarrhea]] (2.5%).

===Clinical Trials Experience===

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice.

====Monotherapy====

In 10 double-blind, placebo-controlled clinical trials, 2396 patients with primary [[hyperlipidemia]] (age range 9–86 years, 50% women, 90% Caucasians, 5% Blacks, 3% Hispanics, 2% Asians) and elevated LDL-C were treated with Ezetimibe 10 mg/day for a median treatment duration of 12 weeks (range 0 to 39 weeks).

Adverse reactions reported in ≥2% of patients treated with Ezetimibe and at an incidence greater than placebo in placebo-controlled studies of Ezetimibe, regardless of causality assessment, are shown in Table 1.
[[File:Zetia01.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

====Combination with a statin====

In 28 double-blind, controlled (placebo or active-controlled) clinical trials, 11,308 patients with primary [[hyperlipidemia]] (age range 10–93 years, 48% women, 85% Caucasians, 7% Blacks, 4% Hispanics, 3% Asians) and elevated LDL-C were treated with Ezetimibe 10 mg/day concurrently with or added to on-going [[statin]] therapy for a median treatment duration of 8 weeks (range 0 to 112 weeks).

The incidence of consecutive increased transaminases (≥3 × ULN) was higher in patients receiving Ezetimibe administered with [[statins]] (1.3%) than in patients treated with [[statins]] alone (0.4%).

Clinical adverse reactions reported in ≥2% of patients treated with Ezetimibe + statin and at an incidence greater than [[statin]], regardless of causality assessment, are shown in Table 2.
[[File:Zetia02.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

====Combination with Fenofibrate====

*This clinical study involving 625 patients with mixed dyslipidemia (age range 20–76 years, 44% women, 79% Caucasians, 0.1% Blacks, 11% Hispanics, 5% Asians) treated for up to 12 weeks and 576 patients treated for up to an additional 48 weeks evaluated coadministration of Ezetimibe and [[Fenofibrate]].
*This study was not designed to compare treatment groups for infrequent events.
*Incidence rates (95% CI) for clinically important elevations (≥3 × ULN, consecutive) in hepatic transaminase levels were 4.5% (1.9, 8.8) and 2.7% (1.2, 5.4) for [[Fenofibrate]] monotherapy (n=188) and Ezetimibe coadministered with [[Fenofibrate]] (n=183), respectively, adjusted for treatment exposure.
*Corresponding incidence rates for cholecystectomy were 0.6% (95% CI: 0.0%, 3.1%) and 1.7% (95% CI: 0.6%, 4.0%) for Fenofibrate monotherapy and Ezetimibe coadministered with [[Fenofibrate]], respectively.
*The numbers of patients exposed to coadministration therapy as well as [[Fenofibrate]] and ezetimibe monotherapy were inadequate to assess gallbladder disease risk.
*There were no CPK elevations >10 × ULN in any of the treatment groups.
|postmarketing=Because the reactions below are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following additional adverse reactions have been identified during post-approval use of Ezetimibe:

[[Hypersensitivity]] reactions, including [[anaphylaxis]], [[angioedema]], [[rash]], and [[urticaria]]; [[erythema multiforme]]; [[arthralgia]]; [[myalgia]]; elevated [[creatine phosphokinase]]; [[myopathy]]/[[Rhabdomyolysis]]; [[elevated liver transaminases|elevations in liver transaminases]]; [[hepatitis]]; [[abdominal pain]]; [[thrombocytopenia]]; [[pancreatitis]]; [[nausea]]; [[dizziness]]; [[paresthesia]]; [[depression]]; [[headache]]; [[cholelithiasis]]; [[cholecystitis]].
|drugInteractions=====Cyclosporine====

Caution should be exercised when using Ezetimibe and [[cyclosporine]] concomitantly due to increased exposure to both ezetimibe and [[cyclosporine]]. Cyclosporine concentrations should be monitored in patients receiving Ezetimibe and [[cyclosporine]].

The degree of increase in ezetimibe exposure may be greater in patients with severe [[renal insufficiency]]. In patients treated with [[cyclosporine]], the potential effects of the increased exposure to ezetimibe from concomitant use should be carefully weighed against the benefits of alterations in lipid levels provided by ezetimibe.

===Fibrates===

The efficacy and safety of coadministration of ezetimibe with [[fibrates]] other than [[fenofibrate]] have not been studied.

[[Fibrates]] may increase cholesterol excretion into the bile, leading to cholelithiasis. In a preclinical study in dogs, ezetimibe increased cholesterol in the gallbladder bile. Coadministration of Ezetimibe with [[Fibrates]] other than [[fenofibrate]] is not recommended until use in patients is adequately studied.

===Fenofibrate===

If cholelithiasis is suspected in a patient receiving Ezetimibe and [[fenofibrate]], gallbladder studies are indicated and alternative lipid-lowering therapy should be considered and the product labeling for [[fenofibrate]].

===Cholestyramine===

Concomitant [[cholestyramine ]]administration decreased the mean area under the curve (AUC) of total ezetimibe approximately 55%. The incremental LDL-C reduction due to adding ezetimibe to cholestyramine may be reduced by this interaction.

===Coumarin Anticoagulants===

If ezetimibe is added to [[warfarin]], a coumarin [[anticoagulant]], the [[International Normalized Ratio ]]([[INR]]) should be appropriately monitored.
|FDAPregCat=C
|useInPregnancyFDA=There are no adequate and well-controlled studies of ezetimibe in pregnant women. Ezetimibe should be used during pregnancy only if the potential benefit justifies the risk to the fetus.

In oral (gavage) embryo-fetal development studies of ezetimibe conducted in rats and rabbits during organogenesis, there was no evidence of embryolethal effects at the doses tested (250, 500, 1000 mg/kg/day). In rats, increased incidences of common fetal skeletal findings (extra pair of thoracic ribs, unossified cervical vertebral centra, shortened ribs) were observed at 1000 mg/kg/day (~10 × the human exposure at 10 mg daily based on AUC0–24hr for total ezetimibe). In rabbits treated with ezetimibe, an increased incidence of extra thoracic ribs was observed at 1000 mg/kg/day (150 × the human exposure at 10 mg daily based on AUC0–24hr for total ezetimibe). Ezetimibe crossed the placenta when pregnant rats and rabbits were given multiple oral doses.

Multiple-dose studies of ezetimibe given in combination with [[statins]] in rats and rabbits during organogenesis result in higher ezetimibe and statin exposures. Reproductive findings occur at lower doses in combination therapy compared to monotherapy.

All [[statins]] are contraindicated in pregnant and nursing women. When Ezetimibe is administered with a statin in a woman of childbearing potential, refer to the pregnancy category and product labeling for the statin.
|useInNursing=It is not known whether ezetimibe is excreted into human breast milk. In rat studies, exposure to total ezetimibe in nursing pups was up to half of that observed in maternal plasma. Because many drugs are excreted in human milk, caution should be exercised when Ezetimibe is administered to a nursing woman. Ezetimibe should not be used in nursing mothers unless the potential benefit justifies the potential risk to the infant.
|useInPed=The effects of Ezetimibe coadministered with [[simvastatin]] (n=126) compared to [[simvastatin]] monotherapy (n=122) have been evaluated in adolescent boys and girls with [[heterozygous familial hypercholesterolemia]] (HeFH). In a multicenter, double-blind, controlled study followed by an open-label phase, 142 boys and 106 postmenarchal girls, 10 to 17 years of age (mean age 14.2 years, 43% females, 82% Caucasians, 4% Asian, 2% Blacks, 13% multi-racial) with HeFH were randomized to receive either Ezetimibe coadministered with [[simvastatin]] or [[simvastatin]] monotherapy. Inclusion in the study required 1) a baseline LDL-C level between 160 and 400 mg/dL and 2) a medical history and clinical presentation consistent with HeFH. The mean baseline LDL-C value was 225 mg/dL (range: 161–351 mg/dL) in the Ezetimibe coadministered with [[simvastatin]] group compared to 219 mg/dL (range: 149–336 mg/dL) in the [[simvastatin]] monotherapy group. The patients received coadministered Ezetimibe and [[simvastatin]] (10 mg, 20 mg, or 40 mg) or [[simvastatin]] monotherapy (10 mg, 20 mg, or 40 mg) for 6 weeks, coadministered Ezetimibe and 40-mg [[simvastatin]] or 40-mg [[simvastatin]] monotherapy for the next 27 weeks, and open-label coadministered Ezetimibe and [[simvastatin]] (10 mg, 20 mg, or 40 mg) for 20 weeks thereafter.

The results of the study at Week 6 are summarized in Table 3. Results at Week 33 were consistent with those at Week 6.
[[File:Zetia03.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

From the start of the trial to the end of Week 33, discontinuations due to an adverse reaction occurred in 7 (6%) patients in the Ezetimibe coadministered with simvastatin group and in 2 (2%) patients in the [[simvastatin]] monotherapy group.

During the trial, hepatic transaminase elevations (two consecutive measurements for ALT and/or AST ≥3 × ULN) occurred in four (3%) individuals in the Ezetimibe coadministered with [[simvastatin]] group and in two (2%) individuals in the [[simvastatin]] monotherapy group. Elevations of CPK (≥10 × ULN) occurred in two (2%) individuals in the Ezetimibe coadministered with [[simvastatin]] group and in zero individuals in the [[simvastatin]] monotherapy group.

In this limited controlled study, there was no significant effect on growth or sexual maturation in the adolescent boys or girls, or on menstrual cycle length in girls.

Coadministration of Ezetimibe with [[simvastatin]] at doses greater than 40 mg/day has not been studied in adolescents. Also, Ezetimibe has not been studied in patients younger than 10 years of age or in pre-menarchal girls.

Based on total ezetimibe (ezetimibe + ezetimibe-glucuronide), there are no pharmacokinetic differences between adolescents and adults. Pharmacokinetic data in the pediatric population less than 10 years of age are not available.
|useInGeri=====Monotherapy Studies====

Of the 2396 patients who received Ezetimibe in clinical studies, 669 (28%) were 65 and older, and 111 (5%) were 75 and older.

====Statin Coadministration Studies====

Of the 11,308 patients who received Ezetimibe + [[statin]] in clinical studies, 3587 (32%) were 65 and older, and 924 (8%) were 75 and older.

No overall differences in safety and effectiveness were observed between these patients and younger patients, 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.
|useInRenalImpair=When used as monotherapy, no dosage adjustment of Ezetimibe is necessary.

In the Study of Heart and Renal Protection (SHARP) trial of 9270 patients with moderate to severe renal impairment (6247 non-dialysis patients with median serum creatinine 2.5 mg/dL and median estimated glomerular filtration rate 25.6 mL/min/1.73 m2, and 3023 dialysis patients), the incidence of serious adverse events, adverse events leading to discontinuation of study treatment, or adverse events of special interest (musculoskeletal adverse events, liver enzyme abnormalities, incident cancer) was similar between patients ever assigned to ezetimibe 10 mg plus [[simvastatin]] 20 mg (n=4650) or placebo (n=4620) during a median follow-up of 4.9 years. However, because renal impairment is a risk factor for statin-associated myopathy, doses of [[simvastatin]] exceeding 20 mg should be used with caution and close monitoring when administered concomitantly with Ezetimibe in patients with moderate to severe renal impairment.
|useInHepaticImpair=Ezetimibe is not recommended in patients with moderate to severe [[hepatic impairment]].

Ezetimibe given concomitantly with a statin is contraindicated in patients with active liver disease or unexplained persistent elevations of hepatic transaminase levels.
|administration=Oral
|monitoring=FDA Package Insert for ezetimibe contains no information regarding drug monitoring.
|IVCompat=FDA Package Insert for ezetimibe contains no information regarding IV Compatibility.
|overdose=In clinical studies, administration of ezetimibe, 50 mg/day to 15 healthy subjects for up to 14 days, 40 mg/day to 18 patients with primary [[hyperlipidemia]] for up to 56 days, and 40 mg/day to 27 patients with homozygous sitosterolemia for 26 weeks was generally well tolerated. One female patient with [[homozygous sitosterolemia ]]took an accidental overdose of ezetimibe 120 mg/day for 28 days with no reported clinical or laboratory adverse events.

In the event of an overdose, symptomatic and supportive measures should be employed.
|drugBox={{Drugbox2
| Watchedfields = changed
| verifiedrevid = 461098524
| IUPAC_name = (3''R'',4''S'')-1-(4-fluorophenyl)-3-[(3''S'')-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one
| image = Ezetimibe.png
| width = 200


| tradename = Ezetimibe
| Drugs.com = {{drugs.com|monograph|ezetimibe}}
| MedlinePlus = a603015
| pregnancy_AU = C
| pregnancy_US = C
| legal_AU = S4
| legal_CA = Rx-only
| legal_UK = POM
| legal_US = Rx-only
| routes_of_administration = Oral


| bioavailability = 35–65%
| protein_bound = >90%
| metabolism = Intestinal wall, hepatic
| elimination_half-life = 19–30 hours
| excretion = Renal 11%, faecal 78%


| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 163222-33-1
| ATC_prefix = C10
| ATC_suffix = AX09
| PubChem = 150311
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00973
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 132493
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = EOR26LQQ24
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D01966
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 49040
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1138


| C=24 | H=21 | F=2 | N=1 | O=3
| molecular_weight = 409.4 g·mol<sup>−1</sup>
| smiles = Fc1ccc(cc1)[C@@H](O)CC[C@H]4C(=O)N(c2ccc(F)cc2)[C@@H]4c3ccc(O)cc3
| InChI = 1/C24H21F2NO3/c25-17-5-1-15(2-6-17)22(29)14-13-21-23(16-3-11-20(28)12-4-16)27(24(21)30)19-9-7-18(26)8-10-19/h1-12,21-23,28-29H,13-14H2/t21-,22+,23-/m1/s1
| InChIKey = OLNTVTPDXPETLC-XPWALMASBY
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C24H21F2NO3/c25-17-5-1-15(2-6-17)22(29)14-13-21-23(16-3-11-20(28)12-4-16)27(24(21)30)19-9-7-18(26)8-10-19/h1-12,21-23,28-29H,13-14H2/t21-,22+,23-/m1/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = OLNTVTPDXPETLC-XPWALMASSA-N
| melting_point = 164
| melting_high = 166
}}
|mechAction=Ezetimibe reduces blood cholesterol by inhibiting the absorption of cholesterol by the small intestine. In a 2-week clinical study in 18 hypercholesterolemic patients, Ezetimibe inhibited intestinal cholesterol absorption by 54%, compared with placebo. Ezetimibe had no clinically meaningful effect on the plasma concentrations of the fat-soluble vitamins A, D, and E (in a study of 113 patients), and did not impair adrenocortical steroid hormone production (in a study of 118 patients).
The cholesterol content of the liver is derived predominantly from three sources. The liver can synthesize cholesterol, take up cholesterol from the blood from circulating lipoproteins, or take up cholesterol absorbed by the small intestine. Intestinal cholesterol is derived primarily from cholesterol secreted in the bile and from dietary cholesterol.
Ezetimibe has a mechanism of action that differs from those of other classes of cholesterol-reducing compounds (statins, bile acid sequestrants [resins], fibric acid derivatives, and plant stanols). The molecular target of ezetimibe has been shown to be the sterol transporter, Niemann-Pick C1-Like 1 (NPC1L1), which is involved in the intestinal uptake of cholesterol and phytosterols.
Ezetimibe does not inhibit cholesterol synthesis in the liver, or increase bile acid excretion. Instead, ezetimibe localizes at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood; this distinct mechanism is complementary to that of statins and of fenofibrate.
|structure=Ezetimibe (ezetimibe) is in a class of lipid-lowering compounds that selectively inhibits the intestinal absorption of cholesterol and related phytosterols. The chemical name of ezetimibe is 1-(4-fluorophenyl)-3(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphenyl)-2-azetidinone. The empirical formula is C24H21F2NO3. Its molecular weight is 409.4 and its structural formula is:
[[File:Zetia04.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

Ezetimibe is a white, crystalline powder that is freely to very soluble in ethanol, methanol, and acetone and practically insoluble in water. Ezetimibe has a melting point of about 163°C and is stable at ambient temperature. Ezetimibe is available as a tablet for oral administration containing 10 mg of ezetimibe and the following inactive ingredients: croscarmellose sodium NF, lactose monohydrate NF, magnesium stearate NF, microcrystalline cellulose NF, povidone USP, and sodium lauryl sulfate NF.
|PD=Clinical studies have demonstrated that elevated levels of total-C, LDL-C and Apo B, the major protein constituent of LDL, promote human [[atherosclerosis]]. In addition, decreased levels of HDL-C are associated with the development of [[atherosclerosis]]. Epidemiologic studies have established that cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C and inversely with the level of HDL-C. Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and remnants, can also promote [[atherosclerosis]]. The independent effect of raising HDL-C or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.

Ezetimibe reduces total-C, LDL-C, Apo B, non-HDL-C, and TG, and increases HDL-C in patients with [[hyperlipidemia]]. Administration of Ezetimibe with a [[statin]] is effective in improving serum total-C, LDL-C, Apo B, non-HDL-C, TG, and HDL-C beyond either treatment alone. Administration of Ezetimibe with [[fenofibrate]] is effective in improving serum total-C, LDL-C, Apo B, and non-HDL-C in patients with mixed [[hyperlipidemia]] as compared to either treatment alone. The effects of ezetimibe given either alone or in addition to a [[statin]] or [[fenofibrate]] on cardiovascular morbidity and mortality have not been established.
|PK=====Absorption====
After oral administration, ezetimibe is absorbed and extensively conjugated to a pharmacologically active phenolic glucuronide (ezetimibe-glucuronide). After a single 10-mg dose of Ezetimibe to fasted adults, mean ezetimibe peak plasma concentrations (Cmax) of 3.4 to 5.5 ng/mL were attained within 4 to 12 hours (Tmax). Ezetimibe-glucuronide mean Cmax values of 45 to 71 ng/mL were achieved between 1 and 2 hours (Tmax). There was no substantial deviation from dose proportionality between 5 and 20 mg. The absolute bioavailability of ezetimibe cannot be determined, as the compound is virtually insoluble in aqueous media suitable for injection.

====Effect of Food on Oral Absorption====

Concomitant food administration (high-fat or non-fat meals) had no effect on the extent of absorption of ezetimibe when administered as Ezetimibe 10-mg tablets. The Cmaxvalue of ezetimibe was increased by 38% with consumption of high-fat meals. Ezetimibe can be administered with or without food.

====Distribution====

Ezetimibe and ezetimibe-glucuronide are highly bound (>90%) to human plasma proteins.

====Metabolism and Excretion====

Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide conjugation (a phase II reaction) with subsequent biliary and renal excretion. Minimal oxidative metabolism (a phase I reaction) has been observed in all species evaluated.

In humans, ezetimibe is rapidly metabolized to ezetimibe-glucuronide. Ezetimibe and ezetimibe-glucuronide are the major drug-derived compounds detected in plasma, constituting approximately 10 to 20% and 80 to 90% of the total drug in plasma, respectively. Both ezetimibe and ezetimibe-glucuronide are eliminated from plasma with a half-life of approximately 22 hours for both ezetimibe and ezetimibe-glucuronide. Plasma concentration-time profiles exhibit multiple peaks, suggesting enterohepatic recycling.

Following oral administration of 14C-ezetimibe (20 mg) to human subjects, total ezetimibe (ezetimibe + ezetimibe-glucuronide) accounted for approximately 93% of the total radioactivity in plasma. After 48 hours, there were no detectable levels of radioactivity in the plasma.

Approximately 78% and 11% of the administered radioactivity were recovered in the feces and urine, respectively, over a 10-day collection period. Ezetimibe was the major component in feces and accounted for 69% of the administered dose, while ezetimibe-glucuronide was the major component in urine and accounted for 9% of the administered dose.

====Specific Populations====

'''Geriatric Patients''': In a multiple-dose study with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were about 2-fold higher in older (≥65 years) healthy subjects compared to younger subjects.

'''Pediatric Patients''':

'''Gender''': In a multiple-dose study with ezetimibe given 10 mg once daily for 10 days, plasma concentrations for total ezetimibe were slightly higher (less than 20%) in women than in men.

'''Race''': Based on a meta-analysis of multiple-dose pharmacokinetic studies, there were no pharmacokinetic differences between Black and Caucasian subjects. Studies in Asian subjects indicated that the pharmacokinetics of ezetimibe were similar to those seen in Caucasian subjects.

'''Hepatic Impairment''': After a single 10-mg dose of ezetimibe, the mean AUC for total ezetimibe was increased approximately 1.7-fold in patients with mild [[hepatic impairment]] (Child-Pugh score 5 to 6), compared to healthy subjects. The mean AUC values for total ezetimibe and ezetimibe were increased approximately 3- to 4-fold and 5- to 6-fold, respectively, in patients with moderate (Child-Pugh score 7 to 9) or severe [[hepatic impairment]] (Child-Pugh score 10 to 15). In a 14-day, multiple-dose study (10 mg daily) in patients with moderate [[hepatic impairment]], the mean AUC values for total ezetimibe and ezetimibe were increased approximately 4-fold on Day 1 and Day 14 compared to healthy subjects. Due to the unknown effects of the increased exposure to ezetimibe in patients with moderate or severe [[hepatic impairment]], Ezetimibe is not recommended in these patients.

'''Renal Impairment''': After a single 10-mg dose of ezetimibe in patients with severe [[renal disease ]](n=8; mean CrCl ≤30 mL/min/1.73 m2), the mean AUC values for total ezetimibe, ezetimibe-glucuronide, and ezetimibe were increased approximately 1.5-fold, compared to healthy subjects (n=9).
|nonClinToxic=Clinical studies have demonstrated that elevated levels of total-C, LDL-C and Apo B, the major protein constituent of LDL, promote human [[atherosclerosis]]. In addition, decreased levels of HDL-C are associated with the development of [[atherosclerosis]]. Epidemiologic studies have established that cardiovascular morbidity and mortality vary directly with the level of total-C and LDL-C and inversely with the level of HDL-C. Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and remnants, can also promote [[atherosclerosis]]. The independent effect of raising HDL-C or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined.

Ezetimibe reduces total-C, LDL-C, Apo B, non-HDL-C, and TG, and increases HDL-C in patients with [[hyperlipidemia]]. Administration of Ezetimibe with a [[statin]] is effective in improving serum total-C, LDL-C, Apo B, non-HDL-C, TG, and HDL-C beyond either treatment alone. Administration of Ezetimibe with [[fenofibrate]] is effective in improving serum total-C, LDL-C, Apo B, and non-HDL-C in patients with mixed [[hyperlipidemia]] as compared to either treatment alone. The effects of ezetimibe given either alone or in addition to a [[statin]] or [[fenofibrate]] on cardiovascular morbidity and mortality have not been established.
|clinicalStudies====Primary [[hyperlipidemia]]===

Ezetimibe reduces total-C, LDL-C, Apo B, non-HDL-C, and TG, and increases HDL-C in patients with [[hyperlipidemia]]. Maximal to near maximal response is generally achieved within 2 weeks and maintained during chronic therapy.

====Monotherapy====

In two multicenter, double-blind, placebo-controlled, 12-week studies in 1719 patients with primary [[hyperlipidemia]], Ezetimibe significantly lowered total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared to placebo (Table 6). Reduction in LDL-C was consistent across age, sex, and baseline LDL-C.
[[File:Zetia07.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

====Combination with [[statins]]====

=====Ezetimibe Added to On-going Statin Therapy=====

In a multicenter, double-blind, placebo-controlled, 8-week study, 769 patients with primary [[hyperlipidemia]], known coronary heart disease or multiple cardiovascular risk factors who were already receiving statin monotherapy, but who had not met their NCEP ATP II target LDL-C goal were randomized to receive either Ezetimibe or placebo in addition to their on-going statin.

Ezetimibe, added to on-going statin therapy, significantly lowered total-C, LDL-C, Apo B, non-HDL-C, and TG, and increased HDL-C compared with a statin administered alone (see Table 7). LDL-C reductions induced by Ezetimibe were generally consistent across all [[statins]].
[[File:Zetia08.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

=====Ezetimibe Initiated Concurrently with a Statin=====

In four multicenter, double-blind, placebo-controlled, 12-week trials, in 2382 hyperlipidemic patients, Ezetimibe or placebo was administered alone or with various doses of [[atorvastatin]],[[simvastatin]], [[pravastatin]], or [[lovastatin]].

When all patients receiving Ezetimibe with a statin were compared to all those receiving the corresponding statin alone, Ezetimibe significantly lowered total-C, LDL-C, Apo B, non-HDL-C, and TG, and, with the exception of pravastatin, increased HDL-C compared to the [[statin]] administered alone. LDL-C reductions induced by Ezetimibe were generally consistent across all [[statins]].
[[File:Zetia09.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]
[[File:Zetia10.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]
[[File:Zetia11.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]
[[File:Zetia12.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

====Combination with [[fenofibrate]]====

In a multicenter, double-blind, placebo-controlled, clinical study in patients with mixed [[hyperlipidemia]], 625 patients were treated for up to 12 weeks and 576 for up to an additional 48 weeks. Patients were randomized to receive placebo, Ezetimibe alone, 160-mg [[fenofibrate]] alone, or Ezetimibe and 160-mg [[fenofibrate]] in the 12-week study. After completing the 12-week study, eligible patients were assigned to Ezetimibe coadministered with [[fenofibrate]] or [[fenofibrate]] monotherapy for an additional 48 weeks.

Ezetimibe coadministered with [[fenofibrate]] significantly lowered total-C, LDL-C, Apo B, and non-HDL-C compared to [[fenofibrate]] administered alone. The percent decrease in TG and percent increase in HDL-C for Ezetimibe coadministered with [[fenofibrate]] were comparable to those for [[fenofibrate]] administered alone (see Table 12).
[[File:Zetia13.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

The changes in lipid endpoints after an additional 48 weeks of treatment with Ezetimibe coadministered with [[fenofibrate]] or with [[fenofibrate]] alone were consistent with the 12-week data displayed above.

===Homozygous Familial Hypercholesterolemia (HoFH)===

A study was conducted to assess the efficacy of Ezetimibe in the treatment of HoFH. This double-blind, randomized, 12-week study enrolled 50 patients with a clinical and/or genotypic diagnosis of HoFH, with or without concomitant LDL apheresis, already receiving atorvastatin or simvastatin (40 mg). Patients were randomized to one of three treatment groups, atorvastatin or simvastatin (80 mg), Ezetimibe administered with atorvastatin or simvastatin (40 mg), or Ezetimibe administered with atorvastatin or simvastatin (80 mg). Due to decreased bioavailability of ezetimibe in patients concomitantly receiving cholestyramine, ezetimibe was dosed at least 4 hours before or after administration of resins. Mean baseline LDL-C was 341 mg/dL in those patients randomized to atorvastatin 80 mg or simvastatin 80 mg alone and 316 mg/dL in the group randomized to Ezetimibe plus atorvastatin 40 or 80 mg or simvastatin 40 or 80 mg. Ezetimibe, administered with atorvastatin or simvastatin (40- and 80-mg statin groups, pooled), significantly reduced LDL-C (21%) compared with increasing the dose of simvastatin or atorvastatin monotherapy from 40 to 80 mg (7%). In those treated with Ezetimibe plus 80-mg atorvastatin or with Ezetimibe plus 80-mg simvastatin, LDL-C was reduced by 27%.

===Homozygous Sitosterolemia (Phytosterolemia)===

A study was conducted to assess the efficacy of Ezetimibe in the treatment of homozygous sitosterolemia. In this multicenter, double-blind, placebo-controlled, 8-week trial, 37 patients with homozygous [[sitosterolemia]] with elevated plasma sitosterol levels (more than 5 mg/dL) on their current therapeutic regimen (diet, bile-acid-binding resins, [[statins]], ileal bypass surgery and/or LDL apheresis), were randomized to receive Ezetimibe (n=30) or placebo (n=7). Due to decreased bioavailability of ezetimibe in patients concomitantly receiving [[cholestyramine]], ezetimibe was dosed at least 2 hours before or 4 hours after resins were administered. Excluding the one subject receiving LDL apheresis, Ezetimibe significantly lowered plasma [[sitosterol]] and [[campesterol]], by 21% and 24% from baseline, respectively. In contrast, patients who received placebo had increases in [[sitosterol]] and [[campesterol ]]of 4% and 3% from baseline, respectively. For patients treated with Ezetimibe, mean plasma levels of plant sterols were reduced progressively over the course of the study. The effects of reducing plasma [[sitosterol]] and [[campesterol ]]on reducing the risks of cardiovascular morbidity and mortality have not been established.

Reductions in [[sitosterol ]]and [[campesterol]]were consistent between patients taking Ezetimibe concomitantly with bile acid sequestrants (n=8) and patients not on concomitant bile acid sequestrant therapy (n=21).

====Limitations of Use====

The effect of Ezetimibe on cardiovascular morbidity and mortality has not been determined.
|howSupplied=No. 3861 — Tablets Ezetimibe, 10 mg, are white to off-white, capsule-shaped tablets debossed with "414" on one side. They are supplied as follows:
NDC 66582-414-31 bottles of 30 NDC 66582-414-54 bottles of 90 NDC 66582-414-74 bottles of 500 NDC 66582-414-76 bottles of 5000 NDC 66582-414-28 unit dose packages of 100.
|storage=Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F). [USP Controlled Room Temperature.] Protect from moisture.
|fdaPatientInfo=See FDA-Approved Patient Labeling (Patient Information).

Patients should be advised to adhere to their National Cholesterol Education Program (NCEP)-recommended diet, a regular exercise program, and periodic testing of a fasting lipid panel.

===Muscle Pain===

All patients starting therapy with ezetimibe should be advised of the risk of [[myopathy ]]and told to report promptly any unexplained muscle pain, tenderness or weakness. The risk of this occurring is increased when taking certain types of medication. Patients should discuss all medication, both prescription and over-the-counter, with their physician.

===Liver Enzymes===

Liver tests should be performed when Ezetimibe is added to [[statin]] therapy and according to [[statin]] recommendations.

===Pregnancy===

Women of childbearing age should be advised to use an effective method of birth control to prevent pregnancy while using Ezetimibe added to [[statin]] therapy. Discuss future pregnancy plans with your patients, and discuss when to stop combination Ezetimibe and [[statin]] therapy if they are trying to conceive. Patients should be advised that if they become pregnant they should stop taking combination Ezetimibe and [[statin]] therapy and call their healthcare professional.

===Breastfeeding===

Women who are breastfeeding should be advised to not use Ezetimibe added to [[statin]] therapy. Patients who have a lipid disorder and are breastfeeding should be advised to discuss the options with their healthcare professionals.
|alcohol=Alcohol-Ezetimibe interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|lookAlike=Ezetimibe - Zebeta
Ezetimibe - Zestril<ref name="www.ismp.org">{{Cite web | last = | first = | title =https://www.ismp.org | url = https://www.ismp.org | publisher = | date = | accessdate = }}</ref>
}}
{{PillImage
|fileName=Ezetimibe_10 mg_NDC 66582-414.jpg
|drugName=Ezetimibe
|NDC=66582-414
|drugAuthor=Merck Sharp & Dohme Corp.
|ingredients=croscarmellose sodium, lactose monohydrate, magnesium stearate, cellulose, microcrystalline, povidones, sodium lauryl sulfate
|pillImprint=414
|dosageValue=10
|dosageUnit=mg
|pillColor=White
|pillShape=Oval
|pillSize=8.00
|pillScore=1
}}
{{LabelImage
|fileName=Ezetimibe label 01.jpg
}}
{{LabelImage
|fileName=Ezetimibe panel 01.png
}}
{{LabelImage
|fileName=Ezetimibe panel 02.png
}}

[[Category:Drug]]
[[Category:Cardiovascular Drugs]]
[[Category:Hypolipidemic agents]]

Exemestane

2015-03-18T15:37:27Z

Sree Teja Yelamanchili:

{{DrugProjectFormSinglePage
|authorTag={{GP}}; {{STY}}
|genericName=Exemestane
|aOrAn=an
|drugClass=[[aromatase Inhibitor]]
|indicationType=treatment
|indication=advanced [[breast cancer]] in [[menopause|postmenopausal women]] and adjuvant treatment of [[menopause|postmenopausal women]]
|adverseReactions=[[hot flushes]], [[fatigue]], [[arthralgia]], [[headache]], [[insomnia]], and [[sweating|increased sweating]], [[nausea]], [[fatigue]] and [[increased appetite]]
|blackBoxWarningTitle=<b><span style="color:#FF0000;">TITLE</span></b>
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)
|fdaLIADAdult======Adjuvant Treatment of Postmenopausal Women=====
* Exemestane is indicated for adjuvant treatment of [[menopause|postmenopausal women]] with estrogen-receptor positive early [[breast cancer]] who have received two to three years of [[tamoxifen]] and are switched to exemestane for completion of a total of five consecutive years of adjuvant [[hormonal therapy]].
* Dosage: 25 mg tablet once daily after a meal.

=====Advanced Breast Cancer in Postmenopausal Women=====
* Exemestane is indicated for the treatment of advanced [[breast cancer]] in postmenopausal women whose disease has progressed following [[tamoxifen]] therapy.
* Dosage: 25 mg tablet once daily after a meal.
|offLabelAdultGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Exemestane in adult patients.
|offLabelAdultNoGuideSupport=* Prophylaxis of invasive [[breast cancer]] in postmenopausal women at increased risk.
:* Dosage: 25 mg/day for 5 years <ref name="pmid23835710">{{cite journal| author=Visvanathan K, Hurley P, Bantug E, Brown P, Col NF, Cuzick J et al.| title=Use of pharmacologic interventions for breast cancer risk reduction: American Society of Clinical Oncology clinical practice guideline. | journal=J Clin Oncol | year= 2013 | volume= 31 | issue= 23 | pages= 2942-62 | pmid=23835710 | doi=10.1200/JCO.2013.49.3122 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23835710 }} </ref>
* Neoadjuvant treatment of [[menopause|postmenopausal women]] with [[breast cancer]] hormone-receptor positive.
|fdaLIADPed=Safety and effectiveness not established in pediatric patients
|offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Exemestane in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Exemestane in pediatric patients.
|contraindications======Hypersensitivity=====
* Exemestane tablets are contraindicated in patients with a known [[hypersensitivity]] to the drug or to any of the excipients.

=====Pregnancy=====
* Exemestane may cause fetal harm when administered to a pregnant woman. Based on its mechanism of action exemestane is expected to result in adverse reproductive effects. In non-clinical studies in rats and rabbits, exemestane was embryotoxic, fetotoxic, and abortifacient.
* Exemestane is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
|warnings======Administration with Estrogen-Containing Agents=====
Exemestane should not be coadministered with estrogen-containing agents as these could interfere with its pharmacologic action.

=====Laboratory Tests=====
*In patients with early breast cancer, the incidence of hematological abnormalities of Common Toxicity Criteria (CTC) grade ≥1 was lower in the exemestane treatment group, compared with [[tamoxifen]].
*Incidence of CTC grade 3 or 4 abnormalities was low (approximately 0.1%) in both treatment groups.
*Approximately 20% of patients receiving exemestane in clinical studies in advanced [[breast cancer]] experienced CTC grade 3 or 4 [[lymphocytopenia]]. *Of these patients, 89% had a pre-existing lower grade [[lymphopenia]].
*Forty percent of patients either recovered or improved to a lesser severity while on treatment.
*Patients did not have a significant increase in viral infections, and no [[opportunistic infections]] were observed.
*Elevations of serum levels of [[AST]], [[ALT]], [[alkaline phosphatase]], and [[gamma glutamyl transferase]] >5 times the upper value of the normal range (i.e., ≥ CTC grade 3) have been rarely reported in patients treated for advanced breast cancer but appear mostly attributable to the underlying presence of liver and/or bone metastases.
*In the comparative study in advanced [[breast cancer]] patients, CTC grade 3 or 4 elevation of [[gamma glutamyl transferase]] without documented evidence of liver metastasis was reported in 2.7% of patients treated with exemestane and in 1.8% of patients treated with megestrol acetate.

*In patients with early [[breast cancer]], [[elevations in bilirubin]], [[alkaline phosphatase]], and [[creatinine]] were more common in those receiving exemestane than either tamoxifen or placebo.
*Treatment-emergent bilirubin elevations (any CTC grade) occurred in 5.3% of exemestane patients and 0.8% of tamoxifen patients on the Intergroup Exemestane Study (IES), and in 6.9% of exemestane treated patients vs. 0% of placebo treated patients in the 027 study.
*CTC grade 3–4 increases in [[bilirubin]] occurred in 0.9% of exemestane treated patients compared to 0.1% of tamoxifen treated patients.
*[[Alkaline phosphatase]] elevations of any CTC grade occurred in 15.0% of exemestane treated patients on the IES compared to 2.6% of tamoxifen treated patients, and in 13.7% of exemestane treated patients compared to 6.9% of placebo treated patients in study 027.
*[[Creatinine]] elevations occurred in 5.8% of exemestane treated patients and 4.3% of tamoxifen treated patients on the IES and in 5.5% of exemestane treated patients and 0% of placebo treated patients in study 027.

=====Reductions in Bone Mineral Density (BMD)=====
Reductions in [[bone mineral density]] (BMD) over time are seen with exemestane use. Table 1 describes changes in BMD from baseline to 24 months in patients receiving exemestane compared to patients receiving tamoxifen (IES) or placebo (027). Concomitant use of [[bisphosphonates]], [[vitamin D]] supplementation, and [[calcium]] was not allowed.

[[File:Exemestane Percent Change in BMD from Baseline to 24 months, Exemestane vs. Control.png|thumb|none|500px]]

During adjuvant treatment with exemestane, women with [[osteoporosis]] or at risk of [[osteoporosis]] should have their bone mineral density formally assessed by [[bone densitometry]] at the commencement of treatment. Monitor patients for bone mineral density loss and treat as appropriate.

=====Vitamin D Assessment=====
Routine assessment of [[25-hydroxy vitamin D]] levels prior to the start of [[aromatase inhibitor]] treatment should be performed, due to the high prevalence of vitamin D deficiency in women with early [[breast cancer]] (EBC). Women with [[vitamin D deficiency]] should receive supplementation with vitamin D.
|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

======Adjuvant Therapy======
*The data described below reflect exposure to exemestane in 2325 postmenopausal women with early breast cancer.
*Exemestane tolerability in postmenopausal women with early breast cancer was evaluated in two well-controlled trials: the IES study (14.1) and the 027 study (a randomized, placebo-controlled, double-blind, parallel group study specifically designed to assess the effects of exemestane on bone metabolism, hormones, lipids, and coagulation factors over 2 years of treatment).

*The median duration of adjuvant treatment was 27.4 months and 27.3 months for patients receiving exemestane or [[tamoxifen]], respectively, within the IES study and 23.9 months for patients receiving exemestane or placebo within the 027 study. Median duration of observation after randomization for exemestane was 34.5 months and for tamoxifen was 34.6 months. Median duration of observation was 30 months for both groups in the 027 study.

*Certain adverse events, which were expected based on the known pharmacological properties and side effect profiles of test drugs, were actively sought through a positive checklist. Signs and symptoms were graded for severity using CTC in both studies. Within the IES study, the presence of some illnesses/conditions was monitored through a positive checklist without assessment of severity. These included [[myocardial infarction]], other cardiovascular disorders, gynecological disorders, [[osteoporosis]], osteoporotic fractures, other primary cancer, and hospitalizations.

*Exemestane was generally well tolerated and adverse events were usually mild to moderate. Within the IES study, discontinuations due to adverse events occurred in 6.3% and 5.1% of patients receiving exemestane and [[tamoxifen]], respectively, and in 12.3% and 4.1% of patients receiving exemestane or placebo respectively within study 027.

*Deaths due to any cause were reported for 1.3% of the exemestane treated patients and 1.4% of the tamoxifen treated patients within the IES study. There were 6 deaths due to stroke on the exemestane arm compared to 2 on [[tamoxifen]]. There were 5 deaths due to cardiac failure on the exemestane arm compared to 2 on tamoxifen.

*The incidence of cardiac ischemic events ([[myocardial infarction]], [[angina]], and [[myocardial ischemia]]) was 1.6% in exemestane treated patients and 0.6% in [[tamoxifen]] treated patients in the IES study. Cardiac failure was observed in 0.4% of exemestane treated patients and 0.3% of tamoxifen treated patients.

*Treatment-emergent adverse events and illnesses including all causalities and occurring with an incidence of ≥5% in either treatment group of the IES study during or within one month of the end of treatment are shown in Table 2.

[[File:Exemestane Incidence of Adverse Events of all Grades and Illnesses.png|thumb|none|600px]]

*In the IES study, as compared to tamoxifen, exemestane was associated with a higher incidence of events in musculoskeletal disorders and in nervous system disorders, including the following events occurring with frequency lower than 5% ([[osteoporosis]] [4.6% vs. 2.8%], [[osteochondrosis]] and [[trigger finger]] [0.3% vs. 0 for both events], [[paresthesia]] [2.6% vs. 0.9%], [[carpal tunnel syndrome]] [2.4% vs. 0.2%], and [[neuropathy]] [0.6% vs. 0.1%]).
*[[Diarrhea]] was also more frequent in the exemestane group (4.2% vs. 2.2%). *Clinical fractures were reported in 94 patients receiving exemestane (4.2%) and 71 patients receiving tamoxifen (3.1%).
*After a median duration of therapy of about 30 months and a median follow-up of about 52 months, [[gastric ulcer]] was observed at a slightly higher frequency in the exemestane group compared to tamoxifen (0.7% vs. <0.1%).
*The majority of patients on exemestane with [[gastric ulcer]] received concomitant treatment with [[NSAIDS|non-steroidal anti-inflammatory agents]] and/or had a prior history.

*[[Tamoxifen]] was associated with a higher incidence of muscle cramps [3.1% vs. 1.5%], [[thromboembolism]] [2.0% vs. 0.9%], [[endometrial hyperplasia]] [1.7% vs. 0.6%], and [[uterine polyps]] [2.4% vs. 0.4%].

[[File:Exemestane Incidence of Selected Treatment-Emergent Adverse Events.png|thumb|none|600px]]

======Treatment of Advanced Breast Cancer======
*A total of 1058 patients were treated with exemestane 25 mg once daily in the clinical trials program.
*Only one death was considered possibly related to treatment with exemestane; an 80-year-old woman with known coronary artery disease had a [[myocardial infarction]] with multiple organ failure after 9 weeks on study treatment.
*In the clinical trials program, only 3% of the patients discontinued treatment with exemestane because of adverse events, mainly within the first 10 weeks of treatment; late discontinuations because of adverse events were uncommon (0.3%).

*In the comparative study, adverse reactions were assessed for 358 patients treated with exemestane and 400 patients treated with [[megestrol acetate]]. *Fewer patients receiving exemestane discontinued treatment because of adverse events than those treated with [[megestrol acetate]] (2% vs. 5%). *Adverse events that were considered drug related or of indeterminate cause included [[hot flashes]] (13% vs. 5%), [[nausea]] (9% vs. 5%), [[fatigue]] (8% vs. 10%), [[increased sweating]] (4% vs. 8%), and increased appetite (3% vs. 6%) for exemestane and [[megestrol acetate]], respectively.
*The proportion of patients experiencing an excessive weight gain (>10% of their baseline weight) was significantly higher with megestrol acetate than with exemestane (17% vs. 8%). Table 4 shows the adverse events of all CTC grades, regardless of causality, reported in 5% or greater of patients in the study treated either with exemestane or [[megestrol acetate]].

[[File:Exemestane Adverse Reactions Advanced Breast Cancer.png|thumb|none|600px]]

*Less frequent adverse events of any cause (from 2% to 5%) reported in the comparative study for patients receiving exemestane 25 mg once daily were [[fever]], generalized weakness, [[paresthesia]], pathological fracture, [[bronchitis]], [[sinusitis]], [[rash]], [[itching]], [[urinary tract infection]], and [[lymphedema]].

*Additional adverse events of any cause observed in the overall clinical trials program (N = 1058) in 5% or greater of patients treated with exemestane 25 mg once daily but not in the comparative study included pain at tumor sites (8%), [[asthenia]] (6%), and [[fever]] (5%).
*Adverse events of any cause reported in 2% to 5% of all patients treated with exemestane 25 mg in the overall clinical trials program but not in the comparative study included [[chest pain]], [[hypoesthesia]], [[confusion]], [[dyspepsia]], [[arthralgia]], [[back pain]], [[skeletal pain]], [[infection]], [[upper respiratory tract infection]], [[pharyngitis]], [[rhinitis]], and [[alopecia]].
|postmarketing=The following adverse reactions have been identified during post approval use of exemestane. Because reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
* Immune system disorders: [[hypersensitivity]]
* Hepatobiliary disorders: [[hepatitis]] including [[cholestatic jaundice|cholestatic hepatitis]]
* Nervous system disorders: [[paresthesia]]
* Skin and subcutaneous tissue disorders: [[pustulosis|acute generalized exanthematous pustulosis]], [[urticaria]], [[pruritus]]
|drugInteractions=Drugs That Induce CYP 3A4
* Co-medications that [[CYP3A4 inducer|induce CYP 3A4]] (e.g., [[rifampicin]], [[phenytoin]], [[carbamazepine]], [[phenobarbital]], or [[St John's wort]]) may significantly decrease exposure to exemestane.
* Dose modification is recommended for patients who are also receiving a strong CYP 3A4 inducer
|FDAPregCat=X
|useInPregnancyFDA=Exemestane can cause fetal harm when administered to a pregnant woman and the clinical benefit to premenopausal women with breast cancer has not been demonstrated. exemestane is contraindicated in women who are or may become pregnant. There are no adequate and well-controlled studies of exemestane in pregnant women.

In non-clinical studies in rats and rabbits, exemestane was embryotoxic, fetotoxic, and abortifacient. Radioactivity related to 14C-exemestane crossed the placenta of rats following oral administration of 1 mg/kg exemestane. The concentration of exemestane and its metabolites was approximately equivalent in maternal and fetal blood. When rats were administered exemestane from 14 days prior to mating until either days 15 or 20 of gestation, and resuming for the 21 days of lactation, an increase in placental weight was seen at 4 mg/kg/day (approximately 1.5 times the recommended human daily dose on a mg/m2 basis). Prolonged gestation and abnormal or difficult labor was observed at doses equal to or greater than 20 mg/kg/day. Increased resorption, reduced number of live fetuses, decreased fetal weight, and retarded ossification were also observed at these doses. No malformations were noted when exemestane was administered to pregnant rats during the organogenesis period at doses up to 810 mg/kg/day (approximately 320 times the recommended human dose on a mg/m2 basis). Daily doses of exemestane, given to rabbits during organogenesis, caused a decrease in placental weight at 90 mg/kg/day (approximately 70 times the recommended human daily dose on a mg/m2 basis). Abortions, an increase in resorptions, and a reduction in fetal body weight were seen at 270 mg/kg/day. There was no increase in the incidence of malformations in rabbits at doses up to 270 mg/kg/day (approximately 210 times the recommended human dose on a mg/m2 basis).

If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus and the potential risk for pregnancy loss.
|AUSPregCat=C
|useInNursing=Exemestane is only indicated in postmenopausal women. However, radioactivity related to exemestane appeared in rat milk within 15 minutes of oral administration of radiolabeled exemestane. Concentrations of exemestane and its metabolites were approximately equivalent in the milk and plasma of rats for 24 hours after a single oral dose of 1 mg/kg 14C-exemestane. It is not known whether exemestane is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reaction in nursing infants from exemestane, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother.
|useInPed=Safety and effectiveness in pediatric patients have not been established.
|useInGeri=Healthy postmenopausal women aged 43 to 68 years were studied in the pharmacokinetic trials. Age-related alterations in exemestane pharmacokinetics were not seen over this age range.
|useInGender=The pharmacokinetics of exemestane following administration of a single, 25-mg tablet to fasted healthy males (mean age 32 years) were similar to the pharmacokinetics of exemestane in fasted healthy postmenopausal women (mean age 55 years).
|useInRace=The influence of race on exemestane pharmacokinetics has not been evaluated.
|useInRenalImpair=The AUC of exemestane was increased in subjects with moderate or severe renal impairment (creatinine clearance <35 mL/min/1.73 m2). However, based on experience with exemestane at repeated doses up to 200 mg daily that demonstrated a moderate increase in non life- threatening adverse events, dosage adjustment does not appear to be necessary.
|useInHepaticImpair=The AUC of exemestane was increased in subjects with moderate or severe hepatic impairment (Childs-Pugh B or C). However, based on experience with exemestane at repeated doses up to 200 mg daily that demonstrated a moderate increase in non life-threatening adverse events, dosage adjustment does not appear to be necessary.
|useInReproPotential=In a pilot reproductive study in rats, male rats were treated with doses of 125–1000 mg/kg/day exemestane, beginning 63 days prior to and during cohabitation. Untreated female rats showed reduced fertility when mated to males treated with ≥500 mg/kg/day exemestane (≥200 times the recommended human dose on a mg/m2 basis). In a separate study, exemestane was given to female rats at 4–100 mg/kg/day beginning 14 days prior to mating and through day 15 or 20 of gestation. Exemestane increased the placental weights at ≥4 mg/kg/day (≥1.5 times the human dose on a mg/m2 basis). Exemestane showed no effects on ovarian function, mating behavior, and conception rate in rats given doses up to 20 mg/kg/day (approximately 8 times the recommended human dose on a mg/m2 basis); however, decreases in mean litter size and fetal body weight, along with delayed ossification were evidenced at ≥20 mg/kg/day. In general toxicology studies, changes in the ovary, including hyperplasia, an increase in the incidence of ovarian cysts, and a decrease in corpora lutea were observed with variable frequency in mice, rats, and dogs at doses that ranged from 3–20 times the human dose on a mg/m2 basis.
|administration=Oral
|overdose=Clinical trials have been conducted with exemestane given as a single dose to healthy female volunteers at doses as high as 800 mg and daily for 12 weeks to postmenopausal women with advanced breast cancer at doses as high as 600 mg. These dosages were well tolerated. There is no specific antidote to overdosage and treatment must be symptomatic. General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated.

A male child (age unknown) accidentally ingested a 25-mg tablet of exemestane. The initial physical examination was normal, but blood tests performed 1 hour after ingestion indicated leucocytosis (WBC 25000/mm3 with 90% neutrophils). Blood tests were repeated 4 days after the incident and were normal. No treatment was given.

In mice, mortality was observed after a single oral dose of exemestane of 3200 mg/kg, the lowest dose tested (about 640 times the recommended human dose on a mg/m2 basis). In rats and dogs, mortality was observed after single oral doses of exemestane of 5000 mg/kg (about 2000 times the recommended human dose on a mg/m2 basis) and of 3000 mg/kg (about 4000 times the recommended human dose on a mg/m2 basis), respectively.

Convulsions were observed after single doses of exemestane of 400 mg/kg and 3000 mg/kg in mice and dogs (approximately 80 and 4000 times the recommended human dose on a mg/m2 basis), respectively.
|drugBox={{Drugbox2
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 461098446
| IUPAC_name = 6-Methylideneandrosta-1,4-diene-3,17-dione
| image = Exemestane structure.png


| tradename = Aromasin
| Drugs.com = {{drugs.com|monograph|exemestane}}
| MedlinePlus = a607006
| pregnancy_category = D
| legal_status = Rx only
| routes_of_administration = Oral


| bioavailability = ~60%
| protein_bound = 90%
| elimination_half-life = 24 hours


| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 107868-30-4
| ATC_prefix = L02
| ATC_suffix = BG06
| PubChem = 60198
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00990
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 54278
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = NY22HMQ4BX
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00963
| ChEBI_Ref = {{ebicite|changed|EBI}}
| ChEBI = 4953
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1200374


| C=20 | H=24 | O=2
| molecular_weight = 296.403 g/mol
| smiles = O=C\1\C=C/[C@]3(C(=C/1)/C(=C)C[C@H]4[C@@H]2CCC(=O)[C@]2(CC[C@H]34)C)C
| InChI = 1/C20H24O2/c1-12-10-14-15-4-5-18(22)20(15,3)9-7-16(14)19(2)8-6-13(21)11-17(12)19/h6,8,11,14-16H,1,4-5,7,9-10H2,2-3H3/t14-,15-,16-,19+,20-/m0/s1
| InChIKey = BFYIZQONLCFLEV-DAELLWKTBA
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C20H24O2/c1-12-10-14-15-4-5-18(22)20(15,3)9-7-16(14)19(2)8-6-13(21)11-17(12)19/h6,8,11,14-16H,1,4-5,7,9-10H2,2-3H3/t14-,15-,16-,19+,20-/m0/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = BFYIZQONLCFLEV-DAELLWKTSA-N
}}
|mechAction=Breast cancer cell growth may be estrogen-dependent. Aromatase is the principal enzyme that converts androgens to estrogens both in pre- and postmenopausal women. While the main source of estrogen (primarily estradiol) is the ovary in premenopausal women, the principal source of circulating estrogens in postmenopausal women is from conversion of adrenal and ovarian androgens (androstenedione and testosterone) to estrogens (estrone and estradiol) by the aromatase enzyme in peripheral tissues. Estrogen deprivation through aromatase inhibition is an effective and selective treatment for some postmenopausal patients with hormone-dependent breast cancer.

Exemestane is an irreversible, steroidal aromatase inactivator, structurally related to the natural substrate androstenedione. It acts as a false substrate for the aromatase enzyme, and is processed to an intermediate that binds irreversibly to the active site of the enzyme, causing its inactivation, an effect also known as "suicide inhibition." Exemestane significantly lowers circulating estrogen concentrations in postmenopausal women, but has no detectable effect on adrenal biosynthesis of corticosteroids or aldosterone. Exemestane has no effect on other enzymes involved in the steroidogenic pathway up to a concentration at least 600 times higher than that inhibiting the aromatase enzyme.
|structure=Exemestane is chemically described as 6-methylenandrosta-1,4-diene-3,17-dione. Its molecular formula is C20H24O2 and its structural formula is as follows:
[[|thumb|none|500px]]
|PD=======Effect on Estrogens======
Multiple doses of exemestane ranging from 0.5 to 600 mg/day were administered to postmenopausal women with advanced breast cancer. Plasma estrogen (estradiol, estrone, and estrone sulfate) suppression was seen starting at a 5-mg daily dose of exemestane, with a maximum suppression of at least 85% to 95% achieved at a 25-mg dose. Exemestane 25 mg daily reduced whole body aromatization (as measured by injecting radiolabeled androstenedione) by 98% in postmenopausal women with breast cancer. After a single dose of exemestane 25 mg, the maximal suppression of circulating estrogens occurred 2 to 3 days after dosing and persisted for 4 to 5 days.

======Effect on Corticosteroids======
In multiple-dose trials of doses up to 200 mg daily, exemestane selectivity was assessed by examining its effect on adrenal steroids. Exemestane did not affect cortisol or aldosterone secretion at baseline or in response to ACTH at any dose. Thus, no glucocorticoid or mineralocorticoid replacement therapy is necessary with exemestane treatment.

======Other Endocrine Effects======
Exemestane does not bind significantly to steroidal receptors, except for a slight affinity for the androgen receptor (0.28% relative to dihydrotestosterone). The binding affinity of its 17-dihydrometabolite for the androgen receptor, however, is 100 times that of the parent compound. Daily doses of exemestane up to 25 mg had no significant effect on circulating levels of androstenedione, dehydroepiandrosterone sulfate, or 17-hydroxyprogesterone, and were associated with small decreases in circulating levels of testosterone. Increases in testosterone and androstenedione levels have been observed at daily doses of 200 mg or more. A dose-dependent decrease in sex hormone binding globulin (SHBG) has been observed with daily exemestane doses of 2.5 mg or higher. Slight, nondose-dependent increases in serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels have been observed even at low doses as a consequence of feedback at the pituitary level. Exemestane 25 mg daily had no significant effect on thyroid function [free triiodothyronine (FT3), free thyroxine (FT4), and thyroid stimulating hormone (TSH)].

======Coagulation and Lipid Effects======
In study 027 of postmenopausal women with early breast cancer treated with exemestane (N=73) or placebo (N=73), there was no change in the coagulation parameters activated partial thromboplastin time [APTT], prothrombin time [PT], and fibrinogen. Plasma HDL cholesterol was decreased 6–9% in exemestane treated patients; total cholesterol, LDL cholesterol, triglycerides, apolipoprotein-A1, apolipoprotein-B, and lipoprotein-a were unchanged. An 18% increase in homocysteine levels was also observed in exemestane treated patients compared with a 12% increase seen with placebo.
|PK=Following oral administration to healthy postmenopausal women, plasma concentrations of exemestane decline polyexponentially with a mean terminal half-life of about 24 hours. The pharmacokinetics of exemestane are dose proportional after single (10 to 200 mg) or repeated oral doses (0.5 to 50 mg). Following repeated daily doses of exemestane 25 mg, plasma concentrations of unchanged drug are similar to levels measured after a single dose. Pharmacokinetic parameters in postmenopausal women with advanced breast cancer following single or repeated doses have been compared with those in healthy, postmenopausal women. After repeated dosing, the average oral clearance in women with advanced breast cancer was 45% lower than the oral clearance in healthy postmenopausal women, with corresponding higher systemic exposure. Mean AUC values following repeated doses in women with breast cancer (75.4 ng∙h/mL) were about twice those in healthy women (41.4 ng∙h/mL).

======Absorption======
Following oral administration, exemestane appeared to be absorbed more rapidly in women with breast cancer than in the healthy women, with a mean -tmax of 1.2 hours in the women with breast cancer and 2.9 hours in healthy women. Approximately 42% of radiolabeled exemestane was absorbed from the gastrointestinal tract. A high-fat breakfast increased AUC and Cmax of exemestane by 59% and 39%, respectively, compared to fasted state.

======Distribution======
Exemestane is distributed extensively into tissues. Exemestane is 90% bound to plasma proteins and the fraction bound is independent of the total concentration. Albumin and α11-acid glycoprotein both contribute to the binding. The distribution of exemestane and its metabolites into blood cells is negligible.

======Metabolism======
Exemestane is extensively metabolized, with levels of the unchanged drug in plasma accounting for less than 10% of the total radioactivity. The initial steps in the metabolism of exemestane are oxidation of the methylene group in position 6 and reduction of the 17-keto group with subsequent formation of many secondary metabolites. Each metabolite accounts only for a limited amount of drug-related material. The metabolites are inactive or inhibit aromatase with decreased potency compared with the parent drug. One metabolite may have androgenic activity. Studies using human liver preparations indicate that cytochrome P 450 3A4 (CYP 3A4) is the principal isoenzyme involved in the oxidation of exemestane. Exemestane is metabolized also by aldoketoreductases.

======Elimination======
Following administration of radiolabeled exemestane to healthy postmenopausal women, the cumulative amounts of radioactivity excreted in urine and feces were similar (42 ± 3% in urine and 42 ± 6% in feces over a 1-week collection period). The amount of drug excreted unchanged in urine was less than 1% of the dose.
|nonClinToxic=======Carcinogenesis and Mutagenesis======
A 2-year carcinogenicity study in mice at doses of 50, 150, and 450 mg/kg/day exemestane (gavage), resulted in an increased incidence of hepatocellular adenomas and/or carcinomas in both genders at the high dose level. Plasma AUC (0–24hr) at the high dose were 2575 ± 386 and 5667 ± 1833 ng.hr/mL in males and females (approx. 34 and 75 fold the AUC in postmenopausal patients at the recommended clinical dose). An increased incidence of renal tubular adenomas was observed in male mice at the high dose of 450 mg/kg/day. Since the doses tested in mice did not achieve an MTD, neoplastic findings in organs other than liver and kidneys remain unknown.

A separate carcinogenicity study was conducted in rats at the doses of 30, 100, and 315 mg/kg/day exemestane (gavage) for 92 weeks in males and 2 years in females. No evidence of carcinogenic activity up to the highest dose tested of 315 mg/kg/day was observed in females. The male rat study was inconclusive since it was terminated prematurely at Week 92. At the highest dose, plasma AUC(0–24hr) levels in male (1418 ± 287 ng.hr/mL) and female (2318 ± 1067 ng.hr/mL) rats were 19 and 31 fold higher than those measured in postmenopausal cancer patients receiving the recommended clinical dose.

Exemestane was not mutagenic in vitro in bacteria (Ames test) or mammalian cells (V79 Chinese hamster lung cells). Exemestane was clastogenic in human lymphocytes in vitro without metabolic activation but was not clastogenic in vivo (micronucleus assay in mouse bone marrow). Exemestane did not increase unscheduled DNA synthesis in rat hepatocytes when tested in vitro.
|clinicalStudies======Adjuvant Treatment in Early Breast Cancer=====
The Intergroup Exemestane Study 031 (IES) was a randomized, double-blind, multicenter, multinational study comparing exemestane (25 mg/day) vs. tamoxifen (20 or 30 mg/day) in postmenopausal women with early breast cancer. Patients who remained disease-free after receiving adjuvant tamoxifen therapy for 2 to 3 years were randomized to receive an additional 3 or 2 years of exemestane or tamoxifen to complete a total of 5 years of hormonal therapy.

The primary objective of the study was to determine whether, in terms of disease-free survival, it was more effective to switch to exemestane rather than continuing tamoxifen therapy for the remainder of five years. Disease-free survival was defined as the time from randomization to time of local or distant recurrence of breast cancer, contralateral invasive breast cancer, or death from any cause.

The secondary objectives were to compare the two regimens in terms of overall survival and long-term tolerability. Time to contralateral invasive breast cancer and distant recurrence-free survival were also evaluated.

A total of 4724 patients in the intent-to-treat (ITT) analysis were randomized to exemestane (exemestane tablets) 25 mg once daily (N = 2352) or to continue to receive tamoxifen once daily at the same dose received before randomization (N = 2372). Demographics and baseline tumor characteristics are presented in Table 5. Prior breast cancer therapy is summarized in Table 6.

[[File:Exemestane Adjuvant Treatment in Early Breast Cancer.png|thumb|none|700px]]

After a median duration of therapy of 27 months and with a median follow-up of 34.5 months, 520 events were reported, 213 in the exemestane group and 307 in the tamoxifen group.

[[File:Exemestane Primary Endpoint Events.png|thumb|none|500px]]

Disease-free survival in the intent-to-treat population was statistically significantly improved [Hazard Ratio (HR) = 0.69, 95% CI: 0.58, 0.82, P = 0.00003, Table 8, Figure 1] in the exemestane arm compared to the tamoxifen arm. In the hormone receptor-positive subpopulation representing about 85% of the trial patients, disease-free survival was also statistically significantly improved (HR = 0.65, 95% CI: 0.53, 0.79, P = 0.00001) in the exemestane arm compared to the tamoxifen arm. Consistent results were observed in the subgroups of patients with node negative or positive disease, and patients who had or had not received prior chemotherapy. Overall survival was not significantly different in the two groups, with 116 deaths occurring in the exemestane group and 137 in the tamoxifen group.

[[File:Exemestane Efficacy Results from the IES Study in Postmenopausal Women with Early Breast Cancer.png|thumb|none|600px]]

=====Treatment of Advanced Breast Cancer=====
Exemestane 25 mg administered once daily was evaluated in a randomized double-blind, multicenter, multinational comparative study and in two multicenter single-arm studies of postmenopausal women with advanced breast cancer who had disease progression after treatment with tamoxifen for metastatic disease or as adjuvant therapy. Some patients also have received prior cytotoxic therapy, either as adjuvant treatment or for metastatic disease.

The primary purpose of the three studies was evaluation of objective response rate (complete response [CR] and partial response [PR]). Time to tumor progression and overall survival were also assessed in the comparative trial. Response rates were assessed based on World Health Organization (WHO) criteria, and in the comparative study, were submitted to an external review committee that was blinded to patient treatment. In the comparative study, 769 patients were randomized to receive exemestane (exemestane tablets) 25 mg once daily (N = 366) or megestrol acetate 40 mg four times daily (N = 403). Demographics and baseline characteristics are presented in Table 9.

[[File:Exemestane Demographics and Baseline Characteristics from the Comparative Study of Postmenopausal Women with Advanced Breast Cancer Whose Disease Had Progressed after Tamoxifen Therapy.png|thumb|none|600px]]

The efficacy results from the comparative study are shown in Table 10. The objective response rates observed in the two treatment arms showed that exemestane was not different from megestrol acetate. Response rates for exemestane from the two single-arm trials were 23.4% and 28.1%.

[[File:Exemestane Efficacy Results from the Comparative Study of Postmenopausal Women with Advanced Breast Cancer Whose Disease Had Progressed after Tamoxifen Therapy.png|thumb|none|500px]]

There were too few deaths occurring across treatment groups to draw conclusions on overall survival differences. The Kaplan-Meier curve for time to tumor progression in the comparative study is shown in Figure 2.

[[File:Exemestane Time to Tumor Progression.png|thumb|none|500px]]
|howSupplied=* Exemestane 25 mg tablets
:* 30 tablet bottle
:* NDC 0009-7663-04
|storage=Store at 25°C (77ºF)
|packLabel=[[File:Exemestane FDA package label.png|thumb|none|600px]]
|fdaPatientInfo======Premenopausal Women=====
Patients should be advised that exemestane is not for use in premenopausal women.

=====Other Estrogen-Containing Agents=====
Patients should be informed that they should not take estrogen-containing agents while they are taking exemestane as these could interfere with its pharmacologic action.

=====Bone Effects=====
Patients should be informed that exemestane lowers the level of estrogen in the body. This may lead to reduction in bone mineral density (BMD) over time. The lower the BMD, the greater the risk of [[osteoporosis]] and [[fracture]].
|alcohol=Alcohol-Exemestane interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=* Aromasin <ref>{{cite web|url=http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=cf066b7a-032a-416c-8d40-15ba581423e3|title=FDA LABEL: AROMASIN- exemestane tablet}}</ref>
}}
{{LabelImage
|fileName=Exemestane 25 mg.png
}}

[[Category:Drug]]
[[Category:Chemotherapeutic agents]]

Exemestane

2015-03-18T14:51:28Z

Sree Teja Yelamanchili:

{{DrugProjectFormSinglePage
|authorTag={{GP}}; {{STY}}
|genericName=Exemestane
|aOrAn=an
|drugClass=[[aromatase Inhibitor]]
|indicationType=treatment
|indication=advanced [[breast cancer]] in [[menopause|postmenopausal women]] and adjuvant treatment of [[menopause|postmenopausal women]]
|adverseReactions=[[hot flushes]], [[fatigue]], [[arthralgia]], [[headache]], [[insomnia]], and [[sweating|increased sweating]], [[nausea]], [[fatigue]] and [[increased appetite]]
|blackBoxWarningTitle=<b><span style="color:#FF0000;">TITLE</span></b>
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)
|fdaLIADAdult======Adjuvant Treatment of Postmenopausal Women=====
* Exemestane is indicated for adjuvant treatment of [[menopause|postmenopausal women]] with estrogen-receptor positive early [[breast cancer]] who have received two to three years of [[tamoxifen]] and are switched to exemestane for completion of a total of five consecutive years of adjuvant [[hormonal therapy]].
* Dosage: 25 mg tablet once daily after a meal.

=====Advanced Breast Cancer in Postmenopausal Women=====
* Exemestane is indicated for the treatment of advanced [[breast cancer]] in postmenopausal women whose disease has progressed following [[tamoxifen]] therapy.
* Dosage: 25 mg tablet once daily after a meal.
|offLabelAdultGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Exemestane in adult patients.
|offLabelAdultNoGuideSupport=* Prophylaxis of invasive [[breast cancer]] in postmenopausal women at increased risk.
:* Dosage: 25 mg/day for 5 years <ref name="pmid23835710">{{cite journal| author=Visvanathan K, Hurley P, Bantug E, Brown P, Col NF, Cuzick J et al.| title=Use of pharmacologic interventions for breast cancer risk reduction: American Society of Clinical Oncology clinical practice guideline. | journal=J Clin Oncol | year= 2013 | volume= 31 | issue= 23 | pages= 2942-62 | pmid=23835710 | doi=10.1200/JCO.2013.49.3122 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23835710 }} </ref>
* Neoadjuvant treatment of [[menopause|postmenopausal women]] with [[breast cancer]] hormone-receptor positive.
|fdaLIADPed=Safety and effectiveness not established in pediatric patients
|offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Exemestane in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Exemestane in pediatric patients.
|contraindications======Hypersensitivity=====
* Exemestane tablets are contraindicated in patients with a known [[hypersensitivity]] to the drug or to any of the excipients.

=====Pregnancy=====
* Exemestane may cause fetal harm when administered to a pregnant woman. Based on its mechanism of action exemestane is expected to result in adverse reproductive effects. In non-clinical studies in rats and rabbits, exemestane was embryotoxic, fetotoxic, and abortifacient.
* Exemestane is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
|warnings======Administration with Estrogen-Containing Agents=====
Exemestane should not be coadministered with estrogen-containing agents as these could interfere with its pharmacologic action.

=====Laboratory Tests=====
*In patients with early breast cancer, the incidence of hematological abnormalities of Common Toxicity Criteria (CTC) grade ≥1 was lower in the exemestane treatment group, compared with [[tamoxifen]].
*Incidence of CTC grade 3 or 4 abnormalities was low (approximately 0.1%) in both treatment groups.
*Approximately 20% of patients receiving exemestane in clinical studies in advanced [[breast cancer]] experienced CTC grade 3 or 4 [[lymphocytopenia]]. *Of these patients, 89% had a pre-existing lower grade [[lymphopenia]].
*Forty percent of patients either recovered or improved to a lesser severity while on treatment.
*Patients did not have a significant increase in viral infections, and no [[opportunistic infections]] were observed.
*Elevations of serum levels of [[AST]], [[ALT]], [[alkaline phosphatase]], and [[gamma glutamyl transferase]] >5 times the upper value of the normal range (i.e., ≥ CTC grade 3) have been rarely reported in patients treated for advanced breast cancer but appear mostly attributable to the underlying presence of liver and/or bone metastases.
*In the comparative study in advanced [[breast cancer]] patients, CTC grade 3 or 4 elevation of [[gamma glutamyl transferase]] without documented evidence of liver metastasis was reported in 2.7% of patients treated with exemestane and in 1.8% of patients treated with megestrol acetate.

*In patients with early [[breast cancer]], [[elevations in bilirubin]], [[alkaline phosphatase]], and [[creatinine]] were more common in those receiving exemestane than either tamoxifen or placebo.
*Treatment-emergent bilirubin elevations (any CTC grade) occurred in 5.3% of exemestane patients and 0.8% of tamoxifen patients on the Intergroup Exemestane Study (IES), and in 6.9% of exemestane treated patients vs. 0% of placebo treated patients in the 027 study.
*CTC grade 3–4 increases in [[bilirubin]] occurred in 0.9% of exemestane treated patients compared to 0.1% of tamoxifen treated patients.
*[[Alkaline phosphatase]] elevations of any CTC grade occurred in 15.0% of exemestane treated patients on the IES compared to 2.6% of tamoxifen treated patients, and in 13.7% of exemestane treated patients compared to 6.9% of placebo treated patients in study 027.
*[[Creatinine]] elevations occurred in 5.8% of exemestane treated patients and 4.3% of tamoxifen treated patients on the IES and in 5.5% of exemestane treated patients and 0% of placebo treated patients in study 027.

=====Reductions in Bone Mineral Density (BMD)=====
Reductions in [[bone mineral density]] (BMD) over time are seen with exemestane use. Table 1 describes changes in BMD from baseline to 24 months in patients receiving exemestane compared to patients receiving tamoxifen (IES) or placebo (027). Concomitant use of [[bisphosphonates]], [[vitamin D]] supplementation, and [[calcium]] was not allowed.

[[File:Exemestane Percent Change in BMD from Baseline to 24 months, Exemestane vs. Control.png|thumb|none|500px]]

During adjuvant treatment with exemestane, women with [[osteoporosis]] or at risk of [[osteoporosis]] should have their bone mineral density formally assessed by [[bone densitometry]] at the commencement of treatment. Monitor patients for bone mineral density loss and treat as appropriate.

=====Vitamin D Assessment=====
Routine assessment of [[25-hydroxy vitamin D]] levels prior to the start of [[aromatase inhibitor]] treatment should be performed, due to the high prevalence of vitamin D deficiency in women with early [[breast cancer]] (EBC). Women with [[vitamin D deficiency]] should receive supplementation with vitamin D.
|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

======Adjuvant Therapy======
The data described below reflect exposure to exemestane in 2325 postmenopausal women with early breast cancer. exemestane tolerability in postmenopausal women with early breast cancer was evaluated in two well-controlled trials: the IES study (14.1) and the 027 study (a randomized, placebo-controlled, double-blind, parallel group study specifically designed to assess the effects of exemestane on bone metabolism, hormones, lipids, and coagulation factors over 2 years of treatment).

The median duration of adjuvant treatment was 27.4 months and 27.3 months for patients receiving exemestane or [[tamoxifen]], respectively, within the IES study and 23.9 months for patients receiving exemestane or placebo within the 027 study. Median duration of observation after randomization for exemestane was 34.5 months and for tamoxifen was 34.6 months. Median duration of observation was 30 months for both groups in the 027 study.

Certain adverse events, which were expected based on the known pharmacological properties and side effect profiles of test drugs, were actively sought through a positive checklist. Signs and symptoms were graded for severity using CTC in both studies. Within the IES study, the presence of some illnesses/conditions was monitored through a positive checklist without assessment of severity. These included [[myocardial infarction]], other cardiovascular disorders, gynecological disorders, [[osteoporosis]], osteoporotic fractures, other primary cancer, and hospitalizations.

Exemestane was generally well tolerated and adverse events were usually mild to moderate. Within the IES study, discontinuations due to adverse events occurred in 6.3% and 5.1% of patients receiving exemestane and [[tamoxifen]], respectively, and in 12.3% and 4.1% of patients receiving exemestane or placebo respectively within study 027.

Deaths due to any cause were reported for 1.3% of the exemestane treated patients and 1.4% of the tamoxifen treated patients within the IES study. There were 6 deaths due to stroke on the exemestane arm compared to 2 on [[tamoxifen]]. There were 5 deaths due to cardiac failure on the exemestane arm compared to 2 on tamoxifen.

The incidence of cardiac ischemic events ([[myocardial infarction]], [[angina]], and [[myocardial ischemia]]) was 1.6% in exemestane treated patients and 0.6% in [[tamoxifen]] treated patients in the IES study. Cardiac failure was observed in 0.4% of exemestane treated patients and 0.3% of tamoxifen treated patients.

Treatment-emergent adverse events and illnesses including all causalities and occurring with an incidence of ≥5% in either treatment group of the IES study during or within one month of the end of treatment are shown in Table 2.

[[File:Exemestane Incidence of Adverse Events of all Grades and Illnesses.png|thumb|none|600px]]

In the IES study, as compared to tamoxifen, exemestane was associated with a higher incidence of events in musculoskeletal disorders and in nervous system disorders, including the following events occurring with frequency lower than 5% ([[osteoporosis]] [4.6% vs. 2.8%], [[osteochondrosis]] and [[trigger finger]] [0.3% vs. 0 for both events], [[paresthesia]] [2.6% vs. 0.9%], [[carpal tunnel syndrome]] [2.4% vs. 0.2%], and [[neuropathy]] [0.6% vs. 0.1%]). [[Diarrhea]] was also more frequent in the exemestane group (4.2% vs. 2.2%). Clinical fractures were reported in 94 patients receiving exemestane (4.2%) and 71 patients receiving tamoxifen (3.1%). After a median duration of therapy of about 30 months and a median follow-up of about 52 months, [[gastric ulcer]] was observed at a slightly higher frequency in the exemestane group compared to tamoxifen (0.7% vs. <0.1%). The majority of patients on exemestane with [[gastric ulcer]] received concomitant treatment with non-steroidal anti-inflammatory agents and/or had a prior history.

Tamoxifen was associated with a higher incidence of muscle cramps [3.1% vs. 1.5%], [[thromboembolism]] [2.0% vs. 0.9%], [[endometrial hyperplasia]] [1.7% vs. 0.6%], and [[uterine polyps]] [2.4% vs. 0.4%].

[[File:Exemestane Incidence of Selected Treatment-Emergent Adverse Events.png|thumb|none|600px]]

======Treatment of Advanced Breast Cancer======
A total of 1058 patients were treated with exemestane 25 mg once daily in the clinical trials program. Only one death was considered possibly related to treatment with exemestane; an 80-year-old woman with known coronary artery disease had a [[myocardial infarction]] with multiple organ failure after 9 weeks on study treatment. In the clinical trials program, only 3% of the patients discontinued treatment with exemestane because of adverse events, mainly within the first 10 weeks of treatment; late discontinuations because of adverse events were uncommon (0.3%).

In the comparative study, adverse reactions were assessed for 358 patients treated with exemestane and 400 patients treated with megestrol acetate. Fewer patients receiving exemestane discontinued treatment because of adverse events than those treated with [[megestrol acetate]] (2% vs. 5%). Adverse events that were considered drug related or of indeterminate cause included [[hot flashes]] (13% vs. 5%), [[nausea]] (9% vs. 5%), [[fatigue]] (8% vs. 10%), [[increased sweating]] (4% vs. 8%), and increased appetite (3% vs. 6%) for exemestane and megestrol acetate, respectively. The proportion of patients experiencing an excessive weight gain (>10% of their baseline weight) was significantly higher with megestrol acetate than with exemestane (17% vs. 8%). Table 4 shows the adverse events of all CTC grades, regardless of causality, reported in 5% or greater of patients in the study treated either with exemestane or [[megestrol acetate]].

[[File:Exemestane Adverse Reactions Advanced Breast Cancer.png|thumb|none|600px]]

Less frequent adverse events of any cause (from 2% to 5%) reported in the comparative study for patients receiving exemestane 25 mg once daily were fever, generalized [[weakness]], [[paresthesia]], pathological fracture, [[bronchitis]], [[sinusitis]], [[rash]], [[itching]], [[urinary tract infection]], and [[lymphedema]].

Additional adverse events of any cause observed in the overall clinical trials program (N = 1058) in 5% or greater of patients treated with exemestane 25 mg once daily but not in the comparative study included pain at tumor sites (8%), [[asthenia]] (6%), and [[fever]] (5%). Adverse events of any cause reported in 2% to 5% of all patients treated with exemestane 25 mg in the overall clinical trials program but not in the comparative study included [[chest pain]], [[hypoesthesia]], [[confusion]], [[dyspepsia]], [[arthralgia]], [[back pain]], [[skeletal pain]], [[infection]], [[upper respiratory tract infection]], [[pharyngitis]], [[rhinitis]], and [[alopecia]].
|postmarketing=The following adverse reactions have been identified during post approval use of exemestane. Because reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
* Immune system disorders: [[hypersensitivity]]
* Hepatobiliary disorders: [[hepatitis]] including [[cholestatic jaundice|cholestatic hepatitis]]
* Nervous system disorders: [[paresthesia]]
* Skin and subcutaneous tissue disorders: [[pustulosis|acute generalized exanthematous pustulosis]], [[urticaria]], [[pruritus]]
|drugInteractions=Drugs That Induce CYP 3A4
* Co-medications that [[CYP3A4 inducer|induce CYP 3A4]] (e.g., [[rifampicin]], [[phenytoin]], [[carbamazepine]], [[phenobarbital]], or [[St John's wort]]) may significantly decrease exposure to exemestane.
* Dose modification is recommended for patients who are also receiving a strong CYP 3A4 inducer
|FDAPregCat=X
|useInPregnancyFDA=Exemestane can cause fetal harm when administered to a pregnant woman and the clinical benefit to premenopausal women with breast cancer has not been demonstrated. exemestane is contraindicated in women who are or may become pregnant. There are no adequate and well-controlled studies of exemestane in pregnant women.

In non-clinical studies in rats and rabbits, exemestane was embryotoxic, fetotoxic, and abortifacient. Radioactivity related to 14C-exemestane crossed the placenta of rats following oral administration of 1 mg/kg exemestane. The concentration of exemestane and its metabolites was approximately equivalent in maternal and fetal blood. When rats were administered exemestane from 14 days prior to mating until either days 15 or 20 of gestation, and resuming for the 21 days of lactation, an increase in placental weight was seen at 4 mg/kg/day (approximately 1.5 times the recommended human daily dose on a mg/m2 basis). Prolonged gestation and abnormal or difficult labor was observed at doses equal to or greater than 20 mg/kg/day. Increased resorption, reduced number of live fetuses, decreased fetal weight, and retarded ossification were also observed at these doses. No malformations were noted when exemestane was administered to pregnant rats during the organogenesis period at doses up to 810 mg/kg/day (approximately 320 times the recommended human dose on a mg/m2 basis). Daily doses of exemestane, given to rabbits during organogenesis, caused a decrease in placental weight at 90 mg/kg/day (approximately 70 times the recommended human daily dose on a mg/m2 basis). Abortions, an increase in resorptions, and a reduction in fetal body weight were seen at 270 mg/kg/day. There was no increase in the incidence of malformations in rabbits at doses up to 270 mg/kg/day (approximately 210 times the recommended human dose on a mg/m2 basis).

If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus and the potential risk for pregnancy loss.
|AUSPregCat=C
|useInNursing=Exemestane is only indicated in postmenopausal women. However, radioactivity related to exemestane appeared in rat milk within 15 minutes of oral administration of radiolabeled exemestane. Concentrations of exemestane and its metabolites were approximately equivalent in the milk and plasma of rats for 24 hours after a single oral dose of 1 mg/kg 14C-exemestane. It is not known whether exemestane is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reaction in nursing infants from exemestane, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother.
|useInPed=Safety and effectiveness in pediatric patients have not been established.
|useInGeri=Healthy postmenopausal women aged 43 to 68 years were studied in the pharmacokinetic trials. Age-related alterations in exemestane pharmacokinetics were not seen over this age range.
|useInGender=The pharmacokinetics of exemestane following administration of a single, 25-mg tablet to fasted healthy males (mean age 32 years) were similar to the pharmacokinetics of exemestane in fasted healthy postmenopausal women (mean age 55 years).
|useInRace=The influence of race on exemestane pharmacokinetics has not been evaluated.
|useInRenalImpair=The AUC of exemestane was increased in subjects with moderate or severe renal impairment (creatinine clearance <35 mL/min/1.73 m2). However, based on experience with exemestane at repeated doses up to 200 mg daily that demonstrated a moderate increase in non life- threatening adverse events, dosage adjustment does not appear to be necessary.
|useInHepaticImpair=The AUC of exemestane was increased in subjects with moderate or severe hepatic impairment (Childs-Pugh B or C). However, based on experience with exemestane at repeated doses up to 200 mg daily that demonstrated a moderate increase in non life-threatening adverse events, dosage adjustment does not appear to be necessary.
|useInReproPotential=In a pilot reproductive study in rats, male rats were treated with doses of 125–1000 mg/kg/day exemestane, beginning 63 days prior to and during cohabitation. Untreated female rats showed reduced fertility when mated to males treated with ≥500 mg/kg/day exemestane (≥200 times the recommended human dose on a mg/m2 basis). In a separate study, exemestane was given to female rats at 4–100 mg/kg/day beginning 14 days prior to mating and through day 15 or 20 of gestation. Exemestane increased the placental weights at ≥4 mg/kg/day (≥1.5 times the human dose on a mg/m2 basis). Exemestane showed no effects on ovarian function, mating behavior, and conception rate in rats given doses up to 20 mg/kg/day (approximately 8 times the recommended human dose on a mg/m2 basis); however, decreases in mean litter size and fetal body weight, along with delayed ossification were evidenced at ≥20 mg/kg/day. In general toxicology studies, changes in the ovary, including hyperplasia, an increase in the incidence of ovarian cysts, and a decrease in corpora lutea were observed with variable frequency in mice, rats, and dogs at doses that ranged from 3–20 times the human dose on a mg/m2 basis.
|administration=Oral
|overdose=Clinical trials have been conducted with exemestane given as a single dose to healthy female volunteers at doses as high as 800 mg and daily for 12 weeks to postmenopausal women with advanced breast cancer at doses as high as 600 mg. These dosages were well tolerated. There is no specific antidote to overdosage and treatment must be symptomatic. General supportive care, including frequent monitoring of vital signs and close observation of the patient, is indicated.

A male child (age unknown) accidentally ingested a 25-mg tablet of exemestane. The initial physical examination was normal, but blood tests performed 1 hour after ingestion indicated leucocytosis (WBC 25000/mm3 with 90% neutrophils). Blood tests were repeated 4 days after the incident and were normal. No treatment was given.

In mice, mortality was observed after a single oral dose of exemestane of 3200 mg/kg, the lowest dose tested (about 640 times the recommended human dose on a mg/m2 basis). In rats and dogs, mortality was observed after single oral doses of exemestane of 5000 mg/kg (about 2000 times the recommended human dose on a mg/m2 basis) and of 3000 mg/kg (about 4000 times the recommended human dose on a mg/m2 basis), respectively.

Convulsions were observed after single doses of exemestane of 400 mg/kg and 3000 mg/kg in mice and dogs (approximately 80 and 4000 times the recommended human dose on a mg/m2 basis), respectively.
|drugBox={{Drugbox2
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 461098446
| IUPAC_name = 6-Methylideneandrosta-1,4-diene-3,17-dione
| image = Exemestane structure.png


| tradename = Aromasin
| Drugs.com = {{drugs.com|monograph|exemestane}}
| MedlinePlus = a607006
| pregnancy_category = D
| legal_status = Rx only
| routes_of_administration = Oral


| bioavailability = ~60%
| protein_bound = 90%
| elimination_half-life = 24 hours


| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 107868-30-4
| ATC_prefix = L02
| ATC_suffix = BG06
| PubChem = 60198
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00990
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 54278
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = NY22HMQ4BX
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00963
| ChEBI_Ref = {{ebicite|changed|EBI}}
| ChEBI = 4953
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1200374


| C=20 | H=24 | O=2
| molecular_weight = 296.403 g/mol
| smiles = O=C\1\C=C/[C@]3(C(=C/1)/C(=C)C[C@H]4[C@@H]2CCC(=O)[C@]2(CC[C@H]34)C)C
| InChI = 1/C20H24O2/c1-12-10-14-15-4-5-18(22)20(15,3)9-7-16(14)19(2)8-6-13(21)11-17(12)19/h6,8,11,14-16H,1,4-5,7,9-10H2,2-3H3/t14-,15-,16-,19+,20-/m0/s1
| InChIKey = BFYIZQONLCFLEV-DAELLWKTBA
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C20H24O2/c1-12-10-14-15-4-5-18(22)20(15,3)9-7-16(14)19(2)8-6-13(21)11-17(12)19/h6,8,11,14-16H,1,4-5,7,9-10H2,2-3H3/t14-,15-,16-,19+,20-/m0/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = BFYIZQONLCFLEV-DAELLWKTSA-N
}}
|mechAction=Breast cancer cell growth may be estrogen-dependent. Aromatase is the principal enzyme that converts androgens to estrogens both in pre- and postmenopausal women. While the main source of estrogen (primarily estradiol) is the ovary in premenopausal women, the principal source of circulating estrogens in postmenopausal women is from conversion of adrenal and ovarian androgens (androstenedione and testosterone) to estrogens (estrone and estradiol) by the aromatase enzyme in peripheral tissues. Estrogen deprivation through aromatase inhibition is an effective and selective treatment for some postmenopausal patients with hormone-dependent breast cancer.

Exemestane is an irreversible, steroidal aromatase inactivator, structurally related to the natural substrate androstenedione. It acts as a false substrate for the aromatase enzyme, and is processed to an intermediate that binds irreversibly to the active site of the enzyme, causing its inactivation, an effect also known as "suicide inhibition." Exemestane significantly lowers circulating estrogen concentrations in postmenopausal women, but has no detectable effect on adrenal biosynthesis of corticosteroids or aldosterone. Exemestane has no effect on other enzymes involved in the steroidogenic pathway up to a concentration at least 600 times higher than that inhibiting the aromatase enzyme.
|structure=Exemestane is chemically described as 6-methylenandrosta-1,4-diene-3,17-dione. Its molecular formula is C20H24O2 and its structural formula is as follows:
[[|thumb|none|500px]]
|PD=======Effect on Estrogens======
Multiple doses of exemestane ranging from 0.5 to 600 mg/day were administered to postmenopausal women with advanced breast cancer. Plasma estrogen (estradiol, estrone, and estrone sulfate) suppression was seen starting at a 5-mg daily dose of exemestane, with a maximum suppression of at least 85% to 95% achieved at a 25-mg dose. Exemestane 25 mg daily reduced whole body aromatization (as measured by injecting radiolabeled androstenedione) by 98% in postmenopausal women with breast cancer. After a single dose of exemestane 25 mg, the maximal suppression of circulating estrogens occurred 2 to 3 days after dosing and persisted for 4 to 5 days.

======Effect on Corticosteroids======
In multiple-dose trials of doses up to 200 mg daily, exemestane selectivity was assessed by examining its effect on adrenal steroids. Exemestane did not affect cortisol or aldosterone secretion at baseline or in response to ACTH at any dose. Thus, no glucocorticoid or mineralocorticoid replacement therapy is necessary with exemestane treatment.

======Other Endocrine Effects======
Exemestane does not bind significantly to steroidal receptors, except for a slight affinity for the androgen receptor (0.28% relative to dihydrotestosterone). The binding affinity of its 17-dihydrometabolite for the androgen receptor, however, is 100 times that of the parent compound. Daily doses of exemestane up to 25 mg had no significant effect on circulating levels of androstenedione, dehydroepiandrosterone sulfate, or 17-hydroxyprogesterone, and were associated with small decreases in circulating levels of testosterone. Increases in testosterone and androstenedione levels have been observed at daily doses of 200 mg or more. A dose-dependent decrease in sex hormone binding globulin (SHBG) has been observed with daily exemestane doses of 2.5 mg or higher. Slight, nondose-dependent increases in serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels have been observed even at low doses as a consequence of feedback at the pituitary level. Exemestane 25 mg daily had no significant effect on thyroid function [free triiodothyronine (FT3), free thyroxine (FT4), and thyroid stimulating hormone (TSH)].

======Coagulation and Lipid Effects======
In study 027 of postmenopausal women with early breast cancer treated with exemestane (N=73) or placebo (N=73), there was no change in the coagulation parameters activated partial thromboplastin time [APTT], prothrombin time [PT], and fibrinogen. Plasma HDL cholesterol was decreased 6–9% in exemestane treated patients; total cholesterol, LDL cholesterol, triglycerides, apolipoprotein-A1, apolipoprotein-B, and lipoprotein-a were unchanged. An 18% increase in homocysteine levels was also observed in exemestane treated patients compared with a 12% increase seen with placebo.
|PK=Following oral administration to healthy postmenopausal women, plasma concentrations of exemestane decline polyexponentially with a mean terminal half-life of about 24 hours. The pharmacokinetics of exemestane are dose proportional after single (10 to 200 mg) or repeated oral doses (0.5 to 50 mg). Following repeated daily doses of exemestane 25 mg, plasma concentrations of unchanged drug are similar to levels measured after a single dose. Pharmacokinetic parameters in postmenopausal women with advanced breast cancer following single or repeated doses have been compared with those in healthy, postmenopausal women. After repeated dosing, the average oral clearance in women with advanced breast cancer was 45% lower than the oral clearance in healthy postmenopausal women, with corresponding higher systemic exposure. Mean AUC values following repeated doses in women with breast cancer (75.4 ng∙h/mL) were about twice those in healthy women (41.4 ng∙h/mL).

======Absorption======
Following oral administration, exemestane appeared to be absorbed more rapidly in women with breast cancer than in the healthy women, with a mean -tmax of 1.2 hours in the women with breast cancer and 2.9 hours in healthy women. Approximately 42% of radiolabeled exemestane was absorbed from the gastrointestinal tract. A high-fat breakfast increased AUC and Cmax of exemestane by 59% and 39%, respectively, compared to fasted state.

======Distribution======
Exemestane is distributed extensively into tissues. Exemestane is 90% bound to plasma proteins and the fraction bound is independent of the total concentration. Albumin and α11-acid glycoprotein both contribute to the binding. The distribution of exemestane and its metabolites into blood cells is negligible.

======Metabolism======
Exemestane is extensively metabolized, with levels of the unchanged drug in plasma accounting for less than 10% of the total radioactivity. The initial steps in the metabolism of exemestane are oxidation of the methylene group in position 6 and reduction of the 17-keto group with subsequent formation of many secondary metabolites. Each metabolite accounts only for a limited amount of drug-related material. The metabolites are inactive or inhibit aromatase with decreased potency compared with the parent drug. One metabolite may have androgenic activity. Studies using human liver preparations indicate that cytochrome P 450 3A4 (CYP 3A4) is the principal isoenzyme involved in the oxidation of exemestane. Exemestane is metabolized also by aldoketoreductases.

======Elimination======
Following administration of radiolabeled exemestane to healthy postmenopausal women, the cumulative amounts of radioactivity excreted in urine and feces were similar (42 ± 3% in urine and 42 ± 6% in feces over a 1-week collection period). The amount of drug excreted unchanged in urine was less than 1% of the dose.
|nonClinToxic=======Carcinogenesis and Mutagenesis======
A 2-year carcinogenicity study in mice at doses of 50, 150, and 450 mg/kg/day exemestane (gavage), resulted in an increased incidence of hepatocellular adenomas and/or carcinomas in both genders at the high dose level. Plasma AUC (0–24hr) at the high dose were 2575 ± 386 and 5667 ± 1833 ng.hr/mL in males and females (approx. 34 and 75 fold the AUC in postmenopausal patients at the recommended clinical dose). An increased incidence of renal tubular adenomas was observed in male mice at the high dose of 450 mg/kg/day. Since the doses tested in mice did not achieve an MTD, neoplastic findings in organs other than liver and kidneys remain unknown.

A separate carcinogenicity study was conducted in rats at the doses of 30, 100, and 315 mg/kg/day exemestane (gavage) for 92 weeks in males and 2 years in females. No evidence of carcinogenic activity up to the highest dose tested of 315 mg/kg/day was observed in females. The male rat study was inconclusive since it was terminated prematurely at Week 92. At the highest dose, plasma AUC(0–24hr) levels in male (1418 ± 287 ng.hr/mL) and female (2318 ± 1067 ng.hr/mL) rats were 19 and 31 fold higher than those measured in postmenopausal cancer patients receiving the recommended clinical dose.

Exemestane was not mutagenic in vitro in bacteria (Ames test) or mammalian cells (V79 Chinese hamster lung cells). Exemestane was clastogenic in human lymphocytes in vitro without metabolic activation but was not clastogenic in vivo (micronucleus assay in mouse bone marrow). Exemestane did not increase unscheduled DNA synthesis in rat hepatocytes when tested in vitro.
|clinicalStudies======Adjuvant Treatment in Early Breast Cancer=====
The Intergroup Exemestane Study 031 (IES) was a randomized, double-blind, multicenter, multinational study comparing exemestane (25 mg/day) vs. tamoxifen (20 or 30 mg/day) in postmenopausal women with early breast cancer. Patients who remained disease-free after receiving adjuvant tamoxifen therapy for 2 to 3 years were randomized to receive an additional 3 or 2 years of exemestane or tamoxifen to complete a total of 5 years of hormonal therapy.

The primary objective of the study was to determine whether, in terms of disease-free survival, it was more effective to switch to exemestane rather than continuing tamoxifen therapy for the remainder of five years. Disease-free survival was defined as the time from randomization to time of local or distant recurrence of breast cancer, contralateral invasive breast cancer, or death from any cause.

The secondary objectives were to compare the two regimens in terms of overall survival and long-term tolerability. Time to contralateral invasive breast cancer and distant recurrence-free survival were also evaluated.

A total of 4724 patients in the intent-to-treat (ITT) analysis were randomized to exemestane (exemestane tablets) 25 mg once daily (N = 2352) or to continue to receive tamoxifen once daily at the same dose received before randomization (N = 2372). Demographics and baseline tumor characteristics are presented in Table 5. Prior breast cancer therapy is summarized in Table 6.

[[File:Exemestane Adjuvant Treatment in Early Breast Cancer.png|thumb|none|700px]]

After a median duration of therapy of 27 months and with a median follow-up of 34.5 months, 520 events were reported, 213 in the exemestane group and 307 in the tamoxifen group.

[[File:Exemestane Primary Endpoint Events.png|thumb|none|500px]]

Disease-free survival in the intent-to-treat population was statistically significantly improved [Hazard Ratio (HR) = 0.69, 95% CI: 0.58, 0.82, P = 0.00003, Table 8, Figure 1] in the exemestane arm compared to the tamoxifen arm. In the hormone receptor-positive subpopulation representing about 85% of the trial patients, disease-free survival was also statistically significantly improved (HR = 0.65, 95% CI: 0.53, 0.79, P = 0.00001) in the exemestane arm compared to the tamoxifen arm. Consistent results were observed in the subgroups of patients with node negative or positive disease, and patients who had or had not received prior chemotherapy. Overall survival was not significantly different in the two groups, with 116 deaths occurring in the exemestane group and 137 in the tamoxifen group.

[[File:Exemestane Efficacy Results from the IES Study in Postmenopausal Women with Early Breast Cancer.png|thumb|none|600px]]

=====Treatment of Advanced Breast Cancer=====
Exemestane 25 mg administered once daily was evaluated in a randomized double-blind, multicenter, multinational comparative study and in two multicenter single-arm studies of postmenopausal women with advanced breast cancer who had disease progression after treatment with tamoxifen for metastatic disease or as adjuvant therapy. Some patients also have received prior cytotoxic therapy, either as adjuvant treatment or for metastatic disease.

The primary purpose of the three studies was evaluation of objective response rate (complete response [CR] and partial response [PR]). Time to tumor progression and overall survival were also assessed in the comparative trial. Response rates were assessed based on World Health Organization (WHO) criteria, and in the comparative study, were submitted to an external review committee that was blinded to patient treatment. In the comparative study, 769 patients were randomized to receive exemestane (exemestane tablets) 25 mg once daily (N = 366) or megestrol acetate 40 mg four times daily (N = 403). Demographics and baseline characteristics are presented in Table 9.

[[File:Exemestane Demographics and Baseline Characteristics from the Comparative Study of Postmenopausal Women with Advanced Breast Cancer Whose Disease Had Progressed after Tamoxifen Therapy.png|thumb|none|600px]]

The efficacy results from the comparative study are shown in Table 10. The objective response rates observed in the two treatment arms showed that exemestane was not different from megestrol acetate. Response rates for exemestane from the two single-arm trials were 23.4% and 28.1%.

[[File:Exemestane Efficacy Results from the Comparative Study of Postmenopausal Women with Advanced Breast Cancer Whose Disease Had Progressed after Tamoxifen Therapy.png|thumb|none|500px]]

There were too few deaths occurring across treatment groups to draw conclusions on overall survival differences. The Kaplan-Meier curve for time to tumor progression in the comparative study is shown in Figure 2.

[[File:Exemestane Time to Tumor Progression.png|thumb|none|500px]]
|howSupplied=* Exemestane 25 mg tablets
:* 30 tablet bottle
:* NDC 0009-7663-04
|storage=Store at 25°C (77ºF)
|packLabel=[[File:Exemestane FDA package label.png|thumb|none|600px]]
|fdaPatientInfo======Premenopausal Women=====
Patients should be advised that exemestane is not for use in premenopausal women.

=====Other Estrogen-Containing Agents=====
Patients should be informed that they should not take estrogen-containing agents while they are taking exemestane as these could interfere with its pharmacologic action.

=====Bone Effects=====
Patients should be informed that exemestane lowers the level of estrogen in the body. This may lead to reduction in bone mineral density (BMD) over time. The lower the BMD, the greater the risk of [[osteoporosis]] and [[fracture]].
|alcohol=Alcohol-Exemestane interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=* Aromasin <ref>{{cite web|url=http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=cf066b7a-032a-416c-8d40-15ba581423e3|title=FDA LABEL: AROMASIN- exemestane tablet}}</ref>
}}
{{LabelImage
|fileName=Exemestane 25 mg.png
}}

[[Category:Drug]]
[[Category:Chemotherapeutic agents]]

Cholestyramine

2015-03-18T14:38:44Z

Sree Teja Yelamanchili:

{{DrugProjectFormSinglePage
|authorTag={{SS}}; {{STY}}
|genericName=Cholestyramine
|aOrAn=a
|drugClass=[[bile acid sequestrant]]
|indicationType=treatment
|indication=elevated [[cholesterol|serum cholesterol]] in patients with primary [[hypercholesterolemia]] (elevated [[low density lipoprotein]] [LDL] cholesterol) who do not respond adequately to diet.
|adverseReactions=[[constipation]]
|blackBoxWarningTitle=<b><span style="color:#FF0000;">TITLE</span></b>
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)
|fdaLIADAdult=<H4>Reduction of elevated serum cholesterol </H4>

* Dosing information

:* Recommended starting adult dose: '''one packet or one level scoopful once or twice a day.'''
:* Recommended maintenance dose for all: '''2 to 4 packets or scoopfuls daily (8-16 grams anhydrous cholestyramine resin) divided into two doses. '''
:* Four grams of anhydrous cholestyramine resin is contained in each measured dose of Cholestyramine as follows:

[[File:Cholestyramine_administration_01.png|thumb|none|500px|This image is provided by the National Library of Medicine.]]

* It is recommended that increases in dose be gradual with periodic assessment of lipid/lipoprotein levels at intervals of not less than 4 weeks. The maximum recommended daily dose is six packets or scoopfuls of cholestyramine for oral suspension (24 grams of anhydrous cholestyramine resin). The suggested time of administration is at mealtime but may be modified to avoid interference with absorption of other medications. Although the recommended dosing schedule is twice daily, cholestyramine for oral suspension may be administered in 1 to 6 doses per day.

* Cholestyramine should not be taken in its dry form. Always mix Cholestyramine with water or other fluids before ingesting.

<h4>Concomitant Therapy</h4>

* Preliminary evidence suggests that the lipid-lowering effects of Cholestyramine on total and LDL-cholesterol are enhanced when combined with a HMG-CoA reductase inhibitor, e.g., [[pravastatin]], [[lovastatin]], [[simvastatin]], and [[fluvastatin]]. Additive effects on LDL-cholesterol are also seen with combined nicotinic acid/Cholestyramine therapy.

<H4>Preparation</H4>

* The color of Cholestyramine may vary somewhat from batch to batch but this variation does not affect the performance of the product. Place the contents of one single-dose packet or one level scoopful of Cholestyramine in a glass or cup. Add an amount of water or other non-carbonated beverage of your choice depending on the product being used:

[[File:Cholestyramine_administration_02.png|thumb|none|500px|This image is provided by the National Library of Medicine.]]

* Stir to a uniform consistency and drink.

* Cholestyramine may also be mixed with highly fluid soups or pulpy fruits with a high moisture content such as applesauce or crushed pineapple.
|offLabelAdultGuideSupport=There is limited information about <i>Off-Label Guideline-Supported Use</i> of Cholestyramine in adult patients.
|offLabelAdultNoGuideSupport=<H4>Bile acid malabsorption syndrome</H4>

* Dosing information

:* ''' 1 to 2 sachets TID'''<ref name="pmid9768525">{{cite journal| author=Sinha L, Liston R, Testa HJ, Moriarty KJ| title=Idiopathic bile acid malabsorption: qualitative and quantitative clinical features and response to cholestyramine. | journal=Aliment Pharmacol Ther | year= 1998 | volume= 12 | issue= 9 | pages= 839-44 | pmid=9768525 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9768525 }} </ref>

<h4>Collagenous colitis</h4>

* Dosing information

:* '''4-grams (g) packets/day '''<ref name="pmid10644309">{{cite journal| author=Ung KA, Gillberg R, Kilander A, Abrahamsson H| title=Role of bile acids and bile acid binding agents in patients with collagenous colitis. | journal=Gut | year= 2000 | volume= 46 | issue= 2 | pages= 170-5 | pmid=10644309 | doi= | pmc=PMC1727822 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10644309 }} </ref>

<h4>Fistula of bile duct</h4>

* Dosing information

:* '''20 g'''<ref name="pmid7427037">{{cite journal| author=Bell SN, Varigos GA| title=Treatment of skin irritations around biliary fistulas with cholestyramine. | journal=Br J Surg | year= 1980 | volume= 67 | issue= 11 | pages= 785 | pmid=7427037 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7427037 }} </ref>

<H4>Generalized atherosclerosis</H4>

* Dosing information

:* '''6 g 4 times per day '''<ref name="pmid6360414">{{cite journal| author=Brensike JF, Levy RI, Kelsey SF, Passamani ER, Richardson JM, Loh IK et al.| title=Effects of therapy with cholestyramine on progression of coronary arteriosclerosis: results of the NHLBI Type II Coronary Intervention Study. | journal=Circulation | year= 1984 | volume= 69 | issue= 2 | pages= 313-24 | pmid=6360414 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6360414 }} </ref>
|fdaLIADPed=<H4>Reduction of elevated serum cholesterol </H4>

* Dosing information

:* '''240 mg/kg/day in 2-3 doses''', normally not to exceed '''8 gm/day''' with dose titration based on response and tolerance
|offLabelPedGuideSupport=There is limited information about <i>Off-Label Guideline-Supported Use</i> of Cholestyramine in pediatric patients.
|offLabelPedNoGuideSupport=<H4>Cholestasis</H4>

* Dosing information

:* Not applicable. <ref name="pmid2990356">{{cite journal| author=Deutsch J, Smith AL, Danks DM, Campbell PE| title=Long term prognosis for babies with neonatal liver disease. | journal=Arch Dis Child | year= 1985 | volume= 60 | issue= 5 | pages= 447-51 | pmid=2990356 | doi= | pmc=PMC1777337 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2990356 }} </ref>

<H4>Toddler diarrhea</H4>

* Dosing information

:* '''2 g BID '''<ref name="pmid3901661">{{cite journal| author=Vesikari T, Isolauri E| title=A comparative trial of cholestyramine and loperamide for acute diarrhoea in infants treated as outpatients. | journal=Acta Paediatr Scand | year= 1985 | volume= 74 | issue= 5 | pages= 650-4 | pmid=3901661 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3901661 }} </ref>
|contraindications=Cholestyramine for oral suspension is contraindicated in patients with complete biliary obstruction where bile is not secreted into the intestine and in those individuals who have shown [[hypersensitivity]] to any of its components.
|warnings=PHENYLKETONURICS: CHOLESTYRAMINE for ORAL SUSPENSION USP, LIGHT CONTAINS 14.0 mg [[PHENYLALANINE]] PER 5 GRAM DOSE.

==PRECAUTIONS==

===General===

*Chronic use of cholestyramine resin may be associated with increased bleeding tendency due to [[hypoprothrombinemia]] associated with [[Vitamin K deficiency]].
*This will usually respond promptly to parenteral Vitamin K1 and recurrences can be prevented by oral administration of Vitamin K1.
*Reduction of serum or red cell [[folate]] has been reported over long term administration of cholestyramine resin.
*Supplementation with [[folic acid]] should be considered in these cases.
*There is a possibility that prolonged use of cholestyramine resin, since it is a chloride form of anion exchange resin, may produce [[hyperchloremic acidosis]].
*This would especially be true in younger and smaller patients where the relative dosage may be higher.
*Caution should also be exercised in patients with [[renal insufficiency]] or volume depletion, and in patients receiving concomitant [[spironolactone]].
*Cholestyramine resin may produce or worsen pre-existing [[constipation]]. *The dosage should be increased gradually in patients to minimize the risk of developing fecal impaction.
*In patients with pre-existing [[constipation]], the starting dose should be 1 packet or 1 scoop once daily for 5 to 7 days, increasing to twice daily with monitoring of [[constipation]] and of serum lipoproteins, at least twice, 4 to 6 weeks apart.
*Increased fluid intake and fiber intake should be encouraged to alleviate [[constipation]] and a stool softener may occasionally be indicated.
*If the initial dose is well tolerated, the dose may be increased as needed by one dose/day (at monthly intervals) with periodic monitoring of serum lipoproteins.
*If [[constipation]] worsens or the desired therapeutic response is not achieved at one to six doses/day, combination therapy or alternate therapy should be considered.
*Particular effort should be made to avoid constipation in patients with symptomatic coronary artery disease.
*Constipation associated with cholestyramine resin may aggravate [[hemorrhoids]].

===Laboratory Tests===

Serum [[cholesterol]] levels should be determined frequently during the first few months of therapy and periodically thereafter. Serum [[triglyceride]] levels should be measured periodically to detect whether significant changes have occurred.
The LRC-CPPT showed a dose-related increase in serum triglycerides of 10.7%–17.1% in the cholestyramine-treated group, compared with an increase of 7.9%–11.7% in the placebo group. Based on the mean values and adjusting for the placebo group, the cholestyramine-treated group showed an increase of 5% over pre-entry levels the first year of the study and an increase of 4.3% the seventh year.
|clinicalTrials=*The most common adverse reaction is [[constipation]].
*When used as a cholesterol-lowering agent predisposing factors for most complaints of constipation are high dose and increased age (more than 60 years old).
*Most instances of [[constipation]] are mild, transient, and controlled with conventional therapy.
*Some patients require a temporary decrease in dosage or discontinuation of therapy.

=====Less Frequent Adverse Reactions=====
*Abdominal discomfort and/or pain, [[flatulence]], [[nausea]], [[vomiting]], [[diarrhea]], [[eructation]], [[anorexia]], and [[steatorrhea]], bleeding tendencies due to [[hypoprothrombinemia]] ([[Vitamin K deficiency]]) as well as [[Vitamin A]] (one case of [[night blindness]] reported) and [[Vitamin D|D]] deficiencies, [[hyperchloremic acidosis]] in children, [[osteoporosis]], [[rash]] and irritation of the skin, tongue and perianal area. Rare reports of [[intestinal obstruction]], including two deaths, have been reported in pediatric patients.
*Occasional calcified material has been observed in the biliary tree, including calcification of the gallbladder, in patients to whom cholestyramine resin has been given.
*However, this may be a manifestation of the liver disease and not drug related.
*One patient experienced biliary colic on each of three occasions on which he took cholestyramine resin.
*One patient diagnosed as acute abdominal symptom complex was found to have a “pasty mass” in the transverse colon on x-ray.
*Other events (not necessarily drug related) reported in patients taking cholestyramine resin include:

'''Gastrointestinal'''—GI-[[rectal bleeding]], [[black stools]], [[hemorrhoids|hemorrhoidal bleeding]], bleeding from known [[duodenal ulcer]], [[dysphagia]], [[hiccups]], ulcer attack, sour taste, [[pancreatitis]], [[rectal pain]], [[diverticulitis]].
'''Laboratory test changes'''—[[Liver function tests abnormality|Liver function abnormalities]].<BR>
'''Hematologic'''—Prolonged [[prothrombin time]], [[ecchymosis]], [[anemia]].<BR>
'''Hypersensitivity'''—[[Urticaria]], [[asthma]], [[wheezing]], [[shortness of breath]].<BR>
'''Musculoskeletal'''—[[Backache]], muscle and joint pains, [[arthritis]].<BR>
'''Neurologic'''—[[Headache]], [[anxiety]], [[vertigo]], [[dizziness]], [[fatigue]], [[tinnitus]], [[syncope]], [[drowsiness]], femoral nerve pain, [[paresthesia]].<BR>
'''Eye'''—[[Uveitis]].<BR>
'''Renal'''—[[Hematuria]], [[dysuria]], burnt odor to urine, [[diuresis]].<BR>
'''Miscellaneous'''—[[Weight loss]], [[weight gain]], increased [[libido]], swollen glands, [[edema]], dental bleeding, [[dental caries]], erosion of tooth enamel, tooth discoloration.<BR>
|postmarketing=There is limited information about the Post marketing Experience.
|drugInteractions=*Cholestyramine for Oral Suspension USP may delay or reduce the absorption of concomitant oral medication such as [[phenylbutazone]], [[warfarin]], [[thiazide diuretics]] (acidic), or [[propranolol]] (basic), as well as [[tetracycline]], [[penicillin G]], [[phenobarbital]], thyroid and thyroxine preparations, [[estrogens]] and [[progestins]], and [[digitalis]]. *Interference with the absorption of oral phosphate supplements has been observed with another positively-charged [[bile acid sequestrant]]. *Cholestyramine may interfere with the pharmacokinetics of drugs that undergo entero-hepatic circulation.
*The discontinuance of Cholestyramine could pose a hazard to health if a potentially toxic drug such as digitalis has been titrated to a maintenance level while the patient was taking Cholestyramine.
*Because cholestyramine binds bile acids, Cholestyramine may interfere with normal fat digestion and absorption and thus may prevent absorption of fat-soluble vitamins such as A, D, E and K.
*When Cholestyramine is given for long periods of time, concomitant supplementation with water-miscible (or parenteral) forms of fat-soluble vitamins should be considered.
*SINCE CHOLESTYRAMINE MAY BIND OTHER DRUGS GIVEN CONCURRENTLY, IT IS RECOMMENDED THAT PATIENTS TAKE OTHER DRUGS AT LEAST ONE HOUR BEFORE OR 4 TO 6 HOURS AFTER CHOLESTYRAMINE (OR AT AS GREAT AN INTERVAL AS POSSIBLE) TO AVOID IMPEDING THEIR ABSORPTION.
|FDAPregCat=C
|useInPregnancyFDA=There are no adequate and well controlled studies in pregnant women. The use of Cholestyramine in pregnancy or lactation or by women of childbearing age requires that the potential benefits of drug therapy be weighed against the possible hazards to the mother and child. Cholestyramine is not absorbed systemically, however, it is known to interfere with absorption of fat-soluble vitamins; accordingly, regular prenatal supplementation may not be adequate.
|useInNursing=Caution should be exercised when Cholestyramine is administered to a nursing mother. The possible lack of proper vitamin absorption described in the “Pregnancy” section may have an effect on nursing infants.
|useInPed=Although an optimal dosage schedule has not been established, standard texts (6,7) list a usual pediatric dose of 240 mg/kg/day of anhydrous cholestyramine resin in two to three divided doses, normally not to exceed 8 gm/day with dose titration based on response and tolerance.
In calculating pediatric dosages, 44.4 mg of anhydrous cholestyramine resin are contained in 100 mg of Cholestyramine for Oral Suspension USP and 80 mg of anhydrous cholestyramine resin are contained in 100 mg of Cholestyramine for Oral Suspension USP, Light.
The effects of long-term administration, as well as its effect in maintaining lowered cholesterol levels in pediatric patients, are unknown.
|administration=Oral
|monitoring=There is limited information about the drug monitoring.
|IVCompat=There is limited information about the IV Compatibility.
|overdose=Overdosage with Cholestyramine has been reported in a patient taking 150% of the maximum recommended daily dosage for a period of several weeks. No ill effects were reported. Should an overdosage occur, the chief potential harm would be obstruction of the gastrointestinal tract. The location of such potential obstruction, the degree of obstruction, and the presence or absence of normal gut motility would determine treatment.
|drugBox={{Drugbox2
| Verifiedfields = changed
| verifiedrevid = 412216968
| IUPAC_name =
| image = Cholestyramine_resin.png


| tradename = Questran
| Drugs.com = {{drugs.com|monograph|cholestyramine-resin}}
| MedlinePlus = a682672
| pregnancy_AU = 
| pregnancy_US = C
| pregnancy_category = C
| legal_AU = 
| legal_UK = 
| legal_US = Rx-only
| legal_status = Rx-only
| routes_of_administration = oral


| bioavailability = low
| protein_bound = unknown
| metabolism = bile acids
| elimination_half-life = .1 hr
| excretion = feces


| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 11041-12-6
| ATC_prefix = C10
| ATC_suffix = AC01
| ATC_supplemental =
| PubChem =
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB01432
| UNII_Ref = {{fdacite|changed|FDA}}
| UNII = 4B33BGI082
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D02690
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 1201625
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = NA


| molecular_weight = Average MW exceeds 10<sup>6</sup> Daltons
}}
|mechAction=There is limited information about the mechanism of action.
|structure=Cholestyramine for Oral Suspension USP, the chloride salt of a basic anion exchange resin, a cholesterol lowering agent, is intended for oral administration. Cholestyramine resin is quite hydrophilic, but insoluble in water. The cholestyramine resin in Cholestyramine is not absorbed from the digestive tract. Four grams of anhydrous cholestyramine resin is contained in 9 grams of Cholestyramine for Oral Suspension USP. Four grams of anhydrous cholestyramine resin is contained in 5 grams of Cholestyramine for Oral Suspension USP, Light. It is represented by the following structural formula:

[[File:Cholestyramine_structure_01.png|thumb|none|500px|This image is provided by the National Library of Medicine.]]

Cholestyramine for Oral Suspension USP contains the following inactive ingredients: acacia, citric acid, D&C Yellow No. 10, FD&C Yellow No. 6, flavor (natural and artificial Orange), polysorbate 80, propylene glycol alginate and sucrose. Cholestyramine for Oral Suspension USP, Light contains the following inactive ingredients: aspartame, citric acid, colloidal silicon dioxide, D&C Yellow No. 10, FD&C Red No. 40, flavor (natural and artificial Orange), maltodextrin, propylene glycol alginate and xanthan gum.
|PD=There is limited information about the pharmacodynamics.
|PK=There is limited information about the pharmacokinetics.
|nonClinToxic=In studies conducted in rats in which cholestyramine resin was used as a tool to investigate the role of various intestinal factors, such as fat, bile salts and microbial flora, in the development of intestinal tumors induced by potent carcinogens, the incidence of such tumors was observed to be greater in cholestyramine resin-treated rats than in control rats.
The relevance of this laboratory observation from studies in rats to the clinical use of Cholestyramine is not known. In the LRC-CPPT study referred to above, the total incidence of fatal and nonfatal neoplasms was similar in both treatment groups. When the many different categories of tumors are examined, various alimentary system cancers were somewhat more prevalent in the cholestyramine group. The small numbers and the multiple categories prevent conclusions from being drawn. However, in view of the fact that cholestyramine resin is confined to the GI tract and not absorbed, and in light of the animal experiments referred to above, a six-year post-trial follow-up of the LRC-CPPT 5 patient population has been completed (a total of 13.4 years of in-trial plus post-trial follow-up) and revealed no significant difference in the incidence of cause-specific mortality or cancer morbidity between cholestyramine and placebo treated patients.
|clinicalStudies=In a large, placebo-controlled, multi-clinic study, LRC-CPPT1 , hypercholesterolemic subjects treated with cholestyramine had mean reductions in total and low-density lipoprotein cholesterol (LDL-C) which exceeded those for diet and placebo treatment by 7.2% and 10.4 %, respectively. Over the seven-year study period the Cholestyramine group experienced a 19% reduction (relative to the incidence in the placebo group) in the combined rate of coronary heart disease death plus non-fatal [[myocardial infarction]] (cumulative incidences of 7% Cholestyramine and 8.6% placebo). The subjects included in the study were men aged 35-59 with serum cholesterol levels above 265 mg/dL and no previous history of heart disease. It is not clear to what extent these findings can be extrapolated to females and other segments of the hypercholesterolemic population.
Two controlled clinical trials have examined the effects of Cholestyramine monotherapy upon coronary atherosclerotic lesions using [[coronary arteriography]]. In the NHLBI Type II Coronary Intervention Trial2, 116 patients (80% male) with [[coronary artery disease]] ([[CAD]]) documented by arteriography were randomized to Cholestyramine or placebo for five years of treatment. Final study arteriography revealed progression of coronary artery disease in 49% of placebo patients compared to 32% of the Cholestyramine group (p<0.05).
In the St. Thomas Atherosclerosis Regression Study (STARS)3, 90 hypercholesteroleic men with CAD were randomized to three blinded treatments: usual care, lipid-lowering diet, and lipid-lowering diet plus Cholestyramine. After 36 months, follow-up coronary arteriography revealed progression of disease in 46% of usual care patients, 15% of patients on lipid-lowering diet and 12% of those receiving diet plus Cholestyramine (p<0.02). The mean absolute width of coronary segments decreased in the usual care group, increased slightly (0.003mm) in the diet group and increased by 0.103mm in the diet plus Cholestyramine group (p<0.05). Thus in these randomized controlled clinical trials using coronary arteriography, Cholestyramine monotherapy has been demonstrated to slow progression2,3 and promote regression3 of atherosclerotic lesions in the coronary arteries of patients with coronary artery disease.
The effect of intensive lipid-lowering therapy on coronary atherosclerosis has been assessed by arteriography in hyperlipidemic patients. In these randomized, controlled clinical trials, patients were treated for two to four years by either conventional measures (diet, placebo, or in some cases low dose resin), or intensive combination therapy using diet plus [[colestipol]] (an anion exchange resin with a mechanism of action and an effect on serum lipids similar to that of Cholestyramine for Oral Suspension USP and Cholestyramine for Oral Suspension USP, Light) plus either [[nicotinic acid]] or [[lovastatin]]. When compared to conventional measures, intensive lipid-lowering combination therapy significantly reduced the frequency of progression and increased the frequency of regression of coronary atherosclerotic lesions in patients with or at risk for coronary artery disease.
|howSupplied=Cholestyramine for Oral Suspension USP is a yellow colored orange flavored powder available in cans containing 378 grams and in cartons of sixty 9 gram packets. Four grams of anhydrous cholestyramine resin are contained in 9 grams of Cholestyramine for Oral Suspension USP. The 378 g can includes a 15 cc scoop. The scoop is not interchangeable with scoops from other products. Made in U.S.A.

[[File:Cholestyramine_how supplied_01.png|thumb|none|500px|This image is provided by the National Library of Medicine.]]

Cholestyramine for Oral Suspension USP, Light is a cream to pale yellow colored orange flavored powder available in cans containing 210 grams and in cartons of sixty 5 gram packets. Four grams of anhydrous cholestyramine resin are contained in 5 grams of Cholestyramine for Oral Suspension USP, Light. The 210 g can includes a 9 cc scoop. The scoop is not interchangeable with scoops from other products. Made in India*

[[File:Cholestyramine_how supplied_02.png|thumb|none|500px|This image is provided by the National Library of Medicine.]]
|storage=Store between 20º to 25ºC (68º to 77ºF). Excursions permitted to 15º to 30ºC (59º to 86ºF).
|fdaPatientInfo=Inform your physician if you are pregnant or plan to become pregnant or are breastfeeding. Drink plenty of fluids and mix each 9 gram dose of Cholestyramine for Oral Suspension USP in at least 2 to 6 ounces of fluid. Mix each 5 gram dose of Cholestyramine for Oral Suspension USP, Light in at least 2 to 6 ounces of fluid before taking. Sipping or holding the resin suspension in the mouth for prolonged periods may lead to changes in the surface of the teeth resulting in discoloration, erosion of enamel or decay; good oral hygiene should be maintained.
|alcohol=Alcohol-Cholestyramine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|lookAlike=There is limited information about the Look-Alike Drug Names.
}}
{{PillImage}}
{{LabelImage
|fileName=Cholestyramine_label_01.jpg
}}
{{LabelImage
|fileName=Cholestyramine_label_02.jpg
}}
{{LabelImage
|fileName=Cholestyramine_label_03.jpg
}}
{{LabelImage
|fileName=Cholestyramine_label_04.jpg
}}
{{LabelImage
|fileName=Cholestyramine_label_05.jpg
}}
{{LabelImage
|fileName=Cholestyramine_label_06.jpg
}}
{{LabelImage
|fileName=Cholestyramine_panel_01.png
}}
{{LabelImage
|fileName=Cholestyramine_panel_02.png
}}
{{LabelImage
|fileName=Cholestyramine_panel_03.png
}}

[[Category:Bile acid sequestrants]]
[[Category: Cardiovascular Drugs]]
[[Category: Drug]]

Cholestyramine

2015-03-18T14:31:25Z

Sree Teja Yelamanchili:

{{DrugProjectFormSinglePage
|authorTag={{SS}}; {{STY}}
|genericName=Cholestyramine
|aOrAn=a
|drugClass=[[bile acid sequestrant]]
|indicationType=treatment
|indication=elevated [[cholesterol|serum cholesterol]] in patients with primary [[hypercholesterolemia]] (elevated [[low density lipoprotein]] [LDL] cholesterol) who do not respond adequately to diet.
|adverseReactions=[[constipation]]
|blackBoxWarningTitle=<b><span style="color:#FF0000;">TITLE</span></b>
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)
|fdaLIADAdult=<H4>Reduction of elevated serum cholesterol </H4>

* Dosing information

:* Recommended starting adult dose: '''one packet or one level scoopful once or twice a day.'''
:* Recommended maintenance dose for all: '''2 to 4 packets or scoopfuls daily (8-16 grams anhydrous cholestyramine resin) divided into two doses. '''
:* Four grams of anhydrous cholestyramine resin is contained in each measured dose of Cholestyramine as follows:

[[File:Cholestyramine_administration_01.png|thumb|none|500px|This image is provided by the National Library of Medicine.]]

* It is recommended that increases in dose be gradual with periodic assessment of lipid/lipoprotein levels at intervals of not less than 4 weeks. The maximum recommended daily dose is six packets or scoopfuls of cholestyramine for oral suspension (24 grams of anhydrous cholestyramine resin). The suggested time of administration is at mealtime but may be modified to avoid interference with absorption of other medications. Although the recommended dosing schedule is twice daily, cholestyramine for oral suspension may be administered in 1 to 6 doses per day.

* Cholestyramine should not be taken in its dry form. Always mix Cholestyramine with water or other fluids before ingesting.

<h4>Concomitant Therapy</h4>

* Preliminary evidence suggests that the lipid-lowering effects of Cholestyramine on total and LDL-cholesterol are enhanced when combined with a HMG-CoA reductase inhibitor, e.g., [[pravastatin]], [[lovastatin]], [[simvastatin]], and [[fluvastatin]]. Additive effects on LDL-cholesterol are also seen with combined nicotinic acid/Cholestyramine therapy.

<H4>Preparation</H4>

* The color of Cholestyramine may vary somewhat from batch to batch but this variation does not affect the performance of the product. Place the contents of one single-dose packet or one level scoopful of Cholestyramine in a glass or cup. Add an amount of water or other non-carbonated beverage of your choice depending on the product being used:

[[File:Cholestyramine_administration_02.png|thumb|none|500px|This image is provided by the National Library of Medicine.]]

* Stir to a uniform consistency and drink.

* Cholestyramine may also be mixed with highly fluid soups or pulpy fruits with a high moisture content such as applesauce or crushed pineapple.
|offLabelAdultGuideSupport=There is limited information about <i>Off-Label Guideline-Supported Use</i> of Cholestyramine in adult patients.
|offLabelAdultNoGuideSupport=<H4>Bile acid malabsorption syndrome</H4>

* Dosing information

:* ''' 1 to 2 sachets TID'''<ref name="pmid9768525">{{cite journal| author=Sinha L, Liston R, Testa HJ, Moriarty KJ| title=Idiopathic bile acid malabsorption: qualitative and quantitative clinical features and response to cholestyramine. | journal=Aliment Pharmacol Ther | year= 1998 | volume= 12 | issue= 9 | pages= 839-44 | pmid=9768525 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9768525 }} </ref>

<h4>Collagenous colitis</h4>

* Dosing information

:* '''4-grams (g) packets/day '''<ref name="pmid10644309">{{cite journal| author=Ung KA, Gillberg R, Kilander A, Abrahamsson H| title=Role of bile acids and bile acid binding agents in patients with collagenous colitis. | journal=Gut | year= 2000 | volume= 46 | issue= 2 | pages= 170-5 | pmid=10644309 | doi= | pmc=PMC1727822 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10644309 }} </ref>

<h4>Fistula of bile duct</h4>

* Dosing information

:* '''20 g'''<ref name="pmid7427037">{{cite journal| author=Bell SN, Varigos GA| title=Treatment of skin irritations around biliary fistulas with cholestyramine. | journal=Br J Surg | year= 1980 | volume= 67 | issue= 11 | pages= 785 | pmid=7427037 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7427037 }} </ref>

<H4>Generalized atherosclerosis</H4>

* Dosing information

:* '''6 g 4 times per day '''<ref name="pmid6360414">{{cite journal| author=Brensike JF, Levy RI, Kelsey SF, Passamani ER, Richardson JM, Loh IK et al.| title=Effects of therapy with cholestyramine on progression of coronary arteriosclerosis: results of the NHLBI Type II Coronary Intervention Study. | journal=Circulation | year= 1984 | volume= 69 | issue= 2 | pages= 313-24 | pmid=6360414 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6360414 }} </ref>
|fdaLIADPed=<H4>Reduction of elevated serum cholesterol </H4>

* Dosing information

:* '''240 mg/kg/day in 2-3 doses''', normally not to exceed '''8 gm/day''' with dose titration based on response and tolerance
|offLabelPedGuideSupport=There is limited information about <i>Off-Label Guideline-Supported Use</i> of Cholestyramine in pediatric patients.
|offLabelPedNoGuideSupport=<H4>Cholestasis</H4>

* Dosing information

:* Not applicable. <ref name="pmid2990356">{{cite journal| author=Deutsch J, Smith AL, Danks DM, Campbell PE| title=Long term prognosis for babies with neonatal liver disease. | journal=Arch Dis Child | year= 1985 | volume= 60 | issue= 5 | pages= 447-51 | pmid=2990356 | doi= | pmc=PMC1777337 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2990356 }} </ref>

<H4>Toddler diarrhea</H4>

* Dosing information

:* '''2 g BID '''<ref name="pmid3901661">{{cite journal| author=Vesikari T, Isolauri E| title=A comparative trial of cholestyramine and loperamide for acute diarrhoea in infants treated as outpatients. | journal=Acta Paediatr Scand | year= 1985 | volume= 74 | issue= 5 | pages= 650-4 | pmid=3901661 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3901661 }} </ref>
|contraindications=Cholestyramine for oral suspension is contraindicated in patients with complete biliary obstruction where bile is not secreted into the intestine and in those individuals who have shown [[hypersensitivity]] to any of its components.
|warnings=PHENYLKETONURICS: CHOLESTYRAMINE for ORAL SUSPENSION USP, LIGHT CONTAINS 14.0 mg [[PHENYLALANINE]] PER 5 GRAM DOSE.

==PRECAUTIONS==

===General===

*Chronic use of cholestyramine resin may be associated with increased bleeding tendency due to [[hypoprothrombinemia]] associated with [[Vitamin K deficiency]].
*This will usually respond promptly to parenteral Vitamin K1 and recurrences can be prevented by oral administration of Vitamin K1.
*Reduction of serum or red cell [[folate]] has been reported over long term administration of cholestyramine resin.
*Supplementation with [[folic acid]] should be considered in these cases.
*There is a possibility that prolonged use of cholestyramine resin, since it is a chloride form of anion exchange resin, may produce [[hyperchloremic acidosis]].
*This would especially be true in younger and smaller patients where the relative dosage may be higher.
*Caution should also be exercised in patients with [[renal insufficiency]] or volume depletion, and in patients receiving concomitant [[spironolactone]].
*Cholestyramine resin may produce or worsen pre-existing [[constipation]]. *The dosage should be increased gradually in patients to minimize the risk of developing fecal impaction.
*In patients with pre-existing [[constipation]], the starting dose should be 1 packet or 1 scoop once daily for 5 to 7 days, increasing to twice daily with monitoring of [[constipation]] and of serum lipoproteins, at least twice, 4 to 6 weeks apart.
*Increased fluid intake and fiber intake should be encouraged to alleviate [[constipation]] and a stool softener may occasionally be indicated.
*If the initial dose is well tolerated, the dose may be increased as needed by one dose/day (at monthly intervals) with periodic monitoring of serum lipoproteins.
*If [[constipation]] worsens or the desired therapeutic response is not achieved at one to six doses/day, combination therapy or alternate therapy should be considered.
*Particular effort should be made to avoid constipation in patients with symptomatic coronary artery disease.
*Constipation associated with cholestyramine resin may aggravate [[hemorrhoids]].

===Laboratory Tests===

Serum [[cholesterol]] levels should be determined frequently during the first few months of therapy and periodically thereafter. Serum [[triglyceride]] levels should be measured periodically to detect whether significant changes have occurred.
The LRC-CPPT showed a dose-related increase in serum triglycerides of 10.7%–17.1% in the cholestyramine-treated group, compared with an increase of 7.9%–11.7% in the placebo group. Based on the mean values and adjusting for the placebo group, the cholestyramine-treated group showed an increase of 5% over pre-entry levels the first year of the study and an increase of 4.3% the seventh year.
|clinicalTrials=*The most common adverse reaction is [[constipation]].
*When used as a cholesterol-lowering agent predisposing factors for most complaints of constipation are high dose and increased age (more than 60 years old).
*Most instances of [[constipation]] are mild, transient, and controlled with conventional therapy.
*Some patients require a temporary decrease in dosage or discontinuation of therapy.

=====Less Frequent Adverse Reactions=====
*Abdominal discomfort and/or pain, [[flatulence]], [[nausea]], [[vomiting]], [[diarrhea]], [[eructation]], [[anorexia]], and [[steatorrhea]], bleeding tendencies due to [[hypoprothrombinemia]] ([[Vitamin K deficiency]]) as well as [[Vitamin A]] (one case of [[night blindness]] reported) and [[Vitamin D|D]] deficiencies, [[hyperchloremic acidosis]] in children, [[osteoporosis]], [[rash]] and irritation of the skin, tongue and perianal area. Rare reports of [[intestinal obstruction]], including two deaths, have been reported in pediatric patients.
*Occasional calcified material has been observed in the biliary tree, including calcification of the gallbladder, in patients to whom cholestyramine resin has been given.
*However, this may be a manifestation of the liver disease and not drug related.
*One patient experienced biliary colic on each of three occasions on which he took cholestyramine resin.
*One patient diagnosed as acute abdominal symptom complex was found to have a “pasty mass” in the transverse colon on x-ray.
*Other events (not necessarily drug related) reported in patients taking cholestyramine resin include:

'''Gastrointestinal'''—GI-[[rectal bleeding]], [[black stools]], [[hemorrhoids|hemorrhoidal bleeding]], bleeding from known [[duodenal ulcer]], [[dysphagia]], [[hiccups]], ulcer attack, sour taste, [[pancreatitis]], [[rectal pain]], [[diverticulitis]].
'''Laboratory test changes'''—[[Liver function tests abnormality|Liver function abnormalities]].<BR>
'''Hematologic'''—Prolonged [[prothrombin time]], [[ecchymosis]], [[anemia]].<BR>
'''Hypersensitivity'''—[[Urticaria]], [[asthma]], [[wheezing]], [[shortness of breath]].<BR>
'''Musculoskeletal'''—[[Backache]], muscle and joint pains, [[arthritis]].<BR>
'''Neurologic'''—[[Headache]], [[anxiety]], [[vertigo]], [[dizziness]], [[fatigue]], [[tinnitus]], [[syncope]], [[drowsiness]], femoral nerve pain, [[paresthesia]].<BR>
'''Eye'''—[[Uveitis]].<BR>
'''Renal'''—[[Hematuria]], [[dysuria]], burnt odor to urine, [[diuresis]].<BR>
'''Miscellaneous'''—[[Weight loss]], [[weight gain]], increased [[libido]], swollen glands, [[edema]], dental bleeding, [[dental caries]], erosion of tooth enamel, tooth discoloration.<BR>
|postmarketing=There is limited information about the Post marketing Experience.
|drugInteractions=*Cholestyramine for Oral Suspension USP may delay or reduce the absorption of concomitant oral medication such as [[phenylbutazone]], [[warfarin]], [[thiazide diuretics]] (acidic), or [[propranolol]] (basic), as well as [[tetracycline]], [[penicillin G]], [[phenobarbital]], thyroid and thyroxine preparations, [[estrogens]] and [[progestins]], and [[digitalis]]. *Interference with the absorption of oral phosphate supplements has been observed with another positively-charged [[bile acid sequestrant]]. *Cholestyramine may interfere with the pharmacokinetics of drugs that undergo entero-hepatic circulation.
*The discontinuance of Cholestyramine could pose a hazard to health if a potentially toxic drug such as digitalis has been titrated to a maintenance level while the patient was taking Cholestyramine.
*Because cholestyramine binds bile acids, Cholestyramine may interfere with normal fat digestion and absorption and thus may prevent absorption of fat-soluble vitamins such as A, D, E and K.
*When Cholestyramine is given for long periods of time, concomitant supplementation with water-miscible (or parenteral) forms of fat-soluble vitamins should be considered.
*SINCE CHOLESTYRAMINE MAY BIND OTHER DRUGS GIVEN CONCURRENTLY, IT IS RECOMMENDED THAT PATIENTS TAKE OTHER DRUGS AT LEAST ONE HOUR BEFORE OR 4 TO 6 HOURS AFTER CHOLESTYRAMINE (OR AT AS GREAT AN INTERVAL AS POSSIBLE) TO AVOID IMPEDING THEIR ABSORPTION.
|FDAPregCat=C
|useInPregnancyFDA=There are no adequate and well controlled studies in pregnant women. The use of Cholestyramine in pregnancy or lactation or by women of childbearing age requires that the potential benefits of drug therapy be weighed against the possible hazards to the mother and child. Cholestyramine is not absorbed systemically, however, it is known to interfere with absorption of fat-soluble vitamins; accordingly, regular prenatal supplementation may not be adequate.
|useInNursing=Caution should be exercised when Cholestyramine is administered to a nursing mother. The possible lack of proper vitamin absorption described in the “Pregnancy” section may have an effect on nursing infants.
|useInPed=Although an optimal dosage schedule has not been established, standard texts (6,7) list a usual pediatric dose of 240 mg/kg/day of anhydrous cholestyramine resin in two to three divided doses, normally not to exceed 8 gm/day with dose titration based on response and tolerance.
In calculating pediatric dosages, 44.4 mg of anhydrous cholestyramine resin are contained in 100 mg of Cholestyramine for Oral Suspension USP and 80 mg of anhydrous cholestyramine resin are contained in 100 mg of Cholestyramine for Oral Suspension USP, Light.
The effects of long-term administration, as well as its effect in maintaining lowered cholesterol levels in pediatric patients, are unknown.
|administration=Oral
|monitoring=There is limited information about the drug monitoring.
|IVCompat=There is limited information about the IV Compatibility.
|overdose=Overdosage with Cholestyramine has been reported in a patient taking 150% of the maximum recommended daily dosage for a period of several weeks. No ill effects were reported. Should an overdosage occur, the chief potential harm would be obstruction of the gastrointestinal tract. The location of such potential obstruction, the degree of obstruction, and the presence or absence of normal gut motility would determine treatment.
|drugBox={{Drugbox2
| Verifiedfields = changed
| verifiedrevid = 412216968
| IUPAC_name =
| image = Cholestyramine_resin.png


| tradename = Questran
| Drugs.com = {{drugs.com|monograph|cholestyramine-resin}}
| MedlinePlus = a682672
| pregnancy_AU = 
| pregnancy_US = C
| pregnancy_category = C
| legal_AU = 
| legal_UK = 
| legal_US = Rx-only
| legal_status = Rx-only
| routes_of_administration = oral


| bioavailability = low
| protein_bound = unknown
| metabolism = bile acids
| elimination_half-life = .1 hr
| excretion = feces


| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 11041-12-6
| ATC_prefix = C10
| ATC_suffix = AC01
| ATC_supplemental =
| PubChem =
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB01432
| UNII_Ref = {{fdacite|changed|FDA}}
| UNII = 4B33BGI082
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D02690
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 1201625
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = NA


| molecular_weight = Average MW exceeds 10<sup>6</sup> Daltons
}}
|mechAction=There is limited information about the mechanism of action.
|structure=Cholestyramine for Oral Suspension USP, the chloride salt of a basic anion exchange resin, a cholesterol lowering agent, is intended for oral administration. Cholestyramine resin is quite hydrophilic, but insoluble in water. The cholestyramine resin in Cholestyramine is not absorbed from the digestive tract. Four grams of anhydrous cholestyramine resin is contained in 9 grams of Cholestyramine for Oral Suspension USP. Four grams of anhydrous cholestyramine resin is contained in 5 grams of Cholestyramine for Oral Suspension USP, Light. It is represented by the following structural formula:

[[File:Cholestyramine_structure_01.png|thumb|none|500px|This image is provided by the National Library of Medicine.]]

Cholestyramine for Oral Suspension USP contains the following inactive ingredients: acacia, citric acid, D&C Yellow No. 10, FD&C Yellow No. 6, flavor (natural and artificial Orange), polysorbate 80, propylene glycol alginate and sucrose. Cholestyramine for Oral Suspension USP, Light contains the following inactive ingredients: aspartame, citric acid, colloidal silicon dioxide, D&C Yellow No. 10, FD&C Red No. 40, flavor (natural and artificial Orange), maltodextrin, propylene glycol alginate and xanthan gum.
|PD=There is limited information about the pharmacodynamics.
|PK=There is limited information about the pharmacokinetics.
|nonClinToxic=In studies conducted in rats in which cholestyramine resin was used as a tool to investigate the role of various intestinal factors, such as fat, bile salts and microbial flora, in the development of intestinal tumors induced by potent carcinogens, the incidence of such tumors was observed to be greater in cholestyramine resin-treated rats than in control rats.
The relevance of this laboratory observation from studies in rats to the clinical use of Cholestyramine is not known. In the LRC-CPPT study referred to above, the total incidence of fatal and nonfatal neoplasms was similar in both treatment groups. When the many different categories of tumors are examined, various alimentary system cancers were somewhat more prevalent in the cholestyramine group. The small numbers and the multiple categories prevent conclusions from being drawn. However, in view of the fact that cholestyramine resin is confined to the GI tract and not absorbed, and in light of the animal experiments referred to above, a six-year post-trial follow-up of the LRC-CPPT 5 patient population has been completed (a total of 13.4 years of in-trial plus post-trial follow-up) and revealed no significant difference in the incidence of cause-specific mortality or cancer morbidity between cholestyramine and placebo treated patients.
|clinicalStudies=In a large, placebo-controlled, multi-clinic study, LRC-CPPT1 , hypercholesterolemic subjects treated with Cholestyramine had mean reductions in total and low-density lipoprotein cholesterol (LDL-C) which exceeded those for diet and placebo treatment by 7.2% and 10.4 %, respectively. Over the seven-year study period the Cholestyramine group experienced a 19% reduction (relative to the incidence in the placebo group) in the combined rate of coronary heart disease death plus non-fatal [[myocardial infarction]] (cumulative incidences of 7% Cholestyramine and 8.6% placebo). The subjects included in the study were men aged 35-59 with serum cholesterol levels above 265 mg/dL and no previous history of heart disease. It is not clear to what extent these findings can be extrapolated to females and other segments of the hypercholesterolemic population.
Two controlled clinical trials have examined the effects of Cholestyramine monotherapy upon coronary atherosclerotic lesions using [[coronary arteriography]]. In the NHLBI Type II Coronary Intervention Trial2, 116 patients (80% male) with [[coronary artery disease]] ([[CAD]]) documented by arteriography were randomized to Cholestyramine or placebo for five years of treatment. Final study arteriography revealed progression of coronary artery disease in 49% of placebo patients compared to 32% of the Cholestyramine group (p<0.05).
In the St. Thomas Atherosclerosis Regression Study (STARS)3, 90 hypercholesteroleic men with CAD were randomized to three blinded treatments: usual care, lipid-lowering diet, and lipid-lowering diet plus Cholestyramine. After 36 months, follow-up coronary arteriography revealed progression of disease in 46% of usual care patients, 15% of patients on lipid-lowering diet and 12% of those receiving diet plus Cholestyramine (p<0.02). The mean absolute width of coronary segments decreased in the usual care group, increased slightly (0.003mm) in the diet group and increased by 0.103mm in the diet plus Cholestyramine group (p<0.05). Thus in these randomized controlled clinical trials using coronary arteriography, Cholestyramine monotherapy has been demonstrated to slow progression2,3 and promote regression3 of atherosclerotic lesions in the coronary arteries of patients with coronary artery disease.
The effect of intensive lipid-lowering therapy on coronary atherosclerosis has been assessed by arteriography in hyperlipidemic patients. In these randomized, controlled clinical trials, patients were treated for two to four years by either conventional measures (diet, placebo, or in some cases low dose resin), or intensive combination therapy using diet plus [[colestipol]] (an anion exchange resin with a mechanism of action and an effect on serum lipids similar to that of Cholestyramine for Oral Suspension USP and Cholestyramine for Oral Suspension USP, Light) plus either [[nicotinic acid]] or [[lovastatin]]. When compared to conventional measures, intensive lipid-lowering combination therapy significantly reduced the frequency of progression and increased the frequency of regression of coronary atherosclerotic lesions in patients with or at risk for coronary artery disease.
|howSupplied=Cholestyramine for Oral Suspension USP is a yellow colored orange flavored powder available in cans containing 378 grams and in cartons of sixty 9 gram packets. Four grams of anhydrous cholestyramine resin are contained in 9 grams of Cholestyramine for Oral Suspension USP. The 378 g can includes a 15 cc scoop. The scoop is not interchangeable with scoops from other products. Made in U.S.A.

[[File:Cholestyramine_how supplied_01.png|thumb|none|500px|This image is provided by the National Library of Medicine.]]

Cholestyramine for Oral Suspension USP, Light is a cream to pale yellow colored orange flavored powder available in cans containing 210 grams and in cartons of sixty 5 gram packets. Four grams of anhydrous cholestyramine resin are contained in 5 grams of Cholestyramine for Oral Suspension USP, Light. The 210 g can includes a 9 cc scoop. The scoop is not interchangeable with scoops from other products. Made in India*

[[File:Cholestyramine_how supplied_02.png|thumb|none|500px|This image is provided by the National Library of Medicine.]]
|storage=Store between 20º to 25ºC (68º to 77ºF). Excursions permitted to 15º to 30ºC (59º to 86ºF).
|fdaPatientInfo=Inform your physician if you are pregnant or plan to become pregnant or are breastfeeding. Drink plenty of fluids and mix each 9 gram dose of Cholestyramine for Oral Suspension USP in at least 2 to 6 ounces of fluid. Mix each 5 gram dose of Cholestyramine for Oral Suspension USP, Light in at least 2 to 6 ounces of fluid before taking. Sipping or holding the resin suspension in the mouth for prolonged periods may lead to changes in the surface of the teeth resulting in discoloration, erosion of enamel or decay; good oral hygiene should be maintained.
|alcohol=Alcohol-Cholestyramine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|lookAlike=There is limited information about the Look-Alike Drug Names.
}}
{{PillImage}}
{{LabelImage
|fileName=Cholestyramine_label_01.jpg
}}
{{LabelImage
|fileName=Cholestyramine_label_02.jpg
}}
{{LabelImage
|fileName=Cholestyramine_label_03.jpg
}}
{{LabelImage
|fileName=Cholestyramine_label_04.jpg
}}
{{LabelImage
|fileName=Cholestyramine_label_05.jpg
}}
{{LabelImage
|fileName=Cholestyramine_label_06.jpg
}}
{{LabelImage
|fileName=Cholestyramine_panel_01.png
}}
{{LabelImage
|fileName=Cholestyramine_panel_02.png
}}
{{LabelImage
|fileName=Cholestyramine_panel_03.png
}}

[[Category:Bile acid sequestrants]]
[[Category: Cardiovascular Drugs]]
[[Category: Drug]]

Cholestyramine

2015-03-18T14:29:42Z

Sree Teja Yelamanchili:

{{DrugProjectFormSinglePage
|authorTag={{SS}}; {{STY}}
|genericName=Cholestyramine
|aOrAn=a
|drugClass=bile acid sequestrant
|indicationType=treatment
|indication=elevated [[cholesterol|serum cholesterol]] in patients with primary [[hypercholesterolemia]] (elevated [[low density lipoprotein]] [LDL] cholesterol) who do not respond adequately to diet.
|adverseReactions=[[constipation]]
|blackBoxWarningTitle=<b><span style="color:#FF0000;">TITLE</span></b>
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)
|fdaLIADAdult=<H4>Reduction of elevated serum cholesterol </H4>

* Dosing information

:* Recommended starting adult dose: '''one packet or one level scoopful once or twice a day.'''
:* Recommended maintenance dose for all: '''2 to 4 packets or scoopfuls daily (8-16 grams anhydrous cholestyramine resin) divided into two doses. '''
:* Four grams of anhydrous cholestyramine resin is contained in each measured dose of Cholestyramine as follows:

[[File:Cholestyramine_administration_01.png|thumb|none|500px|This image is provided by the National Library of Medicine.]]

* It is recommended that increases in dose be gradual with periodic assessment of lipid/lipoprotein levels at intervals of not less than 4 weeks. The maximum recommended daily dose is six packets or scoopfuls of cholestyramine for oral suspension (24 grams of anhydrous cholestyramine resin). The suggested time of administration is at mealtime but may be modified to avoid interference with absorption of other medications. Although the recommended dosing schedule is twice daily, cholestyramine for oral suspension may be administered in 1 to 6 doses per day.

* Cholestyramine should not be taken in its dry form. Always mix Cholestyramine with water or other fluids before ingesting.

<h4>Concomitant Therapy</h4>

* Preliminary evidence suggests that the lipid-lowering effects of Cholestyramine on total and LDL-cholesterol are enhanced when combined with a HMG-CoA reductase inhibitor, e.g., [[pravastatin]], [[lovastatin]], [[simvastatin]], and [[fluvastatin]]. Additive effects on LDL-cholesterol are also seen with combined nicotinic acid/Cholestyramine therapy.

<H4>Preparation</H4>

* The color of Cholestyramine may vary somewhat from batch to batch but this variation does not affect the performance of the product. Place the contents of one single-dose packet or one level scoopful of Cholestyramine in a glass or cup. Add an amount of water or other non-carbonated beverage of your choice depending on the product being used:

[[File:Cholestyramine_administration_02.png|thumb|none|500px|This image is provided by the National Library of Medicine.]]

* Stir to a uniform consistency and drink.

* Cholestyramine may also be mixed with highly fluid soups or pulpy fruits with a high moisture content such as applesauce or crushed pineapple.
|offLabelAdultGuideSupport=There is limited information about <i>Off-Label Guideline-Supported Use</i> of Cholestyramine in adult patients.
|offLabelAdultNoGuideSupport=<H4>Bile acid malabsorption syndrome</H4>

* Dosing information

:* ''' 1 to 2 sachets TID'''<ref name="pmid9768525">{{cite journal| author=Sinha L, Liston R, Testa HJ, Moriarty KJ| title=Idiopathic bile acid malabsorption: qualitative and quantitative clinical features and response to cholestyramine. | journal=Aliment Pharmacol Ther | year= 1998 | volume= 12 | issue= 9 | pages= 839-44 | pmid=9768525 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9768525 }} </ref>

<h4>Collagenous colitis</h4>

* Dosing information

:* '''4-grams (g) packets/day '''<ref name="pmid10644309">{{cite journal| author=Ung KA, Gillberg R, Kilander A, Abrahamsson H| title=Role of bile acids and bile acid binding agents in patients with collagenous colitis. | journal=Gut | year= 2000 | volume= 46 | issue= 2 | pages= 170-5 | pmid=10644309 | doi= | pmc=PMC1727822 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10644309 }} </ref>

<h4>Fistula of bile duct</h4>

* Dosing information

:* '''20 g'''<ref name="pmid7427037">{{cite journal| author=Bell SN, Varigos GA| title=Treatment of skin irritations around biliary fistulas with cholestyramine. | journal=Br J Surg | year= 1980 | volume= 67 | issue= 11 | pages= 785 | pmid=7427037 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7427037 }} </ref>

<H4>Generalized atherosclerosis</H4>

* Dosing information

:* '''6 g 4 times per day '''<ref name="pmid6360414">{{cite journal| author=Brensike JF, Levy RI, Kelsey SF, Passamani ER, Richardson JM, Loh IK et al.| title=Effects of therapy with cholestyramine on progression of coronary arteriosclerosis: results of the NHLBI Type II Coronary Intervention Study. | journal=Circulation | year= 1984 | volume= 69 | issue= 2 | pages= 313-24 | pmid=6360414 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6360414 }} </ref>
|fdaLIADPed=<H4>Reduction of elevated serum cholesterol </H4>

* Dosing information

:* '''240 mg/kg/day in 2-3 doses''', normally not to exceed '''8 gm/day''' with dose titration based on response and tolerance
|offLabelPedGuideSupport=There is limited information about <i>Off-Label Guideline-Supported Use</i> of Cholestyramine in pediatric patients.
|offLabelPedNoGuideSupport=<H4>Cholestasis</H4>

* Dosing information

:* Not applicable. <ref name="pmid2990356">{{cite journal| author=Deutsch J, Smith AL, Danks DM, Campbell PE| title=Long term prognosis for babies with neonatal liver disease. | journal=Arch Dis Child | year= 1985 | volume= 60 | issue= 5 | pages= 447-51 | pmid=2990356 | doi= | pmc=PMC1777337 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2990356 }} </ref>

<H4>Toddler diarrhea</H4>

* Dosing information

:* '''2 g BID '''<ref name="pmid3901661">{{cite journal| author=Vesikari T, Isolauri E| title=A comparative trial of cholestyramine and loperamide for acute diarrhoea in infants treated as outpatients. | journal=Acta Paediatr Scand | year= 1985 | volume= 74 | issue= 5 | pages= 650-4 | pmid=3901661 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3901661 }} </ref>
|contraindications=Cholestyramine for oral suspension is contraindicated in patients with complete biliary obstruction where bile is not secreted into the intestine and in those individuals who have shown [[hypersensitivity]] to any of its components.
|warnings=PHENYLKETONURICS: CHOLESTYRAMINE for ORAL SUSPENSION USP, LIGHT CONTAINS 14.0 mg [[PHENYLALANINE]] PER 5 GRAM DOSE.

==PRECAUTIONS==

===General===

*Chronic use of cholestyramine resin may be associated with increased bleeding tendency due to [[hypoprothrombinemia]] associated with [[Vitamin K deficiency]].
*This will usually respond promptly to parenteral Vitamin K1 and recurrences can be prevented by oral administration of Vitamin K1.
*Reduction of serum or red cell [[folate]] has been reported over long term administration of cholestyramine resin.
*Supplementation with [[folic acid]] should be considered in these cases.
*There is a possibility that prolonged use of cholestyramine resin, since it is a chloride form of anion exchange resin, may produce [[hyperchloremic acidosis]].
*This would especially be true in younger and smaller patients where the relative dosage may be higher.
*Caution should also be exercised in patients with [[renal insufficiency]] or volume depletion, and in patients receiving concomitant [[spironolactone]].
*Cholestyramine resin may produce or worsen pre-existing [[constipation]]. *The dosage should be increased gradually in patients to minimize the risk of developing fecal impaction.
*In patients with pre-existing [[constipation]], the starting dose should be 1 packet or 1 scoop once daily for 5 to 7 days, increasing to twice daily with monitoring of [[constipation]] and of serum lipoproteins, at least twice, 4 to 6 weeks apart.
*Increased fluid intake and fiber intake should be encouraged to alleviate [[constipation]] and a stool softener may occasionally be indicated.
*If the initial dose is well tolerated, the dose may be increased as needed by one dose/day (at monthly intervals) with periodic monitoring of serum lipoproteins.
*If [[constipation]] worsens or the desired therapeutic response is not achieved at one to six doses/day, combination therapy or alternate therapy should be considered.
*Particular effort should be made to avoid constipation in patients with symptomatic coronary artery disease.
*Constipation associated with cholestyramine resin may aggravate [[hemorrhoids]].

===Laboratory Tests===

Serum [[cholesterol]] levels should be determined frequently during the first few months of therapy and periodically thereafter. Serum [[triglyceride]] levels should be measured periodically to detect whether significant changes have occurred.
The LRC-CPPT showed a dose-related increase in serum triglycerides of 10.7%–17.1% in the cholestyramine-treated group, compared with an increase of 7.9%–11.7% in the placebo group. Based on the mean values and adjusting for the placebo group, the cholestyramine-treated group showed an increase of 5% over pre-entry levels the first year of the study and an increase of 4.3% the seventh year.
|clinicalTrials=*The most common adverse reaction is [[constipation]].
*When used as a cholesterol-lowering agent predisposing factors for most complaints of constipation are high dose and increased age (more than 60 years old).
*Most instances of [[constipation]] are mild, transient, and controlled with conventional therapy.
*Some patients require a temporary decrease in dosage or discontinuation of therapy.

=====Less Frequent Adverse Reactions=====
*Abdominal discomfort and/or pain, [[flatulence]], [[nausea]], [[vomiting]], [[diarrhea]], [[eructation]], [[anorexia]], and [[steatorrhea]], bleeding tendencies due to [[hypoprothrombinemia]] ([[Vitamin K deficiency]]) as well as [[Vitamin A]] (one case of [[night blindness]] reported) and [[Vitamin D|D]] deficiencies, [[hyperchloremic acidosis]] in children, [[osteoporosis]], [[rash]] and irritation of the skin, tongue and perianal area. Rare reports of [[intestinal obstruction]], including two deaths, have been reported in pediatric patients.
*Occasional calcified material has been observed in the biliary tree, including calcification of the gallbladder, in patients to whom cholestyramine resin has been given.
*However, this may be a manifestation of the liver disease and not drug related.
*One patient experienced biliary colic on each of three occasions on which he took cholestyramine resin.
*One patient diagnosed as acute abdominal symptom complex was found to have a “pasty mass” in the transverse colon on x-ray.
*Other events (not necessarily drug related) reported in patients taking cholestyramine resin include:

'''Gastrointestinal'''—GI-[[rectal bleeding]], [[black stools]], [[hemorrhoids|hemorrhoidal bleeding]], bleeding from known [[duodenal ulcer]], [[dysphagia]], [[hiccups]], ulcer attack, sour taste, [[pancreatitis]], [[rectal pain]], [[diverticulitis]].
'''Laboratory test changes'''—[[Liver function tests abnormality|Liver function abnormalities]].<BR>
'''Hematologic'''—Prolonged [[prothrombin time]], [[ecchymosis]], [[anemia]].<BR>
'''Hypersensitivity'''—[[Urticaria]], [[asthma]], [[wheezing]], [[shortness of breath]].<BR>
'''Musculoskeletal'''—[[Backache]], muscle and joint pains, [[arthritis]].<BR>
'''Neurologic'''—[[Headache]], [[anxiety]], [[vertigo]], [[dizziness]], [[fatigue]], [[tinnitus]], [[syncope]], [[drowsiness]], femoral nerve pain, [[paresthesia]].<BR>
'''Eye'''—[[Uveitis]].<BR>
'''Renal'''—[[Hematuria]], [[dysuria]], burnt odor to urine, [[diuresis]].<BR>
'''Miscellaneous'''—[[Weight loss]], [[weight gain]], increased [[libido]], swollen glands, [[edema]], dental bleeding, [[dental caries]], erosion of tooth enamel, tooth discoloration.<BR>
|postmarketing=There is limited information about the Post marketing Experience.
|drugInteractions=*Cholestyramine for Oral Suspension USP may delay or reduce the absorption of concomitant oral medication such as [[phenylbutazone]], [[warfarin]], [[thiazide diuretics]] (acidic), or [[propranolol]] (basic), as well as [[tetracycline]], [[penicillin G]], [[phenobarbital]], thyroid and thyroxine preparations, [[estrogens]] and [[progestins]], and [[digitalis]]. *Interference with the absorption of oral phosphate supplements has been observed with another positively-charged [[bile acid sequestrant]]. *Cholestyramine may interfere with the pharmacokinetics of drugs that undergo entero-hepatic circulation.
*The discontinuance of Cholestyramine could pose a hazard to health if a potentially toxic drug such as digitalis has been titrated to a maintenance level while the patient was taking Cholestyramine.
*Because cholestyramine binds bile acids, Cholestyramine may interfere with normal fat digestion and absorption and thus may prevent absorption of fat-soluble vitamins such as A, D, E and K.
*When Cholestyramine is given for long periods of time, concomitant supplementation with water-miscible (or parenteral) forms of fat-soluble vitamins should be considered.
*SINCE CHOLESTYRAMINE MAY BIND OTHER DRUGS GIVEN CONCURRENTLY, IT IS RECOMMENDED THAT PATIENTS TAKE OTHER DRUGS AT LEAST ONE HOUR BEFORE OR 4 TO 6 HOURS AFTER CHOLESTYRAMINE (OR AT AS GREAT AN INTERVAL AS POSSIBLE) TO AVOID IMPEDING THEIR ABSORPTION.
|FDAPregCat=C
|useInPregnancyFDA=There are no adequate and well controlled studies in pregnant women. The use of Cholestyramine in pregnancy or lactation or by women of childbearing age requires that the potential benefits of drug therapy be weighed against the possible hazards to the mother and child. Cholestyramine is not absorbed systemically, however, it is known to interfere with absorption of fat-soluble vitamins; accordingly, regular prenatal supplementation may not be adequate.
|useInNursing=Caution should be exercised when Cholestyramine is administered to a nursing mother. The possible lack of proper vitamin absorption described in the “Pregnancy” section may have an effect on nursing infants.
|useInPed=Although an optimal dosage schedule has not been established, standard texts (6,7) list a usual pediatric dose of 240 mg/kg/day of anhydrous cholestyramine resin in two to three divided doses, normally not to exceed 8 gm/day with dose titration based on response and tolerance.
In calculating pediatric dosages, 44.4 mg of anhydrous cholestyramine resin are contained in 100 mg of Cholestyramine for Oral Suspension USP and 80 mg of anhydrous cholestyramine resin are contained in 100 mg of Cholestyramine for Oral Suspension USP, Light.
The effects of long-term administration, as well as its effect in maintaining lowered cholesterol levels in pediatric patients, are unknown.
|administration=Oral
|monitoring=There is limited information about the drug monitoring.
|IVCompat=There is limited information about the IV Compatibility.
|overdose=Overdosage with Cholestyramine has been reported in a patient taking 150% of the maximum recommended daily dosage for a period of several weeks. No ill effects were reported. Should an overdosage occur, the chief potential harm would be obstruction of the gastrointestinal tract. The location of such potential obstruction, the degree of obstruction, and the presence or absence of normal gut motility would determine treatment.
|drugBox={{Drugbox2
| Verifiedfields = changed
| verifiedrevid = 412216968
| IUPAC_name =
| image = Cholestyramine_resin.png


| tradename = Questran
| Drugs.com = {{drugs.com|monograph|cholestyramine-resin}}
| MedlinePlus = a682672
| pregnancy_AU = 
| pregnancy_US = C
| pregnancy_category = C
| legal_AU = 
| legal_UK = 
| legal_US = Rx-only
| legal_status = Rx-only
| routes_of_administration = oral


| bioavailability = low
| protein_bound = unknown
| metabolism = bile acids
| elimination_half-life = .1 hr
| excretion = feces


| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 11041-12-6
| ATC_prefix = C10
| ATC_suffix = AC01
| ATC_supplemental =
| PubChem =
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB01432
| UNII_Ref = {{fdacite|changed|FDA}}
| UNII = 4B33BGI082
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D02690
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 1201625
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = NA


| molecular_weight = Average MW exceeds 10<sup>6</sup> Daltons
}}
|mechAction=There is limited information about the mechanism of action.
|structure=Cholestyramine for Oral Suspension USP, the chloride salt of a basic anion exchange resin, a cholesterol lowering agent, is intended for oral administration. Cholestyramine resin is quite hydrophilic, but insoluble in water. The cholestyramine resin in Cholestyramine is not absorbed from the digestive tract. Four grams of anhydrous cholestyramine resin is contained in 9 grams of Cholestyramine for Oral Suspension USP. Four grams of anhydrous cholestyramine resin is contained in 5 grams of Cholestyramine for Oral Suspension USP, Light. It is represented by the following structural formula:

[[File:Cholestyramine_structure_01.png|thumb|none|500px|This image is provided by the National Library of Medicine.]]

Cholestyramine for Oral Suspension USP contains the following inactive ingredients: acacia, citric acid, D&C Yellow No. 10, FD&C Yellow No. 6, flavor (natural and artificial Orange), polysorbate 80, propylene glycol alginate and sucrose. Cholestyramine for Oral Suspension USP, Light contains the following inactive ingredients: aspartame, citric acid, colloidal silicon dioxide, D&C Yellow No. 10, FD&C Red No. 40, flavor (natural and artificial Orange), maltodextrin, propylene glycol alginate and xanthan gum.
|PD=There is limited information about the pharmacodynamics.
|PK=There is limited information about the pharmacokinetics.
|nonClinToxic=In studies conducted in rats in which cholestyramine resin was used as a tool to investigate the role of various intestinal factors, such as fat, bile salts and microbial flora, in the development of intestinal tumors induced by potent carcinogens, the incidence of such tumors was observed to be greater in cholestyramine resin-treated rats than in control rats.
The relevance of this laboratory observation from studies in rats to the clinical use of Cholestyramine is not known. In the LRC-CPPT study referred to above, the total incidence of fatal and nonfatal neoplasms was similar in both treatment groups. When the many different categories of tumors are examined, various alimentary system cancers were somewhat more prevalent in the cholestyramine group. The small numbers and the multiple categories prevent conclusions from being drawn. However, in view of the fact that cholestyramine resin is confined to the GI tract and not absorbed, and in light of the animal experiments referred to above, a six-year post-trial follow-up of the LRC-CPPT 5 patient population has been completed (a total of 13.4 years of in-trial plus post-trial follow-up) and revealed no significant difference in the incidence of cause-specific mortality or cancer morbidity between cholestyramine and placebo treated patients.
|clinicalStudies=In a large, placebo-controlled, multi-clinic study, LRC-CPPT1 , hypercholesterolemic subjects treated with Cholestyramine had mean reductions in total and low-density lipoprotein cholesterol (LDL-C) which exceeded those for diet and placebo treatment by 7.2% and 10.4 %, respectively. Over the seven-year study period the Cholestyramine group experienced a 19% reduction (relative to the incidence in the placebo group) in the combined rate of coronary heart disease death plus non-fatal [[myocardial infarction]] (cumulative incidences of 7% Cholestyramine and 8.6% placebo). The subjects included in the study were men aged 35-59 with serum cholesterol levels above 265 mg/dL and no previous history of heart disease. It is not clear to what extent these findings can be extrapolated to females and other segments of the hypercholesterolemic population.
Two controlled clinical trials have examined the effects of Cholestyramine monotherapy upon coronary atherosclerotic lesions using [[coronary arteriography]]. In the NHLBI Type II Coronary Intervention Trial2, 116 patients (80% male) with [[coronary artery disease]] ([[CAD]]) documented by arteriography were randomized to Cholestyramine or placebo for five years of treatment. Final study arteriography revealed progression of coronary artery disease in 49% of placebo patients compared to 32% of the Cholestyramine group (p<0.05).
In the St. Thomas Atherosclerosis Regression Study (STARS)3, 90 hypercholesteroleic men with CAD were randomized to three blinded treatments: usual care, lipid-lowering diet, and lipid-lowering diet plus Cholestyramine. After 36 months, follow-up coronary arteriography revealed progression of disease in 46% of usual care patients, 15% of patients on lipid-lowering diet and 12% of those receiving diet plus Cholestyramine (p<0.02). The mean absolute width of coronary segments decreased in the usual care group, increased slightly (0.003mm) in the diet group and increased by 0.103mm in the diet plus Cholestyramine group (p<0.05). Thus in these randomized controlled clinical trials using coronary arteriography, Cholestyramine monotherapy has been demonstrated to slow progression2,3 and promote regression3 of atherosclerotic lesions in the coronary arteries of patients with coronary artery disease.
The effect of intensive lipid-lowering therapy on coronary atherosclerosis has been assessed by arteriography in hyperlipidemic patients. In these randomized, controlled clinical trials, patients were treated for two to four years by either conventional measures (diet, placebo, or in some cases low dose resin), or intensive combination therapy using diet plus [[colestipol]] (an anion exchange resin with a mechanism of action and an effect on serum lipids similar to that of Cholestyramine for Oral Suspension USP and Cholestyramine for Oral Suspension USP, Light) plus either [[nicotinic acid]] or [[lovastatin]]. When compared to conventional measures, intensive lipid-lowering combination therapy significantly reduced the frequency of progression and increased the frequency of regression of coronary atherosclerotic lesions in patients with or at risk for coronary artery disease.
|howSupplied=Cholestyramine for Oral Suspension USP is a yellow colored orange flavored powder available in cans containing 378 grams and in cartons of sixty 9 gram packets. Four grams of anhydrous cholestyramine resin are contained in 9 grams of Cholestyramine for Oral Suspension USP. The 378 g can includes a 15 cc scoop. The scoop is not interchangeable with scoops from other products. Made in U.S.A.

[[File:Cholestyramine_how supplied_01.png|thumb|none|500px|This image is provided by the National Library of Medicine.]]

Cholestyramine for Oral Suspension USP, Light is a cream to pale yellow colored orange flavored powder available in cans containing 210 grams and in cartons of sixty 5 gram packets. Four grams of anhydrous cholestyramine resin are contained in 5 grams of Cholestyramine for Oral Suspension USP, Light. The 210 g can includes a 9 cc scoop. The scoop is not interchangeable with scoops from other products. Made in India*

[[File:Cholestyramine_how supplied_02.png|thumb|none|500px|This image is provided by the National Library of Medicine.]]
|storage=Store between 20º to 25ºC (68º to 77ºF). Excursions permitted to 15º to 30ºC (59º to 86ºF).
|fdaPatientInfo=Inform your physician if you are pregnant or plan to become pregnant or are breastfeeding. Drink plenty of fluids and mix each 9 gram dose of Cholestyramine for Oral Suspension USP in at least 2 to 6 ounces of fluid. Mix each 5 gram dose of Cholestyramine for Oral Suspension USP, Light in at least 2 to 6 ounces of fluid before taking. Sipping or holding the resin suspension in the mouth for prolonged periods may lead to changes in the surface of the teeth resulting in discoloration, erosion of enamel or decay; good oral hygiene should be maintained.
|alcohol=Alcohol-Cholestyramine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|lookAlike=There is limited information about the Look-Alike Drug Names.
}}
{{PillImage}}
{{LabelImage
|fileName=Cholestyramine_label_01.jpg
}}
{{LabelImage
|fileName=Cholestyramine_label_02.jpg
}}
{{LabelImage
|fileName=Cholestyramine_label_03.jpg
}}
{{LabelImage
|fileName=Cholestyramine_label_04.jpg
}}
{{LabelImage
|fileName=Cholestyramine_label_05.jpg
}}
{{LabelImage
|fileName=Cholestyramine_label_06.jpg
}}
{{LabelImage
|fileName=Cholestyramine_panel_01.png
}}
{{LabelImage
|fileName=Cholestyramine_panel_02.png
}}
{{LabelImage
|fileName=Cholestyramine_panel_03.png
}}

[[Category:Bile acid sequestrants]]
[[Category: Cardiovascular Drugs]]
[[Category: Drug]]

Cholestyramine

2015-03-18T14:26:25Z

Sree Teja Yelamanchili:

{{DrugProjectFormSinglePage
|authorTag={{SS}}; {{STY}}
|genericName=Cholestyramine
|aOrAn=a
|drugClass=bile acid sequestrant
|indicationType=treatment
|indication=elevated [[cholesterol|serum cholesterol]] in patients with primary [[hypercholesterolemia]] (elevated [[low density lipoprotein]] [LDL] cholesterol) who do not respond adequately to diet.
|adverseReactions=[[constipation]]
|blackBoxWarningTitle=<b><span style="color:#FF0000;">TITLE</span></b>
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)
|fdaLIADAdult=<H4>Reduction of elevated serum cholesterol </H4>

* Dosing information

:* Recommended starting adult dose: '''one packet or one level scoopful once or twice a day.'''
:* Recommended maintenance dose for all: '''2 to 4 packets or scoopfuls daily (8-16 grams anhydrous cholestyramine resin) divided into two doses. '''
:* Four grams of anhydrous cholestyramine resin is contained in each measured dose of Cholestyramine as follows:

[[File:Cholestyramine_administration_01.png|thumb|none|500px|This image is provided by the National Library of Medicine.]]

* It is recommended that increases in dose be gradual with periodic assessment of lipid/lipoprotein levels at intervals of not less than 4 weeks. The maximum recommended daily dose is six packets or scoopfuls of cholestyramine for oral suspension (24 grams of anhydrous cholestyramine resin). The suggested time of administration is at mealtime but may be modified to avoid interference with absorption of other medications. Although the recommended dosing schedule is twice daily, cholestyramine for oral suspension may be administered in 1 to 6 doses per day.

* Cholestyramine should not be taken in its dry form. Always mix Cholestyramine with water or other fluids before ingesting.

<h4>Concomitant Therapy</h4>

* Preliminary evidence suggests that the lipid-lowering effects of Cholestyramine on total and LDL-cholesterol are enhanced when combined with a HMG-CoA reductase inhibitor, e.g., [[pravastatin]], [[lovastatin]], [[simvastatin]], and [[fluvastatin]]. Additive effects on LDL-cholesterol are also seen with combined nicotinic acid/Cholestyramine therapy.

<H4>Preparation</H4>

* The color of Cholestyramine may vary somewhat from batch to batch but this variation does not affect the performance of the product. Place the contents of one single-dose packet or one level scoopful of Cholestyramine in a glass or cup. Add an amount of water or other non-carbonated beverage of your choice depending on the product being used:

[[File:Cholestyramine_administration_02.png|thumb|none|500px|This image is provided by the National Library of Medicine.]]

* Stir to a uniform consistency and drink.

* Cholestyramine may also be mixed with highly fluid soups or pulpy fruits with a high moisture content such as applesauce or crushed pineapple.
|offLabelAdultGuideSupport=There is limited information about <i>Off-Label Guideline-Supported Use</i> of Cholestyramine in adult patients.
|offLabelAdultNoGuideSupport=<H4>Bile acid malabsorption syndrome</H4>

* Dosing information

:* ''' 1 to 2 sachets TID'''<ref name="pmid9768525">{{cite journal| author=Sinha L, Liston R, Testa HJ, Moriarty KJ| title=Idiopathic bile acid malabsorption: qualitative and quantitative clinical features and response to cholestyramine. | journal=Aliment Pharmacol Ther | year= 1998 | volume= 12 | issue= 9 | pages= 839-44 | pmid=9768525 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9768525 }} </ref>

<h4>Collagenous colitis</h4>

* Dosing information

:* '''4-grams (g) packets/day '''<ref name="pmid10644309">{{cite journal| author=Ung KA, Gillberg R, Kilander A, Abrahamsson H| title=Role of bile acids and bile acid binding agents in patients with collagenous colitis. | journal=Gut | year= 2000 | volume= 46 | issue= 2 | pages= 170-5 | pmid=10644309 | doi= | pmc=PMC1727822 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10644309 }} </ref>

<h4>Fistula of bile duct</h4>

* Dosing information

:* '''20 g'''<ref name="pmid7427037">{{cite journal| author=Bell SN, Varigos GA| title=Treatment of skin irritations around biliary fistulas with cholestyramine. | journal=Br J Surg | year= 1980 | volume= 67 | issue= 11 | pages= 785 | pmid=7427037 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7427037 }} </ref>

<H4>Generalized atherosclerosis</H4>

* Dosing information

:* '''6 g 4 times per day '''<ref name="pmid6360414">{{cite journal| author=Brensike JF, Levy RI, Kelsey SF, Passamani ER, Richardson JM, Loh IK et al.| title=Effects of therapy with cholestyramine on progression of coronary arteriosclerosis: results of the NHLBI Type II Coronary Intervention Study. | journal=Circulation | year= 1984 | volume= 69 | issue= 2 | pages= 313-24 | pmid=6360414 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6360414 }} </ref>
|fdaLIADPed=<H4>Reduction of elevated serum cholesterol </H4>

* Dosing information

:* '''240 mg/kg/day in 2-3 doses''', normally not to exceed '''8 gm/day''' with dose titration based on response and tolerance
|offLabelPedGuideSupport=There is limited information about <i>Off-Label Guideline-Supported Use</i> of Cholestyramine in pediatric patients.
|offLabelPedNoGuideSupport=<H4>Cholestasis</H4>

* Dosing information

:* Not applicable. <ref name="pmid2990356">{{cite journal| author=Deutsch J, Smith AL, Danks DM, Campbell PE| title=Long term prognosis for babies with neonatal liver disease. | journal=Arch Dis Child | year= 1985 | volume= 60 | issue= 5 | pages= 447-51 | pmid=2990356 | doi= | pmc=PMC1777337 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2990356 }} </ref>

<H4>Toddler diarrhea</H4>

* Dosing information

:* '''2 g BID '''<ref name="pmid3901661">{{cite journal| author=Vesikari T, Isolauri E| title=A comparative trial of cholestyramine and loperamide for acute diarrhoea in infants treated as outpatients. | journal=Acta Paediatr Scand | year= 1985 | volume= 74 | issue= 5 | pages= 650-4 | pmid=3901661 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3901661 }} </ref>
|contraindications=Cholestyramine for oral suspension is contraindicated in patients with complete biliary obstruction where bile is not secreted into the intestine and in those individuals who have shown [[hypersensitivity]] to any of its components.
|warnings=PHENYLKETONURICS: CHOLESTYRAMINE for ORAL SUSPENSION USP, LIGHT CONTAINS 14.0 mg [[PHENYLALANINE]] PER 5 GRAM DOSE.

==PRECAUTIONS==

===General===

*Chronic use of cholestyramine resin may be associated with increased bleeding tendency due to [[hypoprothrombinemia]] associated with [[Vitamin K deficiency]].
*This will usually respond promptly to parenteral Vitamin K1 and recurrences can be prevented by oral administration of Vitamin K1.
*Reduction of serum or red cell [[folate]] has been reported over long term administration of cholestyramine resin.
*Supplementation with [[folic acid]] should be considered in these cases.
*There is a possibility that prolonged use of cholestyramine resin, since it is a chloride form of anion exchange resin, may produce [[hyperchloremic acidosis]].
*This would especially be true in younger and smaller patients where the relative dosage may be higher.
*Caution should also be exercised in patients with [[renal insufficiency]] or volume depletion, and in patients receiving concomitant [[spironolactone]].
*Cholestyramine resin may produce or worsen pre-existing [[constipation]]. *The dosage should be increased gradually in patients to minimize the risk of developing fecal impaction.
*In patients with pre-existing [[constipation]], the starting dose should be 1 packet or 1 scoop once daily for 5 to 7 days, increasing to twice daily with monitoring of [[constipation]] and of serum lipoproteins, at least twice, 4 to 6 weeks apart.
*Increased fluid intake and fiber intake should be encouraged to alleviate [[constipation]] and a stool softener may occasionally be indicated.
*If the initial dose is well tolerated, the dose may be increased as needed by one dose/day (at monthly intervals) with periodic monitoring of serum lipoproteins.
*If [[constipation]] worsens or the desired therapeutic response is not achieved at one to six doses/day, combination therapy or alternate therapy should be considered.
*Particular effort should be made to avoid constipation in patients with symptomatic coronary artery disease.
*Constipation associated with cholestyramine resin may aggravate [[hemorrhoids]].

===Laboratory Tests===

Serum [[cholesterol]] levels should be determined frequently during the first few months of therapy and periodically thereafter. Serum [[triglyceride]] levels should be measured periodically to detect whether significant changes have occurred.
The LRC-CPPT showed a dose-related increase in serum triglycerides of 10.7%–17.1% in the cholestyramine-treated group, compared with an increase of 7.9%–11.7% in the placebo group. Based on the mean values and adjusting for the placebo group, the cholestyramine-treated group showed an increase of 5% over pre-entry levels the first year of the study and an increase of 4.3% the seventh year.
|clinicalTrials=*The most common adverse reaction is [[constipation]].
*When used as a cholesterol-lowering agent predisposing factors for most complaints of constipation are high dose and increased age (more than 60 years old).
*Most instances of [[constipation]] are mild, transient, and controlled with conventional therapy.
*Some patients require a temporary decrease in dosage or discontinuation of therapy.

=====Less Frequent Adverse Reactions=====
*Abdominal discomfort and/or pain, [[flatulence]], [[nausea]], [[vomiting]], [[diarrhea]], [[eructation]], [[anorexia]], and [[steatorrhea]], bleeding tendencies due to [[hypoprothrombinemia]] ([[Vitamin K deficiency]]) as well as [[Vitamin A]] (one case of night blindness reported) and [[Vitamin D|D]] deficiencies, [[hyperchloremic acidosis]] in children, [[osteoporosis]], [[rash]] and irritation of the skin, tongue and perianal area. Rare reports of [[intestinal obstruction]], including two deaths, have been reported in pediatric patients.
*Occasional calcified material has been observed in the biliary tree, including calcification of the gallbladder, in patients to whom cholestyramine resin has been given.
*However, this may be a manifestation of the liver disease and not drug related.
*One patient experienced biliary colic on each of three occasions on which he took cholestyramine resin.
*One patient diagnosed as acute abdominal symptom complex was found to have a “pasty mass” in the transverse colon on x-ray.
*Other events (not necessarily drug related) reported in patients taking cholestyramine resin include:

'''Gastrointestinal'''—GI-[[rectal bleeding]], [[black stools]], [[hemorrhoids|hemorrhoidal bleeding]], bleeding from known [[duodenal ulcer]], [[dysphagia]], [[hiccups]], ulcer attack, sour taste, [[pancreatitis]], [[rectal pain]], [[diverticulitis]].
'''Laboratory test changes'''—[[Liver function tests abnormality|Liver function abnormalities]].<BR>
'''Hematologic'''—Prolonged [[prothrombin time]], [[ecchymosis]], [[anemia]].<BR>
'''Hypersensitivity'''—[[Urticaria]], [[asthma]], [[wheezing]], [[shortness of breath]].<BR>
'''Musculoskeletal'''—[[Backache]], muscle and joint pains, [[arthritis]].<BR>
'''Neurologic'''—[[Headache]], [[anxiety]], [[vertigo]], [[dizziness]], [[fatigue]], [[tinnitus]], [[syncope]], [[drowsiness]], femoral nerve pain, [[paresthesia]].<BR>
'''Eye'''—[[Uveitis]].<BR>
'''Renal'''—[[Hematuria]], [[dysuria]], burnt odor to urine, [[diuresis]].<BR>
'''Miscellaneous'''—[[Weight loss]], [[weight gain]], increased [[libido]], swollen glands, [[edema]], dental bleeding, [[dental caries]], erosion of tooth enamel, tooth discoloration.<BR>
|postmarketing=There is limited information about the Post marketing Experience.
|drugInteractions=*Cholestyramine for Oral Suspension USP may delay or reduce the absorption of concomitant oral medication such as [[phenylbutazone]], [[warfarin]], [[thiazide diuretics]] (acidic), or [[propranolol]] (basic), as well as [[tetracycline]], [[penicillin G]], [[phenobarbital]], thyroid and thyroxine preparations, [[estrogens]] and [[progestins]], and [[digitalis]]. *Interference with the absorption of oral phosphate supplements has been observed with another positively-charged [[bile acid sequestrant]]. *Cholestyramine may interfere with the pharmacokinetics of drugs that undergo entero-hepatic circulation.
*The discontinuance of Cholestyramine could pose a hazard to health if a potentially toxic drug such as digitalis has been titrated to a maintenance level while the patient was taking Cholestyramine.
*Because cholestyramine binds bile acids, Cholestyramine may interfere with normal fat digestion and absorption and thus may prevent absorption of fat-soluble vitamins such as A, D, E and K.
*When Cholestyramine is given for long periods of time, concomitant supplementation with water-miscible (or parenteral) forms of fat-soluble vitamins should be considered.
*SINCE CHOLESTYRAMINE MAY BIND OTHER DRUGS GIVEN CONCURRENTLY, IT IS RECOMMENDED THAT PATIENTS TAKE OTHER DRUGS AT LEAST ONE HOUR BEFORE OR 4 TO 6 HOURS AFTER CHOLESTYRAMINE (OR AT AS GREAT AN INTERVAL AS POSSIBLE) TO AVOID IMPEDING THEIR ABSORPTION.
|FDAPregCat=C
|useInPregnancyFDA=There are no adequate and well controlled studies in pregnant women. The use of Cholestyramine in pregnancy or lactation or by women of childbearing age requires that the potential benefits of drug therapy be weighed against the possible hazards to the mother and child. Cholestyramine is not absorbed systemically, however, it is known to interfere with absorption of fat-soluble vitamins; accordingly, regular prenatal supplementation may not be adequate.
|useInNursing=Caution should be exercised when Cholestyramine is administered to a nursing mother. The possible lack of proper vitamin absorption described in the “Pregnancy” section may have an effect on nursing infants.
|useInPed=Although an optimal dosage schedule has not been established, standard texts (6,7) list a usual pediatric dose of 240 mg/kg/day of anhydrous cholestyramine resin in two to three divided doses, normally not to exceed 8 gm/day with dose titration based on response and tolerance.
In calculating pediatric dosages, 44.4 mg of anhydrous cholestyramine resin are contained in 100 mg of Cholestyramine for Oral Suspension USP and 80 mg of anhydrous cholestyramine resin are contained in 100 mg of Cholestyramine for Oral Suspension USP, Light.
The effects of long-term administration, as well as its effect in maintaining lowered cholesterol levels in pediatric patients, are unknown.
|administration=Oral
|monitoring=There is limited information about the drug monitoring.
|IVCompat=There is limited information about the IV Compatibility.
|overdose=Overdosage with Cholestyramine has been reported in a patient taking 150% of the maximum recommended daily dosage for a period of several weeks. No ill effects were reported. Should an overdosage occur, the chief potential harm would be obstruction of the gastrointestinal tract. The location of such potential obstruction, the degree of obstruction, and the presence or absence of normal gut motility would determine treatment.
|drugBox={{Drugbox2
| Verifiedfields = changed
| verifiedrevid = 412216968
| IUPAC_name =
| image = Cholestyramine_resin.png


| tradename = Questran
| Drugs.com = {{drugs.com|monograph|cholestyramine-resin}}
| MedlinePlus = a682672
| pregnancy_AU = 
| pregnancy_US = C
| pregnancy_category = C
| legal_AU = 
| legal_UK = 
| legal_US = Rx-only
| legal_status = Rx-only
| routes_of_administration = oral


| bioavailability = low
| protein_bound = unknown
| metabolism = bile acids
| elimination_half-life = .1 hr
| excretion = feces


| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 11041-12-6
| ATC_prefix = C10
| ATC_suffix = AC01
| ATC_supplemental =
| PubChem =
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB01432
| UNII_Ref = {{fdacite|changed|FDA}}
| UNII = 4B33BGI082
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D02690
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 1201625
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = NA


| molecular_weight = Average MW exceeds 10<sup>6</sup> Daltons
}}
|mechAction=There is limited information about the mechanism of action.
|structure=Cholestyramine for Oral Suspension USP, the chloride salt of a basic anion exchange resin, a cholesterol lowering agent, is intended for oral administration. Cholestyramine resin is quite hydrophilic, but insoluble in water. The cholestyramine resin in Cholestyramine is not absorbed from the digestive tract. Four grams of anhydrous cholestyramine resin is contained in 9 grams of Cholestyramine for Oral Suspension USP. Four grams of anhydrous cholestyramine resin is contained in 5 grams of Cholestyramine for Oral Suspension USP, Light. It is represented by the following structural formula:

[[File:Cholestyramine_structure_01.png|thumb|none|500px|This image is provided by the National Library of Medicine.]]

Cholestyramine for Oral Suspension USP contains the following inactive ingredients: acacia, citric acid, D&C Yellow No. 10, FD&C Yellow No. 6, flavor (natural and artificial Orange), polysorbate 80, propylene glycol alginate and sucrose. Cholestyramine for Oral Suspension USP, Light contains the following inactive ingredients: aspartame, citric acid, colloidal silicon dioxide, D&C Yellow No. 10, FD&C Red No. 40, flavor (natural and artificial Orange), maltodextrin, propylene glycol alginate and xanthan gum.
|PD=There is limited information about the pharmacodynamics.
|PK=There is limited information about the pharmacokinetics.
|nonClinToxic=In studies conducted in rats in which cholestyramine resin was used as a tool to investigate the role of various intestinal factors, such as fat, bile salts and microbial flora, in the development of intestinal tumors induced by potent carcinogens, the incidence of such tumors was observed to be greater in cholestyramine resin-treated rats than in control rats.
The relevance of this laboratory observation from studies in rats to the clinical use of Cholestyramine is not known. In the LRC-CPPT study referred to above, the total incidence of fatal and nonfatal neoplasms was similar in both treatment groups. When the many different categories of tumors are examined, various alimentary system cancers were somewhat more prevalent in the cholestyramine group. The small numbers and the multiple categories prevent conclusions from being drawn. However, in view of the fact that cholestyramine resin is confined to the GI tract and not absorbed, and in light of the animal experiments referred to above, a six-year post-trial follow-up of the LRC-CPPT 5 patient population has been completed (a total of 13.4 years of in-trial plus post-trial follow-up) and revealed no significant difference in the incidence of cause-specific mortality or cancer morbidity between cholestyramine and placebo treated patients.
|clinicalStudies=In a large, placebo-controlled, multi-clinic study, LRC-CPPT1 , hypercholesterolemic subjects treated with Cholestyramine had mean reductions in total and low-density lipoprotein cholesterol (LDL-C) which exceeded those for diet and placebo treatment by 7.2% and 10.4 %, respectively. Over the seven-year study period the Cholestyramine group experienced a 19% reduction (relative to the incidence in the placebo group) in the combined rate of coronary heart disease death plus non-fatal [[myocardial infarction]] (cumulative incidences of 7% Cholestyramine and 8.6% placebo). The subjects included in the study were men aged 35-59 with serum cholesterol levels above 265 mg/dL and no previous history of heart disease. It is not clear to what extent these findings can be extrapolated to females and other segments of the hypercholesterolemic population.
Two controlled clinical trials have examined the effects of Cholestyramine monotherapy upon coronary atherosclerotic lesions using [[coronary arteriography]]. In the NHLBI Type II Coronary Intervention Trial2, 116 patients (80% male) with [[coronary artery disease]] ([[CAD]]) documented by arteriography were randomized to Cholestyramine or placebo for five years of treatment. Final study arteriography revealed progression of coronary artery disease in 49% of placebo patients compared to 32% of the Cholestyramine group (p<0.05).
In the St. Thomas Atherosclerosis Regression Study (STARS)3, 90 hypercholesteroleic men with CAD were randomized to three blinded treatments: usual care, lipid-lowering diet, and lipid-lowering diet plus Cholestyramine. After 36 months, follow-up coronary arteriography revealed progression of disease in 46% of usual care patients, 15% of patients on lipid-lowering diet and 12% of those receiving diet plus Cholestyramine (p<0.02). The mean absolute width of coronary segments decreased in the usual care group, increased slightly (0.003mm) in the diet group and increased by 0.103mm in the diet plus Cholestyramine group (p<0.05). Thus in these randomized controlled clinical trials using coronary arteriography, Cholestyramine monotherapy has been demonstrated to slow progression2,3 and promote regression3 of atherosclerotic lesions in the coronary arteries of patients with coronary artery disease.
The effect of intensive lipid-lowering therapy on coronary atherosclerosis has been assessed by arteriography in hyperlipidemic patients. In these randomized, controlled clinical trials, patients were treated for two to four years by either conventional measures (diet, placebo, or in some cases low dose resin), or intensive combination therapy using diet plus [[colestipol]] (an anion exchange resin with a mechanism of action and an effect on serum lipids similar to that of Cholestyramine for Oral Suspension USP and Cholestyramine for Oral Suspension USP, Light) plus either [[nicotinic acid]] or [[lovastatin]]. When compared to conventional measures, intensive lipid-lowering combination therapy significantly reduced the frequency of progression and increased the frequency of regression of coronary atherosclerotic lesions in patients with or at risk for coronary artery disease.
|howSupplied=Cholestyramine for Oral Suspension USP is a yellow colored orange flavored powder available in cans containing 378 grams and in cartons of sixty 9 gram packets. Four grams of anhydrous cholestyramine resin are contained in 9 grams of Cholestyramine for Oral Suspension USP. The 378 g can includes a 15 cc scoop. The scoop is not interchangeable with scoops from other products. Made in U.S.A.

[[File:Cholestyramine_how supplied_01.png|thumb|none|500px|This image is provided by the National Library of Medicine.]]

Cholestyramine for Oral Suspension USP, Light is a cream to pale yellow colored orange flavored powder available in cans containing 210 grams and in cartons of sixty 5 gram packets. Four grams of anhydrous cholestyramine resin are contained in 5 grams of Cholestyramine for Oral Suspension USP, Light. The 210 g can includes a 9 cc scoop. The scoop is not interchangeable with scoops from other products. Made in India*

[[File:Cholestyramine_how supplied_02.png|thumb|none|500px|This image is provided by the National Library of Medicine.]]
|storage=Store between 20º to 25ºC (68º to 77ºF). Excursions permitted to 15º to 30ºC (59º to 86ºF).
|fdaPatientInfo=Inform your physician if you are pregnant or plan to become pregnant or are breastfeeding. Drink plenty of fluids and mix each 9 gram dose of Cholestyramine for Oral Suspension USP in at least 2 to 6 ounces of fluid. Mix each 5 gram dose of Cholestyramine for Oral Suspension USP, Light in at least 2 to 6 ounces of fluid before taking. Sipping or holding the resin suspension in the mouth for prolonged periods may lead to changes in the surface of the teeth resulting in discoloration, erosion of enamel or decay; good oral hygiene should be maintained.
|alcohol=Alcohol-Cholestyramine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|lookAlike=There is limited information about the Look-Alike Drug Names.
}}
{{PillImage}}
{{LabelImage
|fileName=Cholestyramine_label_01.jpg
}}
{{LabelImage
|fileName=Cholestyramine_label_02.jpg
}}
{{LabelImage
|fileName=Cholestyramine_label_03.jpg
}}
{{LabelImage
|fileName=Cholestyramine_label_04.jpg
}}
{{LabelImage
|fileName=Cholestyramine_label_05.jpg
}}
{{LabelImage
|fileName=Cholestyramine_label_06.jpg
}}
{{LabelImage
|fileName=Cholestyramine_panel_01.png
}}
{{LabelImage
|fileName=Cholestyramine_panel_02.png
}}
{{LabelImage
|fileName=Cholestyramine_panel_03.png
}}

[[Category:Bile acid sequestrants]]
[[Category: Cardiovascular Drugs]]
[[Category: Drug]]

Cholestyramine

2015-03-18T14:24:14Z

Sree Teja Yelamanchili:

{{DrugProjectFormSinglePage
|authorTag={{SS}}; {{STY}}
|genericName=Cholestyramine
|aOrAn=a
|drugClass=bile acid sequestrant
|indicationType=treatment
|indication=elevated [[cholesterol|serum cholesterol]] in patients with primary [[hypercholesterolemia]] (elevated [[low density lipoprotein]] [LDL] cholesterol) who do not respond adequately to diet.
|adverseReactions=[[constipation]]
|blackBoxWarningTitle=<b><span style="color:#FF0000;">TITLE</span></b>
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)
|fdaLIADAdult=<H4>Reduction of elevated serum cholesterol </H4>

* Dosing information

:* Recommended starting adult dose: '''one packet or one level scoopful once or twice a day.'''
:* Recommended maintenance dose for all: '''2 to 4 packets or scoopfuls daily (8-16 grams anhydrous cholestyramine resin) divided into two doses. '''
:* Four grams of anhydrous cholestyramine resin is contained in each measured dose of Cholestyramine as follows:

[[File:Cholestyramine_administration_01.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

* It is recommended that increases in dose be gradual with periodic assessment of lipid/lipoprotein levels at intervals of not less than 4 weeks. The maximum recommended daily dose is six packets or scoopfuls of cholestyramine for oral suspension (24 grams of anhydrous cholestyramine resin). The suggested time of administration is at mealtime but may be modified to avoid interference with absorption of other medications. Although the recommended dosing schedule is twice daily, cholestyramine for oral suspension may be administered in 1 to 6 doses per day.

* Cholestyramine should not be taken in its dry form. Always mix Cholestyramine with water or other fluids before ingesting.

<h4>Concomitant Therapy</h4>

* Preliminary evidence suggests that the lipid-lowering effects of Cholestyramine on total and LDL-cholesterol are enhanced when combined with a HMG-CoA reductase inhibitor, e.g., [[pravastatin]], [[lovastatin]], [[simvastatin]], and [[fluvastatin]]. Additive effects on LDL-cholesterol are also seen with combined nicotinic acid/Cholestyramine therapy.

<H4>Preparation</H4>

* The color of Cholestyramine may vary somewhat from batch to batch but this variation does not affect the performance of the product. Place the contents of one single-dose packet or one level scoopful of Cholestyramine in a glass or cup. Add an amount of water or other non-carbonated beverage of your choice depending on the product being used:

[[File:Cholestyramine_administration_02.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

* Stir to a uniform consistency and drink.

* Cholestyramine may also be mixed with highly fluid soups or pulpy fruits with a high moisture content such as applesauce or crushed pineapple.
|offLabelAdultGuideSupport=There is limited information about <i>Off-Label Guideline-Supported Use</i> of Cholestyramine in adult patients.
|offLabelAdultNoGuideSupport=<H4>Bile acid malabsorption syndrome</H4>

* Dosing information

:* ''' 1 to 2 sachets TID'''<ref name="pmid9768525">{{cite journal| author=Sinha L, Liston R, Testa HJ, Moriarty KJ| title=Idiopathic bile acid malabsorption: qualitative and quantitative clinical features and response to cholestyramine. | journal=Aliment Pharmacol Ther | year= 1998 | volume= 12 | issue= 9 | pages= 839-44 | pmid=9768525 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9768525 }} </ref>

<h4>Collagenous colitis</h4>

* Dosing information

:* '''4-grams (g) packets/day '''<ref name="pmid10644309">{{cite journal| author=Ung KA, Gillberg R, Kilander A, Abrahamsson H| title=Role of bile acids and bile acid binding agents in patients with collagenous colitis. | journal=Gut | year= 2000 | volume= 46 | issue= 2 | pages= 170-5 | pmid=10644309 | doi= | pmc=PMC1727822 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10644309 }} </ref>

<h4>Fistula of bile duct</h4>

* Dosing information

:* '''20 g'''<ref name="pmid7427037">{{cite journal| author=Bell SN, Varigos GA| title=Treatment of skin irritations around biliary fistulas with cholestyramine. | journal=Br J Surg | year= 1980 | volume= 67 | issue= 11 | pages= 785 | pmid=7427037 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7427037 }} </ref>

<H4>Generalized atherosclerosis</H4>

* Dosing information

:* '''6 g 4 times per day '''<ref name="pmid6360414">{{cite journal| author=Brensike JF, Levy RI, Kelsey SF, Passamani ER, Richardson JM, Loh IK et al.| title=Effects of therapy with cholestyramine on progression of coronary arteriosclerosis: results of the NHLBI Type II Coronary Intervention Study. | journal=Circulation | year= 1984 | volume= 69 | issue= 2 | pages= 313-24 | pmid=6360414 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6360414 }} </ref>
|fdaLIADPed=<H4>Reduction of elevated serum cholesterol </H4>

* Dosing information

:* '''240 mg/kg/day in 2-3 doses''', normally not to exceed '''8 gm/day''' with dose titration based on response and tolerance
|offLabelPedGuideSupport=There is limited information about <i>Off-Label Guideline-Supported Use</i> of Cholestyramine in pediatric patients.
|offLabelPedNoGuideSupport=<H4>Cholestasis</H4>

* Dosing information

:* Not applicable. <ref name="pmid2990356">{{cite journal| author=Deutsch J, Smith AL, Danks DM, Campbell PE| title=Long term prognosis for babies with neonatal liver disease. | journal=Arch Dis Child | year= 1985 | volume= 60 | issue= 5 | pages= 447-51 | pmid=2990356 | doi= | pmc=PMC1777337 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2990356 }} </ref>

<H4>Toddler diarrhea</H4>

* Dosing information

:* '''2 g BID '''<ref name="pmid3901661">{{cite journal| author=Vesikari T, Isolauri E| title=A comparative trial of cholestyramine and loperamide for acute diarrhoea in infants treated as outpatients. | journal=Acta Paediatr Scand | year= 1985 | volume= 74 | issue= 5 | pages= 650-4 | pmid=3901661 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3901661 }} </ref>
|contraindications=Cholestyramine for oral suspension is contraindicated in patients with complete biliary obstruction where bile is not secreted into the intestine and in those individuals who have shown [[hypersensitivity]] to any of its components.
|warnings=PHENYLKETONURICS: CHOLESTYRAMINE for ORAL SUSPENSION USP, LIGHT CONTAINS 14.0 mg [[PHENYLALANINE]] PER 5 GRAM DOSE.

==PRECAUTIONS==

===General===

*Chronic use of cholestyramine resin may be associated with increased bleeding tendency due to [[hypoprothrombinemia]] associated with [[Vitamin K deficiency]].
*This will usually respond promptly to parenteral Vitamin K1 and recurrences can be prevented by oral administration of Vitamin K1.
*Reduction of serum or red cell [[folate]] has been reported over long term administration of cholestyramine resin.
*Supplementation with [[folic acid]] should be considered in these cases.
*There is a possibility that prolonged use of cholestyramine resin, since it is a chloride form of anion exchange resin, may produce [[hyperchloremic acidosis]].
*This would especially be true in younger and smaller patients where the relative dosage may be higher.
*Caution should also be exercised in patients with [[renal insufficiency]] or volume depletion, and in patients receiving concomitant [[spironolactone]].
*Cholestyramine resin may produce or worsen pre-existing [[constipation]]. *The dosage should be increased gradually in patients to minimize the risk of developing fecal impaction.
*In patients with pre-existing [[constipation]], the starting dose should be 1 packet or 1 scoop once daily for 5 to 7 days, increasing to twice daily with monitoring of [[constipation]] and of serum lipoproteins, at least twice, 4 to 6 weeks apart.
*Increased fluid intake and fiber intake should be encouraged to alleviate [[constipation]] and a stool softener may occasionally be indicated.
*If the initial dose is well tolerated, the dose may be increased as needed by one dose/day (at monthly intervals) with periodic monitoring of serum lipoproteins.
*If [[constipation]] worsens or the desired therapeutic response is not achieved at one to six doses/day, combination therapy or alternate therapy should be considered.
*Particular effort should be made to avoid constipation in patients with symptomatic coronary artery disease.
*Constipation associated with cholestyramine resin may aggravate [[hemorrhoids]].

===Laboratory Tests===

Serum [[cholesterol]] levels should be determined frequently during the first few months of therapy and periodically thereafter. Serum [[triglyceride]] levels should be measured periodically to detect whether significant changes have occurred.
The LRC-CPPT showed a dose-related increase in serum triglycerides of 10.7%–17.1% in the cholestyramine-treated group, compared with an increase of 7.9%–11.7% in the placebo group. Based on the mean values and adjusting for the placebo group, the cholestyramine-treated group showed an increase of 5% over pre-entry levels the first year of the study and an increase of 4.3% the seventh year.
|clinicalTrials=*The most common adverse reaction is [[constipation]].
*When used as a cholesterol-lowering agent predisposing factors for most complaints of constipation are high dose and increased age (more than 60 years old).
*Most instances of [[constipation]] are mild, transient, and controlled with conventional therapy.
*Some patients require a temporary decrease in dosage or discontinuation of therapy.

=====Less Frequent Adverse Reactions=====
*Abdominal discomfort and/or pain, [[flatulence]], [[nausea]], [[vomiting]], [[diarrhea]], [[eructation]], [[anorexia]], and [[steatorrhea]], bleeding tendencies due to [[hypoprothrombinemia]] ([[Vitamin K deficiency]]) as well as [[Vitamin A]] (one case of night blindness reported) and [[Vitamin D|D]] deficiencies, [[hyperchloremic acidosis]] in children, [[osteoporosis]], [[rash]] and irritation of the skin, tongue and perianal area. Rare reports of [[intestinal obstruction]], including two deaths, have been reported in pediatric patients.
*Occasional calcified material has been observed in the biliary tree, including calcification of the gallbladder, in patients to whom cholestyramine resin has been given.
*However, this may be a manifestation of the liver disease and not drug related.
*One patient experienced biliary colic on each of three occasions on which he took cholestyramine resin.
*One patient diagnosed as acute abdominal symptom complex was found to have a “pasty mass” in the transverse colon on x-ray.
*Other events (not necessarily drug related) reported in patients taking cholestyramine resin include:

'''Gastrointestinal'''—GI-[[rectal bleeding]], [[black stools]], [[hemorrhoids|hemorrhoidal bleeding]], bleeding from known [[duodenal ulcer]], [[dysphagia]], [[hiccups]], ulcer attack, sour taste, [[pancreatitis]], [[rectal pain]], [[diverticulitis]].
'''Laboratory test changes'''—[[Liver function tests abnormality|Liver function abnormalities]].<BR>
'''Hematologic'''—Prolonged [[prothrombin time]], [[ecchymosis]], [[anemia]].<BR>
'''Hypersensitivity'''—[[Urticaria]], [[asthma]], [[wheezing]], [[shortness of breath]].<BR>
'''Musculoskeletal'''—[[Backache]], muscle and joint pains, [[arthritis]].<BR>
'''Neurologic'''—[[Headache]], [[anxiety]], [[vertigo]], [[dizziness]], [[fatigue]], [[tinnitus]], [[syncope]], [[drowsiness]], femoral nerve pain, [[paresthesia]].<BR>
'''Eye'''—[[Uveitis]].<BR>
'''Renal'''—[[Hematuria]], [[dysuria]], burnt odor to urine, [[diuresis]].<BR>
'''Miscellaneous'''—[[Weight loss]], [[weight gain]], increased [[libido]], swollen glands, [[edema]], dental bleeding, [[dental caries]], erosion of tooth enamel, tooth discoloration.<BR>
|postmarketing=There is limited information about the Post marketing Experience.
|drugInteractions=*Cholestyramine for Oral Suspension USP may delay or reduce the absorption of concomitant oral medication such as [[phenylbutazone]], [[warfarin]], [[thiazide diuretics]] (acidic), or [[propranolol]] (basic), as well as [[tetracycline]], [[penicillin G]], [[phenobarbital]], thyroid and thyroxine preparations, [[estrogens]] and [[progestins]], and [[digitalis]]. *Interference with the absorption of oral phosphate supplements has been observed with another positively-charged [[bile acid sequestrant]]. *Cholestyramine may interfere with the pharmacokinetics of drugs that undergo entero-hepatic circulation.
*The discontinuance of Cholestyramine could pose a hazard to health if a potentially toxic drug such as digitalis has been titrated to a maintenance level while the patient was taking Cholestyramine.
*Because cholestyramine binds bile acids, Cholestyramine may interfere with normal fat digestion and absorption and thus may prevent absorption of fat-soluble vitamins such as A, D, E and K.
*When Cholestyramine is given for long periods of time, concomitant supplementation with water-miscible (or parenteral) forms of fat-soluble vitamins should be considered.
*SINCE CHOLESTYRAMINE MAY BIND OTHER DRUGS GIVEN CONCURRENTLY, IT IS RECOMMENDED THAT PATIENTS TAKE OTHER DRUGS AT LEAST ONE HOUR BEFORE OR 4 TO 6 HOURS AFTER CHOLESTYRAMINE (OR AT AS GREAT AN INTERVAL AS POSSIBLE) TO AVOID IMPEDING THEIR ABSORPTION.
|FDAPregCat=C
|useInPregnancyFDA=There are no adequate and well controlled studies in pregnant women. The use of Cholestyramine in pregnancy or lactation or by women of childbearing age requires that the potential benefits of drug therapy be weighed against the possible hazards to the mother and child. Cholestyramine is not absorbed systemically, however, it is known to interfere with absorption of fat-soluble vitamins; accordingly, regular prenatal supplementation may not be adequate.
|useInNursing=Caution should be exercised when Cholestyramine is administered to a nursing mother. The possible lack of proper vitamin absorption described in the “Pregnancy” section may have an effect on nursing infants.
|useInPed=Although an optimal dosage schedule has not been established, standard texts (6,7) list a usual pediatric dose of 240 mg/kg/day of anhydrous cholestyramine resin in two to three divided doses, normally not to exceed 8 gm/day with dose titration based on response and tolerance.
In calculating pediatric dosages, 44.4 mg of anhydrous cholestyramine resin are contained in 100 mg of Cholestyramine for Oral Suspension USP and 80 mg of anhydrous cholestyramine resin are contained in 100 mg of Cholestyramine for Oral Suspension USP, Light.
The effects of long-term administration, as well as its effect in maintaining lowered cholesterol levels in pediatric patients, are unknown.
|administration=Oral
|monitoring=There is limited information about the drug monitoring.
|IVCompat=There is limited information about the IV Compatibility.
|overdose=Overdosage with Cholestyramine has been reported in a patient taking 150% of the maximum recommended daily dosage for a period of several weeks. No ill effects were reported. Should an overdosage occur, the chief potential harm would be obstruction of the gastrointestinal tract. The location of such potential obstruction, the degree of obstruction, and the presence or absence of normal gut motility would determine treatment.
|drugBox={{Drugbox2
| Verifiedfields = changed
| verifiedrevid = 412216968
| IUPAC_name =
| image = Cholestyramine_resin.png


| tradename = Questran
| Drugs.com = {{drugs.com|monograph|cholestyramine-resin}}
| MedlinePlus = a682672
| pregnancy_AU = 
| pregnancy_US = C
| pregnancy_category = C
| legal_AU = 
| legal_UK = 
| legal_US = Rx-only
| legal_status = Rx-only
| routes_of_administration = oral


| bioavailability = low
| protein_bound = unknown
| metabolism = bile acids
| elimination_half-life = .1 hr
| excretion = feces


| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 11041-12-6
| ATC_prefix = C10
| ATC_suffix = AC01
| ATC_supplemental =
| PubChem =
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB01432
| UNII_Ref = {{fdacite|changed|FDA}}
| UNII = 4B33BGI082
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D02690
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 1201625
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = NA


| molecular_weight = Average MW exceeds 10<sup>6</sup> Daltons
}}
|mechAction=There is limited information about the mechanism of action.
|structure=Cholestyramine for Oral Suspension USP, the chloride salt of a basic anion exchange resin, a cholesterol lowering agent, is intended for oral administration. Cholestyramine resin is quite hydrophilic, but insoluble in water. The cholestyramine resin in Cholestyramine is not absorbed from the digestive tract. Four grams of anhydrous cholestyramine resin is contained in 9 grams of Cholestyramine for Oral Suspension USP. Four grams of anhydrous cholestyramine resin is contained in 5 grams of Cholestyramine for Oral Suspension USP, Light. It is represented by the following structural formula:

[[File:Cholestyramine_structure_01.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

Cholestyramine for Oral Suspension USP contains the following inactive ingredients: acacia, citric acid, D&C Yellow No. 10, FD&C Yellow No. 6, flavor (natural and artificial Orange), polysorbate 80, propylene glycol alginate and sucrose. Cholestyramine for Oral Suspension USP, Light contains the following inactive ingredients: aspartame, citric acid, colloidal silicon dioxide, D&C Yellow No. 10, FD&C Red No. 40, flavor (natural and artificial Orange), maltodextrin, propylene glycol alginate and xanthan gum.
|PD=There is limited information about the pharmacodynamics.
|PK=There is limited information about the pharmacokinetics.
|nonClinToxic=In studies conducted in rats in which cholestyramine resin was used as a tool to investigate the role of various intestinal factors, such as fat, bile salts and microbial flora, in the development of intestinal tumors induced by potent carcinogens, the incidence of such tumors was observed to be greater in cholestyramine resin-treated rats than in control rats.
The relevance of this laboratory observation from studies in rats to the clinical use of Cholestyramine is not known. In the LRC-CPPT study referred to above, the total incidence of fatal and nonfatal neoplasms was similar in both treatment groups. When the many different categories of tumors are examined, various alimentary system cancers were somewhat more prevalent in the cholestyramine group. The small numbers and the multiple categories prevent conclusions from being drawn. However, in view of the fact that cholestyramine resin is confined to the GI tract and not absorbed, and in light of the animal experiments referred to above, a six-year post-trial follow-up of the LRC-CPPT 5 patient population has been completed (a total of 13.4 years of in-trial plus post-trial follow-up) and revealed no significant difference in the incidence of cause-specific mortality or cancer morbidity between cholestyramine and placebo treated patients.
|clinicalStudies=In a large, placebo-controlled, multi-clinic study, LRC-CPPT1 , hypercholesterolemic subjects treated with Cholestyramine had mean reductions in total and low-density lipoprotein cholesterol (LDL-C) which exceeded those for diet and placebo treatment by 7.2% and 10.4 %, respectively. Over the seven-year study period the Cholestyramine group experienced a 19% reduction (relative to the incidence in the placebo group) in the combined rate of coronary heart disease death plus non-fatal [[myocardial infarction]] (cumulative incidences of 7% Cholestyramine and 8.6% placebo). The subjects included in the study were men aged 35-59 with serum cholesterol levels above 265 mg/dL and no previous history of heart disease. It is not clear to what extent these findings can be extrapolated to females and other segments of the hypercholesterolemic population.
Two controlled clinical trials have examined the effects of Cholestyramine monotherapy upon coronary atherosclerotic lesions using [[coronary arteriography]]. In the NHLBI Type II Coronary Intervention Trial2, 116 patients (80% male) with [[coronary artery disease]] ([[CAD]]) documented by arteriography were randomized to Cholestyramine or placebo for five years of treatment. Final study arteriography revealed progression of coronary artery disease in 49% of placebo patients compared to 32% of the Cholestyramine group (p<0.05).
In the St. Thomas Atherosclerosis Regression Study (STARS)3, 90 hypercholesteroleic men with CAD were randomized to three blinded treatments: usual care, lipid-lowering diet, and lipid-lowering diet plus Cholestyramine. After 36 months, follow-up coronary arteriography revealed progression of disease in 46% of usual care patients, 15% of patients on lipid-lowering diet and 12% of those receiving diet plus Cholestyramine (p<0.02). The mean absolute width of coronary segments decreased in the usual care group, increased slightly (0.003mm) in the diet group and increased by 0.103mm in the diet plus Cholestyramine group (p<0.05). Thus in these randomized controlled clinical trials using coronary arteriography, Cholestyramine monotherapy has been demonstrated to slow progression2,3 and promote regression3 of atherosclerotic lesions in the coronary arteries of patients with coronary artery disease.
The effect of intensive lipid-lowering therapy on coronary atherosclerosis has been assessed by arteriography in hyperlipidemic patients. In these randomized, controlled clinical trials, patients were treated for two to four years by either conventional measures (diet, placebo, or in some cases low dose resin), or intensive combination therapy using diet plus [[colestipol]] (an anion exchange resin with a mechanism of action and an effect on serum lipids similar to that of Cholestyramine for Oral Suspension USP and Cholestyramine for Oral Suspension USP, Light) plus either [[nicotinic acid]] or [[lovastatin]]. When compared to conventional measures, intensive lipid-lowering combination therapy significantly reduced the frequency of progression and increased the frequency of regression of coronary atherosclerotic lesions in patients with or at risk for coronary artery disease.
|howSupplied=Cholestyramine for Oral Suspension USP is a yellow colored orange flavored powder available in cans containing 378 grams and in cartons of sixty 9 gram packets. Four grams of anhydrous cholestyramine resin are contained in 9 grams of Cholestyramine for Oral Suspension USP. The 378 g can includes a 15 cc scoop. The scoop is not interchangeable with scoops from other products. Made in U.S.A.

[[File:Cholestyramine_how supplied_01.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

Cholestyramine for Oral Suspension USP, Light is a cream to pale yellow colored orange flavored powder available in cans containing 210 grams and in cartons of sixty 5 gram packets. Four grams of anhydrous cholestyramine resin are contained in 5 grams of Cholestyramine for Oral Suspension USP, Light. The 210 g can includes a 9 cc scoop. The scoop is not interchangeable with scoops from other products. Made in India*

[[File:Cholestyramine_how supplied_02.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|storage=Store between 20º to 25ºC (68º to 77ºF). Excursions permitted to 15º to 30ºC (59º to 86ºF).
|fdaPatientInfo=Inform your physician if you are pregnant or plan to become pregnant or are breastfeeding. Drink plenty of fluids and mix each 9 gram dose of Cholestyramine for Oral Suspension USP in at least 2 to 6 ounces of fluid. Mix each 5 gram dose of Cholestyramine for Oral Suspension USP, Light in at least 2 to 6 ounces of fluid before taking. Sipping or holding the resin suspension in the mouth for prolonged periods may lead to changes in the surface of the teeth resulting in discoloration, erosion of enamel or decay; good oral hygiene should be maintained.
|alcohol=Alcohol-Cholestyramine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|lookAlike=There is limited information about the Look-Alike Drug Names.
}}
{{PillImage}}
{{LabelImage
|fileName=Cholestyramine_label_01.jpg
}}
{{LabelImage
|fileName=Cholestyramine_label_02.jpg
}}
{{LabelImage
|fileName=Cholestyramine_label_03.jpg
}}
{{LabelImage
|fileName=Cholestyramine_label_04.jpg
}}
{{LabelImage
|fileName=Cholestyramine_label_05.jpg
}}
{{LabelImage
|fileName=Cholestyramine_label_06.jpg
}}
{{LabelImage
|fileName=Cholestyramine_panel_01.png
}}
{{LabelImage
|fileName=Cholestyramine_panel_02.png
}}
{{LabelImage
|fileName=Cholestyramine_panel_03.png
}}

[[Category:Bile acid sequestrants]]
[[Category: Cardiovascular Drugs]]
[[Category: Drug]]

Varicella Zoster Immune Globulin

2015-03-12T23:05:03Z

Sree Teja Yelamanchili:

{{DrugProjectFormSinglePage
|authorTag={{STY}}
|genericName=Varicella Zoster Immune Globulin
|aOrAn=an
|drugClass=immune serum
|indicationType=prophylaxis
|indication=post exposure [[varicella]].
|adverseReactions=[[injection site reaction|injection site pain]] (overall, 2%; pregnant women, 9% ) and [[headache]]
|blackBoxWarningTitle=<b><span style="color:#FF0000;">TITLE</span></b>
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)
|fdaLIADAdult======Indications=====
Varicella Zoster Immune Globulin is indicated for post-exposure prophylaxis of [[varicella]] in high risk individuals. High risk groups include:

*immunocompromised children and adults
*newborns of mothers with [[varicella]] shortly before or after delivery
*premature infants
*neonates and infants less than one year of age
*adults without evidence of immunity
*pregnant women
Varicella Zoster Immune Globulin administration is intended to reduce the severity of varicella.

Administer Varicella Zoster Immune Globulin as soon as possible following [[varicella zoster virus]] (VZV) exposure, ideally within 96 hours for greatest effectiveness.

*There is no convincing evidence that Varicella Zoster Immune Globulin reduces the incidence of chickenpox infection after exposure to VZV.
*There is no convincing evidence that established infections with VZV can be modified by Varicella Zoster Immune Globulin administration.
*There is no indication for the prophylactic use of Varicella Zoster Immune Globulin in immunodeficient children or adults when there is a past history of varicella, unless the patient is undergoing [[bone marrow transplantation]].

=====Dosage=====
*Dosing of Varicella Zoster Immune Globulin is based on body weight. Administer a single dose of Varicella Zoster Immune Globulin intramuscularly as recommended in TABLE 1.
*The minimum dose is 62.5 International Units (IU) for small infants under two kilograms body weight; the maximum dose of 625 IU should be administered for all patients greater than 40 kilograms in weight.

[[File:Varicella zoster immune globulin (human) 1.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

Consider a second full dose of Varicella Zoster Immune Globulin for high risk patients who have additional exposures to varicella greater than three weeks after initial Varicella Zoster Immune Globulin administration.

=====Reconstitution=====
Reconstitute Varicella Zoster Immune Globulin according to TABLE 2. Only use the accompanying Sterile Diluent with aseptic technique throughout. Reconstitute shortly before use.

[[File:Varicella zoster immune globulin (human) 2.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

To reconstitute:
Remove caps from the Sterile Diluent and Varicella Zoster Immune Globulin vials.
Wipe exposed central portion of each rubber stopper with suitable disinfectant.
Withdraw 1.25 milliliter of the Sterile Diluent using a suitable syringe and needle.
Inject diluents slowly into the Varicella Zoster Immune Globulin vial at an angle so that the liquid is directed onto the inside glass wall of the vial containing the freeze-dried pellet.
Wet pellet by gently tilting and inverting the vial. Avoid frothing. Gently swirl upright vial until dissolved (less than ten minutes). Do not shake.
Inspect Varicella Zoster Immune Globulin visually for particulate matter and discoloration prior to administration.
Do not use if turbid and/or discoloration is observed.
Reconstituted product can be stored for up to 12 hours at 2 to 8°C (36 to 46ºF) prior to use.
Do not freeze. Solutions that have been frozen should not be used.
Varicella Zoster Immune Globulin is for single use only. Partially used vials, including the remaining Sterile Diluent, should be discarded.

=====Administration=====
*For intramuscular use only.
*Divide the intramuscular dose and administer in two or more injection sites, depending on patient size. Do not exceed 3 milliliters per injection site.
*Inject into the deltoid muscle or the anterolateral aspects of the upper thigh.
*Due to the risk of sciatic nerve injury, do not use the gluteal region as a routine injection site.
*If the gluteal region is used, only use the upper, outer quadrant.
*To prevent the transmission of infectious agents from one person to another, use a new disposable sterile syringe and needle for each individual patient.

=====Dosage forms and Strenghts=====
Varicella Zoster Immune Globulin is supplied as a sterile lyophilized powder for solution for intramuscular injection and is available in a single-use vial of 125 IU. Varicella Zoster Immune Globulin is accompanied by a vial containing 8.5 milliliters of Sterile Diluent for reconstitution. Each 125 IU vial of Varicella Zoster Immune Globulin contains less than 250 milligrams of total protein, mostly human immune globulin G (IgG). Varicella Zoster Immune Globulin contains no preservative and is intended for single use only. Varicella Zoster Immune Globulin does not contain mercury.
|offLabelAdultGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Varicella Zoster Immune Globulin in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Varicella Zoster Immune Globulin in adult patients.
|fdaLIADPed=The dosing recommendations in the treatment of pediatric patients are by body weight.
|offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Varicella Zoster Immune Globulin in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Varicella Zoster Immune Globulin in pediatric patients.
|contraindications=*Individuals known to have anaphylactic or severe systemic ([[hypersensitivity]]) reactions to human immune globulin preparations should not receive Varicella Zoster Immune Globulin.
*[[IgA deficiency|IgA-deficient]] patients with [[antibodies]] against IgA and a history of hypersensitivity may have an [[anaphylactoid reaction]].
*Varicella Zoster Immune Globulin contains less than 40 micrograms per milliliter of [[IgA]].
|warnings=====Thrombotic Events====
Thrombotic events may occur during or following treatment with immune globulin products (1,2,3). Patients at risk include those with a history of [[atherosclerosis]], multiple cardiovascular risk factors, advanced age, impaired cardiac output, coagulation disorders, prolonged periods of immobilization, and/or known/suspected [[hyperviscosity]]. Consider baseline assessment of blood viscosity in patients at risk for hyperviscosity including those with [[cryoglobulins]], fasting [[chylomicronemia]]/markedly high triacylglycerols ([[triglycerides]]), or monoclonal gammopathies.

====Coagulation Disorders====
Administer Varicella Zoster Immune Globulin intramuscularly only. In patients who have severe [[thrombocytopenia]] or any coagulation disorder that would contraindicate intramuscular injections, only administer Varicella Zoster Immune Globulin if the expected benefits outweigh the potential risks.

====Hypersensitivity====
Severe [[hypersensitivity]] reactions may occur following Varicella Zoster Immune Globulin administration. Administer Varicella Zoster Immune Globulin in a setting with appropriate equipment, medication and personnel trained in the management of hypersensitivity, [[anaphylaxis]] and [[shock]]. In the case of hypersensitivity, discontinue administration of Varicella Zoster Immune Globulin immediately and provide appropriate treatment.

Varicella Zoster Immune Globulin contains trace amounts of IgA (less than 40 micrograms per milliliter). Patients with known antibodies to IgA have a greater risk of severe hypersensitivity and anaphylactic reactions. Varicella Zoster Immune Globulin is contraindicated in IgA deficient patients with antibodies against [[IgA]] and history of hypersensitivity reactions.

====Transmissible Infectious Agents====
Because Varicella Zoster Immune Globulin is made from human plasma, it may carry a risk of transmitting infectious agents, e.g., viruses, the variant [[Creutzfeldt-Jakob disease]] (vCJD) agent and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. The plasma donors are screened for the presence of certain infectious agents and the manufacturing process for Varicella Zoster Immune Globulin includes measures to inactivate and remove certain viruses. Despite these measures, products derived from human plasma can still potentially transmit diseases. No cases of transmission of viral diseases, vCJD or CJD have been associated with the use of Varicella Zoster Immune Globulin.
|clinicalTrials=The most common adverse drug reactions observed in clinical trials for all subjects and patients are the following:
*[[injection site reaction|injection site pain]] (2%)
*[[headache]] (2%).

Less common adverse drug reactions reported include the following:
*[[chills]],
*[[fatigue]],
*[[rash]]
*[[nausea]]
*[[thrombosis]]

====Clinical Trial Experience====
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Three hundred and seventy seven high risk individuals received Varicella Zoster Immune Globulin intramuscularly in two [[clinical trials]] which included pregnant women, infants and immunocompromised pediatric and adult patients. The highest incidence of adverse reactions occurred in pregnant women (n=90), including [[injection site reaction|injection site pain]] (9%), [[headache]] (4%), [[chills]] (2%) and [[fatigue]] (2%). All other adverse reactions occurred in 1% or less of clinical trial subjects within each high risk group. A single incidence of serum sickness (approximately one in 400 patients treated with Varicella Zoster Immune Globulin) was observed in an immunocompromised adolescent patient.

There were six reported adverse events related to the coagulation system (one [[deep vein thrombosis]]) in 372 subjects in the open-label, Expanded Access Protocol (EAP); the study was not designed to differentiate between adverse events attributed to the underlying medical condition and adverse reactions to Varicella Zoster Immune Globulin.
|drugInteractions=The passive transfer of [[antibody|antibodies]] with [[immune globulin]] administration may impair the efficacy of live attenuated virus vaccines such as [[measles]], [[rubella]], [[mumps]] and [[varicella]]. Defer vaccination with live virus vaccines until approximately three months after Varicella Zoster Immune Globulin administration. Inform the immunizing physician of recent therapy with Varicella Zoster Immune Globulin so that appropriate measures can be taken.
|useInPregnancyFDA=Pregnancy category C. Animal reproduction studies have not been conducted with Varicella Zoster Immune Globulin. It also is not known whether Varicella Zoster Immune Globulin can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Varicella Zoster Immune Globulin should be given to a pregnant woman only if clearly needed.
|useInNursing=It is not known whether Varicella Zoster Immune Globulin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Varicella Zoster Immune Globulin is administered to a nursing mother.
|useInPed=The safety and effectiveness of Varicella Zoster Immune Globulin have been evaluated for post-exposure prophylaxis in the Varicella Zoster Immune Globulin expanded access clinical trial in 265 pediatric patients, including immunocompromised pediatric patients:
70 preterm newborns and infants
38 term newborns
28 infants and toddlers
99 children and
30 adolescents.
In the EAP, follow up data were available for 81 Varicella Zoster Immune Globulin treatments in 78 infants (including newborns, pre-term infants, and infants <1 year old). Two severe infections were reported, with pox count >100. One of these patients also developed probable [[varicella]] [[encephalitis]].
|useInGeri=*Clinical studies of Varicella Zoster Immune Globulin administered intramuscularly for post-exposure prophylaxis did not include sufficient numbers of geriatric subjects (aged 65 and over) to determine whether they respond differently from younger subjects.
*Use caution when administering Varicella Zoster Immune Globulin to patients age 65 and over who are judged to be at increased risk of thrombotic events. Do not exceed recommended doses and administer Varicella Zoster Immune Globulin intramuscularly only.
|useInImmunocomp=In the EAP, eight immunocompromised subjects developed clinical varicella, and none developed [[varicella]] [[pneumonitis]]; however five are reported to have received concomitant [[cyclovir]].
|administration=*Intramuscular use only
|monitoring=*Reduction in severity of clinical signs and symptoms of varicella zoster infection may indicate efficacy.
*Blood viscosity assessment; consider at baseline in patients at risk for hyperviscosity (eg, patients with [[cryoglobulins]], fasting [[chylomicronemia]], severe [[hypertriglyceridemia]], or [[Monoclonal gammopathy|monoclonal gammopathies]])
|overdose=Manifestations of an overdose of Varicella Zoster Immune Globulin administered intramuscularly are expected to be pain and tenderness at the injection site.
|mechAction=Varicella Zoster Immune Globulin provides passive immunization for non-immune individuals exposed to VZV, reducing the severity of varicella infections.
|structure=Varicella Zoster Immune Globulin is a solvent/detergent-treated sterile lyophilized preparation of purified human immune globulin G (IgG) containing antibodies to [[varicella|varicella zoster virus]] (anti-VZV). VZV is the causative agent of chickenpox. Varicella Zoster Immune Globulin is prepared from plasma donated by healthy, screened donors with high titers of antibodies to VZV, which is purified by an anion-exchange column chromatography manufacturing method. This donor selection process includes donors with high anti-VZV titers due to recent natural infection by VZV, or due to recurrent zoster infection (shingles).

Varicella Zoster Immune Globulin is supplied as a kit containing a single-use vial of Varicella Zoster Immune Globulin (lyophilized powder for solution for intramuscular injection with a potency of 125 IU) and a vial of 8.5 milliliters Sterile Diluent, which is used for reconstitution of the product prior to administration. Varicella Zoster Immune Globulin is intended for single use and should be administered intramuscularly.

The product potency is expressed in IU by comparison to the World Health Organization (WHO) international reference preparation for anti-VZV immune globulin. Each vial contains 125 IU of anti-VZV. The lyophilized Varicella Zoster Immune Globulin is formulated as 0.04 M sodium chloride, 0.1 M glycine and 0.01% polysorbate 80. The accompanying Sterile Diluent contains 0.8% sodium chloride and 10 mM sodium phosphate. The reconstituted Varicella Zoster Immune Globulin has a pH of 7 and contains no preservative.

Varicella Zoster Immune Globulin has not been tested for the presence of anti-Protein S antibodies that have been reported to arise transiently after VZV infection (4); however, it is assumed that the requirement that donors be healthy will alleviate this concern.

The source plasma used in the manufacture of this product was tested by FDA licensed nucleic acid testing (NAT) for human immunodeficiency virus-1 (HIV-1), [[hepatitis B virus]] (HBV) and [[hepatitis C virus]] (HCV) and found to be negative. Plasma also was tested by in-process NAT for hepatitis A virus (HAV) and [[parvovirus B19]] (B19) via minipool testing; the limit for B19 in the manufacturing pool is set not to exceed 104 IU of B19 DNA per milliliter.

The manufacturing process contains two steps implemented specifically for virus clearance. The solvent/detergent step (using tri-n-butyl phosphate and Triton X-100) is effective in the inactivation of enveloped viruses, such as HBV, HCV and HIV-1. Virus filtration, using a Planova 20N virus filter, is effective for the removal of viruses based on their size, including some non-enveloped viruses. These two viral clearance steps are designed to increase product safety by reducing the risk of transmission of enveloped and non-enveloped viruses. In addition to these two specific steps, the process step of anion-exchange chromatography was identified as contributing to the overall viral clearance capacity for small non-enveloped viruses.

The inactivation and reduction of known enveloped and non-enveloped model viruses were validated in laboratory studies as summarized in TABLE 3. The viruses employed for spiking studies were selected to represent those viruses that are potential contaminants in the product, and to represent a wide range of physiochemical properties in order to challenge the manufacturing process’s ability for viral clearance in general.

[[File:Varizig 1.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|PK=In a comparative pharmacokinetic clinical trial, 35 volunteers were administered an intramuscular dose of 12.5 IU/kg of Varicella Zoster Immune Globulin (n=18) or the comparator product VZIG™ (n=17). The dose of 12.5 IU/kg of VZIG or Varicella Zoster Immune Globulin given to the subjects was based on the assumption that the potency was similar for both products. For the bioequivalence analysis, a potency correction factor was applied (concentrations of Varicella Zoster Immune Globulin were multiplied by 2.3) to account for higher measured potency of the comparator product. The mean peak concentration (Cmax) of varicella antibodies occurred within five days of administration for both products. In the trial, baseline levels of anti-VZV antibodies ranged from 0 to 720 mIU/mL, therefore baseline levels were taken into account for pharmacokinetic calculations, to better represent the indicated population. After potency correction, baseline correction, and exclusion of subjects with baseline values of anti-VZV antibody levels of >200 mIU/mL, the two products were pharmacokinetically comparable.

[[File:Varizig 2.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|clinicalStudies=====Pregnant Women Exposed to Varicella Zoster Virus====
A randomized, open-label, multicenter, active controlled clinical trial was conducted in 60 pregnant women without immunity to VZV as confirmed by a latex agglutination test. Patients were stratified on the basis of time from first exposure to varicella as follows:
*one to four days post-exposure and
*five to 14 days post-exposure.
The women were randomized into one of three study arms as follows:

a single intravenous dose of 125 IU/10 kg body weight to a maximum dose of 625 IU of Varicella Zoster Immune Globulin
a single intramuscular dose of 125 IU/10 kg body weight to a maximum dose of 625 IU of Varicella Zoster Immune Globulin, or
a single intramuscular dose of 125 IU/10 kg body weight to a maximum dose of 625 IU of VZIG (licensed comparator product).
Patients were followed for 42 days.

Incidence of clinical varicella was similar across all treatment groups with an overall incidence of 33%; however, in the subset of 28 subjects with more than 24 hours exposure to varicella, the incidence of clinical varicella in the combined treatment groups was 64%.

Mean weighted constitutional illness scores (CIS) (6) were similar across all groups and none of the subjects had serious complications of varicella. The small number of subjects in each treatment stratum and the lack of agreed upon pre-specified hypothesis testing precluded formal statistical comparisons between groups.
|howSupplied=Varicella Zoster Immune Globulin is supplied as a kit in a carton box containing approximately 125 IUof anti-VZV supplied freeze-dried in a 6 mL type 1 glass tubing vial fitted with a 20 mm rubber lyophilization stopper and a 20 mm flip-off seal, one single dose vial of Sterile Diluent, non-pyrogenic for reconstitution of Varicella Zoster Immune Globulin and a package insert.
|storage=Store Varicella Zoster Immune Globulin at 2 to 8°C (36 to 46°F). Do not freeze. Do not use after expiration date. Use the product within 12 hours of reconstitution if stored at 2 to 8°C.
|packLabel=[[File:Varizig 3.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

[[File:Varizig 4.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|fdaPatientInfo=Inform patients of the following:

*Varicella Zoster Immune Globulin is intended to reduce the severity of chickenpox infections. Please see your doctor if you develop the signs and symptoms of [[varicella]].
*Varicella Zoster Immune Globulin is prepared from human plasma and therefore, may contain infectious agents such as viruses that can cause disease.
*The risk that products derived from human plasma will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and/or removing certain viruses during manufacturing.
*Despite these measures, products derived from human plasma can still potentially transmit disease.
*There is also the possibility that unknown infectious agents may be present in such products.
*Tell patients that persons known to have severe, potentially life-threatening reactions to human [[immune globulin]] products should not receive Varicella Zoster Immune Globulin or any other immune globulin products unless the risk has been justified.
*Tell patients that persons who are deficient in IgA may have the potential for developing anti-IgA antibodies and have severe potentially life threatening allergic reactions.
*In the case of allergic or [[anaphylaxis|anaphylactic reaction]], administration should be stopped immediately.
In the case of shock, the current medical standards for treatment of shock should be administered.
Inform patients that administration of immune globulin may interfere with the response to live virus vaccines (e.g. [[measles]], [[mumps]], [[rubella]] and [[varicella]]), and instruct them to notify their immunizing physician of recent therapy with Varicella Zoster Immune Globulin.
|alcohol=Alcohol-Varicella Zoster Immune Globulin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=*Varicella Zoster Immune Globulin
*Varicella Zoster Immune Globulin
}}

Varicella Zoster Immune Globulin

2015-03-12T20:05:43Z

Sree Teja Yelamanchili:

{{DrugProjectFormSinglePage
|authorTag={{STY}}
|genericName=Varicella Zoster Immune Globulin
|aOrAn=an
|drugClass=immune serum
|indicationType=prophylaxis
|indication=post exposure [[varicella]].
|adverseReactions=[[injection site reaction|injection site pain]] (overall, 2%; pregnant women, 9% ) and [[headache]]
|blackBoxWarningTitle=<b><span style="color:#FF0000;">TITLE</span></b>
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)
|fdaLIADAdult======Indications=====
Varicella Zoster Immune Globulin is indicated for post-exposure prophylaxis of [[varicella]] in high risk individuals. High risk groups include:

*immunocompromised children and adults
*newborns of mothers with [[varicella]] shortly before or after delivery
*premature infants
*neonates and infants less than one year of age
*adults without evidence of immunity
*pregnant women
Varicella Zoster Immune Globulin administration is intended to reduce the severity of varicella.

Administer Varicella Zoster Immune Globulin as soon as possible following [[varicella zoster virus]] (VZV) exposure, ideally within 96 hours for greatest effectiveness.

*There is no convincing evidence that Varicella Zoster Immune Globulin reduces the incidence of chickenpox infection after exposure to VZV.
*There is no convincing evidence that established infections with VZV can be modified by Varicella Zoster Immune Globulin administration.
*There is no indication for the prophylactic use of Varicella Zoster Immune Globulin in immunodeficient children or adults when there is a past history of varicella, unless the patient is undergoing [[bone marrow transplantation]].

=====Dosage=====
*Dosing of Varicella Zoster Immune Globulin is based on body weight. Administer a single dose of Varicella Zoster Immune Globulin intramuscularly as recommended in TABLE 1.
*The minimum dose is 62.5 International Units (IU) for small infants under two kilograms body weight; the maximum dose of 625 IU should be administered for all patients greater than 40 kilograms in weight.

[[File:Varicella zoster immune globulin (human) 1.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

Consider a second full dose of Varicella Zoster Immune Globulin for high risk patients who have additional exposures to varicella greater than three weeks after initial Varicella Zoster Immune Globulin administration.

=====Reconstitution=====
Reconstitute Varicella Zoster Immune Globulin according to TABLE 2. Only use the accompanying Sterile Diluent with aseptic technique throughout. Reconstitute shortly before use.

[[File:Varicella zoster immune globulin (human) 2.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

To reconstitute:
Remove caps from the Sterile Diluent and Varicella Zoster Immune Globulin vials.
Wipe exposed central portion of each rubber stopper with suitable disinfectant.
Withdraw 1.25 milliliter of the Sterile Diluent using a suitable syringe and needle.
Inject diluents slowly into the Varicella Zoster Immune Globulin vial at an angle so that the liquid is directed onto the inside glass wall of the vial containing the freeze-dried pellet.
Wet pellet by gently tilting and inverting the vial. Avoid frothing. Gently swirl upright vial until dissolved (less than ten minutes). Do not shake.
Inspect Varicella Zoster Immune Globulin visually for particulate matter and discoloration prior to administration.
Do not use if turbid and/or discoloration is observed.
Reconstituted product can be stored for up to 12 hours at 2 to 8°C (36 to 46ºF) prior to use.
Do not freeze. Solutions that have been frozen should not be used.
Varicella Zoster Immune Globulin is for single use only. Partially used vials, including the remaining Sterile Diluent, should be discarded.

=====Administration=====
*For intramuscular use only.
*Divide the intramuscular dose and administer in two or more injection sites, depending on patient size. Do not exceed 3 milliliters per injection site.
*Inject into the deltoid muscle or the anterolateral aspects of the upper thigh.
*Due to the risk of sciatic nerve injury, do not use the gluteal region as a routine injection site.
*If the gluteal region is used, only use the upper, outer quadrant.
*To prevent the transmission of infectious agents from one person to another, use a new disposable sterile syringe and needle for each individual patient.

=====Dosage forms and Strenghts=====
Varicella Zoster Immune Globulin is supplied as a sterile lyophilized powder for solution for intramuscular injection and is available in a single-use vial of 125 IU. Varicella Zoster Immune Globulin is accompanied by a vial containing 8.5 milliliters of Sterile Diluent for reconstitution. Each 125 IU vial of Varicella Zoster Immune Globulin contains less than 250 milligrams of total protein, mostly human immune globulin G (IgG). Varicella Zoster Immune Globulin contains no preservative and is intended for single use only. Varicella Zoster Immune Globulin does not contain mercury.
|offLabelAdultGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Varicella Zoster Immune Globulin in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Varicella Zoster Immune Globulin in adult patients.
|fdaLIADPed=The dosing recommendations in the treatment of pediatric patients are by body weight.
|offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Varicella Zoster Immune Globulin in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Varicella Zoster Immune Globulin in pediatric patients.
|contraindications=*Individuals known to have anaphylactic or severe systemic ([[hypersensitivity]]) reactions to human immune globulin preparations should not receive Varicella Zoster Immune Globulin.
*[[IgA deficiency|IgA-deficient]] patients with [[antibodies]] against IgA and a history of hypersensitivity may have an [[anaphylactoid reaction]].
*Varicella Zoster Immune Globulin contains less than 40 micrograms per milliliter of [[IgA]].
|warnings=====Thrombotic Events====
Thrombotic events may occur during or following treatment with immune globulin products (1,2,3). Patients at risk include those with a history of [[atherosclerosis]], multiple cardiovascular risk factors, advanced age, impaired cardiac output, coagulation disorders, prolonged periods of immobilization, and/or known/suspected [[hyperviscosity]]. Consider baseline assessment of blood viscosity in patients at risk for hyperviscosity including those with [[cryoglobulins]], fasting [[chylomicronemia]]/markedly high triacylglycerols ([[triglycerides]]), or monoclonal gammopathies.

====Coagulation Disorders====
Administer Varicella Zoster Immune Globulin intramuscularly only. In patients who have severe [[thrombocytopenia]] or any coagulation disorder that would contraindicate intramuscular injections, only administer Varicella Zoster Immune Globulin if the expected benefits outweigh the potential risks.

====Hypersensitivity====
Severe [[hypersensitivity]] reactions may occur following Varicella Zoster Immune Globulin administration. Administer Varicella Zoster Immune Globulin in a setting with appropriate equipment, medication and personnel trained in the management of hypersensitivity, [[anaphylaxis]] and [[shock]]. In the case of hypersensitivity, discontinue administration of Varicella Zoster Immune Globulin immediately and provide appropriate treatment.

Varicella Zoster Immune Globulin contains trace amounts of IgA (less than 40 micrograms per milliliter). Patients with known antibodies to IgA have a greater risk of severe hypersensitivity and anaphylactic reactions. Varicella Zoster Immune Globulin is contraindicated in IgA deficient patients with antibodies against [[IgA]] and history of hypersensitivity reactions.

====Transmissible Infectious Agents====
Because Varicella Zoster Immune Globulin is made from human plasma, it may carry a risk of transmitting infectious agents, e.g., viruses, the variant [[Creutzfeldt-Jakob disease]] (vCJD) agent and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. The plasma donors are screened for the presence of certain infectious agents and the manufacturing process for Varicella Zoster Immune Globulin includes measures to inactivate and remove certain viruses. Despite these measures, products derived from human plasma can still potentially transmit diseases. No cases of transmission of viral diseases, vCJD or CJD have been associated with the use of Varicella Zoster Immune Globulin.
|clinicalTrials=The most common adverse drug reactions observed in clinical trials for all subjects and patients are the following:
*[[injection site reaction|injection site pain]] (2%)
*[[headache]] (2%).

Less common adverse drug reactions reported include the following:
*[[chills]],
*[[fatigue]],
*[[rash]]
*[[nausea]]
*[[thrombosis]]

====Clinical Trial Experience====
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Three hundred and seventy seven high risk individuals received Varicella Zoster Immune Globulin intramuscularly in two [[clinical trials]] which included pregnant women, infants and immunocompromised pediatric and adult patients. The highest incidence of adverse reactions occurred in pregnant women (n=90), including [[injection site reaction|injection site pain]] (9%), [[headache]] (4%), [[chills]] (2%) and [[fatigue]] (2%). All other adverse reactions occurred in 1% or less of clinical trial subjects within each high risk group. A single incidence of serum sickness (approximately one in 400 patients treated with Varicella Zoster Immune Globulin) was observed in an immunocompromised adolescent patient.

There were six reported adverse events related to the coagulation system (one [[deep vein thrombosis]]) in 372 subjects in the open-label, Expanded Access Protocol (EAP); the study was not designed to differentiate between adverse events attributed to the underlying medical condition and adverse reactions to Varicella Zoster Immune Globulin.
|drugInteractions=The passive transfer of [[antibody|antibodies]] with [[immune globulin]] administration may impair the efficacy of live attenuated virus vaccines such as [[measles]], [[rubella]], [[mumps]] and [[varicella]]. Defer vaccination with live virus vaccines until approximately three months after Varicella Zoster Immune Globulin administration. Inform the immunizing physician of recent therapy with Varicella Zoster Immune Globulin so that appropriate measures can be taken.
|useInPregnancyFDA=Pregnancy category C. Animal reproduction studies have not been conducted with Varicella Zoster Immune Globulin. It also is not known whether Varicella Zoster Immune Globulin can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Varicella Zoster Immune Globulin should be given to a pregnant woman only if clearly needed.
|useInNursing=It is not known whether Varicella Zoster Immune Globulin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Varicella Zoster Immune Globulin is administered to a nursing mother.
|useInPed=The safety and effectiveness of Varicella Zoster Immune Globulin have been evaluated for post-exposure prophylaxis in the Varicella Zoster Immune Globulin expanded access clinical trial in 265 pediatric patients, including immunocompromised pediatric patients:
70 preterm newborns and infants
38 term newborns
28 infants and toddlers
99 children and
30 adolescents.
In the EAP, follow up data were available for 81 Varicella Zoster Immune Globulin treatments in 78 infants (including newborns, pre-term infants, and infants <1 year old). Two severe infections were reported, with pox count >100. One of these patients also developed probable [[varicella]] [[encephalitis]].
|useInGeri=*Clinical studies of Varicella Zoster Immune Globulin administered intramuscularly for post-exposure prophylaxis did not include sufficient numbers of geriatric subjects (aged 65 and over) to determine whether they respond differently from younger subjects.
*Use caution when administering Varicella Zoster Immune Globulin to patients age 65 and over who are judged to be at increased risk of thrombotic events. Do not exceed recommended doses and administer Varicella Zoster Immune Globulin intramuscularly only.
|useInImmunocomp=In the EAP, eight immunocompromised subjects developed clinical varicella, and none developed [[varicella]] [[pneumonitis]]; however five are reported to have received concomitant [[cyclovir]].
|administration=*Intramuscular use only
|monitoring=*Reduction in severity of clinical signs and symptoms of varicella zoster infection may indicate efficacy.
*Blood viscosity assessment; consider at baseline in patients at risk for hyperviscosity (eg, patients with [[cryoglobulins]], fasting [[chylomicronemia]], severe [[hypertriglyceridemia]], or [[Monoclonal gammopathy|monoclonal gammopathies]])
|overdose=Manifestations of an overdose of Varicella Zoster Immune Globulin administered intramuscularly are expected to be pain and tenderness at the injection site.
|mechAction=Varicella Zoster Immune Globulin provides passive immunization for non-immune individuals exposed to VZV, reducing the severity of varicella infections.
|structure=Varicella Zoster Immune Globulin is a solvent/detergent-treated sterile lyophilized preparation of purified human immune globulin G (IgG) containing antibodies to [[varicella|varicella zoster virus]] (anti-VZV). VZV is the causative agent of chickenpox. Varicella Zoster Immune Globulin is prepared from plasma donated by healthy, screened donors with high titers of antibodies to VZV, which is purified by an anion-exchange column chromatography manufacturing method. This donor selection process includes donors with high anti-VZV titers due to recent natural infection by VZV, or due to recurrent zoster infection (shingles).

Varicella Zoster Immune Globulin is supplied as a kit containing a single-use vial of Varicella Zoster Immune Globulin (lyophilized powder for solution for intramuscular injection with a potency of 125 IU) and a vial of 8.5 milliliters Sterile Diluent, which is used for reconstitution of the product prior to administration. Varicella Zoster Immune Globulin is intended for single use and should be administered intramuscularly.

The product potency is expressed in IU by comparison to the World Health Organization (WHO) international reference preparation for anti-VZV immune globulin. Each vial contains 125 IU of anti-VZV. The lyophilized Varicella Zoster Immune Globulin is formulated as 0.04 M sodium chloride, 0.1 M glycine and 0.01% polysorbate 80. The accompanying Sterile Diluent contains 0.8% sodium chloride and 10 mM sodium phosphate. The reconstituted Varicella Zoster Immune Globulin has a pH of 7 and contains no preservative.

Varicella Zoster Immune Globulin has not been tested for the presence of anti-Protein S antibodies that have been reported to arise transiently after VZV infection (4); however, it is assumed that the requirement that donors be healthy will alleviate this concern.

The source plasma used in the manufacture of this product was tested by FDA licensed nucleic acid testing (NAT) for human immunodeficiency virus-1 (HIV-1), [[hepatitis B virus]] (HBV) and [[hepatitis C virus]] (HCV) and found to be negative. Plasma also was tested by in-process NAT for hepatitis A virus (HAV) and [[parvovirus B19]] (B19) via minipool testing; the limit for B19 in the manufacturing pool is set not to exceed 104 IU of B19 DNA per milliliter.

The manufacturing process contains two steps implemented specifically for virus clearance. The solvent/detergent step (using tri-n-butyl phosphate and Triton X-100) is effective in the inactivation of enveloped viruses, such as HBV, HCV and HIV-1. Virus filtration, using a Planova 20N virus filter, is effective for the removal of viruses based on their size, including some non-enveloped viruses. These two viral clearance steps are designed to increase product safety by reducing the risk of transmission of enveloped and non-enveloped viruses. In addition to these two specific steps, the process step of anion-exchange chromatography was identified as contributing to the overall viral clearance capacity for small non-enveloped viruses.

The inactivation and reduction of known enveloped and non-enveloped model viruses were validated in laboratory studies as summarized in TABLE 3. The viruses employed for spiking studies were selected to represent those viruses that are potential contaminants in the product, and to represent a wide range of physiochemical properties in order to challenge the manufacturing process’s ability for viral clearance in general.

[[File:Varicella Zoster Immune Globulin 1.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|PK=In a comparative pharmacokinetic clinical trial, 35 volunteers were administered an intramuscular dose of 12.5 IU/kg of Varicella Zoster Immune Globulin (n=18) or the comparator product VZIG™ (n=17). The dose of 12.5 IU/kg of VZIG or Varicella Zoster Immune Globulin given to the subjects was based on the assumption that the potency was similar for both products. For the bioequivalence analysis, a potency correction factor was applied (concentrations of Varicella Zoster Immune Globulin were multiplied by 2.3) to account for higher measured potency of the comparator product. The mean peak concentration (Cmax) of varicella antibodies occurred within five days of administration for both products. In the trial, baseline levels of anti-VZV antibodies ranged from 0 to 720 mIU/mL, therefore baseline levels were taken into account for pharmacokinetic calculations, to better represent the indicated population. After potency correction, baseline correction, and exclusion of subjects with baseline values of anti-VZV antibody levels of >200 mIU/mL, the two products were pharmacokinetically comparable.

[[File:Varicella Zoster Immune Globulin 2.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|clinicalStudies=====Pregnant Women Exposed to Varicella Zoster Virus====
A randomized, open-label, multicenter, active controlled clinical trial was conducted in 60 pregnant women without immunity to VZV as confirmed by a latex agglutination test. Patients were stratified on the basis of time from first exposure to varicella as follows:
*one to four days post-exposure and
*five to 14 days post-exposure.
The women were randomized into one of three study arms as follows:

a single intravenous dose of 125 IU/10 kg body weight to a maximum dose of 625 IU of Varicella Zoster Immune Globulin
a single intramuscular dose of 125 IU/10 kg body weight to a maximum dose of 625 IU of Varicella Zoster Immune Globulin, or
a single intramuscular dose of 125 IU/10 kg body weight to a maximum dose of 625 IU of VZIG (licensed comparator product).
Patients were followed for 42 days.

Incidence of clinical varicella was similar across all treatment groups with an overall incidence of 33%; however, in the subset of 28 subjects with more than 24 hours exposure to varicella, the incidence of clinical varicella in the combined treatment groups was 64%.

Mean weighted constitutional illness scores (CIS) (6) were similar across all groups and none of the subjects had serious complications of varicella. The small number of subjects in each treatment stratum and the lack of agreed upon pre-specified hypothesis testing precluded formal statistical comparisons between groups.
|howSupplied=Varicella Zoster Immune Globulin is supplied as a kit in a carton box containing approximately 125 IUof anti-VZV supplied freeze-dried in a 6 mL type 1 glass tubing vial fitted with a 20 mm rubber lyophilization stopper and a 20 mm flip-off seal, one single dose vial of Sterile Diluent, non-pyrogenic for reconstitution of Varicella Zoster Immune Globulin and a package insert.
|storage=Store Varicella Zoster Immune Globulin at 2 to 8°C (36 to 46°F). Do not freeze. Do not use after expiration date. Use the product within 12 hours of reconstitution if stored at 2 to 8°C.
|packLabel=[[File:Varicella Zoster Immune Globulin 3.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

[[File:Varicella Zoster Immune Globulin 4.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|fdaPatientInfo=Inform patients of the following:

*Varicella Zoster Immune Globulin is intended to reduce the severity of chickenpox infections. Please see your doctor if you develop the signs and symptoms of [[varicella]].
*Varicella Zoster Immune Globulin is prepared from human plasma and therefore, may contain infectious agents such as viruses that can cause disease.
*The risk that products derived from human plasma will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and/or removing certain viruses during manufacturing.
*Despite these measures, products derived from human plasma can still potentially transmit disease.
*There is also the possibility that unknown infectious agents may be present in such products.
*Tell patients that persons known to have severe, potentially life-threatening reactions to human [[immune globulin]] products should not receive Varicella Zoster Immune Globulin or any other immune globulin products unless the risk has been justified.
*Tell patients that persons who are deficient in IgA may have the potential for developing anti-IgA antibodies and have severe potentially life threatening allergic reactions.
*In the case of allergic or [[anaphylaxis|anaphylactic reaction]], administration should be stopped immediately.
In the case of shock, the current medical standards for treatment of shock should be administered.
Inform patients that administration of immune globulin may interfere with the response to live virus vaccines (e.g. [[measles]], [[mumps]], [[rubella]] and [[varicella]]), and instruct them to notify their immunizing physician of recent therapy with Varicella Zoster Immune Globulin.
|alcohol=Alcohol-Varicella Zoster Immune Globulin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=*Varicella Zoster Immune Globulin
*Varicella Zoster Immune Globulin
}}

Varicella Zoster Immune Globulin

2015-03-12T19:51:45Z

Sree Teja Yelamanchili:

{{DrugProjectFormSinglePage
|authorTag={{STY}}
|genericName=Varicella Zoster Immune Globulin
|aOrAn=an
|drugClass=immune serum
|indicationType=prophylaxis
|indication=post exposure [[varicella]].
|adverseReactions=[[injection site reaction|injection site pain]] (overall, 2%; pregnant women, 9% ) and [[headache]]
|blackBoxWarningTitle=<b><span style="color:#FF0000;">TITLE</span></b>
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)
|fdaLIADAdult======Indications=====
Varicella Zoster Immune Globulin is indicated for post-exposure prophylaxis of [[varicella]] in high risk individuals. High risk groups include:

*immunocompromised children and adults
*newborns of mothers with [[varicella]] shortly before or after delivery
*premature infants
*neonates and infants less than one year of age
*adults without evidence of immunity
*pregnant women
Varicella Zoster Immune Globulin administration is intended to reduce the severity of varicella.

Administer Varicella Zoster Immune Globulin as soon as possible following [[varicella zoster virus]] (VZV) exposure, ideally within 96 hours for greatest effectiveness.

*There is no convincing evidence that Varicella Zoster Immune Globulin reduces the incidence of chickenpox infection after exposure to VZV.
*There is no convincing evidence that established infections with VZV can be modified by Varicella Zoster Immune Globulin administration.
*There is no indication for the prophylactic use of Varicella Zoster Immune Globulin in immunodeficient children or adults when there is a past history of varicella, unless the patient is undergoing [[bone marrow transplantation]].

=====Dosage=====
*Dosing of Varicella Zoster Immune Globulin is based on body weight. Administer a single dose of Varicella Zoster Immune Globulin intramuscularly as recommended in TABLE 1.
*The minimum dose is 62.5 International Units (IU) for small infants under two kilograms body weight; the maximum dose of 625 IU should be administered for all patients greater than 40 kilograms in weight.

[[File:Varicella zoster immune globulin (human) 1.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

Consider a second full dose of Varicella Zoster Immune Globulin for high risk patients who have additional exposures to varicella greater than three weeks after initial Varicella Zoster Immune Globulin administration.

=====Reconstitution=====
Reconstitute Varicella Zoster Immune Globulin according to TABLE 2. Only use the accompanying Sterile Diluent with aseptic technique throughout. Reconstitute shortly before use.

[[File:Varicella zoster immune globulin (human) 2.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

To reconstitute:
Remove caps from the Sterile Diluent and Varicella Zoster Immune Globulin vials.
Wipe exposed central portion of each rubber stopper with suitable disinfectant.
Withdraw 1.25 milliliter of the Sterile Diluent using a suitable syringe and needle.
Inject diluents slowly into the Varicella Zoster Immune Globulin vial at an angle so that the liquid is directed onto the inside glass wall of the vial containing the freeze-dried pellet.
Wet pellet by gently tilting and inverting the vial. Avoid frothing. Gently swirl upright vial until dissolved (less than ten minutes). Do not shake.
Inspect Varicella Zoster Immune Globulin visually for particulate matter and discoloration prior to administration.
Do not use if turbid and/or discoloration is observed.
Reconstituted product can be stored for up to 12 hours at 2 to 8°C (36 to 46ºF) prior to use.
Do not freeze. Solutions that have been frozen should not be used.
Varicella Zoster Immune Globulin is for single use only. Partially used vials, including the remaining Sterile Diluent, should be discarded.

=====Administration=====
*For intramuscular use only.
*Divide the intramuscular dose and administer in two or more injection sites, depending on patient size. Do not exceed 3 milliliters per injection site.
*Inject into the deltoid muscle or the anterolateral aspects of the upper thigh.
*Due to the risk of sciatic nerve injury, do not use the gluteal region as a routine injection site.
*If the gluteal region is used, only use the upper, outer quadrant.
*To prevent the transmission of infectious agents from one person to another, use a new disposable sterile syringe and needle for each individual patient.

=====Dosage forms and Strenghts=====
Varicella Zoster Immune Globulin is supplied as a sterile lyophilized powder for solution for intramuscular injection and is available in a single-use vial of 125 IU. Varicella Zoster Immune Globulin is accompanied by a vial containing 8.5 milliliters of Sterile Diluent for reconstitution. Each 125 IU vial of Varicella Zoster Immune Globulin contains less than 250 milligrams of total protein, mostly human immune globulin G (IgG). Varicella Zoster Immune Globulin contains no preservative and is intended for single use only. Varicella Zoster Immune Globulin does not contain mercury.
|offLabelAdultGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Varicella Zoster Immune Globulin in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Varicella Zoster Immune Globulin in adult patients.
|fdaLIADPed=The dosing recommendations in the treatment of pediatric patients are by body weight.
|offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Varicella Zoster Immune Globulin in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Varicella Zoster Immune Globulin in pediatric patients.
|contraindications=*Individuals known to have anaphylactic or severe systemic ([[hypersensitivity]]) reactions to human immune globulin preparations should not receive Varicella Zoster Immune Globulin.
*[[IgA deficiency|IgA-deficient]] patients with [[antibodies]] against IgA and a history of hypersensitivity may have an [[anaphylactoid reaction]].
*Varicella Zoster Immune Globulin contains less than 40 micrograms per milliliter of [[IgA]].
|warnings=====Thrombotic Events====
Thrombotic events may occur during or following treatment with immune globulin products (1,2,3). Patients at risk include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, coagulation disorders, prolonged periods of immobilization, and/or known/suspected hyperviscosity. Consider baseline assessment of blood viscosity in patients at risk for hyperviscosity including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies.

====Coagulation Disorders====
Administer Varicella Zoster Immune Globulin intramuscularly only. In patients who have severe thrombocytopenia or any coagulation disorder that would contraindicate intramuscular injections, only administer Varicella Zoster Immune Globulin if the expected benefits outweigh the potential risks.

====Hypersensitivity====
Severe hypersensitivity reactions may occur following Varicella Zoster Immune Globulin administration. Administer Varicella Zoster Immune Globulin in a setting with appropriate equipment, medication and personnel trained in the management of hypersensitivity, anaphylaxis and shock. In the case of hypersensitivity, discontinue administration of Varicella Zoster Immune Globulin immediately and provide appropriate treatment.

Varicella Zoster Immune Globulin contains trace amounts of IgA (less than 40 micrograms per milliliter). Patients with known antibodies to IgA have a greater risk of severe hypersensitivity and anaphylactic reactions. Varicella Zoster Immune Globulin is contraindicated in IgA deficient patients with antibodies against IgA and history of hypersensitivity reactions.

====Transmissible Infectious Agents====
Because Varicella Zoster Immune Globulin is made from human plasma, it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. The plasma donors are screened for the presence of certain infectious agents and the manufacturing process for Varicella Zoster Immune Globulin includes measures to inactivate and remove certain viruses [see11 DESCRIPTION]. Despite these measures, products derived from human plasma can still potentially transmit diseases. No cases of transmission of viral diseases, vCJD or CJD have been associated with the use of Varicella Zoster Immune Globulin.
|clinicalTrials=The most common adverse drug reactions observed in clinical trials for all subjects and patients are the following:
*[[injection site reaction|injection site pain]] (2%)
*[[headache]] (2%).

Less common adverse drug reactions reported include the following:
*[[chills]],
*[[fatigue]],
*[[rash]]
*[[nausea]]
*[[thrombosis]]

====Clinical Trial Experience====
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Three hundred and seventy seven high risk individuals received Varicella Zoster Immune Globulin intramuscularly in two [[clinical trials]] which included pregnant women, infants and immunocompromised pediatric and adult patients. The highest incidence of adverse reactions occurred in pregnant women (n=90), including [[injection site reaction|injection site pain]] (9%), [[headache]] (4%), [[chills]] (2%) and [[fatigue]] (2%). All other adverse reactions occurred in 1% or less of clinical trial subjects within each high risk group. A single incidence of serum sickness (approximately one in 400 patients treated with Varicella Zoster Immune Globulin) was observed in an immunocompromised adolescent patient.

There were six reported adverse events related to the coagulation system (one [[deep vein thrombosis]]) in 372 subjects in the open-label, Expanded Access Protocol (EAP); the study was not designed to differentiate between adverse events attributed to the underlying medical condition and adverse reactions to Varicella Zoster Immune Globulin.
|drugInteractions=The passive transfer of [[antibody|antibodies]] with [[immune globulin]] administration may impair the efficacy of live attenuated virus vaccines such as [[measles]], [[rubella]], [[mumps]] and [[varicella]]. Defer vaccination with live virus vaccines until approximately three months after Varicella Zoster Immune Globulin administration. Inform the immunizing physician of recent therapy with Varicella Zoster Immune Globulin so that appropriate measures can be taken.
|useInPregnancyFDA=Pregnancy category C. Animal reproduction studies have not been conducted with Varicella Zoster Immune Globulin. It also is not known whether Varicella Zoster Immune Globulin can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Varicella Zoster Immune Globulin should be given to a pregnant woman only if clearly needed.
|useInNursing=It is not known whether Varicella Zoster Immune Globulin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Varicella Zoster Immune Globulin is administered to a nursing mother.
|useInPed=The safety and effectiveness of Varicella Zoster Immune Globulin have been evaluated for post-exposure prophylaxis in the Varicella Zoster Immune Globulin expanded access clinical trial in 265 pediatric patients, including immunocompromised pediatric patients:
70 preterm newborns and infants
38 term newborns
28 infants and toddlers
99 children and
30 adolescents.
In the EAP, follow up data were available for 81 Varicella Zoster Immune Globulin treatments in 78 infants (including newborns, pre-term infants, and infants <1 year old). Two severe infections were reported, with pox count >100. One of these patients also developed probable [[varicella]] [[encephalitis]].
|useInGeri=*Clinical studies of Varicella Zoster Immune Globulin administered intramuscularly for post-exposure prophylaxis did not include sufficient numbers of geriatric subjects (aged 65 and over) to determine whether they respond differently from younger subjects.
*Use caution when administering Varicella Zoster Immune Globulin to patients age 65 and over who are judged to be at increased risk of thrombotic events. Do not exceed recommended doses and administer Varicella Zoster Immune Globulin intramuscularly only.
|useInImmunocomp=In the EAP, eight immunocompromised subjects developed clinical varicella, and none developed [[varicella]] [[pneumonitis]]; however five are reported to have received concomitant [[cyclovir]].
|administration=*Intramuscular use only
|monitoring=*Reduction in severity of clinical signs and symptoms of varicella zoster infection may indicate efficacy.
*Blood viscosity assessment; consider at baseline in patients at risk for hyperviscosity (eg, patients with [[cryoglobulins]], fasting [[chylomicronemia]], severe [[hypertriglyceridemia]], or [[Monoclonal gammopathy|monoclonal gammopathies]])
|overdose=Manifestations of an overdose of Varicella Zoster Immune Globulin administered intramuscularly are expected to be pain and tenderness at the injection site.
|mechAction=Varicella Zoster Immune Globulin provides passive immunization for non-immune individuals exposed to VZV, reducing the severity of varicella infections.
|structure=Varicella Zoster Immune Globulin is a solvent/detergent-treated sterile lyophilized preparation of purified human immune globulin G (IgG) containing antibodies to [[varicella|varicella zoster virus]] (anti-VZV). VZV is the causative agent of chickenpox. Varicella Zoster Immune Globulin is prepared from plasma donated by healthy, screened donors with high titers of antibodies to VZV, which is purified by an anion-exchange column chromatography manufacturing method. This donor selection process includes donors with high anti-VZV titers due to recent natural infection by VZV, or due to recurrent zoster infection (shingles).

Varicella Zoster Immune Globulin is supplied as a kit containing a single-use vial of Varicella Zoster Immune Globulin (lyophilized powder for solution for intramuscular injection with a potency of 125 IU) and a vial of 8.5 milliliters Sterile Diluent, which is used for reconstitution of the product prior to administration. Varicella Zoster Immune Globulin is intended for single use and should be administered intramuscularly.

The product potency is expressed in IU by comparison to the World Health Organization (WHO) international reference preparation for anti-VZV immune globulin. Each vial contains 125 IU of anti-VZV. The lyophilized Varicella Zoster Immune Globulin is formulated as 0.04 M sodium chloride, 0.1 M glycine and 0.01% polysorbate 80. The accompanying Sterile Diluent contains 0.8% sodium chloride and 10 mM sodium phosphate. The reconstituted Varicella Zoster Immune Globulin has a pH of 7 and contains no preservative.

Varicella Zoster Immune Globulin has not been tested for the presence of anti-Protein S antibodies that have been reported to arise transiently after VZV infection (4); however, it is assumed that the requirement that donors be healthy will alleviate this concern.

The source plasma used in the manufacture of this product was tested by FDA licensed nucleic acid testing (NAT) for human immunodeficiency virus-1 (HIV-1), [[hepatitis B virus]] (HBV) and [[hepatitis C virus]] (HCV) and found to be negative. Plasma also was tested by in-process NAT for hepatitis A virus (HAV) and [[parvovirus B19]] (B19) via minipool testing; the limit for B19 in the manufacturing pool is set not to exceed 104 IU of B19 DNA per milliliter.

The manufacturing process contains two steps implemented specifically for virus clearance. The solvent/detergent step (using tri-n-butyl phosphate and Triton X-100) is effective in the inactivation of enveloped viruses, such as HBV, HCV and HIV-1. Virus filtration, using a Planova 20N virus filter, is effective for the removal of viruses based on their size, including some non-enveloped viruses. These two viral clearance steps are designed to increase product safety by reducing the risk of transmission of enveloped and non-enveloped viruses. In addition to these two specific steps, the process step of anion-exchange chromatography was identified as contributing to the overall viral clearance capacity for small non-enveloped viruses.

The inactivation and reduction of known enveloped and non-enveloped model viruses were validated in laboratory studies as summarized in TABLE 3. The viruses employed for spiking studies were selected to represent those viruses that are potential contaminants in the product, and to represent a wide range of physiochemical properties in order to challenge the manufacturing process’s ability for viral clearance in general.

[[File:Varicella Zoster Immune Globulin 1.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|PK=In a comparative pharmacokinetic clinical trial, 35 volunteers were administered an intramuscular dose of 12.5 IU/kg of Varicella Zoster Immune Globulin (n=18) or the comparator product VZIG™ (n=17). The dose of 12.5 IU/kg of VZIG or Varicella Zoster Immune Globulin given to the subjects was based on the assumption that the potency was similar for both products. For the bioequivalence analysis, a potency correction factor was applied (concentrations of Varicella Zoster Immune Globulin were multiplied by 2.3) to account for higher measured potency of the comparator product. The mean peak concentration (Cmax) of varicella antibodies occurred within five days of administration for both products. In the trial, baseline levels of anti-VZV antibodies ranged from 0 to 720 mIU/mL, therefore baseline levels were taken into account for pharmacokinetic calculations, to better represent the indicated population. After potency correction, baseline correction, and exclusion of subjects with baseline values of anti-VZV antibody levels of >200 mIU/mL, the two products were pharmacokinetically comparable.

[[File:Varicella Zoster Immune Globulin 2.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|clinicalStudies=====Pregnant Women Exposed to Varicella Zoster Virus====
A randomized, open-label, multicenter, active controlled clinical trial was conducted in 60 pregnant women without immunity to VZV as confirmed by a latex agglutination test. Patients were stratified on the basis of time from first exposure to varicella as follows:
*one to four days post-exposure and
*five to 14 days post-exposure.
The women were randomized into one of three study arms as follows:

a single intravenous dose of 125 IU/10 kg body weight to a maximum dose of 625 IU of Varicella Zoster Immune Globulin
a single intramuscular dose of 125 IU/10 kg body weight to a maximum dose of 625 IU of Varicella Zoster Immune Globulin, or
a single intramuscular dose of 125 IU/10 kg body weight to a maximum dose of 625 IU of VZIG (licensed comparator product).
Patients were followed for 42 days.

Incidence of clinical varicella was similar across all treatment groups with an overall incidence of 33%; however, in the subset of 28 subjects with more than 24 hours exposure to varicella, the incidence of clinical varicella in the combined treatment groups was 64%.

Mean weighted constitutional illness scores (CIS) (6) were similar across all groups and none of the subjects had serious complications of varicella. The small number of subjects in each treatment stratum and the lack of agreed upon pre-specified hypothesis testing precluded formal statistical comparisons between groups.
|howSupplied=Varicella Zoster Immune Globulin is supplied as a kit in a carton box containing approximately 125 IUof anti-VZV supplied freeze-dried in a 6 mL type 1 glass tubing vial fitted with a 20 mm rubber lyophilization stopper and a 20 mm flip-off seal, one single dose vial of Sterile Diluent, non-pyrogenic for reconstitution of Varicella Zoster Immune Globulin and a package insert.
|storage=Store Varicella Zoster Immune Globulin at 2 to 8°C (36 to 46°F). Do not freeze. Do not use after expiration date. Use the product within 12 hours of reconstitution if stored at 2 to 8°C.
|packLabel=[[File:Varicella Zoster Immune Globulin 3.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

[[File:Varicella Zoster Immune Globulin 4.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|fdaPatientInfo=Inform patients of the following:

*Varicella Zoster Immune Globulin is intended to reduce the severity of chickenpox infections. Please see your doctor if you develop the signs and symptoms of [[varicella]].
*Varicella Zoster Immune Globulin is prepared from human plasma and therefore, may contain infectious agents such as viruses that can cause disease.
*The risk that products derived from human plasma will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and/or removing certain viruses during manufacturing.
*Despite these measures, products derived from human plasma can still potentially transmit disease.
*There is also the possibility that unknown infectious agents may be present in such products.
*Tell patients that persons known to have severe, potentially life-threatening reactions to human [[immune globulin]] products should not receive Varicella Zoster Immune Globulin or any other immune globulin products unless the risk has been justified.
*Tell patients that persons who are deficient in IgA may have the potential for developing anti-IgA antibodies and have severe potentially life threatening allergic reactions.
*In the case of allergic or [[anaphylaxis|anaphylactic reaction]], administration should be stopped immediately.
In the case of shock, the current medical standards for treatment of shock should be administered.
Inform patients that administration of immune globulin may interfere with the response to live virus vaccines (e.g. [[measles]], [[mumps]], [[rubella]] and [[varicella]]), and instruct them to notify their immunizing physician of recent therapy with Varicella Zoster Immune Globulin.
|alcohol=Alcohol-Varicella Zoster Immune Globulin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=*Varicella Zoster Immune Globulin
*Varicella Zoster Immune Globulin
}}

Varicella Zoster Immune Globulin

2015-03-12T19:50:14Z

Sree Teja Yelamanchili:

{{DrugProjectFormSinglePage
|authorTag={{STY}}
|genericName=Varicella Zoster Immune Globulin
|aOrAn=an
|drugClass=immune serum
|indicationType=prophylaxis
|indication=post exposure [[varicella]].
|adverseReactions=[[injection site reaction|injection site pain]] (overall, 2%; pregnant women, 9% ) and [[headache]]
|blackBoxWarningTitle=<b><span style="color:#FF0000;">TITLE</span></b>
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)
|fdaLIADAdult======Indications=====
Varicella Zoster Immune Globulin is indicated for post-exposure prophylaxis of [[varicella]] in high risk individuals. High risk groups include:

*immunocompromised children and adults
*newborns of mothers with [[varicella]] shortly before or after delivery
*premature infants
*neonates and infants less than one year of age
*adults without evidence of immunity
*pregnant women
VARIZIG administration is intended to reduce the severity of varicella.

Administer VARIZIG as soon as possible following [[varicella zoster virus]] (VZV) exposure, ideally within 96 hours for greatest effectiveness.

*There is no convincing evidence that VARIZIG reduces the incidence of chickenpox infection after exposure to VZV.
*There is no convincing evidence that established infections with VZV can be modified by VARIZIG administration.
*There is no indication for the prophylactic use of VARIZIG in immunodeficient children or adults when there is a past history of varicella, unless the patient is undergoing [[bone marrow transplantation]].

=====Dosage=====
*Dosing of VARIZIG is based on body weight. Administer a single dose of VARIZIG intramuscularly as recommended in TABLE 1.
*The minimum dose is 62.5 International Units (IU) for small infants under two kilograms body weight; the maximum dose of 625 IU should be administered for all patients greater than 40 kilograms in weight.

[[File:Varicella zoster immune globulin (human) 1.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

Consider a second full dose of VARIZIG for high risk patients who have additional exposures to varicella greater than three weeks after initial VARIZIG administration.

=====Reconstitution=====
Reconstitute VARIZIG according to TABLE 2. Only use the accompanying Sterile Diluent with aseptic technique throughout. Reconstitute shortly before use.

[[File:Varicella zoster immune globulin (human) 2.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

To reconstitute:
Remove caps from the Sterile Diluent and VARIZIG vials.
Wipe exposed central portion of each rubber stopper with suitable disinfectant.
Withdraw 1.25 milliliter of the Sterile Diluent using a suitable syringe and needle.
Inject diluents slowly into the VARIZIG vial at an angle so that the liquid is directed onto the inside glass wall of the vial containing the freeze-dried pellet.
Wet pellet by gently tilting and inverting the vial. Avoid frothing. Gently swirl upright vial until dissolved (less than ten minutes). Do not shake.
Inspect VARIZIG visually for particulate matter and discoloration prior to administration.
Do not use if turbid and/or discoloration is observed.
Reconstituted product can be stored for up to 12 hours at 2 to 8°C (36 to 46ºF) prior to use.
Do not freeze. Solutions that have been frozen should not be used.
VARIZIG is for single use only. Partially used vials, including the remaining Sterile Diluent, should be discarded.

=====Administration=====
*For intramuscular use only.
*Divide the intramuscular dose and administer in two or more injection sites, depending on patient size. Do not exceed 3 milliliters per injection site.
*Inject into the deltoid muscle or the anterolateral aspects of the upper thigh.
*Due to the risk of sciatic nerve injury, do not use the gluteal region as a routine injection site.
*If the gluteal region is used, only use the upper, outer quadrant.
*To prevent the transmission of infectious agents from one person to another, use a new disposable sterile syringe and needle for each individual patient.

=====Dosage forms and Strenghts=====
VARIZIG is supplied as a sterile lyophilized powder for solution for intramuscular injection and is available in a single-use vial of 125 IU. VARIZIG is accompanied by a vial containing 8.5 milliliters of Sterile Diluent for reconstitution. Each 125 IU vial of VARIZIG contains less than 250 milligrams of total protein, mostly human immune globulin G (IgG). VARIZIG contains no preservative and is intended for single use only. VARIZIG does not contain mercury.
|offLabelAdultGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Varicella Zoster Immune Globulin in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Varicella Zoster Immune Globulin in adult patients.
|fdaLIADPed=The dosing recommendations in the treatment of pediatric patients are by body weight.
|offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Varicella Zoster Immune Globulin in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Varicella Zoster Immune Globulin in pediatric patients.
|contraindications=*Individuals known to have anaphylactic or severe systemic ([[hypersensitivity]]) reactions to human immune globulin preparations should not receive VARIZIG.
*[[IgA deficiency|IgA-deficient]] patients with [[antibodies]] against IgA and a history of hypersensitivity may have an [[anaphylactoid reaction]].
*VARIZIG contains less than 40 micrograms per milliliter of [[IgA]].
|warnings=====Thrombotic Events====
Thrombotic events may occur during or following treatment with immune globulin products (1,2,3). Patients at risk include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, coagulation disorders, prolonged periods of immobilization, and/or known/suspected hyperviscosity. Consider baseline assessment of blood viscosity in patients at risk for hyperviscosity including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies.

====Coagulation Disorders====
Administer VARIZIG intramuscularly only. In patients who have severe thrombocytopenia or any coagulation disorder that would contraindicate intramuscular injections, only administer VARIZIG if the expected benefits outweigh the potential risks.

====Hypersensitivity====
Severe hypersensitivity reactions may occur following VARIZIG administration. Administer VARIZIG in a setting with appropriate equipment, medication and personnel trained in the management of hypersensitivity, anaphylaxis and shock. In the case of hypersensitivity, discontinue administration of VARIZIG immediately and provide appropriate treatment.

VARIZIG contains trace amounts of IgA (less than 40 micrograms per milliliter). Patients with known antibodies to IgA have a greater risk of severe hypersensitivity and anaphylactic reactions. VARIZIG is contraindicated in IgA deficient patients with antibodies against IgA and history of hypersensitivity reactions.

====Transmissible Infectious Agents====
Because VARIZIG is made from human plasma, it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. The plasma donors are screened for the presence of certain infectious agents and the manufacturing process for VARIZIG includes measures to inactivate and remove certain viruses [see11 DESCRIPTION]. Despite these measures, products derived from human plasma can still potentially transmit diseases. No cases of transmission of viral diseases, vCJD or CJD have been associated with the use of VARIZIG.
|clinicalTrials=The most common adverse drug reactions observed in clinical trials for all subjects and patients are the following:
*[[injection site reaction|injection site pain]] (2%)
*[[headache]] (2%).

Less common adverse drug reactions reported include the following:
*[[chills]],
*[[fatigue]],
*[[rash]]
*[[nausea]]
*[[thrombosis]]

====Clinical Trial Experience====
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Three hundred and seventy seven high risk individuals received VARIZIG intramuscularly in two [[clinical trials]] which included pregnant women, infants and immunocompromised pediatric and adult patients. The highest incidence of adverse reactions occurred in pregnant women (n=90), including [[injection site reaction|injection site pain]] (9%), [[headache]] (4%), [[chills]] (2%) and [[fatigue]] (2%). All other adverse reactions occurred in 1% or less of clinical trial subjects within each high risk group. A single incidence of serum sickness (approximately one in 400 patients treated with VARIZIG) was observed in an immunocompromised adolescent patient.

There were six reported adverse events related to the coagulation system (one [[deep vein thrombosis]]) in 372 subjects in the open-label, Expanded Access Protocol (EAP); the study was not designed to differentiate between adverse events attributed to the underlying medical condition and adverse reactions to VARIZIG.
|drugInteractions=The passive transfer of [[antibody|antibodies]] with [[immune globulin]] administration may impair the efficacy of live attenuated virus vaccines such as [[measles]], [[rubella]], [[mumps]] and [[varicella]]. Defer vaccination with live virus vaccines until approximately three months after VARIZIG administration. Inform the immunizing physician of recent therapy with VARIZIG so that appropriate measures can be taken.
|useInPregnancyFDA=Pregnancy category C. Animal reproduction studies have not been conducted with VARIZIG. It also is not known whether VARIZIG can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. VARIZIG should be given to a pregnant woman only if clearly needed.
|useInNursing=It is not known whether VARIZIG is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when VARIZIG is administered to a nursing mother.
|useInPed=The safety and effectiveness of VARIZIG have been evaluated for post-exposure prophylaxis in the VARIZIG expanded access clinical trial in 265 pediatric patients, including immunocompromised pediatric patients:
70 preterm newborns and infants
38 term newborns
28 infants and toddlers
99 children and
30 adolescents.
In the EAP, follow up data were available for 81 VARIZIG treatments in 78 infants (including newborns, pre-term infants, and infants <1 year old). Two severe infections were reported, with pox count >100. One of these patients also developed probable [[varicella]] [[encephalitis]].
|useInGeri=*Clinical studies of VARIZIG administered intramuscularly for post-exposure prophylaxis did not include sufficient numbers of geriatric subjects (aged 65 and over) to determine whether they respond differently from younger subjects.
*Use caution when administering VARIZIG to patients age 65 and over who are judged to be at increased risk of thrombotic events. Do not exceed recommended doses and administer VARIZIG intramuscularly only.
|useInImmunocomp=In the EAP, eight immunocompromised subjects developed clinical varicella, and none developed [[varicella]] [[pneumonitis]]; however five are reported to have received concomitant [[cyclovir]].
|administration=*Intramuscular use only
|monitoring=*Reduction in severity of clinical signs and symptoms of varicella zoster infection may indicate efficacy.
*Blood viscosity assessment; consider at baseline in patients at risk for hyperviscosity (eg, patients with [[cryoglobulins]], fasting [[chylomicronemia]], severe [[hypertriglyceridemia]], or [[Monoclonal gammopathy|monoclonal gammopathies]])
|overdose=Manifestations of an overdose of VARIZIG administered intramuscularly are expected to be pain and tenderness at the injection site.
|mechAction=VARIZIG provides passive immunization for non-immune individuals exposed to VZV, reducing the severity of varicella infections.
|structure=Varicella Zoster Immune Globulin is a solvent/detergent-treated sterile lyophilized preparation of purified human immune globulin G (IgG) containing antibodies to [[varicella|varicella zoster virus]] (anti-VZV). VZV is the causative agent of chickenpox. VARIZIG is prepared from plasma donated by healthy, screened donors with high titers of antibodies to VZV, which is purified by an anion-exchange column chromatography manufacturing method. This donor selection process includes donors with high anti-VZV titers due to recent natural infection by VZV, or due to recurrent zoster infection (shingles).

VARIZIG is supplied as a kit containing a single-use vial of VARIZIG (lyophilized powder for solution for intramuscular injection with a potency of 125 IU) and a vial of 8.5 milliliters Sterile Diluent, which is used for reconstitution of the product prior to administration. VARIZIG is intended for single use and should be administered intramuscularly.

The product potency is expressed in IU by comparison to the World Health Organization (WHO) international reference preparation for anti-VZV immune globulin. Each vial contains 125 IU of anti-VZV. The lyophilized VARIZIG is formulated as 0.04 M sodium chloride, 0.1 M glycine and 0.01% polysorbate 80. The accompanying Sterile Diluent contains 0.8% sodium chloride and 10 mM sodium phosphate. The reconstituted VARIZIG has a pH of 7 and contains no preservative.

VARIZIG has not been tested for the presence of anti-Protein S antibodies that have been reported to arise transiently after VZV infection (4); however, it is assumed that the requirement that donors be healthy will alleviate this concern.

The source plasma used in the manufacture of this product was tested by FDA licensed nucleic acid testing (NAT) for human immunodeficiency virus-1 (HIV-1), [[hepatitis B virus]] (HBV) and [[hepatitis C virus]] (HCV) and found to be negative. Plasma also was tested by in-process NAT for hepatitis A virus (HAV) and [[parvovirus B19]] (B19) via minipool testing; the limit for B19 in the manufacturing pool is set not to exceed 104 IU of B19 DNA per milliliter.

The manufacturing process contains two steps implemented specifically for virus clearance. The solvent/detergent step (using tri-n-butyl phosphate and Triton X-100) is effective in the inactivation of enveloped viruses, such as HBV, HCV and HIV-1. Virus filtration, using a Planova 20N virus filter, is effective for the removal of viruses based on their size, including some non-enveloped viruses. These two viral clearance steps are designed to increase product safety by reducing the risk of transmission of enveloped and non-enveloped viruses. In addition to these two specific steps, the process step of anion-exchange chromatography was identified as contributing to the overall viral clearance capacity for small non-enveloped viruses.

The inactivation and reduction of known enveloped and non-enveloped model viruses were validated in laboratory studies as summarized in TABLE 3. The viruses employed for spiking studies were selected to represent those viruses that are potential contaminants in the product, and to represent a wide range of physiochemical properties in order to challenge the manufacturing process’s ability for viral clearance in general.

[[File:Varizig 1.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|PK=In a comparative pharmacokinetic clinical trial, 35 volunteers were administered an intramuscular dose of 12.5 IU/kg of VARIZIG (n=18) or the comparator product VZIG™ (n=17). The dose of 12.5 IU/kg of VZIG or VARIZIG given to the subjects was based on the assumption that the potency was similar for both products. For the bioequivalence analysis, a potency correction factor was applied (concentrations of VARIZIG were multiplied by 2.3) to account for higher measured potency of the comparator product. The mean peak concentration (Cmax) of varicella antibodies occurred within five days of administration for both products. In the trial, baseline levels of anti-VZV antibodies ranged from 0 to 720 mIU/mL, therefore baseline levels were taken into account for pharmacokinetic calculations, to better represent the indicated population. After potency correction, baseline correction, and exclusion of subjects with baseline values of anti-VZV antibody levels of >200 mIU/mL, the two products were pharmacokinetically comparable.

[[File:Varizig 2.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|clinicalStudies=====Pregnant Women Exposed to Varicella Zoster Virus====
A randomized, open-label, multicenter, active controlled clinical trial was conducted in 60 pregnant women without immunity to VZV as confirmed by a latex agglutination test. Patients were stratified on the basis of time from first exposure to varicella as follows:
*one to four days post-exposure and
*five to 14 days post-exposure.
The women were randomized into one of three study arms as follows:

a single intravenous dose of 125 IU/10 kg body weight to a maximum dose of 625 IU of VARIZIG
a single intramuscular dose of 125 IU/10 kg body weight to a maximum dose of 625 IU of VARIZIG, or
a single intramuscular dose of 125 IU/10 kg body weight to a maximum dose of 625 IU of VZIG (licensed comparator product).
Patients were followed for 42 days.

Incidence of clinical varicella was similar across all treatment groups with an overall incidence of 33%; however, in the subset of 28 subjects with more than 24 hours exposure to varicella, the incidence of clinical varicella in the combined treatment groups was 64%.

Mean weighted constitutional illness scores (CIS) (6) were similar across all groups and none of the subjects had serious complications of varicella. The small number of subjects in each treatment stratum and the lack of agreed upon pre-specified hypothesis testing precluded formal statistical comparisons between groups.
|howSupplied=Varicella Zoster Immune Globulin is supplied as a kit in a carton box containing approximately 125 IUof anti-VZV supplied freeze-dried in a 6 mL type 1 glass tubing vial fitted with a 20 mm rubber lyophilization stopper and a 20 mm flip-off seal, one single dose vial of Sterile Diluent, non-pyrogenic for reconstitution of VARIZIG and a package insert.
|storage=Store VARIZIG at 2 to 8°C (36 to 46°F). Do not freeze. Do not use after expiration date. Use the product within 12 hours of reconstitution if stored at 2 to 8°C.
|packLabel=[[File:Varizig 3.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

[[File:Varizig 4.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|fdaPatientInfo=Inform patients of the following:

*VARIZIG is intended to reduce the severity of chickenpox infections. Please see your doctor if you develop the signs and symptoms of [[varicella]].
*VARIZIG is prepared from human plasma and therefore, may contain infectious agents such as viruses that can cause disease.
*The risk that products derived from human plasma will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and/or removing certain viruses during manufacturing.
*Despite these measures, products derived from human plasma can still potentially transmit disease.
*There is also the possibility that unknown infectious agents may be present in such products.
*Tell patients that persons known to have severe, potentially life-threatening reactions to human [[immune globulin]] products should not receive VARIZIG or any other immune globulin products unless the risk has been justified.
*Tell patients that persons who are deficient in IgA may have the potential for developing anti-IgA antibodies and have severe potentially life threatening allergic reactions.
*In the case of allergic or [[anaphylaxis|anaphylactic reaction]], administration should be stopped immediately.
In the case of shock, the current medical standards for treatment of shock should be administered.
Inform patients that administration of immune globulin may interfere with the response to live virus vaccines (e.g. [[measles]], [[mumps]], [[rubella]] and [[varicella]]), and instruct them to notify their immunizing physician of recent therapy with VARIZIG.
|alcohol=Alcohol-Varicella Zoster Immune Globulin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=*Varicella Zoster Immune Globulin
*Varizig
}}

Varicella Zoster Immune Globulin

2015-03-12T19:47:45Z

Sree Teja Yelamanchili:

{{DrugProjectFormSinglePage
|authorTag={{STY}}
|genericName=Varicella Zoster Immune Globulin
|aOrAn=an
|drugClass=immune serum
|indicationType=prophylaxis
|indication=post exposure [[varicella]].
|adverseReactions=[[injection site reaction|injection site pain]] (overall, 2%; pregnant women, 9% ) and [[headache]]
|blackBoxWarningTitle=<b><span style="color:#FF0000;">TITLE</span></b>
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)
|fdaLIADAdult======Indications=====
Varicella Zoster Immune Globulin is indicated for post-exposure prophylaxis of [[varicella]] in high risk individuals. High risk groups include:

*immunocompromised children and adults
*newborns of mothers with [[varicella]] shortly before or after delivery
*premature infants
*neonates and infants less than one year of age
*adults without evidence of immunity
*pregnant women
VARIZIG administration is intended to reduce the severity of varicella.

Administer VARIZIG as soon as possible following [[varicella zoster virus]] (VZV) exposure, ideally within 96 hours for greatest effectiveness.

*There is no convincing evidence that VARIZIG reduces the incidence of chickenpox infection after exposure to VZV.
*There is no convincing evidence that established infections with VZV can be modified by VARIZIG administration.
*There is no indication for the prophylactic use of VARIZIG in immunodeficient children or adults when there is a past history of varicella, unless the patient is undergoing [[bone marrow transplantation]].

=====Dosage=====
*Dosing of VARIZIG is based on body weight. Administer a single dose of VARIZIG intramuscularly as recommended in TABLE 1.
*The minimum dose is 62.5 International Units (IU) for small infants under two kilograms body weight; the maximum dose of 625 IU should be administered for all patients greater than 40 kilograms in weight.

[[File:Varicella zoster immune globulin (human) 1.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

Consider a second full dose of VARIZIG for high risk patients who have additional exposures to varicella greater than three weeks after initial VARIZIG administration.

=====Reconstitution=====
Reconstitute VARIZIG according to TABLE 2. Only use the accompanying Sterile Diluent with aseptic technique throughout. Reconstitute shortly before use.

[[File:Varicella zoster immune globulin (human) 2.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

To reconstitute:
Remove caps from the Sterile Diluent and VARIZIG vials.
Wipe exposed central portion of each rubber stopper with suitable disinfectant.
Withdraw 1.25 milliliter of the Sterile Diluent using a suitable syringe and needle.
Inject diluents slowly into the VARIZIG vial at an angle so that the liquid is directed onto the inside glass wall of the vial containing the freeze-dried pellet.
Wet pellet by gently tilting and inverting the vial. Avoid frothing. Gently swirl upright vial until dissolved (less than ten minutes). Do not shake.
Inspect VARIZIG visually for particulate matter and discoloration prior to administration.
Do not use if turbid and/or discoloration is observed.
Reconstituted product can be stored for up to 12 hours at 2 to 8°C (36 to 46ºF) prior to use.
Do not freeze. Solutions that have been frozen should not be used.
VARIZIG is for single use only. Partially used vials, including the remaining Sterile Diluent, should be discarded.

=====Administration=====
*For intramuscular use only.
*Divide the intramuscular dose and administer in two or more injection sites, depending on patient size. Do not exceed 3 milliliters per injection site.
*Inject into the deltoid muscle or the anterolateral aspects of the upper thigh.
*Due to the risk of sciatic nerve injury, do not use the gluteal region as a routine injection site.
*If the gluteal region is used, only use the upper, outer quadrant.
*To prevent the transmission of infectious agents from one person to another, use a new disposable sterile syringe and needle for each individual patient.

=====Dosage forms and Strenghts=====
VARIZIG is supplied as a sterile lyophilized powder for solution for intramuscular injection and is available in a single-use vial of 125 IU. VARIZIG is accompanied by a vial containing 8.5 milliliters of Sterile Diluent for reconstitution. Each 125 IU vial of VARIZIG contains less than 250 milligrams of total protein, mostly human immune globulin G (IgG). VARIZIG contains no preservative and is intended for single use only. VARIZIG does not contain mercury.
|offLabelAdultGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Varicella Zoster Immune Globulin in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Varicella Zoster Immune Globulin in adult patients.
|fdaLIADPed=The dosing recommendations in the treatment of pediatric patients are by body weight.
|offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Varicella Zoster Immune Globulin in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Varicella Zoster Immune Globulin in pediatric patients.
|contraindications=*Individuals known to have anaphylactic or severe systemic ([[hypersensitivity]]) reactions to human immune globulin preparations should not receive VARIZIG.
*[[IgA deficiency|IgA-deficient]] patients with [[antibodies]] against IgA and a history of hypersensitivity may have an [[anaphylactoid reaction]].
*VARIZIG contains less than 40 micrograms per milliliter of [[IgA]].
|warnings=====Thrombotic Events====
Thrombotic events may occur during or following treatment with immune globulin products (1,2,3). Patients at risk include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, coagulation disorders, prolonged periods of immobilization, and/or known/suspected hyperviscosity. Consider baseline assessment of blood viscosity in patients at risk for hyperviscosity including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies.

====Coagulation Disorders====
Administer VARIZIG intramuscularly only. In patients who have severe thrombocytopenia or any coagulation disorder that would contraindicate intramuscular injections, only administer VARIZIG if the expected benefits outweigh the potential risks.

====Hypersensitivity====
Severe hypersensitivity reactions may occur following VARIZIG administration. Administer VARIZIG in a setting with appropriate equipment, medication and personnel trained in the management of hypersensitivity, anaphylaxis and shock. In the case of hypersensitivity, discontinue administration of VARIZIG immediately and provide appropriate treatment.

VARIZIG contains trace amounts of IgA (less than 40 micrograms per milliliter). Patients with known antibodies to IgA have a greater risk of severe hypersensitivity and anaphylactic reactions. VARIZIG is contraindicated in IgA deficient patients with antibodies against IgA and history of hypersensitivity reactions [see4 CONTRAINDICATIONS].

====Transmissible Infectious Agents====
Because VARIZIG is made from human plasma, it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. The plasma donors are screened for the presence of certain infectious agents and the manufacturing process for VARIZIG includes measures to inactivate and remove certain viruses [see11 DESCRIPTION]. Despite these measures, products derived from human plasma can still potentially transmit diseases. No cases of transmission of viral diseases, vCJD or CJD have been associated with the use of VARIZIG.
|clinicalTrials=The most common adverse drug reactions observed in clinical trials for all subjects and patients are the following:
*[[injection site reaction|injection site pain]] (2%)
*[[headache]] (2%).

Less common adverse drug reactions reported include the following:
*[[chills]],
*[[fatigue]],
*[[rash]]
*[[nausea]]
*[[thrombosis]]

====Clinical Trial Experience====
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Three hundred and seventy seven high risk individuals received VARIZIG intramuscularly in two [[clinical trials]] which included pregnant women, infants and immunocompromised pediatric and adult patients. The highest incidence of adverse reactions occurred in pregnant women (n=90), including [[injection site reaction|injection site pain]] (9%), [[headache]] (4%), [[chills]] (2%) and [[fatigue]] (2%). All other adverse reactions occurred in 1% or less of clinical trial subjects within each high risk group. A single incidence of serum sickness (approximately one in 400 patients treated with VARIZIG) was observed in an immunocompromised adolescent patient.

There were six reported adverse events related to the coagulation system (one [[deep vein thrombosis]]) in 372 subjects in the open-label, Expanded Access Protocol (EAP); the study was not designed to differentiate between adverse events attributed to the underlying medical condition and adverse reactions to VARIZIG.
|drugInteractions=The passive transfer of [[antibody|antibodies]] with [[immune globulin]] administration may impair the efficacy of live attenuated virus vaccines such as [[measles]], [[rubella]], [[mumps]] and [[varicella]]. Defer vaccination with live virus vaccines until approximately three months after VARIZIG administration. Inform the immunizing physician of recent therapy with VARIZIG so that appropriate measures can be taken.
|useInPregnancyFDA=Pregnancy category C. Animal reproduction studies have not been conducted with VARIZIG. It also is not known whether VARIZIG can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. VARIZIG should be given to a pregnant woman only if clearly needed.
|useInNursing=It is not known whether VARIZIG is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when VARIZIG is administered to a nursing mother.
|useInPed=The safety and effectiveness of VARIZIG have been evaluated for post-exposure prophylaxis in the VARIZIG expanded access clinical trial in 265 pediatric patients, including immunocompromised pediatric patients:
70 preterm newborns and infants
38 term newborns
28 infants and toddlers
99 children and
30 adolescents.
In the EAP, follow up data were available for 81 VARIZIG treatments in 78 infants (including newborns, pre-term infants, and infants <1 year old). Two severe infections were reported, with pox count >100. One of these patients also developed probable [[varicella]] [[encephalitis]].
|useInGeri=*Clinical studies of VARIZIG administered intramuscularly for post-exposure prophylaxis did not include sufficient numbers of geriatric subjects (aged 65 and over) to determine whether they respond differently from younger subjects.
*Use caution when administering VARIZIG to patients age 65 and over who are judged to be at increased risk of thrombotic events. Do not exceed recommended doses and administer VARIZIG intramuscularly only.
|useInImmunocomp=In the EAP, eight immunocompromised subjects developed clinical varicella, and none developed [[varicella]] [[pneumonitis]]; however five are reported to have received concomitant [[cyclovir]].
|administration=*Intramuscular use only
|monitoring=*Reduction in severity of clinical signs and symptoms of varicella zoster infection may indicate efficacy.
*Blood viscosity assessment; consider at baseline in patients at risk for hyperviscosity (eg, patients with [[cryoglobulins]], fasting [[chylomicronemia]], severe [[hypertriglyceridemia]], or [[Monoclonal gammopathy|monoclonal gammopathies]])
|overdose=Manifestations of an overdose of VARIZIG administered intramuscularly are expected to be pain and tenderness at the injection site.
|mechAction=VARIZIG provides passive immunization for non-immune individuals exposed to VZV, reducing the severity of varicella infections.
|structure=Varicella Zoster Immune Globulin is a solvent/detergent-treated sterile lyophilized preparation of purified human immune globulin G (IgG) containing antibodies to [[varicella|varicella zoster virus]] (anti-VZV). VZV is the causative agent of chickenpox. VARIZIG is prepared from plasma donated by healthy, screened donors with high titers of antibodies to VZV, which is purified by an anion-exchange column chromatography manufacturing method. This donor selection process includes donors with high anti-VZV titers due to recent natural infection by VZV, or due to recurrent zoster infection (shingles).

VARIZIG is supplied as a kit containing a single-use vial of VARIZIG (lyophilized powder for solution for intramuscular injection with a potency of 125 IU) and a vial of 8.5 milliliters Sterile Diluent, which is used for reconstitution of the product prior to administration. VARIZIG is intended for single use and should be administered intramuscularly.

The product potency is expressed in IU by comparison to the World Health Organization (WHO) international reference preparation for anti-VZV immune globulin. Each vial contains 125 IU of anti-VZV. The lyophilized VARIZIG is formulated as 0.04 M sodium chloride, 0.1 M glycine and 0.01% polysorbate 80. The accompanying Sterile Diluent contains 0.8% sodium chloride and 10 mM sodium phosphate. The reconstituted VARIZIG has a pH of 7 and contains no preservative.

VARIZIG has not been tested for the presence of anti-Protein S antibodies that have been reported to arise transiently after VZV infection (4); however, it is assumed that the requirement that donors be healthy will alleviate this concern.

The source plasma used in the manufacture of this product was tested by FDA licensed nucleic acid testing (NAT) for human immunodeficiency virus-1 (HIV-1), [[hepatitis B virus]] (HBV) and [[hepatitis C virus]] (HCV) and found to be negative. Plasma also was tested by in-process NAT for hepatitis A virus (HAV) and [[parvovirus B19]] (B19) via minipool testing; the limit for B19 in the manufacturing pool is set not to exceed 104 IU of B19 DNA per milliliter.

The manufacturing process contains two steps implemented specifically for virus clearance. The solvent/detergent step (using tri-n-butyl phosphate and Triton X-100) is effective in the inactivation of enveloped viruses, such as HBV, HCV and HIV-1. Virus filtration, using a Planova 20N virus filter, is effective for the removal of viruses based on their size, including some non-enveloped viruses. These two viral clearance steps are designed to increase product safety by reducing the risk of transmission of enveloped and non-enveloped viruses. In addition to these two specific steps, the process step of anion-exchange chromatography was identified as contributing to the overall viral clearance capacity for small non-enveloped viruses.

The inactivation and reduction of known enveloped and non-enveloped model viruses were validated in laboratory studies as summarized in TABLE 3. The viruses employed for spiking studies were selected to represent those viruses that are potential contaminants in the product, and to represent a wide range of physiochemical properties in order to challenge the manufacturing process’s ability for viral clearance in general.

[[File:Varizig 1.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|PK=In a comparative pharmacokinetic clinical trial, 35 volunteers were administered an intramuscular dose of 12.5 IU/kg of VARIZIG (n=18) or the comparator product VZIG™ (n=17). The dose of 12.5 IU/kg of VZIG or VARIZIG given to the subjects was based on the assumption that the potency was similar for both products. For the bioequivalence analysis, a potency correction factor was applied (concentrations of VARIZIG were multiplied by 2.3) to account for higher measured potency of the comparator product. The mean peak concentration (Cmax) of varicella antibodies occurred within five days of administration for both products. In the trial, baseline levels of anti-VZV antibodies ranged from 0 to 720 mIU/mL, therefore baseline levels were taken into account for pharmacokinetic calculations, to better represent the indicated population. After potency correction, baseline correction, and exclusion of subjects with baseline values of anti-VZV antibody levels of >200 mIU/mL, the two products were pharmacokinetically comparable.

[[File:Varizig 2.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|clinicalStudies=====Pregnant Women Exposed to Varicella Zoster Virus====
A randomized, open-label, multicenter, active controlled clinical trial was conducted in 60 pregnant women without immunity to VZV as confirmed by a latex agglutination test. Patients were stratified on the basis of time from first exposure to varicella as follows:
*one to four days post-exposure and
*five to 14 days post-exposure.
The women were randomized into one of three study arms as follows:

a single intravenous dose of 125 IU/10 kg body weight to a maximum dose of 625 IU of VARIZIG
a single intramuscular dose of 125 IU/10 kg body weight to a maximum dose of 625 IU of VARIZIG, or
a single intramuscular dose of 125 IU/10 kg body weight to a maximum dose of 625 IU of VZIG (licensed comparator product).
Patients were followed for 42 days.

Incidence of clinical varicella was similar across all treatment groups with an overall incidence of 33%; however, in the subset of 28 subjects with more than 24 hours exposure to varicella, the incidence of clinical varicella in the combined treatment groups was 64%.

Mean weighted constitutional illness scores (CIS) (6) were similar across all groups and none of the subjects had serious complications of varicella. The small number of subjects in each treatment stratum and the lack of agreed upon pre-specified hypothesis testing precluded formal statistical comparisons between groups.
|howSupplied=Varicella Zoster Immune Globulin is supplied as a kit in a carton box containing approximately 125 IUof anti-VZV supplied freeze-dried in a 6 mL type 1 glass tubing vial fitted with a 20 mm rubber lyophilization stopper and a 20 mm flip-off seal, one single dose vial of Sterile Diluent, non-pyrogenic for reconstitution of VARIZIG and a package insert.
|storage=Store VARIZIG at 2 to 8°C (36 to 46°F). Do not freeze. Do not use after expiration date. Use the product within 12 hours of reconstitution if stored at 2 to 8°C.
|packLabel=[[File:Varizig 3.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]

[[File:Varizig 4.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|fdaPatientInfo=Inform patients of the following:

*VARIZIG is intended to reduce the severity of chickenpox infections. Please see your doctor if you develop the signs and symptoms of [[varicella]].
*VARIZIG is prepared from human plasma and therefore, may contain infectious agents such as viruses that can cause disease.
*The risk that products derived from human plasma will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and/or removing certain viruses during manufacturing.
*Despite these measures, products derived from human plasma can still potentially transmit disease.
*There is also the possibility that unknown infectious agents may be present in such products.
*Tell patients that persons known to have severe, potentially life-threatening reactions to human [[immune globulin]] products should not receive VARIZIG or any other immune globulin products unless the risk has been justified.
*Tell patients that persons who are deficient in IgA may have the potential for developing anti-IgA antibodies and have severe potentially life threatening allergic reactions.
*In the case of allergic or [[anaphylaxis|anaphylactic reaction]], administration should be stopped immediately.
In the case of shock, the current medical standards for treatment of shock should be administered.
Inform patients that administration of immune globulin may interfere with the response to live virus vaccines (e.g. [[measles]], [[mumps]], [[rubella]] and [[varicella]]), and instruct them to notify their immunizing physician of recent therapy with VARIZIG.
|alcohol=Alcohol-Varicella Zoster Immune Globulin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=*Varicella Zoster Immune Globulin
*Varizig

}}

File:Varizig 4.png

2015-03-12T19:33:05Z

Sree Teja Yelamanchili:

File:Varizig 3.png

2015-03-12T19:32:47Z

Sree Teja Yelamanchili:

File:Varizig 2.png

2015-03-12T19:32:19Z

Sree Teja Yelamanchili:

File:Varizig 1.png

2015-03-12T19:32:06Z

Sree Teja Yelamanchili:

File:Varicella zoster immune globulin (human) 2.jpg

2015-03-12T19:31:42Z

Sree Teja Yelamanchili:

File:Varicella zoster immune globulin (human) 1.jpg

2015-03-12T19:31:24Z

Sree Teja Yelamanchili:

Varicella Zoster Immune Globulin

2015-03-12T17:53:25Z

Sree Teja Yelamanchili:

{{DrugProjectFormSinglePage
|authorTag={{STY}}
|genericName=Varicella Zoster Immune Globulin
|aOrAn=an
|drugClass=immune serum
|indicationType=
|indication=post exposure prophylaxis of varicella.
|adverseReactions=[[injection site reaction|injection site pain]] (overall, 2%; pregnant women, 9% ) and [[headache]]
|blackBoxWarningTitle=<b><span style="color:#FF0000;">TITLE</span></b>
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)
|offLabelAdultGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Varicella Zoster Immune Globulin in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Varicella Zoster Immune Globulin in adult patients.
|offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Varicella Zoster Immune Globulin in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Varicella Zoster Immune Globulin in pediatric patients.
|alcohol=Alcohol-Varicella Zoster Immune Globulin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
}}

Varicella Zoster Immune Globulin

2015-03-12T17:52:15Z

Sree Teja Yelamanchili:

{{DrugProjectFormSinglePage
|authorTag={{STY}}
|genericName=Varicella Zoster Immune Globulin
|aOrAn=an
|drugClass=immune serum
|indicationType
|indication=post exposure prophylaxis of varicella.
|adverseReactions=[[injection site reaction|injection site pain]] (overall, 2%; pregnant women, 9% ) and [[headache]]
|blackBoxWarningTitle=<b><span style="color:#FF0000;">TITLE</span></b>
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)
|offLabelAdultGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Varicella Zoster Immune Globulin in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Varicella Zoster Immune Globulin in adult patients.
|offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Varicella Zoster Immune Globulin in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Varicella Zoster Immune Globulin in pediatric patients.
|alcohol=Alcohol-Varicella Zoster Immune Globulin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
}}

Varicella Zoster Immune Globulin

2015-03-12T17:47:28Z

Sree Teja Yelamanchili:

Varicella Zoster Immune Globulin

2015-03-12T17:45:54Z

Sree Teja Yelamanchili: Created page with "{{DrugProjectFormSinglePage |authorTag={{STY}} |genericName=Varicella Zoster Immune Globulin |aOrAn=an |drugClass=immune serum |indicationType=prophylaxis |indication=post exp..."

Aclidinium

2015-03-12T15:53:49Z

Sree Teja Yelamanchili:

{{DrugProjectFormSinglePage
|authorTag={{STY}}
|genericName=Aclidinium bromide
|aOrAn=an
|drugClass=[[antimuscarinic]] and [[bronchodilator]]
|indicationType=treatment
|indication=long-term maintenance treatment of [[bronchospasm]] associated with [[chronic obstructive pulmonary disease]] ([[COPD]]), including [[chronic bronchitis]] and [[emphysema]].
|adverseReactions=[[headache]], [[cough]], and [[nasopharyngitis]].
|blackBoxWarningTitle=<b><span style="color:#FF0000;">TITLE</span></b>
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)
|fdaLIADAdult=*The recommended dose of Aclidinium bromide is one oral inhalation of 400 mcg, twice daily.

*Inhalation Powder- Aclidinium bromide is a breath-actuated multi-dose dry powder inhaler metering 400 mcg of aclidinium bromide per actuation.
|offLabelAdultGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Aclidinium in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Aclidinium in adult patients.
|offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Aclidinium in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Aclidinium in pediatric patients.
|contraindications=None.
|warnings=====Not for Acute Use====
Aclidinium bromide is intended as a twice-daily maintenance treatment for [[COPD]] and is not indicated for the initial treatment of acute episodes of [[bronchospasm]] (i.e., rescue therapy).

====Paradoxical Bronchospasm====
Inhaled medicines, including Aclidinium bromide, may cause paradoxical [[bronchospasm]]. If this occurs, treatment with Aclidinium bromide should be stopped and other treatments considered.

====Worsening of Narrow-Angle Glaucoma====
Aclidinium bromide should be used with caution in patients with [[narrow-angle glaucoma]]. Prescribers and patients should be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., [[eye pain]] or discomfort, [[blurred vision]], visual halos or colored images in association with red eyes from conjunctival congestion and [[corneal edema]]). Instruct patients to consult a physician immediately should any of these signs or symptoms develop.

====Worsening of Urinary Retention====
Aclidinium bromide should be used with caution in patients with urinary retention. Prescribers and patients should be alert for signs and symptoms of [[Benign prostatic hyperplasia|prostatic hyperplasia]] or bladder-neck obstruction (e.g., difficulty passing urine, painful urination). Instruct patients to consult a physician immediately should any of these signs or symptoms develop.

====Immediate Hypersensitivity Reactions====
Immediate [[hypersensitivity]] reactions may occur after administration of Aclidinium bromide. If such a reaction occurs, therapy with Aclidinium bromide should be stopped at once and alternative treatments should be considered. Given the similar structural formula of [[atropine]] to aclidinium, patients with a history of hypersensitivity reactions to atropine should be closely monitored for similar [[hypersensitivity]] reactions to Aclidinium bromide. In addition, Aclidinium bromide should be used with caution in patients with severe hypersensitivity to milk proteins.
|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

====3-Month and 6-Month Trials====

*Aclidinium bromide was studied in two 3-month (Trials B and C) and one 6-month (Trial D) placebo-controlled trials in patients with COPD. In these trials, 636 patients were treated with Aclidinium bromide at the recommended dose of 400 mcg twice daily.

*The population had a mean age of 64 years (ranging from 40 to 89 years), with 58% males, 94% Caucasian, and had COPD with a mean pre-bronchodilator forced expiratory volume in one second (FEV1) percent predicted of 48%. Patients with unstable [[cardiac disease]], [[Acute angle-closure glaucoma|narrow-angle glaucoma]], or symptomatic [[prostatic hypertrophy]] or bladder outlet obstruction were excluded from these trials.

TABLE 1 shows all adverse reactions that occurred with a frequency of greater than or equal to 1% in the Aclidinium bromide group in the two 3-month and one 6-month placebo-controlled trials where the rates in the Aclidinium bromide group exceeded placebo.

[[File:Aclidinium bromide inhalant 1.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

In addition, among the adverse reactions observed in the clinical trials with an incidence of less than 1% were [[diabetes mellitus]], [[dry mouth]], [[1st degree AV block]], [[osteoarthritis]], [[cardiac failure]], and [[cardio-respiratory arrest]].

====Long-term Safety Trials====

Aclidinium bromide was studied in three long term safety trials, two double blind and one open label, ranging from 40 to 52 weeks in patients with moderate to severe [[COPD]]. Two of these trials were extensions of the 3-month trials, and one was a dedicated long term safety trial. In these trials, 891 patients were treated with Aclidinium bromide at the recommended dose of 400 mcg twice daily. The demographic and baseline characteristics of the long term safety trials were similar to those of the placebo-controlled trials. The adverse events reported in the long term safety trials were similar to those occurring in the placebo-controlled trials of 3 to 6 months. No new safety findings were reported compared to the placebo controlled trials.
|drugInteractions=In vitro studies suggest limited potential for [[CYP450]]-related metabolic drug interactions, thus no formal drug interaction studies have been performed with Aclidinium bromide.

====Sympathomimetics, Methylxanthines, Steroids====
In clinical studies, concurrent administration of aclidinium bromide and other drugs commonly used in the treatment of [[COPD]] including [[Sympathomimetic agents|sympathomimetics]] (short-acting [[Beta-agonists|beta2 agonists]]), [[methylxanthines]], and oral and inhaled [[steroids]] showed no increases in adverse drug reactions.

====Anticholinergics====
There is a potential for an additive interaction with concomitantly used [[anticholinergic]] medications. Therefore, avoid coadministration of Aclidinium bromide with other [[Anticholinergics|anticholinergic-containing drugs]] as this may lead to an increase in [[anticholinergic]] effects.
|useInPregnancyFDA=<u>Teratogenic effects</u>

====Pregnancy Category C====
There are no adequate and well controlled studies in pregnant women. Adverse development effects were observed in rats and rabbits exposed to aclidinium bromide. Aclidinium bromide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Effects of aclidinium bromide on embryo-fetal development were examined in rats and rabbits. No evidence of structural alterations was observed in rats exposed during the period of [[organogenesis]] at approximately 15 times the recommended human daily dose (RHDD) [based on summed AUCs of aclidinium bromide and its metabolites at inhaled doses less than or equal to 5.0 mg/kg/day]. However, decreased pup weights were observed from dams exposed during the lactation period at approximately 5 times the RHDD [based on summed AUCs of aclidinium bromide and its metabolites at inhaled doses greater than or equal to 0.2 mg/kg/day]. Maternal toxicity was also observed at inhaled doses greater than or equal to 0.2 mg/kg/day.

No evidence of structural alterations was observed in Himalayan rabbits exposed during the period of organogenesis at approximately 20 times the RHDD [based on summed AUCs of aclidinium bromide and its metabolites at inhaled doses less than or equal to 3.6 mg/kg/day]. However, increased incidences of additional liver lobes (3-5%), as compared to 0% in the control group, were observed at approximately 1,400 times the RHDD [based on summed AUCs of aclidinium bromide and its metabolites at oral doses greater than or equal to 150 mg/kg/day], and decreased fetal body weights were observed at approximately 2,300 times the RHDD [based on summed AUCs of aclidinium bromide and its metabolites at oral doses greater than or equal to 300 mg/kg/day]. These fetal findings were observed in the presence of maternal toxicity.
|useInLaborDelivery=*The effect of Aclidinium bromide on labor and delivery is unknown.
*Aclidinium bromide should be used during labor and delivery only if the potential benefit to the patient justifies the potential risk to the fetus.
|useInNursing=*Aclidinium bromide is excreted into the milk of lactating female rats, and decreased pup weights were observed.
*Excretion of aclidinium into human milk is probable.
*There are no human studies that have investigated the effects of Aclidinium bromide on breast-fed infants.
*Caution should be exercised when Aclidinium bromide is administered to nursing women.
|useInPed=*Aclidinium bromide is approved for use in the maintenance treatment of bronchospasm associated with [[COPD]].
*COPD does not normally occur in children.
*The safety and effectiveness of Aclidinium bromide in pediatric patients have not been established.
|useInGeri=*Of the 636 COPD patients exposed to Aclidinium bromide 400 mcg twice daily for up to 24 weeks in three placebo-controlled clinical trials, 197 were less than 60 years, 272 were greater than or equal to 60 to less than 70 years, and 167 were greater than or equal to 70 years of age.
*No overall differences in safety or effectiveness were observed between these subjects and younger subjects.
*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.
*Based on available data for Aclidinium bromide, no adjustment of dosage in geriatric patients is warranted.
|useInRenalImpair=*The pharmacokinetics of Aclidinium bromide were investigated in subjects with normal renal function and in subjects with mild, moderate and severe [[renal impairment]].
*No clinically significant differences in aclidinium pharmacokinetics were noted between these populations.
*Based on available data for Aclidinium bromide, no adjustment of dosage in renally impaired subjects is warranted.
|useInHepaticImpair=The effects of hepatic impairment on the pharmacokinetics of Aclidinium bromide were not studied.
|drugBox=
{{Drugbox2
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 477240902
| IUPAC_name = [(8''R'')-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octan-8-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate bromide
| [[File:320px-Aclidinium bromide.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|


| tradename = Bretaris Genuair, Eklira Genuair, Tudorza Pressair
| pregnancy_category =
| pregnancy_US = C
| legal_status =
| legal_US = Rx-only
| routes_of_administration = [[Inhalational]]
| licence_US = Aclidinium


| bioavailability =
| metabolism =
| elimination_half-life =
| excretion =


| CAS_number_Ref = {{cascite|changed|??}}
| CAS_number = 320345-99-1
| ATC_prefix = R03
| ATC_suffix = BB05
| ATC_supplemental =
| PubChem = 11519741
| ChEBI_Ref = {{ebicite|changed|EBI}}
| ChEBI = 65344
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = 9694529
| UNII_Ref = {{fdacite|changed|FDA}}
| UNII = UQW7UF9N91
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D08837
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 551466


| C=26 | H=30 | Br=1 | N=1 | O=4 | S=2
| molecular_weight = 564.555 g/mol
| smiles = [Br-].O=C(O[C@@H]3C2CC[N+](CCCOc1ccccc1)(CC2)C3)C(O)c4sccc4)c5sccc5
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
| StdInChI = 1S/C26H30NO4S2.BrH/c28-25(26(29,23-9-4-17-32-23)24-10-5-18-33-24)31-22-19-27(14-11-20(22)12-15-27)13-6-16-30-21-7-2-1-3-8-21;/h1-5,7-10,17-18,20,22,29H,6,11-16,19H2;1H/q+1;/p-1/t20?,22-,27?;/m0./s1
| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
| StdInChIKey = XLAKJQPTOJHYDR-QTQXQZBYSA-M
}}

|mechAction=*Aclidinium bromide is a long-acting [[antimuscarinic|antimuscarinic agent]], which is often referred to as an [[anticholinergic]].
*It has similar affinity to the subtypes of [[muscarinic receptors]] M1 to M5.
*In the airways, it exhibits pharmacological effects through inhibition of M3 receptor at the smooth muscle leading to [[bronchodilation]].
*The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations.
*In preclinical in vitro as well as in vivo studies, prevention of [[acetylcholine]]-induced [[bronchoconstriction]] effects was dose-dependent and lasted longer than 24 hours.
*The clinical relevance of these findings is unknown.
*The [[bronchodilation]] following inhalation of aclidinium bromide is predominantly a site-specific effect.
|structure=Aclidinium bromide consists of a dry powder formulation of aclidinium bromide for oral inhalation only.

Aclidinium bromide, the active component of TUDORZA PRESSAIR is an anticholinergic with specificity for muscarinic receptors. Aclidinium bromide is a synthetic, quaternary ammonium compound, chemically described as 1-Azoniabicyclo[2.2.2]octane, 3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)-. The structural formula is:
[[File:Aclidinium bromide inhalant 7.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

Aclidinium bromide is a white powder with a molecular formula of C26H30NO4S2Br and a molecular mass of 564.56. It is very slightly soluble in water and ethanol and sparingly soluble in methanol.

Aclidinium bromide is a breath-actuated multi-dose dry powder inhaler. Each actuation of Aclidinium bromide provides a metered dose of 13 mg of the formulation which contains lactose monohydrate (which may contain milk proteins) as the carrier and 400 mcg of aclidinium bromide. This results in delivery of 375 mcg aclidinium bromide from the mouthpiece, based onin vitro testing at an average flow rate of 63 L/min with constant volume of 2 L. The amount of drug delivered to the lungs will vary depending on patient factors such as inspiratory flow rate and inspiratory time. The PRESSAIR inhaler delivers the target dose at flow rates as low as 35 L/min. Based on a study in adult patients with moderate (N=24) and severe (N=24) COPD the mean peak inspiratory flow (PIF) was 95.3 L/min (range: 54.6 to 129.4 L/min) and 88.7 L/min (range: 72.0 to 106.4 L/min) respectively.
|PD=====Cardiovascular Effects====

*In a thorough QT Study, 200 mcg and 800 mcg Aclidinium bromide was administered to healthy volunteers once daily for 3 days; no effects on prolongation of [[QT interval]] were observed using QTcF heart-rate correction methods.
*Additionally, the effect of Aclidinium bromide on cardiac rhythm was assessed in 336 COPD patients, 164 patients received aclidinium bromide 400 mcg twice daily and 172 patients received placebo, using 24-hr [[Holter monitoring]].
*No clinically significant effects on cardiac rhythm were observed.
|PK=====Absorption====

*The absolute bioavailability of aclidinium bromide is approximately 6% in healthy volunteers.
*Following twice-daily oral inhalation administration of 400 mcg aclidinium bromide in healthy subjects, peak steady state plasma levels were observed within 10 minutes after inhalation.

====Distribution====

*Aclidinium bromide shows a volume of distribution of approximately 300 L following intravenous administration of 400 mcg in humans.

====Metabolism====

*Clinical pharmacokinetics studies, including a mass balance study, indicate that the major route of metabolism of aclidinium bromide is hydrolysis, which occurs both chemically and enzymatically by esterases.
*Aclidinium bromide is rapidly and extensively hydrolyzed to its alcohol and dithienylglycolic acid derivatives, neither of which binds to muscarinic receptors and are devoid of pharmacologic activity.
*Therefore, due to the low plasma levels achieved at the clinically relevant doses, aclidinium bromide and its metabolites are not expected to alter the disposition of drugs metabolized by the human CYP450 enzymes.

====Elimination====

*Total clearance was approximately 170 L/h after an intravenous dose of aclidinium bromide in young healthy volunteers with an inter-individual variability of 36%.
*Intravenously administered radiolabelled aclidinium bromide was administered to healthy volunteers and was extensively metabolized with 1% excreted as unchanged aclidinium.
*Approximately 54% to 65% of the radioactivity was excreted in urine and 20% to 33% of the dose was excreted in feces.
*The combined results indicated that almost the entire aclidinium bromide dose was eliminated by hydrolysis.
*After dry powder inhalation, urinary excretion of aclidinium is about 0.09% of the dose and the estimated effective half-life is 5 to 8 hours.

====Drug Interactions====

*Formal drug interaction studies were not performed.
*In vitro studies using human liver microsomes indicated that aclidinium bromide and its major metabolites do not inhibit CYP450, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5 or 4A9/11 at concentrations up to 1,000-fold higher than the maximum plasma concentration that would be expected to be achieved at the therapeutic dose.
*Therefore, it is unlikely that aclidinium bromide causes [[CYP450]] related drug interactions.

=====Specific Populations=====

=====Elderly Patients=====

The pharmacokinetic profile of aclidinium bromide and its main metabolites was assessed in 12 elderly COPD patients (aged 70 years or older) compared to a younger cohort of 12 COPD patients (40-59 years) that were administered 400 mcg aclidinium bromide once daily for 3 days via inhalation. No clinically significant differences in systemic exposure (AUC and Cmax) were observed when the two groups were compared. No dosage adjustment is necessary in elderly patients.

=====Renal Impairment=====

The impact of renal disease upon the pharmacokinetics of aclidinium bromide was studied in 18 subjects with mild, moderate, or severe [[renal impairment]]. Systemic exposure (AUC and Cmax) to aclidinium bromide and its main metabolites following single doses of 400 mcg aclidinium bromide was similar in renally impaired patients compared with 6 matched healthy control subjects. No dose adjustment is necessary in renally impaired patients.

=====Hepatic Impairment=====

The effects of [[hepatic impairment]] on the pharmacokinetics of aclidinium bromide were not studied. However, hepatic insufficiency is not expected to have relevant influence on aclidinium bromide pharmacokinetics, since it is predominantly metabolized by chemical and enzymatic hydrolysis to products that do not bind to muscarinic receptors.
|nonClinToxic=====Carcinogenesis, Mutagenesis, Impairment of Fertility====
*Two-year inhalation studies were conducted in mice and rats to assess the carcinogenic potential of aclidinium bromide.
*No evidence of tumorigenicity was observed in rats and mice at aclidinium doses up to 0.20 and 2.4 mg/kg/day, respectively [approximately 10 and 80 times the Recommended Human Daily Dose (RHDD), respectively, based on summed AUCs of aclidinium bromide and its metabolites].

*Aclidinium bromide was positive in the in vitro bacterial gene mutation assay and the in vitro thymidine locus mouse lymphoma assay. However, aclidinium bromide was negative in the in vivo mouse micronucleus assay and the in vivo/in vitro unscheduled DNA synthesis assay with rat liver.

*Aclidinium bromide impaired several fertility and reproductive performance indices (increased number of days to mate, decreased conception rate, decreased number of corpora lutea, increased pre-implantation loss with consequent decreased number of implantations and live embryos) in both male and female rats administered inhaled doses greater than or equal to 0.8 mg/kg/day [approximately 15 times the RHDD based on summed AUCs of aclidinium bromide and its metabolites].
|clinicalStudies=====Chronic Obstructive Pulmonary Disease (COPD)=====
The Aclidinium bromide clinical development program included a dose-ranging trial (Trial A) for nominal dose selection and three confirmatory trials (Trials B, C, and D).

====Dose-ranging trial====

Trial A was a randomized, double-blind, placebo-controlled, active-controlled, crossover trial with 7-day treatment periods separated by 5-day washout periods. Trial A enrolled 79 patients who had a clinical diagnosis of [[COPD]], were 40 years of age or older, had a history of smoking at least 10 pack-years, had a [[forced expiratory volume]] in one second ([[FEV1]]) of at least 30% and less than 80% of predicted normal value, and a ratio of FEV1 over forced [[vital capacity]] (FEV1/FVC) of less than 0.7. Trial A included Aclidinium bromide doses of 400 mcg, 200 mcg and 100 mcg twice daily, formoterol active control, and placebo. Trial A demonstrated that the effect on trough [[FEV1]] and serial FEV1 in patients treated with the Aclidinium bromide 100 mcg twice daily and 200 mcg twice daily doses was lower compared to patients treated with the Aclidinium bromide 400 mcg twice daily dose.
[[File:Aclidinium bromide inhalant 2.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

=====Confirmatory trials=====

Trials B, C, and D were three randomized, double-blind, placebo-controlled trials in patients with [[COPD]]. Trials B and C were 3 months in duration, and Trial D was 6 months in duration. These trials enrolled 1,276 patients who had a clinical diagnosis of COPD, were 40 years of age or older, had a history of smoking at least 10 pack-years, had an FEV1 of at least 30% and less than 80% of predicted normal value, and a ratio of FEV1/FVC of less than 0.7; 59% were male, and 93% were Caucasian.

These clinical trials evaluated Aclidinium bromide 400 mcg twice daily (636 patients) and placebo (640 patients). Aclidinium bromide 400 mcg resulted in statistically significantly greater [[bronchodilation]] as measured by change from baseline in morning pre-dose [[FEV1]] at 12 weeks (the primary efficacy endpoint) compared to placebo in all three trials.

[[File:Aclidinium bromide inhalant 3.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

Serial spirometric evaluations were performed throughout daytime hours in a subset of patients in the three trials. The serial FEV1 values over 12 hours for one of the 3-month trials (Trial B) are displayed. Results for the other two placebo-controlled trials were similar to the results for Trial B. Improvement of lung function was maintained for 12 hours after a single dose and was consistent over the 3- or 6-month treatment period.

[[File:Aclidinium bromide inhalant 4.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]
Mean peak improvements in FEV1, for Aclidinium bromide relative to baseline were assessed in all patients in trials B, C and D after the first dose on day 1 and were similar at week 12. In Trials B and D but not in Trial C, patients treated with Aclidinium bromide used less daily rescue [[albuterol]] during the trial compared to patients treated with placebo.
|howSupplied=Aclidinium bromide inhalation powder 400 mcg is supplied in a sealed labeled aluminum pouch and is available in 60 metered doses and 30 metered doses.

The active ingredient is administered using a multi-dose dry powder inhaler, PRESSAIR®, which delivers 60 doses or 30 doses of aclidinium bromide powder for oral inhalation. The PRESSAIR inhaler is a white and green colored device and is comprised of an assembled plastic dosing mechanism with a dose indicator, a drug-product storage unit containing the drug-product formulation, and a mouthpiece covered by a green protective cap. The inhaler should be discarded when the marking “0” with a red background shows in the middle of the dose indicator or when the device locks out, whichever comes first.
|storage=Store Aclidinium bromide in a dry place at 25 C (77 F); excursions permitted to 15-30 C (59-86 F)[see USP Controlled Room Temperature].

The PRESSAIR inhaler should be stored inside the sealed pouch and only be opened immediately before use.

Discard the PRESSAIR inhaler 45 days after opening the pouch, after the marking “0” with a red background shows in the middle of the dose indicator, or when the device locks out, whichever comes first.

Keep out of reach of children.
|packLabel=[[File:Aclidinium bromide inhalant 5.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

[[File:Aclidinium bromide inhalant 6.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|fdaPatientInfo======Instructions for Administering Aclidinium bromide=====
It is important for patients to understand how to correctly use Aclidinium bromide. Inform patients that if they miss a dose, they should take their next dose at the usual time; they should not take 2 doses at one time.

=====Acute Bronchospasm=====
Instruct patients that Aclidinium bromide is a twice daily maintenance [[bronchodilator]] and should not be used for immediate relief of breathing problems (i.e., as a rescue medication).

=====Paradoxical Bronchospasm=====
Inform patients that Aclidinium bromide can cause paradoxical [[bronchospasm]]. Advise patients that if paradoxical bronchospasm occurs, patients should discontinue Aclidinium bromide.

=====Visual Effects=====
Eye pain or discomfort, [[blurred vision]], visual halos or colored images in association with red eyes from conjunctival congestion and [[corneal edema]] may be signs of [[acute narrow-angle glaucoma]]. Inform patients to consult a physician immediately should any of these signs and symptoms develop. Advise patients that miotic eyedrops alone are not considered to be effective treatment.
*Inform patients that care must be taken not to allow the powder to enter into the eyes as this may cause blurring of vision and pupil dilation.

=====Urinary Retention=====
Difficulty passing urine and [[dysuria]] may be symptoms of new or worsening [[Benign prostatic hyperplasia|prostatic hyperplasia]] or bladder outlet obstruction. Patients should be instructed to consult a physician immediately should any of these signs or symptoms develop.
|alcohol=Alcohol-Aclidinium interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=*Aclidinium bromide
}}

Aclidinium

2015-03-12T15:52:43Z

Sree Teja Yelamanchili:

{{DrugProjectFormSinglePage
|authorTag={{STY}}
|genericName=Aclidinium bromide
|aOrAn=an
|drugClass=[[antimuscarinic]] and [[bronchodilator]]
|indicationType=treatment
|indication=long-term maintenance treatment of [[bronchospasm]] associated with [[chronic obstructive pulmonary disease]] ([[COPD]]), including [[chronic bronchitis]] and [[emphysema]].
|adverseReactions=[[headache]], [[cough]], and [[nasopharyngitis]].
|blackBoxWarningTitle=<b><span style="color:#FF0000;">TITLE</span></b>
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)
|fdaLIADAdult=*The recommended dose of Aclidinium bromide is one oral inhalation of 400 mcg, twice daily.

*Inhalation Powder- Aclidinium bromide is a breath-actuated multi-dose dry powder inhaler metering 400 mcg of aclidinium bromide per actuation.
|offLabelAdultGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Aclidinium in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Aclidinium in adult patients.
|offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Aclidinium in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Aclidinium in pediatric patients.
|contraindications=None.
|warnings=====Not for Acute Use====
Aclidinium bromide is intended as a twice-daily maintenance treatment for [[COPD]] and is not indicated for the initial treatment of acute episodes of [[bronchospasm]] (i.e., rescue therapy).

====Paradoxical Bronchospasm====
Inhaled medicines, including Aclidinium bromide, may cause paradoxical [[bronchospasm]]. If this occurs, treatment with Aclidinium bromide should be stopped and other treatments considered.

====Worsening of Narrow-Angle Glaucoma====
Aclidinium bromide should be used with caution in patients with [[narrow-angle glaucoma]]. Prescribers and patients should be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., [[eye pain]] or discomfort, [[blurred vision]], visual halos or colored images in association with red eyes from conjunctival congestion and [[corneal edema]]). Instruct patients to consult a physician immediately should any of these signs or symptoms develop.

====Worsening of Urinary Retention====
Aclidinium bromide should be used with caution in patients with urinary retention. Prescribers and patients should be alert for signs and symptoms of [[Benign prostatic hyperplasia|prostatic hyperplasia]] or bladder-neck obstruction (e.g., difficulty passing urine, painful urination). Instruct patients to consult a physician immediately should any of these signs or symptoms develop.

====Immediate Hypersensitivity Reactions====
Immediate [[hypersensitivity]] reactions may occur after administration of Aclidinium bromide. If such a reaction occurs, therapy with Aclidinium bromide should be stopped at once and alternative treatments should be considered. Given the similar structural formula of [[atropine]] to aclidinium, patients with a history of hypersensitivity reactions to atropine should be closely monitored for similar [[hypersensitivity]] reactions to Aclidinium bromide. In addition, Aclidinium bromide should be used with caution in patients with severe hypersensitivity to milk proteins.
|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

====3-Month and 6-Month Trials====

*Aclidinium bromide was studied in two 3-month (Trials B and C) and one 6-month (Trial D) placebo-controlled trials in patients with COPD. In these trials, 636 patients were treated with Aclidinium bromide at the recommended dose of 400 mcg twice daily.

*The population had a mean age of 64 years (ranging from 40 to 89 years), with 58% males, 94% Caucasian, and had COPD with a mean pre-bronchodilator forced expiratory volume in one second (FEV1) percent predicted of 48%. Patients with unstable [[cardiac disease]], [[Acute angle-closure glaucoma|narrow-angle glaucoma]], or symptomatic [[prostatic hypertrophy]] or bladder outlet obstruction were excluded from these trials.

TABLE 1 shows all adverse reactions that occurred with a frequency of greater than or equal to 1% in the Aclidinium bromide group in the two 3-month and one 6-month placebo-controlled trials where the rates in the Aclidinium bromide group exceeded placebo.

[[File:Aclidinium bromide inhalant 1.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

In addition, among the adverse reactions observed in the clinical trials with an incidence of less than 1% were [[diabetes mellitus]], [[dry mouth]], [[1st degree AV block]], [[osteoarthritis]], [[cardiac failure]], and [[cardio-respiratory arrest]].

====Long-term Safety Trials====

Aclidinium bromide was studied in three long term safety trials, two double blind and one open label, ranging from 40 to 52 weeks in patients with moderate to severe [[COPD]]. Two of these trials were extensions of the 3-month trials, and one was a dedicated long term safety trial. In these trials, 891 patients were treated with Aclidinium bromide at the recommended dose of 400 mcg twice daily. The demographic and baseline characteristics of the long term safety trials were similar to those of the placebo-controlled trials. The adverse events reported in the long term safety trials were similar to those occurring in the placebo-controlled trials of 3 to 6 months. No new safety findings were reported compared to the placebo controlled trials.
|drugInteractions=In vitro studies suggest limited potential for [[CYP450]]-related metabolic drug interactions, thus no formal drug interaction studies have been performed with Aclidinium bromide.

====Sympathomimetics, Methylxanthines, Steroids====
In clinical studies, concurrent administration of aclidinium bromide and other drugs commonly used in the treatment of [[COPD]] including [[Sympathomimetic agents|sympathomimetics]] (short-acting [[Beta-agonists|beta2 agonists]]), [[methylxanthines]], and oral and inhaled [[steroids]] showed no increases in adverse drug reactions.

====Anticholinergics====
There is a potential for an additive interaction with concomitantly used [[anticholinergic]] medications. Therefore, avoid coadministration of Aclidinium bromide with other [[Anticholinergics|anticholinergic-containing drugs]] as this may lead to an increase in [[anticholinergic]] effects.
|useInPregnancyFDA=<u>Teratogenic effects</u>

====Pregnancy Category C====
There are no adequate and well controlled studies in pregnant women. Adverse development effects were observed in rats and rabbits exposed to aclidinium bromide. Aclidinium bromide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Effects of aclidinium bromide on embryo-fetal development were examined in rats and rabbits. No evidence of structural alterations was observed in rats exposed during the period of [[organogenesis]] at approximately 15 times the recommended human daily dose (RHDD) [based on summed AUCs of aclidinium bromide and its metabolites at inhaled doses less than or equal to 5.0 mg/kg/day]. However, decreased pup weights were observed from dams exposed during the lactation period at approximately 5 times the RHDD [based on summed AUCs of aclidinium bromide and its metabolites at inhaled doses greater than or equal to 0.2 mg/kg/day]. Maternal toxicity was also observed at inhaled doses greater than or equal to 0.2 mg/kg/day.

No evidence of structural alterations was observed in Himalayan rabbits exposed during the period of organogenesis at approximately 20 times the RHDD [based on summed AUCs of aclidinium bromide and its metabolites at inhaled doses less than or equal to 3.6 mg/kg/day]. However, increased incidences of additional liver lobes (3-5%), as compared to 0% in the control group, were observed at approximately 1,400 times the RHDD [based on summed AUCs of aclidinium bromide and its metabolites at oral doses greater than or equal to 150 mg/kg/day], and decreased fetal body weights were observed at approximately 2,300 times the RHDD [based on summed AUCs of aclidinium bromide and its metabolites at oral doses greater than or equal to 300 mg/kg/day]. These fetal findings were observed in the presence of maternal toxicity.
|useInLaborDelivery=*The effect of Aclidinium bromide on labor and delivery is unknown.
*Aclidinium bromide should be used during labor and delivery only if the potential benefit to the patient justifies the potential risk to the fetus.
|useInNursing=*Aclidinium bromide is excreted into the milk of lactating female rats, and decreased pup weights were observed.
*Excretion of aclidinium into human milk is probable.
*There are no human studies that have investigated the effects of Aclidinium bromide on breast-fed infants.
*Caution should be exercised when Aclidinium bromide is administered to nursing women.
|useInPed=*Aclidinium bromide is approved for use in the maintenance treatment of bronchospasm associated with [[COPD]].
*COPD does not normally occur in children.
*The safety and effectiveness of Aclidinium bromide in pediatric patients have not been established.
|useInGeri=*Of the 636 COPD patients exposed to Aclidinium bromide 400 mcg twice daily for up to 24 weeks in three placebo-controlled clinical trials, 197 were less than 60 years, 272 were greater than or equal to 60 to less than 70 years, and 167 were greater than or equal to 70 years of age.
*No overall differences in safety or effectiveness were observed between these subjects and younger subjects.
*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.
*Based on available data for Aclidinium bromide, no adjustment of dosage in geriatric patients is warranted.
|useInRenalImpair=*The pharmacokinetics of Aclidinium bromide were investigated in subjects with normal renal function and in subjects with mild, moderate and severe [[renal impairment]].
*No clinically significant differences in aclidinium pharmacokinetics were noted between these populations.
*Based on available data for Aclidinium bromide, no adjustment of dosage in renally impaired subjects is warranted.
|useInHepaticImpair=The effects of hepatic impairment on the pharmacokinetics of Aclidinium bromide were not studied.
|drugBox=
{{Drugbox2
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 477240902
| IUPAC_name = [(8''R'')-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octan-8-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate bromide
| image = [[File:320px-Aclidinium bromide.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
| width = 320


| tradename = Bretaris Genuair, Eklira Genuair, Tudorza Pressair
| pregnancy_category =
| pregnancy_US = C
| legal_status =
| legal_US = Rx-only
| routes_of_administration = [[Inhalational]]
| licence_US = Aclidinium


| bioavailability =
| metabolism =
| elimination_half-life =
| excretion =


| CAS_number_Ref = {{cascite|changed|??}}
| CAS_number = 320345-99-1
| ATC_prefix = R03
| ATC_suffix = BB05
| ATC_supplemental =
| PubChem = 11519741
| ChEBI_Ref = {{ebicite|changed|EBI}}
| ChEBI = 65344
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = 9694529
| UNII_Ref = {{fdacite|changed|FDA}}
| UNII = UQW7UF9N91
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D08837
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 551466


| C=26 | H=30 | Br=1 | N=1 | O=4 | S=2
| molecular_weight = 564.555 g/mol
| smiles = [Br-].O=C(O[C@@H]3C2CC[N+](CCCOc1ccccc1)(CC2)C3)C(O)c4sccc4)c5sccc5
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
| StdInChI = 1S/C26H30NO4S2.BrH/c28-25(26(29,23-9-4-17-32-23)24-10-5-18-33-24)31-22-19-27(14-11-20(22)12-15-27)13-6-16-30-21-7-2-1-3-8-21;/h1-5,7-10,17-18,20,22,29H,6,11-16,19H2;1H/q+1;/p-1/t20?,22-,27?;/m0./s1
| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
| StdInChIKey = XLAKJQPTOJHYDR-QTQXQZBYSA-M
}}

|mechAction=*Aclidinium bromide is a long-acting [[antimuscarinic|antimuscarinic agent]], which is often referred to as an [[anticholinergic]].
*It has similar affinity to the subtypes of [[muscarinic receptors]] M1 to M5.
*In the airways, it exhibits pharmacological effects through inhibition of M3 receptor at the smooth muscle leading to [[bronchodilation]].
*The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations.
*In preclinical in vitro as well as in vivo studies, prevention of [[acetylcholine]]-induced [[bronchoconstriction]] effects was dose-dependent and lasted longer than 24 hours.
*The clinical relevance of these findings is unknown.
*The [[bronchodilation]] following inhalation of aclidinium bromide is predominantly a site-specific effect.
|structure=Aclidinium bromide consists of a dry powder formulation of aclidinium bromide for oral inhalation only.

Aclidinium bromide, the active component of TUDORZA PRESSAIR is an anticholinergic with specificity for muscarinic receptors. Aclidinium bromide is a synthetic, quaternary ammonium compound, chemically described as 1-Azoniabicyclo[2.2.2]octane, 3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)-. The structural formula is:
[[File:Aclidinium bromide inhalant 7.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

Aclidinium bromide is a white powder with a molecular formula of C26H30NO4S2Br and a molecular mass of 564.56. It is very slightly soluble in water and ethanol and sparingly soluble in methanol.

Aclidinium bromide is a breath-actuated multi-dose dry powder inhaler. Each actuation of Aclidinium bromide provides a metered dose of 13 mg of the formulation which contains lactose monohydrate (which may contain milk proteins) as the carrier and 400 mcg of aclidinium bromide. This results in delivery of 375 mcg aclidinium bromide from the mouthpiece, based onin vitro testing at an average flow rate of 63 L/min with constant volume of 2 L. The amount of drug delivered to the lungs will vary depending on patient factors such as inspiratory flow rate and inspiratory time. The PRESSAIR inhaler delivers the target dose at flow rates as low as 35 L/min. Based on a study in adult patients with moderate (N=24) and severe (N=24) COPD the mean peak inspiratory flow (PIF) was 95.3 L/min (range: 54.6 to 129.4 L/min) and 88.7 L/min (range: 72.0 to 106.4 L/min) respectively.
|PD=====Cardiovascular Effects====

*In a thorough QT Study, 200 mcg and 800 mcg Aclidinium bromide was administered to healthy volunteers once daily for 3 days; no effects on prolongation of [[QT interval]] were observed using QTcF heart-rate correction methods.
*Additionally, the effect of Aclidinium bromide on cardiac rhythm was assessed in 336 COPD patients, 164 patients received aclidinium bromide 400 mcg twice daily and 172 patients received placebo, using 24-hr [[Holter monitoring]].
*No clinically significant effects on cardiac rhythm were observed.
|PK=====Absorption====

*The absolute bioavailability of aclidinium bromide is approximately 6% in healthy volunteers.
*Following twice-daily oral inhalation administration of 400 mcg aclidinium bromide in healthy subjects, peak steady state plasma levels were observed within 10 minutes after inhalation.

====Distribution====

*Aclidinium bromide shows a volume of distribution of approximately 300 L following intravenous administration of 400 mcg in humans.

====Metabolism====

*Clinical pharmacokinetics studies, including a mass balance study, indicate that the major route of metabolism of aclidinium bromide is hydrolysis, which occurs both chemically and enzymatically by esterases.
*Aclidinium bromide is rapidly and extensively hydrolyzed to its alcohol and dithienylglycolic acid derivatives, neither of which binds to muscarinic receptors and are devoid of pharmacologic activity.
*Therefore, due to the low plasma levels achieved at the clinically relevant doses, aclidinium bromide and its metabolites are not expected to alter the disposition of drugs metabolized by the human CYP450 enzymes.

====Elimination====

*Total clearance was approximately 170 L/h after an intravenous dose of aclidinium bromide in young healthy volunteers with an inter-individual variability of 36%.
*Intravenously administered radiolabelled aclidinium bromide was administered to healthy volunteers and was extensively metabolized with 1% excreted as unchanged aclidinium.
*Approximately 54% to 65% of the radioactivity was excreted in urine and 20% to 33% of the dose was excreted in feces.
*The combined results indicated that almost the entire aclidinium bromide dose was eliminated by hydrolysis.
*After dry powder inhalation, urinary excretion of aclidinium is about 0.09% of the dose and the estimated effective half-life is 5 to 8 hours.

====Drug Interactions====

*Formal drug interaction studies were not performed.
*In vitro studies using human liver microsomes indicated that aclidinium bromide and its major metabolites do not inhibit CYP450, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5 or 4A9/11 at concentrations up to 1,000-fold higher than the maximum plasma concentration that would be expected to be achieved at the therapeutic dose.
*Therefore, it is unlikely that aclidinium bromide causes [[CYP450]] related drug interactions.

=====Specific Populations=====

=====Elderly Patients=====

The pharmacokinetic profile of aclidinium bromide and its main metabolites was assessed in 12 elderly COPD patients (aged 70 years or older) compared to a younger cohort of 12 COPD patients (40-59 years) that were administered 400 mcg aclidinium bromide once daily for 3 days via inhalation. No clinically significant differences in systemic exposure (AUC and Cmax) were observed when the two groups were compared. No dosage adjustment is necessary in elderly patients.

=====Renal Impairment=====

The impact of renal disease upon the pharmacokinetics of aclidinium bromide was studied in 18 subjects with mild, moderate, or severe [[renal impairment]]. Systemic exposure (AUC and Cmax) to aclidinium bromide and its main metabolites following single doses of 400 mcg aclidinium bromide was similar in renally impaired patients compared with 6 matched healthy control subjects. No dose adjustment is necessary in renally impaired patients.

=====Hepatic Impairment=====

The effects of [[hepatic impairment]] on the pharmacokinetics of aclidinium bromide were not studied. However, hepatic insufficiency is not expected to have relevant influence on aclidinium bromide pharmacokinetics, since it is predominantly metabolized by chemical and enzymatic hydrolysis to products that do not bind to muscarinic receptors.
|nonClinToxic=====Carcinogenesis, Mutagenesis, Impairment of Fertility====
*Two-year inhalation studies were conducted in mice and rats to assess the carcinogenic potential of aclidinium bromide.
*No evidence of tumorigenicity was observed in rats and mice at aclidinium doses up to 0.20 and 2.4 mg/kg/day, respectively [approximately 10 and 80 times the Recommended Human Daily Dose (RHDD), respectively, based on summed AUCs of aclidinium bromide and its metabolites].

*Aclidinium bromide was positive in the in vitro bacterial gene mutation assay and the in vitro thymidine locus mouse lymphoma assay. However, aclidinium bromide was negative in the in vivo mouse micronucleus assay and the in vivo/in vitro unscheduled DNA synthesis assay with rat liver.

*Aclidinium bromide impaired several fertility and reproductive performance indices (increased number of days to mate, decreased conception rate, decreased number of corpora lutea, increased pre-implantation loss with consequent decreased number of implantations and live embryos) in both male and female rats administered inhaled doses greater than or equal to 0.8 mg/kg/day [approximately 15 times the RHDD based on summed AUCs of aclidinium bromide and its metabolites].
|clinicalStudies=====Chronic Obstructive Pulmonary Disease (COPD)=====
The Aclidinium bromide clinical development program included a dose-ranging trial (Trial A) for nominal dose selection and three confirmatory trials (Trials B, C, and D).

====Dose-ranging trial====

Trial A was a randomized, double-blind, placebo-controlled, active-controlled, crossover trial with 7-day treatment periods separated by 5-day washout periods. Trial A enrolled 79 patients who had a clinical diagnosis of [[COPD]], were 40 years of age or older, had a history of smoking at least 10 pack-years, had a [[forced expiratory volume]] in one second ([[FEV1]]) of at least 30% and less than 80% of predicted normal value, and a ratio of FEV1 over forced [[vital capacity]] (FEV1/FVC) of less than 0.7. Trial A included Aclidinium bromide doses of 400 mcg, 200 mcg and 100 mcg twice daily, formoterol active control, and placebo. Trial A demonstrated that the effect on trough [[FEV1]] and serial FEV1 in patients treated with the Aclidinium bromide 100 mcg twice daily and 200 mcg twice daily doses was lower compared to patients treated with the Aclidinium bromide 400 mcg twice daily dose.
[[File:Aclidinium bromide inhalant 2.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

=====Confirmatory trials=====

Trials B, C, and D were three randomized, double-blind, placebo-controlled trials in patients with [[COPD]]. Trials B and C were 3 months in duration, and Trial D was 6 months in duration. These trials enrolled 1,276 patients who had a clinical diagnosis of COPD, were 40 years of age or older, had a history of smoking at least 10 pack-years, had an FEV1 of at least 30% and less than 80% of predicted normal value, and a ratio of FEV1/FVC of less than 0.7; 59% were male, and 93% were Caucasian.

These clinical trials evaluated Aclidinium bromide 400 mcg twice daily (636 patients) and placebo (640 patients). Aclidinium bromide 400 mcg resulted in statistically significantly greater [[bronchodilation]] as measured by change from baseline in morning pre-dose [[FEV1]] at 12 weeks (the primary efficacy endpoint) compared to placebo in all three trials.

[[File:Aclidinium bromide inhalant 3.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

Serial spirometric evaluations were performed throughout daytime hours in a subset of patients in the three trials. The serial FEV1 values over 12 hours for one of the 3-month trials (Trial B) are displayed. Results for the other two placebo-controlled trials were similar to the results for Trial B. Improvement of lung function was maintained for 12 hours after a single dose and was consistent over the 3- or 6-month treatment period.

[[File:Aclidinium bromide inhalant 4.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]
Mean peak improvements in FEV1, for Aclidinium bromide relative to baseline were assessed in all patients in trials B, C and D after the first dose on day 1 and were similar at week 12. In Trials B and D but not in Trial C, patients treated with Aclidinium bromide used less daily rescue [[albuterol]] during the trial compared to patients treated with placebo.
|howSupplied=Aclidinium bromide inhalation powder 400 mcg is supplied in a sealed labeled aluminum pouch and is available in 60 metered doses and 30 metered doses.

The active ingredient is administered using a multi-dose dry powder inhaler, PRESSAIR®, which delivers 60 doses or 30 doses of aclidinium bromide powder for oral inhalation. The PRESSAIR inhaler is a white and green colored device and is comprised of an assembled plastic dosing mechanism with a dose indicator, a drug-product storage unit containing the drug-product formulation, and a mouthpiece covered by a green protective cap. The inhaler should be discarded when the marking “0” with a red background shows in the middle of the dose indicator or when the device locks out, whichever comes first.
|storage=Store Aclidinium bromide in a dry place at 25 C (77 F); excursions permitted to 15-30 C (59-86 F)[see USP Controlled Room Temperature].

The PRESSAIR inhaler should be stored inside the sealed pouch and only be opened immediately before use.

Discard the PRESSAIR inhaler 45 days after opening the pouch, after the marking “0” with a red background shows in the middle of the dose indicator, or when the device locks out, whichever comes first.

Keep out of reach of children.
|packLabel=[[File:Aclidinium bromide inhalant 5.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

[[File:Aclidinium bromide inhalant 6.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|fdaPatientInfo======Instructions for Administering Aclidinium bromide=====
It is important for patients to understand how to correctly use Aclidinium bromide. Inform patients that if they miss a dose, they should take their next dose at the usual time; they should not take 2 doses at one time.

=====Acute Bronchospasm=====
Instruct patients that Aclidinium bromide is a twice daily maintenance [[bronchodilator]] and should not be used for immediate relief of breathing problems (i.e., as a rescue medication).

=====Paradoxical Bronchospasm=====
Inform patients that Aclidinium bromide can cause paradoxical [[bronchospasm]]. Advise patients that if paradoxical bronchospasm occurs, patients should discontinue Aclidinium bromide.

=====Visual Effects=====
Eye pain or discomfort, [[blurred vision]], visual halos or colored images in association with red eyes from conjunctival congestion and [[corneal edema]] may be signs of [[acute narrow-angle glaucoma]]. Inform patients to consult a physician immediately should any of these signs and symptoms develop. Advise patients that miotic eyedrops alone are not considered to be effective treatment.
*Inform patients that care must be taken not to allow the powder to enter into the eyes as this may cause blurring of vision and pupil dilation.

=====Urinary Retention=====
Difficulty passing urine and [[dysuria]] may be symptoms of new or worsening [[Benign prostatic hyperplasia|prostatic hyperplasia]] or bladder outlet obstruction. Patients should be instructed to consult a physician immediately should any of these signs or symptoms develop.
|alcohol=Alcohol-Aclidinium interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=*Aclidinium bromide
}}

Aclidinium

2015-03-12T15:51:08Z

Sree Teja Yelamanchili:

{{DrugProjectFormSinglePage
|authorTag={{STY}}
|genericName=Aclidinium bromide
|aOrAn=an
|drugClass=[[antimuscarinic]] and [[bronchodilator]]
|indicationType=treatment
|indication=long-term maintenance treatment of [[bronchospasm]] associated with [[chronic obstructive pulmonary disease]] ([[COPD]]), including [[chronic bronchitis]] and [[emphysema]].
|adverseReactions=[[headache]], [[cough]], and [[nasopharyngitis]].
|blackBoxWarningTitle=<b><span style="color:#FF0000;">TITLE</span></b>
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)
|fdaLIADAdult=*The recommended dose of Aclidinium bromide is one oral inhalation of 400 mcg, twice daily.

*Inhalation Powder- Aclidinium bromide is a breath-actuated multi-dose dry powder inhaler metering 400 mcg of aclidinium bromide per actuation.
|offLabelAdultGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Aclidinium in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Aclidinium in adult patients.
|offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Aclidinium in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Aclidinium in pediatric patients.
|contraindications=None.
|warnings=====Not for Acute Use====
Aclidinium bromide is intended as a twice-daily maintenance treatment for [[COPD]] and is not indicated for the initial treatment of acute episodes of [[bronchospasm]] (i.e., rescue therapy).

====Paradoxical Bronchospasm====
Inhaled medicines, including Aclidinium bromide, may cause paradoxical [[bronchospasm]]. If this occurs, treatment with Aclidinium bromide should be stopped and other treatments considered.

====Worsening of Narrow-Angle Glaucoma====
Aclidinium bromide should be used with caution in patients with [[narrow-angle glaucoma]]. Prescribers and patients should be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., [[eye pain]] or discomfort, [[blurred vision]], visual halos or colored images in association with red eyes from conjunctival congestion and [[corneal edema]]). Instruct patients to consult a physician immediately should any of these signs or symptoms develop.

====Worsening of Urinary Retention====
Aclidinium bromide should be used with caution in patients with urinary retention. Prescribers and patients should be alert for signs and symptoms of [[Benign prostatic hyperplasia|prostatic hyperplasia]] or bladder-neck obstruction (e.g., difficulty passing urine, painful urination). Instruct patients to consult a physician immediately should any of these signs or symptoms develop.

====Immediate Hypersensitivity Reactions====
Immediate [[hypersensitivity]] reactions may occur after administration of Aclidinium bromide. If such a reaction occurs, therapy with Aclidinium bromide should be stopped at once and alternative treatments should be considered. Given the similar structural formula of [[atropine]] to aclidinium, patients with a history of hypersensitivity reactions to atropine should be closely monitored for similar [[hypersensitivity]] reactions to Aclidinium bromide. In addition, Aclidinium bromide should be used with caution in patients with severe hypersensitivity to milk proteins.
|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

====3-Month and 6-Month Trials====

*Aclidinium bromide was studied in two 3-month (Trials B and C) and one 6-month (Trial D) placebo-controlled trials in patients with COPD. In these trials, 636 patients were treated with Aclidinium bromide at the recommended dose of 400 mcg twice daily.

*The population had a mean age of 64 years (ranging from 40 to 89 years), with 58% males, 94% Caucasian, and had COPD with a mean pre-bronchodilator forced expiratory volume in one second (FEV1) percent predicted of 48%. Patients with unstable [[cardiac disease]], [[Acute angle-closure glaucoma|narrow-angle glaucoma]], or symptomatic [[prostatic hypertrophy]] or bladder outlet obstruction were excluded from these trials.

TABLE 1 shows all adverse reactions that occurred with a frequency of greater than or equal to 1% in the Aclidinium bromide group in the two 3-month and one 6-month placebo-controlled trials where the rates in the Aclidinium bromide group exceeded placebo.

[[File:Aclidinium bromide inhalant 1.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

In addition, among the adverse reactions observed in the clinical trials with an incidence of less than 1% were [[diabetes mellitus]], [[dry mouth]], [[1st degree AV block]], [[osteoarthritis]], [[cardiac failure]], and [[cardio-respiratory arrest]].

====Long-term Safety Trials====

Aclidinium bromide was studied in three long term safety trials, two double blind and one open label, ranging from 40 to 52 weeks in patients with moderate to severe [[COPD]]. Two of these trials were extensions of the 3-month trials, and one was a dedicated long term safety trial. In these trials, 891 patients were treated with Aclidinium bromide at the recommended dose of 400 mcg twice daily. The demographic and baseline characteristics of the long term safety trials were similar to those of the placebo-controlled trials. The adverse events reported in the long term safety trials were similar to those occurring in the placebo-controlled trials of 3 to 6 months. No new safety findings were reported compared to the placebo controlled trials.
|drugInteractions=In vitro studies suggest limited potential for [[CYP450]]-related metabolic drug interactions, thus no formal drug interaction studies have been performed with Aclidinium bromide.

====Sympathomimetics, Methylxanthines, Steroids====
In clinical studies, concurrent administration of aclidinium bromide and other drugs commonly used in the treatment of [[COPD]] including [[Sympathomimetic agents|sympathomimetics]] (short-acting [[Beta-agonists|beta2 agonists]]), [[methylxanthines]], and oral and inhaled [[steroids]] showed no increases in adverse drug reactions.

====Anticholinergics====
There is a potential for an additive interaction with concomitantly used [[anticholinergic]] medications. Therefore, avoid coadministration of Aclidinium bromide with other [[Anticholinergics|anticholinergic-containing drugs]] as this may lead to an increase in [[anticholinergic]] effects.
|useInPregnancyFDA=<u>Teratogenic effects</u>

====Pregnancy Category C====
There are no adequate and well controlled studies in pregnant women. Adverse development effects were observed in rats and rabbits exposed to aclidinium bromide. Aclidinium bromide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Effects of aclidinium bromide on embryo-fetal development were examined in rats and rabbits. No evidence of structural alterations was observed in rats exposed during the period of [[organogenesis]] at approximately 15 times the recommended human daily dose (RHDD) [based on summed AUCs of aclidinium bromide and its metabolites at inhaled doses less than or equal to 5.0 mg/kg/day]. However, decreased pup weights were observed from dams exposed during the lactation period at approximately 5 times the RHDD [based on summed AUCs of aclidinium bromide and its metabolites at inhaled doses greater than or equal to 0.2 mg/kg/day]. Maternal toxicity was also observed at inhaled doses greater than or equal to 0.2 mg/kg/day.

No evidence of structural alterations was observed in Himalayan rabbits exposed during the period of organogenesis at approximately 20 times the RHDD [based on summed AUCs of aclidinium bromide and its metabolites at inhaled doses less than or equal to 3.6 mg/kg/day]. However, increased incidences of additional liver lobes (3-5%), as compared to 0% in the control group, were observed at approximately 1,400 times the RHDD [based on summed AUCs of aclidinium bromide and its metabolites at oral doses greater than or equal to 150 mg/kg/day], and decreased fetal body weights were observed at approximately 2,300 times the RHDD [based on summed AUCs of aclidinium bromide and its metabolites at oral doses greater than or equal to 300 mg/kg/day]. These fetal findings were observed in the presence of maternal toxicity.
|useInLaborDelivery=*The effect of Aclidinium bromide on labor and delivery is unknown.
*Aclidinium bromide should be used during labor and delivery only if the potential benefit to the patient justifies the potential risk to the fetus.
|useInNursing=*Aclidinium bromide is excreted into the milk of lactating female rats, and decreased pup weights were observed.
*Excretion of aclidinium into human milk is probable.
*There are no human studies that have investigated the effects of Aclidinium bromide on breast-fed infants.
*Caution should be exercised when Aclidinium bromide is administered to nursing women.
|useInPed=*Aclidinium bromide is approved for use in the maintenance treatment of bronchospasm associated with [[COPD]].
*COPD does not normally occur in children.
*The safety and effectiveness of Aclidinium bromide in pediatric patients have not been established.
|useInGeri=*Of the 636 COPD patients exposed to Aclidinium bromide 400 mcg twice daily for up to 24 weeks in three placebo-controlled clinical trials, 197 were less than 60 years, 272 were greater than or equal to 60 to less than 70 years, and 167 were greater than or equal to 70 years of age.
*No overall differences in safety or effectiveness were observed between these subjects and younger subjects.
*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.
*Based on available data for Aclidinium bromide, no adjustment of dosage in geriatric patients is warranted.
|useInRenalImpair=*The pharmacokinetics of Aclidinium bromide were investigated in subjects with normal renal function and in subjects with mild, moderate and severe [[renal impairment]].
*No clinically significant differences in aclidinium pharmacokinetics were noted between these populations.
*Based on available data for Aclidinium bromide, no adjustment of dosage in renally impaired subjects is warranted.
|useInHepaticImpair=The effects of hepatic impairment on the pharmacokinetics of Aclidinium bromide were not studied.
|drugBox={{distinguish|Acridinium bromide|Clidinium bromide}}
{{Drugbox
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 477240902
| IUPAC_name = [(8''R'')-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octan-8-yl] 2-hydroxy-2,2-dithiophen-2-ylacetate bromide
| image = [[File:320px-Aclidinium bromide.png|thumb|none|400px|This image is provided by the National Library of Medicine.]]
| width = 320


| tradename = Bretaris Genuair, Eklira Genuair, Tudorza Pressair
| pregnancy_category =
| pregnancy_US = C
| legal_status =
| legal_US = Rx-only
| routes_of_administration = [[Inhalational]]
| licence_US = Aclidinium


| bioavailability =
| metabolism =
| elimination_half-life =
| excretion =


| CAS_number_Ref = {{cascite|changed|??}}
| CAS_number = 320345-99-1
| ATC_prefix = R03
| ATC_suffix = BB05
| ATC_supplemental =
| PubChem = 11519741
| ChEBI_Ref = {{ebicite|changed|EBI}}
| ChEBI = 65344
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = 9694529
| UNII_Ref = {{fdacite|changed|FDA}}
| UNII = UQW7UF9N91
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D08837
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 551466


| C=26 | H=30 | Br=1 | N=1 | O=4 | S=2
| molecular_weight = 564.555 g/mol
| smiles = [Br-].O=C(O[C@@H]3C2CC[N+](CCCOc1ccccc1)(CC2)C3)C(O)c4sccc4)c5sccc5
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
| StdInChI = 1S/C26H30NO4S2.BrH/c28-25(26(29,23-9-4-17-32-23)24-10-5-18-33-24)31-22-19-27(14-11-20(22)12-15-27)13-6-16-30-21-7-2-1-3-8-21;/h1-5,7-10,17-18,20,22,29H,6,11-16,19H2;1H/q+1;/p-1/t20?,22-,27?;/m0./s1
| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
| StdInChIKey = XLAKJQPTOJHYDR-QTQXQZBYSA-M
}}

|mechAction=*Aclidinium bromide is a long-acting [[antimuscarinic|antimuscarinic agent]], which is often referred to as an [[anticholinergic]].
*It has similar affinity to the subtypes of [[muscarinic receptors]] M1 to M5.
*In the airways, it exhibits pharmacological effects through inhibition of M3 receptor at the smooth muscle leading to [[bronchodilation]].
*The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations.
*In preclinical in vitro as well as in vivo studies, prevention of [[acetylcholine]]-induced [[bronchoconstriction]] effects was dose-dependent and lasted longer than 24 hours.
*The clinical relevance of these findings is unknown.
*The [[bronchodilation]] following inhalation of aclidinium bromide is predominantly a site-specific effect.
|structure=Aclidinium bromide consists of a dry powder formulation of aclidinium bromide for oral inhalation only.

Aclidinium bromide, the active component of TUDORZA PRESSAIR is an anticholinergic with specificity for muscarinic receptors. Aclidinium bromide is a synthetic, quaternary ammonium compound, chemically described as 1-Azoniabicyclo[2.2.2]octane, 3-[(hydroxydi-2-thienylacetyl)oxy]-1-(3-phenoxypropyl)-, bromide, (3R)-. The structural formula is:
[[File:Aclidinium bromide inhalant 7.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

Aclidinium bromide is a white powder with a molecular formula of C26H30NO4S2Br and a molecular mass of 564.56. It is very slightly soluble in water and ethanol and sparingly soluble in methanol.

Aclidinium bromide is a breath-actuated multi-dose dry powder inhaler. Each actuation of Aclidinium bromide provides a metered dose of 13 mg of the formulation which contains lactose monohydrate (which may contain milk proteins) as the carrier and 400 mcg of aclidinium bromide. This results in delivery of 375 mcg aclidinium bromide from the mouthpiece, based onin vitro testing at an average flow rate of 63 L/min with constant volume of 2 L. The amount of drug delivered to the lungs will vary depending on patient factors such as inspiratory flow rate and inspiratory time. The PRESSAIR inhaler delivers the target dose at flow rates as low as 35 L/min. Based on a study in adult patients with moderate (N=24) and severe (N=24) COPD the mean peak inspiratory flow (PIF) was 95.3 L/min (range: 54.6 to 129.4 L/min) and 88.7 L/min (range: 72.0 to 106.4 L/min) respectively.
|PD=====Cardiovascular Effects====

*In a thorough QT Study, 200 mcg and 800 mcg Aclidinium bromide was administered to healthy volunteers once daily for 3 days; no effects on prolongation of [[QT interval]] were observed using QTcF heart-rate correction methods.
*Additionally, the effect of Aclidinium bromide on cardiac rhythm was assessed in 336 COPD patients, 164 patients received aclidinium bromide 400 mcg twice daily and 172 patients received placebo, using 24-hr [[Holter monitoring]].
*No clinically significant effects on cardiac rhythm were observed.
|PK=====Absorption====

*The absolute bioavailability of aclidinium bromide is approximately 6% in healthy volunteers.
*Following twice-daily oral inhalation administration of 400 mcg aclidinium bromide in healthy subjects, peak steady state plasma levels were observed within 10 minutes after inhalation.

====Distribution====

*Aclidinium bromide shows a volume of distribution of approximately 300 L following intravenous administration of 400 mcg in humans.

====Metabolism====

*Clinical pharmacokinetics studies, including a mass balance study, indicate that the major route of metabolism of aclidinium bromide is hydrolysis, which occurs both chemically and enzymatically by esterases.
*Aclidinium bromide is rapidly and extensively hydrolyzed to its alcohol and dithienylglycolic acid derivatives, neither of which binds to muscarinic receptors and are devoid of pharmacologic activity.
*Therefore, due to the low plasma levels achieved at the clinically relevant doses, aclidinium bromide and its metabolites are not expected to alter the disposition of drugs metabolized by the human CYP450 enzymes.

====Elimination====

*Total clearance was approximately 170 L/h after an intravenous dose of aclidinium bromide in young healthy volunteers with an inter-individual variability of 36%.
*Intravenously administered radiolabelled aclidinium bromide was administered to healthy volunteers and was extensively metabolized with 1% excreted as unchanged aclidinium.
*Approximately 54% to 65% of the radioactivity was excreted in urine and 20% to 33% of the dose was excreted in feces.
*The combined results indicated that almost the entire aclidinium bromide dose was eliminated by hydrolysis.
*After dry powder inhalation, urinary excretion of aclidinium is about 0.09% of the dose and the estimated effective half-life is 5 to 8 hours.

====Drug Interactions====

*Formal drug interaction studies were not performed.
*In vitro studies using human liver microsomes indicated that aclidinium bromide and its major metabolites do not inhibit CYP450, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5 or 4A9/11 at concentrations up to 1,000-fold higher than the maximum plasma concentration that would be expected to be achieved at the therapeutic dose.
*Therefore, it is unlikely that aclidinium bromide causes [[CYP450]] related drug interactions.

=====Specific Populations=====

=====Elderly Patients=====

The pharmacokinetic profile of aclidinium bromide and its main metabolites was assessed in 12 elderly COPD patients (aged 70 years or older) compared to a younger cohort of 12 COPD patients (40-59 years) that were administered 400 mcg aclidinium bromide once daily for 3 days via inhalation. No clinically significant differences in systemic exposure (AUC and Cmax) were observed when the two groups were compared. No dosage adjustment is necessary in elderly patients.

=====Renal Impairment=====

The impact of renal disease upon the pharmacokinetics of aclidinium bromide was studied in 18 subjects with mild, moderate, or severe [[renal impairment]]. Systemic exposure (AUC and Cmax) to aclidinium bromide and its main metabolites following single doses of 400 mcg aclidinium bromide was similar in renally impaired patients compared with 6 matched healthy control subjects. No dose adjustment is necessary in renally impaired patients.

=====Hepatic Impairment=====

The effects of [[hepatic impairment]] on the pharmacokinetics of aclidinium bromide were not studied. However, hepatic insufficiency is not expected to have relevant influence on aclidinium bromide pharmacokinetics, since it is predominantly metabolized by chemical and enzymatic hydrolysis to products that do not bind to muscarinic receptors.
|nonClinToxic=====Carcinogenesis, Mutagenesis, Impairment of Fertility====
*Two-year inhalation studies were conducted in mice and rats to assess the carcinogenic potential of aclidinium bromide.
*No evidence of tumorigenicity was observed in rats and mice at aclidinium doses up to 0.20 and 2.4 mg/kg/day, respectively [approximately 10 and 80 times the Recommended Human Daily Dose (RHDD), respectively, based on summed AUCs of aclidinium bromide and its metabolites].

*Aclidinium bromide was positive in the in vitro bacterial gene mutation assay and the in vitro thymidine locus mouse lymphoma assay. However, aclidinium bromide was negative in the in vivo mouse micronucleus assay and the in vivo/in vitro unscheduled DNA synthesis assay with rat liver.

*Aclidinium bromide impaired several fertility and reproductive performance indices (increased number of days to mate, decreased conception rate, decreased number of corpora lutea, increased pre-implantation loss with consequent decreased number of implantations and live embryos) in both male and female rats administered inhaled doses greater than or equal to 0.8 mg/kg/day [approximately 15 times the RHDD based on summed AUCs of aclidinium bromide and its metabolites].
|clinicalStudies=====Chronic Obstructive Pulmonary Disease (COPD)=====
The Aclidinium bromide clinical development program included a dose-ranging trial (Trial A) for nominal dose selection and three confirmatory trials (Trials B, C, and D).

====Dose-ranging trial====

Trial A was a randomized, double-blind, placebo-controlled, active-controlled, crossover trial with 7-day treatment periods separated by 5-day washout periods. Trial A enrolled 79 patients who had a clinical diagnosis of [[COPD]], were 40 years of age or older, had a history of smoking at least 10 pack-years, had a [[forced expiratory volume]] in one second ([[FEV1]]) of at least 30% and less than 80% of predicted normal value, and a ratio of FEV1 over forced [[vital capacity]] (FEV1/FVC) of less than 0.7. Trial A included Aclidinium bromide doses of 400 mcg, 200 mcg and 100 mcg twice daily, formoterol active control, and placebo. Trial A demonstrated that the effect on trough [[FEV1]] and serial FEV1 in patients treated with the Aclidinium bromide 100 mcg twice daily and 200 mcg twice daily doses was lower compared to patients treated with the Aclidinium bromide 400 mcg twice daily dose.
[[File:Aclidinium bromide inhalant 2.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

=====Confirmatory trials=====

Trials B, C, and D were three randomized, double-blind, placebo-controlled trials in patients with [[COPD]]. Trials B and C were 3 months in duration, and Trial D was 6 months in duration. These trials enrolled 1,276 patients who had a clinical diagnosis of COPD, were 40 years of age or older, had a history of smoking at least 10 pack-years, had an FEV1 of at least 30% and less than 80% of predicted normal value, and a ratio of FEV1/FVC of less than 0.7; 59% were male, and 93% were Caucasian.

These clinical trials evaluated Aclidinium bromide 400 mcg twice daily (636 patients) and placebo (640 patients). Aclidinium bromide 400 mcg resulted in statistically significantly greater [[bronchodilation]] as measured by change from baseline in morning pre-dose [[FEV1]] at 12 weeks (the primary efficacy endpoint) compared to placebo in all three trials.

[[File:Aclidinium bromide inhalant 3.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

Serial spirometric evaluations were performed throughout daytime hours in a subset of patients in the three trials. The serial FEV1 values over 12 hours for one of the 3-month trials (Trial B) are displayed. Results for the other two placebo-controlled trials were similar to the results for Trial B. Improvement of lung function was maintained for 12 hours after a single dose and was consistent over the 3- or 6-month treatment period.

[[File:Aclidinium bromide inhalant 4.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]
Mean peak improvements in FEV1, for Aclidinium bromide relative to baseline were assessed in all patients in trials B, C and D after the first dose on day 1 and were similar at week 12. In Trials B and D but not in Trial C, patients treated with Aclidinium bromide used less daily rescue [[albuterol]] during the trial compared to patients treated with placebo.
|howSupplied=Aclidinium bromide inhalation powder 400 mcg is supplied in a sealed labeled aluminum pouch and is available in 60 metered doses and 30 metered doses.

The active ingredient is administered using a multi-dose dry powder inhaler, PRESSAIR®, which delivers 60 doses or 30 doses of aclidinium bromide powder for oral inhalation. The PRESSAIR inhaler is a white and green colored device and is comprised of an assembled plastic dosing mechanism with a dose indicator, a drug-product storage unit containing the drug-product formulation, and a mouthpiece covered by a green protective cap. The inhaler should be discarded when the marking “0” with a red background shows in the middle of the dose indicator or when the device locks out, whichever comes first.
|storage=Store Aclidinium bromide in a dry place at 25 C (77 F); excursions permitted to 15-30 C (59-86 F)[see USP Controlled Room Temperature].

The PRESSAIR inhaler should be stored inside the sealed pouch and only be opened immediately before use.

Discard the PRESSAIR inhaler 45 days after opening the pouch, after the marking “0” with a red background shows in the middle of the dose indicator, or when the device locks out, whichever comes first.

Keep out of reach of children.
|packLabel=[[File:Aclidinium bromide inhalant 5.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

[[File:Aclidinium bromide inhalant 6.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|fdaPatientInfo======Instructions for Administering Aclidinium bromide=====
It is important for patients to understand how to correctly use Aclidinium bromide. Inform patients that if they miss a dose, they should take their next dose at the usual time; they should not take 2 doses at one time.

=====Acute Bronchospasm=====
Instruct patients that Aclidinium bromide is a twice daily maintenance [[bronchodilator]] and should not be used for immediate relief of breathing problems (i.e., as a rescue medication).

=====Paradoxical Bronchospasm=====
Inform patients that Aclidinium bromide can cause paradoxical [[bronchospasm]]. Advise patients that if paradoxical bronchospasm occurs, patients should discontinue Aclidinium bromide.

=====Visual Effects=====
Eye pain or discomfort, [[blurred vision]], visual halos or colored images in association with red eyes from conjunctival congestion and [[corneal edema]] may be signs of [[acute narrow-angle glaucoma]]. Inform patients to consult a physician immediately should any of these signs and symptoms develop. Advise patients that miotic eyedrops alone are not considered to be effective treatment.
*Inform patients that care must be taken not to allow the powder to enter into the eyes as this may cause blurring of vision and pupil dilation.

=====Urinary Retention=====
Difficulty passing urine and [[dysuria]] may be symptoms of new or worsening [[Benign prostatic hyperplasia|prostatic hyperplasia]] or bladder outlet obstruction. Patients should be instructed to consult a physician immediately should any of these signs or symptoms develop.
|alcohol=Alcohol-Aclidinium interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=*Aclidinium bromide
}}

File:320px-Aclidinium bromide.png

2015-03-12T15:50:36Z

Sree Teja Yelamanchili:

File:Aclidinium bromide inhalant 7.jpg

2015-03-12T15:44:50Z

Sree Teja Yelamanchili:

Aclidinium

2015-03-12T15:37:24Z

Sree Teja Yelamanchili:

{{DrugProjectFormSinglePage
|authorTag={{STY}}
|genericName=Aclidinium bromide
|aOrAn=an
|drugClass=[[antimuscarinic]] and [[bronchodilator]]
|indicationType=treatment
|indication=long-term maintenance treatment of [[bronchospasm]] associated with [[chronic obstructive pulmonary disease]] ([[COPD]]), including [[chronic bronchitis]] and [[emphysema]].
|adverseReactions=[[headache]], [[cough]], and [[nasopharyngitis]].
|blackBoxWarningTitle=<b><span style="color:#FF0000;">TITLE</span></b>
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)
|fdaLIADAdult=*The recommended dose of Aclidinium bromide is one oral inhalation of 400 mcg, twice daily.

*Inhalation Powder- Aclidinium bromide is a breath-actuated multi-dose dry powder inhaler metering 400 mcg of aclidinium bromide per actuation.
|offLabelAdultGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Aclidinium in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Aclidinium in adult patients.
|offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Aclidinium in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Aclidinium in pediatric patients.
|contraindications=None.
|warnings=====Not for Acute Use====
Aclidinium bromide is intended as a twice-daily maintenance treatment for [[COPD]] and is not indicated for the initial treatment of acute episodes of [[bronchospasm]] (i.e., rescue therapy).

====Paradoxical Bronchospasm====
Inhaled medicines, including Aclidinium bromide, may cause paradoxical [[bronchospasm]]. If this occurs, treatment with Aclidinium bromide should be stopped and other treatments considered.

====Worsening of Narrow-Angle Glaucoma====
Aclidinium bromide should be used with caution in patients with [[narrow-angle glaucoma]]. Prescribers and patients should be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., [[eye pain]] or discomfort, [[blurred vision]], visual halos or colored images in association with red eyes from conjunctival congestion and [[corneal edema]]). Instruct patients to consult a physician immediately should any of these signs or symptoms develop.

====Worsening of Urinary Retention====
Aclidinium bromide should be used with caution in patients with urinary retention. Prescribers and patients should be alert for signs and symptoms of [[Benign prostatic hyperplasia|prostatic hyperplasia]] or bladder-neck obstruction (e.g., difficulty passing urine, painful urination). Instruct patients to consult a physician immediately should any of these signs or symptoms develop.

====Immediate Hypersensitivity Reactions====
Immediate [[hypersensitivity]] reactions may occur after administration of Aclidinium bromide. If such a reaction occurs, therapy with Aclidinium bromide should be stopped at once and alternative treatments should be considered. Given the similar structural formula of [[atropine]] to aclidinium, patients with a history of hypersensitivity reactions to atropine should be closely monitored for similar [[hypersensitivity]] reactions to Aclidinium bromide. In addition, Aclidinium bromide should be used with caution in patients with severe hypersensitivity to milk proteins.
|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

====3-Month and 6-Month Trials====

*Aclidinium bromide was studied in two 3-month (Trials B and C) and one 6-month (Trial D) placebo-controlled trials in patients with COPD. In these trials, 636 patients were treated with Aclidinium bromide at the recommended dose of 400 mcg twice daily.

*The population had a mean age of 64 years (ranging from 40 to 89 years), with 58% males, 94% Caucasian, and had COPD with a mean pre-bronchodilator forced expiratory volume in one second (FEV1) percent predicted of 48%. Patients with unstable [[cardiac disease]], [[Acute angle-closure glaucoma|narrow-angle glaucoma]], or symptomatic [[prostatic hypertrophy]] or bladder outlet obstruction were excluded from these trials.

TABLE 1 shows all adverse reactions that occurred with a frequency of greater than or equal to 1% in the Aclidinium bromide group in the two 3-month and one 6-month placebo-controlled trials where the rates in the Aclidinium bromide group exceeded placebo.

[[File:Aclidinium bromide inhalant 1.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

In addition, among the adverse reactions observed in the clinical trials with an incidence of less than 1% were [[diabetes mellitus]], [[dry mouth]], [[1st degree AV block]], [[osteoarthritis]], [[cardiac failure]], and [[cardio-respiratory arrest]].

====Long-term Safety Trials====

Aclidinium bromide was studied in three long term safety trials, two double blind and one open label, ranging from 40 to 52 weeks in patients with moderate to severe [[COPD]]. Two of these trials were extensions of the 3-month trials, and one was a dedicated long term safety trial. In these trials, 891 patients were treated with Aclidinium bromide at the recommended dose of 400 mcg twice daily. The demographic and baseline characteristics of the long term safety trials were similar to those of the placebo-controlled trials. The adverse events reported in the long term safety trials were similar to those occurring in the placebo-controlled trials of 3 to 6 months. No new safety findings were reported compared to the placebo controlled trials.
|drugInteractions=In vitro studies suggest limited potential for [[CYP450]]-related metabolic drug interactions, thus no formal drug interaction studies have been performed with Aclidinium bromide.

====Sympathomimetics, Methylxanthines, Steroids====
In clinical studies, concurrent administration of aclidinium bromide and other drugs commonly used in the treatment of [[COPD]] including [[Sympathomimetic agents|sympathomimetics]] (short-acting [[Beta-agonists|beta2 agonists]]), [[methylxanthines]], and oral and inhaled [[steroids]] showed no increases in adverse drug reactions.

====Anticholinergics====
There is a potential for an additive interaction with concomitantly used [[anticholinergic]] medications. Therefore, avoid coadministration of Aclidinium bromide with other [[Anticholinergics|anticholinergic-containing drugs]] as this may lead to an increase in [[anticholinergic]] effects.
|useInPregnancyFDA=<u>Teratogenic effects</u>

====Pregnancy Category C====
There are no adequate and well controlled studies in pregnant women. Adverse development effects were observed in rats and rabbits exposed to aclidinium bromide. Aclidinium bromide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Effects of aclidinium bromide on embryo-fetal development were examined in rats and rabbits. No evidence of structural alterations was observed in rats exposed during the period of [[organogenesis]] at approximately 15 times the recommended human daily dose (RHDD) [based on summed AUCs of aclidinium bromide and its metabolites at inhaled doses less than or equal to 5.0 mg/kg/day]. However, decreased pup weights were observed from dams exposed during the lactation period at approximately 5 times the RHDD [based on summed AUCs of aclidinium bromide and its metabolites at inhaled doses greater than or equal to 0.2 mg/kg/day]. Maternal toxicity was also observed at inhaled doses greater than or equal to 0.2 mg/kg/day.

No evidence of structural alterations was observed in Himalayan rabbits exposed during the period of organogenesis at approximately 20 times the RHDD [based on summed AUCs of aclidinium bromide and its metabolites at inhaled doses less than or equal to 3.6 mg/kg/day]. However, increased incidences of additional liver lobes (3-5%), as compared to 0% in the control group, were observed at approximately 1,400 times the RHDD [based on summed AUCs of aclidinium bromide and its metabolites at oral doses greater than or equal to 150 mg/kg/day], and decreased fetal body weights were observed at approximately 2,300 times the RHDD [based on summed AUCs of aclidinium bromide and its metabolites at oral doses greater than or equal to 300 mg/kg/day]. These fetal findings were observed in the presence of maternal toxicity.
|useInLaborDelivery=*The effect of Aclidinium bromide on labor and delivery is unknown.
*Aclidinium bromide should be used during labor and delivery only if the potential benefit to the patient justifies the potential risk to the fetus.
|useInNursing=*Aclidinium bromide is excreted into the milk of lactating female rats, and decreased pup weights were observed.
*Excretion of aclidinium into human milk is probable.
*There are no human studies that have investigated the effects of Aclidinium bromide on breast-fed infants.
*Caution should be exercised when Aclidinium bromide is administered to nursing women.
|useInPed=*Aclidinium bromide is approved for use in the maintenance treatment of bronchospasm associated with [[COPD]].
*COPD does not normally occur in children.
*The safety and effectiveness of Aclidinium bromide in pediatric patients have not been established.
|useInGeri=*Of the 636 COPD patients exposed to Aclidinium bromide 400 mcg twice daily for up to 24 weeks in three placebo-controlled clinical trials, 197 were less than 60 years, 272 were greater than or equal to 60 to less than 70 years, and 167 were greater than or equal to 70 years of age.
*No overall differences in safety or effectiveness were observed between these subjects and younger subjects.
*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.
*Based on available data for Aclidinium bromide, no adjustment of dosage in geriatric patients is warranted.
|useInRenalImpair=*The pharmacokinetics of Aclidinium bromide were investigated in subjects with normal renal function and in subjects with mild, moderate and severe [[renal impairment]].
*No clinically significant differences in aclidinium pharmacokinetics were noted between these populations.
*Based on available data for Aclidinium bromide, no adjustment of dosage in renally impaired subjects is warranted.
|useInHepaticImpair=The effects of hepatic impairment on the pharmacokinetics of Aclidinium bromide were not studied.
|mechAction=*Aclidinium bromide is a long-acting [[antimuscarinic|antimuscarinic agent]], which is often referred to as an [[anticholinergic]].
*It has similar affinity to the subtypes of [[muscarinic receptors]] M1 to M5.
*In the airways, it exhibits pharmacological effects through inhibition of M3 receptor at the smooth muscle leading to [[bronchodilation]].
*The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations.
*In preclinical in vitro as well as in vivo studies, prevention of [[acetylcholine]]-induced [[bronchoconstriction]] effects was dose-dependent and lasted longer than 24 hours.
*The clinical relevance of these findings is unknown.
*The [[bronchodilation]] following inhalation of aclidinium bromide is predominantly a site-specific effect.
|PD=====Cardiovascular Effects====

*In a thorough QT Study, 200 mcg and 800 mcg Aclidinium bromide was administered to healthy volunteers once daily for 3 days; no effects on prolongation of [[QT interval]] were observed using QTcF heart-rate correction methods.
*Additionally, the effect of Aclidinium bromide on cardiac rhythm was assessed in 336 COPD patients, 164 patients received aclidinium bromide 400 mcg twice daily and 172 patients received placebo, using 24-hr [[Holter monitoring]].
*No clinically significant effects on cardiac rhythm were observed.
|PK=====Absorption====

*The absolute bioavailability of aclidinium bromide is approximately 6% in healthy volunteers.
*Following twice-daily oral inhalation administration of 400 mcg aclidinium bromide in healthy subjects, peak steady state plasma levels were observed within 10 minutes after inhalation.

====Distribution====

*Aclidinium bromide shows a volume of distribution of approximately 300 L following intravenous administration of 400 mcg in humans.

====Metabolism====

*Clinical pharmacokinetics studies, including a mass balance study, indicate that the major route of metabolism of aclidinium bromide is hydrolysis, which occurs both chemically and enzymatically by esterases.
*Aclidinium bromide is rapidly and extensively hydrolyzed to its alcohol and dithienylglycolic acid derivatives, neither of which binds to muscarinic receptors and are devoid of pharmacologic activity.
*Therefore, due to the low plasma levels achieved at the clinically relevant doses, aclidinium bromide and its metabolites are not expected to alter the disposition of drugs metabolized by the human CYP450 enzymes.

====Elimination====

*Total clearance was approximately 170 L/h after an intravenous dose of aclidinium bromide in young healthy volunteers with an inter-individual variability of 36%.
*Intravenously administered radiolabelled aclidinium bromide was administered to healthy volunteers and was extensively metabolized with 1% excreted as unchanged aclidinium.
*Approximately 54% to 65% of the radioactivity was excreted in urine and 20% to 33% of the dose was excreted in feces.
*The combined results indicated that almost the entire aclidinium bromide dose was eliminated by hydrolysis.
*After dry powder inhalation, urinary excretion of aclidinium is about 0.09% of the dose and the estimated effective half-life is 5 to 8 hours.

====Drug Interactions====

*Formal drug interaction studies were not performed.
*In vitro studies using human liver microsomes indicated that aclidinium bromide and its major metabolites do not inhibit CYP450, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5 or 4A9/11 at concentrations up to 1,000-fold higher than the maximum plasma concentration that would be expected to be achieved at the therapeutic dose.
*Therefore, it is unlikely that aclidinium bromide causes [[CYP450]] related drug interactions.

=====Specific Populations=====

=====Elderly Patients=====

The pharmacokinetic profile of aclidinium bromide and its main metabolites was assessed in 12 elderly COPD patients (aged 70 years or older) compared to a younger cohort of 12 COPD patients (40-59 years) that were administered 400 mcg aclidinium bromide once daily for 3 days via inhalation. No clinically significant differences in systemic exposure (AUC and Cmax) were observed when the two groups were compared. No dosage adjustment is necessary in elderly patients.

=====Renal Impairment=====

The impact of renal disease upon the pharmacokinetics of aclidinium bromide was studied in 18 subjects with mild, moderate, or severe [[renal impairment]]. Systemic exposure (AUC and Cmax) to aclidinium bromide and its main metabolites following single doses of 400 mcg aclidinium bromide was similar in renally impaired patients compared with 6 matched healthy control subjects. No dose adjustment is necessary in renally impaired patients.

=====Hepatic Impairment=====

The effects of [[hepatic impairment]] on the pharmacokinetics of aclidinium bromide were not studied. However, hepatic insufficiency is not expected to have relevant influence on aclidinium bromide pharmacokinetics, since it is predominantly metabolized by chemical and enzymatic hydrolysis to products that do not bind to muscarinic receptors.
|nonClinToxic=====Carcinogenesis, Mutagenesis, Impairment of Fertility====
*Two-year inhalation studies were conducted in mice and rats to assess the carcinogenic potential of aclidinium bromide.
*No evidence of tumorigenicity was observed in rats and mice at aclidinium doses up to 0.20 and 2.4 mg/kg/day, respectively [approximately 10 and 80 times the Recommended Human Daily Dose (RHDD), respectively, based on summed AUCs of aclidinium bromide and its metabolites].

*Aclidinium bromide was positive in the in vitro bacterial gene mutation assay and the in vitro thymidine locus mouse lymphoma assay. However, aclidinium bromide was negative in the in vivo mouse micronucleus assay and the in vivo/in vitro unscheduled DNA synthesis assay with rat liver.

*Aclidinium bromide impaired several fertility and reproductive performance indices (increased number of days to mate, decreased conception rate, decreased number of corpora lutea, increased pre-implantation loss with consequent decreased number of implantations and live embryos) in both male and female rats administered inhaled doses greater than or equal to 0.8 mg/kg/day [approximately 15 times the RHDD based on summed AUCs of aclidinium bromide and its metabolites].
|clinicalStudies=====Chronic Obstructive Pulmonary Disease (COPD)=====
The Aclidinium bromide clinical development program included a dose-ranging trial (Trial A) for nominal dose selection and three confirmatory trials (Trials B, C, and D).

====Dose-ranging trial====

Trial A was a randomized, double-blind, placebo-controlled, active-controlled, crossover trial with 7-day treatment periods separated by 5-day washout periods. Trial A enrolled 79 patients who had a clinical diagnosis of [[COPD]], were 40 years of age or older, had a history of smoking at least 10 pack-years, had a [[forced expiratory volume]] in one second ([[FEV1]]) of at least 30% and less than 80% of predicted normal value, and a ratio of FEV1 over forced [[vital capacity]] (FEV1/FVC) of less than 0.7. Trial A included Aclidinium bromide doses of 400 mcg, 200 mcg and 100 mcg twice daily, formoterol active control, and placebo. Trial A demonstrated that the effect on trough [[FEV1]] and serial FEV1 in patients treated with the Aclidinium bromide 100 mcg twice daily and 200 mcg twice daily doses was lower compared to patients treated with the Aclidinium bromide 400 mcg twice daily dose.
[[File:Aclidinium bromide inhalant 2.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

=====Confirmatory trials=====

Trials B, C, and D were three randomized, double-blind, placebo-controlled trials in patients with [[COPD]]. Trials B and C were 3 months in duration, and Trial D was 6 months in duration. These trials enrolled 1,276 patients who had a clinical diagnosis of COPD, were 40 years of age or older, had a history of smoking at least 10 pack-years, had an FEV1 of at least 30% and less than 80% of predicted normal value, and a ratio of FEV1/FVC of less than 0.7; 59% were male, and 93% were Caucasian.

These clinical trials evaluated Aclidinium bromide 400 mcg twice daily (636 patients) and placebo (640 patients). Aclidinium bromide 400 mcg resulted in statistically significantly greater [[bronchodilation]] as measured by change from baseline in morning pre-dose [[FEV1]] at 12 weeks (the primary efficacy endpoint) compared to placebo in all three trials.

[[File:Aclidinium bromide inhalant 3.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

Serial spirometric evaluations were performed throughout daytime hours in a subset of patients in the three trials. The serial FEV1 values over 12 hours for one of the 3-month trials (Trial B) are displayed. Results for the other two placebo-controlled trials were similar to the results for Trial B. Improvement of lung function was maintained for 12 hours after a single dose and was consistent over the 3- or 6-month treatment period.

[[File:Aclidinium bromide inhalant 4.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]
Mean peak improvements in FEV1, for Aclidinium bromide relative to baseline were assessed in all patients in trials B, C and D after the first dose on day 1 and were similar at week 12. In Trials B and D but not in Trial C, patients treated with Aclidinium bromide used less daily rescue [[albuterol]] during the trial compared to patients treated with placebo.
|howSupplied=Aclidinium bromide inhalation powder 400 mcg is supplied in a sealed labeled aluminum pouch and is available in 60 metered doses and 30 metered doses.

The active ingredient is administered using a multi-dose dry powder inhaler, PRESSAIR®, which delivers 60 doses or 30 doses of aclidinium bromide powder for oral inhalation. The PRESSAIR inhaler is a white and green colored device and is comprised of an assembled plastic dosing mechanism with a dose indicator, a drug-product storage unit containing the drug-product formulation, and a mouthpiece covered by a green protective cap. The inhaler should be discarded when the marking “0” with a red background shows in the middle of the dose indicator or when the device locks out, whichever comes first.
|storage=Store Aclidinium bromide in a dry place at 25 C (77 F); excursions permitted to 15-30 C (59-86 F)[see USP Controlled Room Temperature].

The PRESSAIR inhaler should be stored inside the sealed pouch and only be opened immediately before use.

Discard the PRESSAIR inhaler 45 days after opening the pouch, after the marking “0” with a red background shows in the middle of the dose indicator, or when the device locks out, whichever comes first.

Keep out of reach of children.
|packLabel=[[File:Aclidinium bromide inhalant 5.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

[[File:Aclidinium bromide inhalant 6.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|fdaPatientInfo======Instructions for Administering Aclidinium bromide=====
It is important for patients to understand how to correctly use Aclidinium bromide. Inform patients that if they miss a dose, they should take their next dose at the usual time; they should not take 2 doses at one time.

=====Acute Bronchospasm=====
Instruct patients that Aclidinium bromide is a twice daily maintenance [[bronchodilator]] and should not be used for immediate relief of breathing problems (i.e., as a rescue medication).

=====Paradoxical Bronchospasm=====
Inform patients that Aclidinium bromide can cause paradoxical [[bronchospasm]]. Advise patients that if paradoxical bronchospasm occurs, patients should discontinue Aclidinium bromide.

=====Visual Effects=====
Eye pain or discomfort, [[blurred vision]], visual halos or colored images in association with red eyes from conjunctival congestion and [[corneal edema]] may be signs of [[acute narrow-angle glaucoma]]. Inform patients to consult a physician immediately should any of these signs and symptoms develop. Advise patients that miotic eyedrops alone are not considered to be effective treatment.
*Inform patients that care must be taken not to allow the powder to enter into the eyes as this may cause blurring of vision and pupil dilation.

=====Urinary Retention=====
Difficulty passing urine and [[dysuria]] may be symptoms of new or worsening [[Benign prostatic hyperplasia|prostatic hyperplasia]] or bladder outlet obstruction. Patients should be instructed to consult a physician immediately should any of these signs or symptoms develop.
|alcohol=Alcohol-Aclidinium interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=*Aclidinium bromide
}}

Aclidinium

2015-03-12T15:27:50Z

Sree Teja Yelamanchili:

{{DrugProjectFormSinglePage
|authorTag={{STY}}
|genericName=Aclidinium bromide
|aOrAn=an
|drugClass=[[antimuscarinic]] and [[bronchodilator]]
|indicationType=treatment
|indication=long-term maintenance treatment of [[bronchospasm]] associated with [[chronic obstructive pulmonary disease]] ([[COPD]]), including [[chronic bronchitis]] and [[emphysema]].
|adverseReactions=[[headache]], [[cough]], and [[nasopharyngitis]].
|blackBoxWarningTitle=<b><span style="color:#FF0000;">TITLE</span></b>
|blackBoxWarningBody=<i><span style="color:#FF0000;">Condition Name:</span></i> (Content)
|fdaLIADAdult=*The recommended dose of TUDORZA PRESSAIR is one oral inhalation of 400 mcg, twice daily.

*Inhalation Powder- Aclidinium bromide is a breath-actuated multi-dose dry powder inhaler metering 400 mcg of aclidinium bromide per actuation.
|offLabelAdultGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Aclidinium in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Aclidinium in adult patients.
|offLabelPedGuideSupport=There is limited information regarding <i>Off-Label Guideline-Supported Use</i> of Aclidinium in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding <i>Off-Label Non–Guideline-Supported Use</i> of Aclidinium in pediatric patients.
|contraindications=None.
|warnings=====Not for Acute Use====
TUDORZA PRESSAIR is intended as a twice-daily maintenance treatment for [[COPD]] and is not indicated for the initial treatment of acute episodes of [[bronchospasm]] (i.e., rescue therapy).

====Paradoxical Bronchospasm====
Inhaled medicines, including TUDORZA PRESSAIR, may cause paradoxical [[bronchospasm]]. If this occurs, treatment with TUDORZA PRESSAIR should be stopped and other treatments considered.

====Worsening of Narrow-Angle Glaucoma====
TUDORZA PRESSAIR should be used with caution in patients with [[narrow-angle glaucoma]]. Prescribers and patients should be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., [[eye pain]] or discomfort, [[blurred vision]], visual halos or colored images in association with red eyes from conjunctival congestion and [[corneal edema]]). Instruct patients to consult a physician immediately should any of these signs or symptoms develop.

====Worsening of Urinary Retention====
TUDORZA PRESSAIR should be used with caution in patients with urinary retention. Prescribers and patients should be alert for signs and symptoms of [[Benign prostatic hyperplasia|prostatic hyperplasia]] or bladder-neck obstruction (e.g., difficulty passing urine, painful urination). Instruct patients to consult a physician immediately should any of these signs or symptoms develop.

====Immediate Hypersensitivity Reactions====
Immediate [[hypersensitivity]] reactions may occur after administration of TUDORZA PRESSAIR. If such a reaction occurs, therapy with TUDORZA PRESSAIR should be stopped at once and alternative treatments should be considered. Given the similar structural formula of [[atropine]] to aclidinium, patients with a history of hypersensitivity reactions to atropine should be closely monitored for similar [[hypersensitivity]] reactions to TUDORZA PRESSAIR. In addition, TUDORZA PRESSAIR should be used with caution in patients with severe hypersensitivity to milk proteins.
|clinicalTrials=Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

====3-Month and 6-Month Trials====

*TUDORZA PRESSAIR was studied in two 3-month (Trials B and C) and one 6-month (Trial D) placebo-controlled trials in patients with COPD. In these trials, 636 patients were treated with TUDORZA PRESSAIR at the recommended dose of 400 mcg twice daily.

*The population had a mean age of 64 years (ranging from 40 to 89 years), with 58% males, 94% Caucasian, and had COPD with a mean pre-bronchodilator forced expiratory volume in one second (FEV1) percent predicted of 48%. Patients with unstable [[cardiac disease]], [[Acute angle-closure glaucoma|narrow-angle glaucoma]], or symptomatic [[prostatic hypertrophy]] or bladder outlet obstruction were excluded from these trials.

TABLE 1 shows all adverse reactions that occurred with a frequency of greater than or equal to 1% in the TUDORZA PRESSAIR group in the two 3-month and one 6-month placebo-controlled trials where the rates in the TUDORZA PRESSAIR group exceeded placebo.

[[File:Aclidinium bromide inhalant 1.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

In addition, among the adverse reactions observed in the clinical trials with an incidence of less than 1% were [[diabetes mellitus]], [[dry mouth]], [[1st degree AV block]], [[osteoarthritis]], [[cardiac failure]], and [[cardio-respiratory arrest]].

====Long-term Safety Trials====

TUDORZA PRESSAIR was studied in three long term safety trials, two double blind and one open label, ranging from 40 to 52 weeks in patients with moderate to severe [[COPD]]. Two of these trials were extensions of the 3-month trials, and one was a dedicated long term safety trial. In these trials, 891 patients were treated with TUDORZA PRESSAIR at the recommended dose of 400 mcg twice daily. The demographic and baseline characteristics of the long term safety trials were similar to those of the placebo-controlled trials. The adverse events reported in the long term safety trials were similar to those occurring in the placebo-controlled trials of 3 to 6 months. No new safety findings were reported compared to the placebo controlled trials.
|drugInteractions=In vitro studies suggest limited potential for [[CYP450]]-related metabolic drug interactions, thus no formal drug interaction studies have been performed with TUDORZA PRESSAIR.

====Sympathomimetics, Methylxanthines, Steroids====
In clinical studies, concurrent administration of aclidinium bromide and other drugs commonly used in the treatment of [[COPD]] including [[Sympathomimetic agents|sympathomimetics]] (short-acting [[Beta-agonists|beta2 agonists]]), [[methylxanthines]], and oral and inhaled [[steroids]] showed no increases in adverse drug reactions.

====Anticholinergics====
There is a potential for an additive interaction with concomitantly used [[anticholinergic]] medications. Therefore, avoid coadministration of TUDORZA PRESSAIR with other [[Anticholinergics|anticholinergic-containing drugs]] as this may lead to an increase in [[anticholinergic]] effects.
|useInPregnancyFDA=<u>Teratogenic effects</u>

====Pregnancy Category C====
There are no adequate and well controlled studies in pregnant women. Adverse development effects were observed in rats and rabbits exposed to aclidinium bromide. TUDORZA PRESSAIR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Effects of aclidinium bromide on embryo-fetal development were examined in rats and rabbits. No evidence of structural alterations was observed in rats exposed during the period of [[organogenesis]] at approximately 15 times the recommended human daily dose (RHDD) [based on summed AUCs of aclidinium bromide and its metabolites at inhaled doses less than or equal to 5.0 mg/kg/day]. However, decreased pup weights were observed from dams exposed during the lactation period at approximately 5 times the RHDD [based on summed AUCs of aclidinium bromide and its metabolites at inhaled doses greater than or equal to 0.2 mg/kg/day]. Maternal toxicity was also observed at inhaled doses greater than or equal to 0.2 mg/kg/day.

No evidence of structural alterations was observed in Himalayan rabbits exposed during the period of organogenesis at approximately 20 times the RHDD [based on summed AUCs of aclidinium bromide and its metabolites at inhaled doses less than or equal to 3.6 mg/kg/day]. However, increased incidences of additional liver lobes (3-5%), as compared to 0% in the control group, were observed at approximately 1,400 times the RHDD [based on summed AUCs of aclidinium bromide and its metabolites at oral doses greater than or equal to 150 mg/kg/day], and decreased fetal body weights were observed at approximately 2,300 times the RHDD [based on summed AUCs of aclidinium bromide and its metabolites at oral doses greater than or equal to 300 mg/kg/day]. These fetal findings were observed in the presence of maternal toxicity.
|useInLaborDelivery=*The effect of TUDORZA PRESSAIR on labor and delivery is unknown.
*TUDORZA PRESSAIR should be used during labor and delivery only if the potential benefit to the patient justifies the potential risk to the fetus.
|useInNursing=*Aclidinium bromide is excreted into the milk of lactating female rats, and decreased pup weights were observed.
*Excretion of aclidinium into human milk is probable.
*There are no human studies that have investigated the effects of TUDORZA PRESSAIR on breast-fed infants.
*Caution should be exercised when TUDORZA PRESSAIR is administered to nursing women.
|useInPed=*TUDORZA PRESSAIR is approved for use in the maintenance treatment of bronchospasm associated with [[COPD]].
*COPD does not normally occur in children.
*The safety and effectiveness of TUDORZA PRESSAIR in pediatric patients have not been established.
|useInGeri=*Of the 636 COPD patients exposed to TUDORZA PRESSAIR 400 mcg twice daily for up to 24 weeks in three placebo-controlled clinical trials, 197 were less than 60 years, 272 were greater than or equal to 60 to less than 70 years, and 167 were greater than or equal to 70 years of age.
*No overall differences in safety or effectiveness were observed between these subjects and younger subjects.
*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.
*Based on available data for TUDORZA PRESSAIR, no adjustment of dosage in geriatric patients is warranted.
|useInRenalImpair=*The pharmacokinetics of TUDORZA PRESSAIR were investigated in subjects with normal renal function and in subjects with mild, moderate and severe [[renal impairment]].
*No clinically significant differences in aclidinium pharmacokinetics were noted between these populations.
*Based on available data for TUDORZA PRESSAIR, no adjustment of dosage in renally impaired subjects is warranted.
|useInHepaticImpair=The effects of hepatic impairment on the pharmacokinetics of TUDORZA PRESSAIR were not studied.
|mechAction=*Aclidinium bromide is a long-acting [[antimuscarinic|antimuscarinic agent]], which is often referred to as an [[anticholinergic]].
*It has similar affinity to the subtypes of [[muscarinic receptors]] M1 to M5.
*In the airways, it exhibits pharmacological effects through inhibition of M3 receptor at the smooth muscle leading to [[bronchodilation]].
*The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations.
*In preclinical in vitro as well as in vivo studies, prevention of [[acetylcholine]]-induced [[bronchoconstriction]] effects was dose-dependent and lasted longer than 24 hours.
*The clinical relevance of these findings is unknown.
*The [[bronchodilation]] following inhalation of aclidinium bromide is predominantly a site-specific effect.
|PD=====Cardiovascular Effects====

*In a thorough QT Study, 200 mcg and 800 mcg TUDORZA PRESSAIR was administered to healthy volunteers once daily for 3 days; no effects on prolongation of [[QT interval]] were observed using QTcF heart-rate correction methods.
*Additionally, the effect of TUDORZA PRESSAIR on cardiac rhythm was assessed in 336 COPD patients, 164 patients received aclidinium bromide 400 mcg twice daily and 172 patients received placebo, using 24-hr [[Holter monitoring]].
*No clinically significant effects on cardiac rhythm were observed.
|PK=====Absorption====

*The absolute bioavailability of aclidinium bromide is approximately 6% in healthy volunteers.
*Following twice-daily oral inhalation administration of 400 mcg aclidinium bromide in healthy subjects, peak steady state plasma levels were observed within 10 minutes after inhalation.

====Distribution====

*Aclidinium bromide shows a volume of distribution of approximately 300 L following intravenous administration of 400 mcg in humans.

====Metabolism====

*Clinical pharmacokinetics studies, including a mass balance study, indicate that the major route of metabolism of aclidinium bromide is hydrolysis, which occurs both chemically and enzymatically by esterases.
*Aclidinium bromide is rapidly and extensively hydrolyzed to its alcohol and dithienylglycolic acid derivatives, neither of which binds to muscarinic receptors and are devoid of pharmacologic activity.
*Therefore, due to the low plasma levels achieved at the clinically relevant doses, aclidinium bromide and its metabolites are not expected to alter the disposition of drugs metabolized by the human CYP450 enzymes.

====Elimination====

*Total clearance was approximately 170 L/h after an intravenous dose of aclidinium bromide in young healthy volunteers with an inter-individual variability of 36%.
*Intravenously administered radiolabelled aclidinium bromide was administered to healthy volunteers and was extensively metabolized with 1% excreted as unchanged aclidinium.
*Approximately 54% to 65% of the radioactivity was excreted in urine and 20% to 33% of the dose was excreted in feces.
*The combined results indicated that almost the entire aclidinium bromide dose was eliminated by hydrolysis.
*After dry powder inhalation, urinary excretion of aclidinium is about 0.09% of the dose and the estimated effective half-life is 5 to 8 hours.

====Drug Interactions====

*Formal drug interaction studies were not performed.
*In vitro studies using human liver microsomes indicated that aclidinium bromide and its major metabolites do not inhibit CYP450, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4/5 or 4A9/11 at concentrations up to 1,000-fold higher than the maximum plasma concentration that would be expected to be achieved at the therapeutic dose.
*Therefore, it is unlikely that aclidinium bromide causes [[CYP450]] related drug interactions.

=====Specific Populations=====

=====Elderly Patients=====

The pharmacokinetic profile of aclidinium bromide and its main metabolites was assessed in 12 elderly COPD patients (aged 70 years or older) compared to a younger cohort of 12 COPD patients (40-59 years) that were administered 400 mcg aclidinium bromide once daily for 3 days via inhalation. No clinically significant differences in systemic exposure (AUC and Cmax) were observed when the two groups were compared. No dosage adjustment is necessary in elderly patients.

=====Renal Impairment=====

The impact of renal disease upon the pharmacokinetics of aclidinium bromide was studied in 18 subjects with mild, moderate, or severe [[renal impairment]]. Systemic exposure (AUC and Cmax) to aclidinium bromide and its main metabolites following single doses of 400 mcg aclidinium bromide was similar in renally impaired patients compared with 6 matched healthy control subjects. No dose adjustment is necessary in renally impaired patients.

=====Hepatic Impairment=====

The effects of [[hepatic impairment]] on the pharmacokinetics of aclidinium bromide were not studied. However, hepatic insufficiency is not expected to have relevant influence on aclidinium bromide pharmacokinetics, since it is predominantly metabolized by chemical and enzymatic hydrolysis to products that do not bind to muscarinic receptors.
|nonClinToxic=====Carcinogenesis, Mutagenesis, Impairment of Fertility====
*Two-year inhalation studies were conducted in mice and rats to assess the carcinogenic potential of aclidinium bromide.
*No evidence of tumorigenicity was observed in rats and mice at aclidinium doses up to 0.20 and 2.4 mg/kg/day, respectively [approximately 10 and 80 times the Recommended Human Daily Dose (RHDD), respectively, based on summed AUCs of aclidinium bromide and its metabolites].

*Aclidinium bromide was positive in the in vitro bacterial gene mutation assay and the in vitro thymidine locus mouse lymphoma assay. However, aclidinium bromide was negative in the in vivo mouse micronucleus assay and the in vivo/in vitro unscheduled DNA synthesis assay with rat liver.

*Aclidinium bromide impaired several fertility and reproductive performance indices (increased number of days to mate, decreased conception rate, decreased number of corpora lutea, increased pre-implantation loss with consequent decreased number of implantations and live embryos) in both male and female rats administered inhaled doses greater than or equal to 0.8 mg/kg/day [approximately 15 times the RHDD based on summed AUCs of aclidinium bromide and its metabolites].
|clinicalStudies=====Chronic Obstructive Pulmonary Disease (COPD)
The TUDORZA PRESSAIR clinical development program included a dose-ranging trial (Trial A) for nominal dose selection and three confirmatory trials (Trials B, C, and D).

====Dose-ranging trial====

Trial A was a randomized, double-blind, placebo-controlled, active-controlled, crossover trial with 7-day treatment periods separated by 5-day washout periods. Trial A enrolled 79 patients who had a clinical diagnosis of [[COPD]], were 40 years of age or older, had a history of smoking at least 10 pack-years, had a [[forced expiratory volume]] in one second ([[FEV1]]) of at least 30% and less than 80% of predicted normal value, and a ratio of FEV1 over forced [[vital capacity]] (FEV1/FVC) of less than 0.7. Trial A included TUDORZA PRESSAIR doses of 400 mcg, 200 mcg and 100 mcg twice daily, formoterol active control, and placebo. Trial A demonstrated that the effect on trough [[FEV1]] and serial FEV1 in patients treated with the TUDORZA PRESSAIR 100 mcg twice daily and 200 mcg twice daily doses was lower compared to patients treated with the TUDORZA PRESSAIR 400 mcg twice daily dose.
[[File:Aclidinium bromide inhalant 2.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

=====Confirmatory trials=====

Trials B, C, and D were three randomized, double-blind, placebo-controlled trials in patients with [[COPD]]. Trials B and C were 3 months in duration, and Trial D was 6 months in duration. These trials enrolled 1,276 patients who had a clinical diagnosis of COPD, were 40 years of age or older, had a history of smoking at least 10 pack-years, had an FEV1 of at least 30% and less than 80% of predicted normal value, and a ratio of FEV1/FVC of less than 0.7; 59% were male, and 93% were Caucasian.

These clinical trials evaluated TUDORZA PRESSAIR 400 mcg twice daily (636 patients) and placebo (640 patients). TUDORZA PRESSAIR 400 mcg resulted in statistically significantly greater [[bronchodilation]] as measured by change from baseline in morning pre-dose [[FEV1]] at 12 weeks (the primary efficacy endpoint) compared to placebo in all three trials.

[[File:Aclidinium bromide inhalant 3.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

Serial spirometric evaluations were performed throughout daytime hours in a subset of patients in the three trials. The serial FEV1 values over 12 hours for one of the 3-month trials (Trial B) are displayed. Results for the other two placebo-controlled trials were similar to the results for Trial B. Improvement of lung function was maintained for 12 hours after a single dose and was consistent over the 3- or 6-month treatment period.

[[File:Aclidinium bromide inhalant 4.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]
Mean peak improvements in FEV1, for TUDORZA PRESSAIR relative to baseline were assessed in all patients in trials B, C and D after the first dose on day 1 and were similar at week 12. In Trials B and D but not in Trial C, patients treated with TUDORZA PRESSAIR used less daily rescue [[albuterol]] during the trial compared to patients treated with placebo.
|howSupplied=Aclidinium bromide inhalation powder 400 mcg is supplied in a sealed labeled aluminum pouch and is available in 60 metered doses and 30 metered doses.

The active ingredient is administered using a multi-dose dry powder inhaler, PRESSAIR®, which delivers 60 doses or 30 doses of aclidinium bromide powder for oral inhalation. The PRESSAIR inhaler is a white and green colored device and is comprised of an assembled plastic dosing mechanism with a dose indicator, a drug-product storage unit containing the drug-product formulation, and a mouthpiece covered by a green protective cap. The inhaler should be discarded when the marking “0” with a red background shows in the middle of the dose indicator or when the device locks out, whichever comes first.
|storage=Store TUDORZA PRESSAIR in a dry place at 25 C (77 F); excursions permitted to 15-30 C (59-86 F)[see USP Controlled Room Temperature].

The PRESSAIR inhaler should be stored inside the sealed pouch and only be opened immediately before use.

Discard the PRESSAIR inhaler 45 days after opening the pouch, after the marking “0” with a red background shows in the middle of the dose indicator, or when the device locks out, whichever comes first.

Keep out of reach of children.
|packLabel=[[File:Aclidinium bromide inhalant 5.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]

[[File:Aclidinium bromide inhalant 6.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|fdaPatientInfo======Instructions for Administering TUDORZA PRESSAIR=====
It is important for patients to understand how to correctly use TUDORZA PRESSAIR. Inform patients that if they miss a dose, they should take their next dose at the usual time; they should not take 2 doses at one time.

=====Acute Bronchospasm=====
Instruct patients that TUDORZA PRESSAIR is a twice daily maintenance [[bronchodilator]] and should not be used for immediate relief of breathing problems (i.e., as a rescue medication).

=====Paradoxical Bronchospasm=====
Inform patients that TUDORZA PRESSAIR can cause paradoxical [[bronchospasm]]. Advise patients that if paradoxical bronchospasm occurs, patients should discontinue TUDORZA PRESSAIR.

=====Visual Effects=====
Eye pain or discomfort, [[blurred vision]], visual halos or colored images in association with red eyes from conjunctival congestion and [[corneal edema]] may be signs of [[acute narrow-angle glaucoma]]. Inform patients to consult a physician immediately should any of these signs and symptoms develop. Advise patients that miotic eyedrops alone are not considered to be effective treatment.
*Inform patients that care must be taken not to allow the powder to enter into the eyes as this may cause blurring of vision and pupil dilation.

=====Urinary Retention=====
Difficulty passing urine and [[dysuria]] may be symptoms of new or worsening [[Benign prostatic hyperplasia|prostatic hyperplasia]] or bladder outlet obstruction. Patients should be instructed to consult a physician immediately should any of these signs or symptoms develop.
|alcohol=Alcohol-Aclidinium interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=*Tudorza Pressair
}}

File:Aclidinium bromide inhalant 6.jpg

2015-03-12T15:12:58Z

Sree Teja Yelamanchili:

File:Aclidinium bromide inhalant 5.jpg

2015-03-12T15:12:45Z

Sree Teja Yelamanchili:

File:Aclidinium bromide inhalant 4.jpg

2015-03-12T15:12:33Z

Sree Teja Yelamanchili:

File:Aclidinium bromide inhalant 3.jpg

2015-03-12T15:12:20Z

Sree Teja Yelamanchili:

File:Aclidinium bromide inhalant 2.jpg

2015-03-12T15:12:07Z

Sree Teja Yelamanchili: