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CIPRO is indicated for the treatment of infections caused by susceptible isolates of the designated microorganisms in the conditions and patient populations listed below. Please see DOSAGE AND ADMINISTRATION for specific recommendations.
Acute Uncomplicated Cystitis in Females caused by Escherichia coli or Staphylococcus saprophyticus.
Chronic Bacterial Prostatitis caused by Escherichia coli or Proteus mirabilis.
Lower Respiratory Tract Infections caused by Escherichia coli, Klebsiellapneumoniae, Enterobacter cloacae, Proteus mirabilis, Pseudomonas aeruginosa, Haemophilus influenzae, Haemophilus parainfluenzae, or penicillin-susceptible Streptococcus pneumoniae.* Also, Moraxella catarrhalis for the treatment of acute exacerbations of chronic bronchitis.
Ciprofloxacin is not a drug of first choice in the treatment of presumed or confirmed pneumonia secondary to Streptococcus pneumoniae.
Acute Sinusitis caused by Haemophilusinfluenzae, penicillin-susceptible Streptococcus pneumoniae, or Moraxella catarrhalis.
Skin and Skin Structure Infections caused by Escherichia coli, Klebsiellapneumoniae, Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris, Providenciastuartii, Morganellamorganii, Citrobacterfreundii, Pseudomonas aeruginosa, methicillin-susceptible Staphylococcus aureus, methicillin-susceptible Staphylococcus epidermidis, or Streptococcus pyogenes.
Bone and Joint Infections caused by Enterobacter cloacae, Serratiamarcescens, or Pseudomonas aeruginosa.
Complicated Intra-Abdominal Infections (used in combination with metronidazole) caused by Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiellapneumoniae, or Bacteroidesfragilis.
Infectious Diarrhea caused by Escherichia coli (enterotoxigenic isolates), Campylobacter jejuni, Shigella boydii†, Shigella dysenteriae, Shigella flexneri or Shigella sonnei† when antibacterial therapy is indicated.
Although treatment of infections due to this organism in this organ system demonstrated a clinically significant outcome, efficacy was studied in fewer than 10 patients.
Typhoid Fever (Enteric Fever) caused by Salmonella typhi
The efficacy of ciprofloxacin in the eradication of the chronic typhoid carrier state has not been demonstrated.
Uncomplicated Cervical and Urethral Gonorrhea due to Neisseria gonorrhoeae.
Pediatric Patients (1 to 17 years of age)
Complicated Urinary Tract Infections and Pyelonephritis due to Escherichia coli.
Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the pediatric population due to an increased incidence of adverse events compared to controls, including events related to joints and/or surrounding tissues.
Ciprofloxacin, like other fluoroquinolones, is associated with arthropathy and histopathological changes in weight-bearing joints of juvenile animals.
Adult and Pediatric Patients
Inhalational Anthrax (post-exposure): To reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis.
Ciprofloxacin serum concentrations achieved in humans served as a surrogate endpoint reasonably likely to predict clinical benefit and provided the initial basis for approval of this indication.5 Supportive clinical information for ciprofloxacin for anthrax post-exposure prophylaxis was obtained during the anthrax bioterror attacks of October 2001.
If anaerobic organisms are suspected of contributing to the infection, appropriate therapy should be administered. Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify organisms causing infection and to determine their susceptibility to ciprofloxacin. Therapy with CIPRO may be initiated before results of these tests are known; once results become available appropriate therapy should be continued.
As with other drugs, some isolates of Pseudomonas aeruginosa may develop resistance fairly rapidly during treatment with ciprofloxacin. Culture and susceptibility testing performed periodically during therapy will provide information not only on the therapeutic effect of the antimicrobial agent but also on the possible emergence of bacterial resistance.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO Tablets and CIPRO Oral Suspension and other antibacterial drugs, CIPRO Tablets and CIPRO Oral Suspension should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.
When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
The determination of dosage for any particular patient must take into consideration the severity and nature of the infection, the susceptibility of the causative organism, the integrity of the patient's host-defense mechanisms, and the status of renal function and hepatic function.
The duration of treatment depends upon the severity of infection. The usual duration is 7 to 14 days; however, for severe and complicated infections more prolonged therapy may be required. Ciprofloxacin should be administered at least 2 hours before or 6 hours after magnesium/aluminum antacids, polymeric phosphate binders (for example, sevelamer, lanthanum carbonate) or sucralfate, Videx® (didanosine) chewable/buffered tablets or pediatric powder for oral solution, other highly buffered drugs, or other products containing calcium, iron or zinc.
This image is provided by the National Library of Medicine.
This image is provided by the National Library of Medicine.
Conversion of IV to Oral Dosing in Adults
Patients whose therapy is started with CIPRO IV may be switched to CIPRO Tablets or Oral Suspension when clinically indicated at the discretion of the physician.
This image is provided by the National Library of Medicine.
Adults with Impaired Renal Function
Ciprofloxacin is eliminated primarily by renal excretion; however, the drug is also metabolized and partially cleared through the biliary system of the liver and through the intestine. These alternative pathways of drug elimination appear to compensate for the reduced renal excretion in patients with renal impairment. Nonetheless, some modification of dosage is recommended, particularly for patients with severe renal dysfunction.
The following table provides dosage guidelines for use in patients with renal impairment:
This image is provided by the National Library of Medicine.
When only the serum creatinine concentration is known, the following formula may be used to estimate creatinine clearance.
This image is provided by the National Library of Medicine.
The serum creatinine should represent a steady state of renal function.
In patients with severe infections and severe renal impairment, a unit dose of 750 mg may be administered at the intervals noted above. Patients should be carefully monitored.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
Safety and efficacy of extended-release ciprofloxacin (Cipro(R) XR) have not been established for treatment of infections other than UTIs.
Immediate-release and extended-release oral dosage forms are not interchangeable.
Patients initiated on ciprofloxacin IV therapy may be switched to oral ciprofloxacin when clinically indicated.
A desensitization schedule for ciprofloxacin hypersensitivity has been developed by 1 institution.
Bacteremia associated with intravascular line: (due to Ochrobacterium anthropi) 400 mg IV every 12 hours [1]
Bacterial meningitis: 800 to 1200 mg/day IV in divided doses every 8 to 12 hours [2]
Bacterial prostatitis, chronic: mild/moderate, 500 mg ORALLY every 12 hours for 28 days.
Bacterial prostatitis, chronic: mild/moderate, 400 mg IV every 12 hours for 28 days.
Bacterial sinusitis, acute: mild to moderate, 400 mg IV every 12 hours for 10 days.
Bacterial sinusitis, acute: mild to moderate, 500 mg ORALLY every 12 hours for 10 days.
Bronchitis, chronic, acute exacerbations: mild/moderate, 400 mg IV every 12 hours for 7 to 14 days.
Bronchitis, chronic, acute exacerbations: mild/moderate, 500 mg ORALLY every 12 hours for 7 to 14 days.
Bronchitis, chronic, acute exacerbations: severe/complicated, 400 mg IV every 8 hours for 7 to 14 days.
Bronchitis, chronic, acute exacerbations: severe/complicated, 750 mg ORALLY every 12 hours for 7 to 14 days.
Chancroid: 500 mg ORALLY twice a day for 3 days.
Febrile neutropenia, Empiric therapy: 400 mg IV every 8 hours for 7 to 14 days, in combination with piperacillin 50 mg/kg IV every 4 hours (maximum 24 g/day) [2]
Gonorrhea, Uncomplicated: 250 mg ORALLY as a single dose [6]; fluoroquinolones are no longer recommended by the CDC in the United States for the treatment of gonorrhea.
Granuloma inguinale: 750 mg ORALLY twice daily for at least 21 days and lesions are healed completely.[3]
HIV infection - Salmonella gastroenteritis: (mild disease with or without symptomatic bacteremia) 500 to 750 mg ORALLY twice daily or 400 mg IV twice daily; duration of 7 to 14 days if CD4+ count is at least 200/mcL, 2 to 6 weeks if CD4+ count is less than 200/mcL, or at least 6 months for recurrent symptomatic septicemia[4]
Infection of bone - Infectious disorder of joint: mild/moderate, 400 mg IV every 12 hours for at least 4 to 6 weeks.
Infection of bone - Infectious disorder of joint: mild/moderate, 500 mg ORALLY every 12 hours for at least 4 to 6 weeks.
Infection of bone - Infectious disorder of joint: severe/complicated, 400 mg IV every 8 hours for at least 4 to 6 weeks.
Infection of bone - Infectious disorder of joint: severe/complicated, 750 mg ORALLY every 12 hours for at least 4 to 6 weeks.
Infection of skin AND/OR subcutaneous tissue: mild/moderate, 400 mg IV every 12 hours for 7 to 14 days.
Infection of skin AND/OR subcutaneous tissue: mild/moderate, 500 mg ORALLY every 12 hours for 7 to 14 days.
Infection of skin AND/OR subcutaneous tissue: severe/complicated, 400 mg IV every 8 hours for 7 to 14 days.
Infection of skin AND/OR subcutaneous tissue: severe/complicated, 750 mg ORALLY every 12 hours for 7 to 14 days.
Infectious diarrheal disease: 500 mg orally every 12 hours for 5 to 7 days [6]
Infectious disease of abdomen, Complicated: 400 mg IV every 12 hours for 7 to 14 days, in combination with metronidazole.
Infectious disease of abdomen, Complicated: 500 mg ORALLY every 12 hours for 7 to 14 days, in combination with metronidazole.
Infective endocarditis: (native valve, culture-negative) 500 mg ORALLY or 400 mg IV every 12 hours, in combination with vancomycin 15 mg/kg IV every 12 hours AND gentamicin sulfate 1 mg/kg IV/IM every 8 hours, for 4 to 6 weeks [9][10]
Infective endocarditis: (prosthetic valve (late, greater than 1 year), culture-negative) 500 mg ORALLY or 400 mg IV every 12 hours, in combination with vancomycin 15 mg/kg IV every 12 hours AND gentamicin sulfate 1 mg/kg IV/IM every 8 hours, for 4 to 6 weeks AND rifampin 300 mg IV or ORALLY every 8 hours for 6 weeks.
Infective endocarditis: (native and prosthetic valve endocarditis caused by HACEK microorganisms) 500 mg ORALLY or 400 mg IV every 12 hours for 4 to 6 weeks[5]
Inhalational anthrax, Postexposure; Prophylaxis: 400 mg IV every 12 hours for 60 days.
Inhalational anthrax, Postexposure; Prophylaxis: 500 mg ORALLY every 12 hours for 60 days.
Lower respiratory tract infection: mild/moderate, 400 mg IV every 12 hours for 7 to 14 days.
Lower respiratory tract infection: mild/moderate, 500 mg ORALLY every 12 hours for 7 to 14 days.
Lower respiratory tract infection: severe/complicated, 400 mg IV every 8 hours for 7 to 14 days.
Lower respiratory tract infection: severe/complicated, 750 mg ORALLY every 12 hours for 7 to 14 days.
Nosocomial pneumonia: 400 mg IV every 8 hours for 10 to 14 days.
Pyelonephritis, acute, Uncomplicated: extended-release tablets (Cipro(R) XR), 1000 mg ORALLY once daily for 7 to 14 days [1]; clinical guidelines recommend a duration of 7 days for acute pyelonephritis[6]
Typhoid fever: 500 mg orally every 12 hours for 10 days.
Urinary tract infectious disease, Severe or complicated: 400 mg IV every 8 to 12 hours for 7 to 14 days.
Urinary tract infectious disease, Severe or complicated: immediate-release oral suspension, 500 mg ORALLY every 12 hours for 7 to 14 days.
Urinary tract infectious disease, Severe or complicated: extended-release tablets (Cipro(R) XR), 1000 mg ORALLY once daily for 7 to 14 days.
Urinary tract infectious disease, Uncomplicated: mild to moderate, 200 mg IV every 12 hours for 7 to 14 days.
Urinary tract infectious disease, Uncomplicated: acute cystitis (oral suspension), 250 mg ORALLY every 12 hours for 3 days.
Urinary tract infectious disease, Uncomplicated: mild/moderate (oral suspension), 250 mg ORALLY every 12 hours for 7 to 14 days.
Urinary tract infectious disease, Uncomplicated: acute cystitis (extended-release tablets Cipro(R) XR), 500 mg ORALLY once daily for 3 days.
Non–Guideline-Supported Use
Condition1
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ciprofloxacin (oral) in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
CIPRO Tablets and Oral Suspension should be administered orally as described in the DOSAGE GUIDELINES TABLE. An increased incidence of adverse events compared to controls, including events related to joints and/or surrounding tissues, has been observed.
Dosing and initial route of therapy (that is, IV or oral) for complicated urinary tract infection or pyelonephritis should be determined by the severity of the infection. In the clinical trial, pediatric patients with moderate to severe infection were initiated on 6 to 10 mg/kg IV every 8 hours and allowed to switch to oral therapy (10 to 20 mg/kg every 12 hours), at the discretion of the physician.
This image is provided by the National Library of Medicine.
Pediatric patients with moderate to severe renal insufficiency were excluded from the clinical trial of complicated urinary tract infection and pyelonephritis.
No information is available on dosing adjustments necessary for pediatric patients with moderate to severe renal insufficiency (that is, creatinine clearance of < 50 mL/min/1.73m2).
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
Condition1
Developed by:
Class of Recommendation:
Strength of Evidence:
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Guideline-Supported Use of Ciprofloxacin (oral) in pediatric patients.
Non–Guideline-Supported Use
Condition1
Dosing Information
Dosage
Condition2
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ciprofloxacin (oral) in pediatric patients.
Contraindications
Ciprofloxacin is contraindicated in persons with a history of hypersensitivity to ciprofloxacin, any member of the quinolone class of antimicrobial agents, or any of the product components.
Concomitant administration with tizanidine is contraindicated.
Warnings
Tendinopathy and Tendon Rupture
Fluoroquinolones, including CIPRO, are associated with an increased risk of tendinitis and tendon rupture in all ages. This adverse reaction most frequently involves the Achilles tendon, and rupture of the Achilles tendon may require surgical repair.
Tendinitis and tendon rupture in the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendon sites have also been reported.
The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants.
Factors, in addition to age and corticosteroid use, that may independently increase the risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis.
Tendinitis and tendon rupture have also occurred in patients taking fluoroquinolones who do not have the above risk factors. Inflammation and tendon rupture can occur, sometimes bilaterally, even within the first 48 hours, during or after completion of therapy; cases occurring up to several months after completion of therapy have been reported.
CIPRO should be used with caution in patients with a history of tendon disorders. CIPRO should be discontinued if the patient experiences pain, swelling, inflammation or rupture of a tendon. Patients should be advised to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding changing to a non-quinolone antimicrobial drug.
Exacerbation of Myasthenia Gravis
Fluoroquinolones, including CIPRO, have neuromuscular blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis.
Postmarketing serious adverse events, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in persons with myasthenia gravis. Avoid CIPRO in patients with known history of myasthenia gravis.
Pregnant Women
THE SAFETY AND EFFECTIVENESS OF CIPROFLOXACIN IN PREGNANT AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED.
Hypersensitivity Reactions
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving quinolone therapy. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria, and itching. Only a few patients had a history of hypersensitivity reactions. Serious anaphylactic reactions require immediate emergency treatment with epinephrine.
Oxygen, intravenous steroids, and airway management, including intubation, should be administered as indicated.
Other Serious and Sometimes Fatal Reactions
Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain etiology, have been reported rarely in patients receiving therapy with quinolones, including ciprofloxacin. These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following:
Fever, rash, or severe dermatologic reactions (for example, toxic epidermal necrolysis, Stevens-Johnson syndrome);
Vasculitis; arthralgia; myalgia; serum sickness;
Allergic pneumonitis;
Interstitial nephritis; acute renal insufficiency or failure;
Hepatitis; jaundice; acute hepatic necrosis or failure;
Anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic abnormalities.
The drug should be discontinued immediately at the first appearance of a skin rash, jaundice, or any other sign of hypersensitivity and supportive measures instituted .
Hepatobiliary System
Cases of severe hepatotoxicity, includinghepatic necrosis, life-threatening hepatic failure, and fatal events,have been reported with ciprofloxacin.
Acute liver injury is rapid in onset (range 1-39 days), and is often associated with hypersensitivity. The pattern of injury can be hepatocellular, cholestatic or mixed.
Most patients with fatal outcomes were older than 55 years old. In the event of any signs and symptoms of hepatitis (such as anorexia, jaundice, dark urine, pruritus, or tender abdomen), treatment should be discontinued immediately.
There can be a temporary increase in transaminases, alkaline phosphatase, or cholestatic jaundice, especially in patients with previous liver damage, who are treated with ciprofloxacin.
Theophylline
SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED IN PATIENTS RECEIVINGCONCURRENT ADMINISTRATION OF CIPROFLOXACIN AND THEOPHYLLINE. These reactions have included cardiac arrest, seizure, status epilepticus, and respiratory failure.
Although similar serious adverse effects have been reported in patients receiving theophylline alone, the possibility that these reactions may be potentiated by ciprofloxacin cannot be eliminated. If concomitant use cannot be avoided, serum levels of theophylline should be monitored and dosage adjustments made as appropriate.
Central Nervous System Effects
Convulsions, increased intracranial pressure (including pseudotumor cerebri), and toxic psychosis have been reported in patients receiving fluoroquinolones, including ciprofloxacin. Ciprofloxacin may also cause central nervous system (CNS) events including: dizziness, confusion, tremors, hallucinations, depression, and, rarely, psychotic reactions have progressed to suicidal ideations/thoughts and self-injurious behavior such as attempted or completed suicide. These reactions may occur following the first dose.
If these reactions occur in patients receiving ciprofloxacin, the drug should be discontinued, patients should be advised to inform their healthcare provider immediately and appropriate measures instituted. Cipro, like other fluoroquinolones, is known to trigger seizures or lower the seizure threshold.
As with all fluoroquinolones, ciprofloxacin should be used with caution in epileptic patients and patients with known or suspected CNS disorders that may predispose to seizures or lower the seizure threshold (for example, severe cerebral arteriosclerosis, previous history of convulsion, reduced cerebral blood flow, altered brain structure, or stroke), or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold (for example, certain drug therapy, renal dysfunction).
CIPRO should only be used where the benefits of treatment exceed the risks, since these patients are endangered because of possible undesirable CNS side effects. Cases of status epilepticus have been reported. If seizures occur, ciprofloxacin should be discontinued.
Clostridium Difficile-Associated Diarrhea
Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including CIPRO, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
C. difficileproduces toxins A and B which contribute to the development of CDAD. Hypertoxin producing isolates of C. difficilecause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy.
CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficilemay need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.
Peripheral Neuropathy
Rare cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving quinolones, including ciprofloxacin.
Ciprofloxacin should be discontinued if the patient experiences symptoms of neuropathy including pain, burning, tingling, numbness, and/or weakness, or is found to have deficits in light touch, pain, temperature, position sense, vibratory sensation, and/or motor strength in order to prevent the development of an irreversible condition.
Patients treated with CIPRO should be advised to inform their healthcare provider prior to continuing treatment if symptoms of neuropathy develop.
Musculoskeletal Disorders in Pediatric Patients and Arthropathic Effects in Animals
An increased incidence of adverse events compared to controls, including events related to joints and/or surrounding tissues, has been observed.
In pre-clinical studies, oral administration of ciprofloxacin caused lameness in immature dogs. Histopathological examination of the weight-bearing joints of these dogs revealed permanent lesions of the cartilage. Related quinolone-class drugs also produce erosions of cartilage of weight-bearing joints and other signs of arthropathy in immature animals of various species.
Prolongation of the QT Interval
Some fluoroquinolones, including ciprofloxacin, have been associated with prolongation of the QT interval on the electrocardiogram and infrequent cases of arrhythmia.
Rare cases of torsade de pointes have been spontaneously reported during postmarketing surveillance in patients receiving fluoroquinolones, including ciprofloxacin.
Ciprofloxacin should be avoided in patients with known prolongation of the QT interval, risk factors for QT prolongation or torsade de pointes (for example, congenital long QT syndrome , uncorrected electrolyte imbalance, such as hypokalemia or hypomagnesemia and cardiac disease, such as heart failure, myocardial infarction, or bradycardia), and patients receiving Class IA antiarrhythmic agents (quinidine, procainamide), or Class III antiarrhthmic agents (amiodarone, sotalol), tricyclic antidepressants, macrolides, and antipsychotics.
Elderly patients may also be more susceptible to drug-associated effects on the QT interval.
Cytochrome P450 (CYP450) Drug Interactions
Ciprofloxacin is an inhibitor of the hepatic CYP1A2 enzyme pathway. Coadministration of ciprofloxacin and other drugs primarily metabolized by CYP1A2 (for example, theophylline, methylxanthines, caffeine, tizanidine, ropinirole, clozapine, olanzapine) results in increased plasma concentrations of the coadministered drug and could lead to clinically significant pharmacodynamic side effects of the coadministered drug.
Syphilis
Ciprofloxacin has not been shown to be effective in the treatment of syphilis. Antimicrobial agents used in high dose for short periods of time to treat gonorrhea may mask or delay the symptoms of incubating syphilis.
All patients with gonorrhea should have a serologic test for syphilis at the time of diagnosis. Patients treated with ciprofloxacin should have a follow-up serologic test for syphilis after three months.
Adverse Reactions
Clinical Trials Experience
Adverse Reactions in Adult Patients
During clinical investigations with oral and parenteral ciprofloxacin, 49,038 patients received courses of the drug. Most of the adverse events reported were described as only mild or moderate in severity, abated soon after the drug was discontinued, and required no treatment.
Ciprofloxacin was discontinued because of an adverse event in 1% of orally treated patients.
The most frequently reported drug related events, from clinical trials of all formulations, all dosages, all drug-therapy durations, and for all indications of ciprofloxacin therapy were nausea (2.5%), diarrhea (1.6%), liver function tests abnormal (1.3%), vomiting (1%), and rash (1%).
Additional medically important events that occurred in less than 1% of ciprofloxacin patients are listed below.
BODY AS A WHOLE: headache, abdominal pain/discomfort, foot pain, pain, pain in extremities, injection site reaction (ciprofloxacin intravenous)
SKIN/HYPERSENSITIVITY: allergic reaction, pruritus, urticaria, photosensitivity/phototoxicity reaction, flushing, fever, chills, angioedema, edema of the face, neck, lips, conjunctivae or hands, cutaneous candidiasis, hyperpigmentation, erythema nodosum, sweating
SPECIAL SENSES: blurred vision, disturbed vision (change in color perception, overbrightness of lights), decreased visual acuity, diplopia, eye pain, tinnitus, hearing loss, bad taste, chromatopsia
In several instances nausea, vomiting, tremor, irritability, or palpitation were judged by investigators to be related to elevated serum levels of theophylline possibly as a result of drug interaction with ciprofloxacin.
In randomized, double-blind controlled clinical trials comparing ciprofloxacin tablets (500 mg BID) to cefuroxime axetil (250 mg - 500 mg BID) and to clarithromycin (500 mg BID) in patients with respiratory tract infections, ciprofloxacin demonstrated a CNS adverse event profile comparable to the control drugs.
Adverse Reactions in Pediatric Patients
Ciprofloxacin, administered IV and /or orally, was compared to a cephalosporin for treatment of complicated urinary tract infections (cUTI) or pyelonephritis in pediatric patients 1 to 17 years of age (mean age of 6 ± 4 years). The trial was conducted in the US, Canada, Argentina, Peru, Costa Rica, Mexico, South Africa, and Germany. The duration of therapy was 10 to 21 days (mean duration of treatment was 11 days with a range of 1 to 88 days). The primary objective of the study was to assess musculoskeletal and neurological safety within 6 weeks of therapy and through one year of follow-up in the 335 ciprofloxacin- and 349 comparator-treated patients enrolled.
An Independent Pediatric Safety Committee (IPSC) reviewed all cases of musculoskeletal adverse events as well as all patients with an abnormal gait or abnormal joint exam (baseline or treatment-emergent). These events were evaluated in a comprehensive fashion and included such conditions as arthralgia, abnormal gait, abnormal joint exam, joint sprains, leg pain, back pain, arthrosis, bone pain, pain, myalgia, arm pain, and decreased range of motion in a joint. The affected joints included: knee, elbow, ankle, hip, wrist, and shoulder. Within 6 weeks of treatment initiation, the rates of these events were 9.3% (31/335) in the ciprofloxacin-treated group versus 6 % (21/349) in comparator-treated patients.
The majority of these events were mild or moderate in intensity. All musculoskeletal events occurring by 6 weeks resolved (clinical resolution of signs and symptoms), usually within 30 days of end of treatment. Radiological evaluations were not routinely used to confirm resolution of the events.
The events occurred more frequently in ciprofloxacin-treated patients than control patients, regardless of whether they received IV or oral therapy. Ciprofloxacin-treated patients were more likely to report more than one event and on more than one occasion compared to control patients. These events occurred in all age groups and the rates were consistently higher in the ciprofloxacin group compared to the control group. At the end of 1 year, the rate of these events reported at any time during that period was 13.7% (46/335) in the ciprofloxacin-treated group versus 9.5% (33/349) comparator-treated patients.
An adolescent female discontinued ciprofloxacin for wrist pain that developed during treatment. An MRI performed 4 weeks later showed a tear in the right ulnar fibrocartilage. A diagnosis of overuse syndrome secondary to sports activity was made, but a contribution from ciprofloxacin cannot be excluded. The patient recovered by 4 months without surgical intervention.
This image is provided by the National Library of Medicine.
The incidence rates of neurological events within 6 weeks of treatment initiation were 3% (9/335) in the ciprofloxacin group versus 2% (7/349) in the comparator group and included dizziness, nervousness, insomnia, and somnolence.
In this trial, the overall incidence rates of adverse events regardless of relationship to study drug and within 6 weeks of treatment initiation were 41% (138/335) in the ciprofloxacin group versus 31% (109/349) in the comparator group. The most frequent events were gastrointestinal: 15% (50/335) of ciprofloxacin patients compared to 9% (31/349) of comparator patients. Serious adverse events were seen in 7.5% (25/335) of ciprofloxacin-treated patients compared to 5.7% (20/349) of control patients.
Discontinuation of drug due to an adverse event was observed in 3% (10/335) of ciprofloxacin-treated patients versus 1.4% (5/349) of comparator patients. Other adverse events that occurred in at least 1% of ciprofloxacin patients were diarrhea 4.8%, vomiting 4.8%, abdominal pain 3.3%, accidental injury 3%, rhinitis 3%, dyspepsia 2.7%, nausea 2.7%, fever 2.1%, asthma 1.8% and rash 1.8%.
In addition to the events reported in pediatric patients in clinical trials, it should be expected that events reported in adults during clinical trials or postmarketing experience may also occur in pediatric patients.
Postmarketing Experience
Acute generalized exanthematous pustulosis (AGEP), The following adverse events have been reported from worldwide marketing experience with fluoroquinolones, including ciprofloxacin. Because these events 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.
Decisions to include these events in labeling are typically based on one or more of the following factors: (1) seriousness of the event, (2) frequency of the reporting, or (3) strength of causal connection to the drug.
Agitation, agranulocytosis, albuminuria, anaphylactic reactions (including life-threatening anaphylactic shock), anosmia, candiduria, cholesterol elevation (serum), confusion, constipation, delirium, dyspepsia, dysphagia, erythema multiforme, exfoliative dermatitis, fixed eruption, flatulence, glucose elevation (blood), hemolytic anemia, hepatic failure (including fatal cases), hepatic necrosis, hyperesthesia, hypertonia, hypesthesia, hypotension (postural), International Normalized Ratio (INR) increased (in patients treated with Vitamin K antagonists),jaundice, marrow depression (life threatening), methemoglobinemia, moniliasis (oral, gastrointestinal, vaginal), myalgia, myasthenia, exacerbation of myasthenia gravis, myoclonus, nystagmus, pancreatitis, pancytopenia (life threatening or fatal outcome), peripheral neuropathy that may be irreversible, phenytoin alteration (serum), photosensitivity/phototoxicity reaction, polyneuropathy, potassium elevation (serum), prothrombin time prolongation or decrease, pseudomembranous colitis (The onset of pseudomembranous colitis symptoms may occur during or after antimicrobial treatment.), psychosis (toxic), QT prolongation, renal calculi, serum sickness like reaction, Stevens-Johnson syndrome, taste loss, tendinitis, tendon rupture, torsade de pointes, toxic epidermal necrolysis (Lyell's Syndrome), triglyceride elevation (serum), twitching, vaginal candidiasis, vasculitis and ventricular arrhythmia.
Adverse events were also reported by persons who received ciprofloxacin for anthrax post-exposure prophylaxis following the anthrax bioterror attacks of October 2001.
Adverse Laboratory Changes: Changes in laboratory parameters listed as adverse events without regard to drug relationship are listed below:
This image is provided by the National Library of Medicine.
Other changes occurring in less than 0.1% of courses were: elevation of serum gammaglutamyl transferase, elevation of serum amylase, reduction in blood glucose, elevated uric acid, decrease in hemoglobin, anemia, bleeding diathesis, increase in blood monocytes, and leukocytosis.
Drug Interactions
When CIPRO Tablet is given concomitantly with food, there is a delay in the absorption of the drug, resulting in peak concentrations that occur closer to 2 hours after dosing rather than 1 hour whereas there is no delay observed when CIPRO Suspension is given with food.
The overall absorption of CIPRO Tablet or CIPRO Suspension, however, is not substantially affected. The pharmacokinetics of ciprofloxacin given as the suspension are also not affected by food. Concurrent administration of antacids containing magnesium hydroxide or aluminum hydroxide may reduce the bioavailability of ciprofloxacin by as much as 90%.
The serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs were given concomitantly.
Concomitant administration with tizanidine is contraindicated. Concomitant administration of ciprofloxacin with theophylline decreases the clearance of theophylline resulting in elevated serum theophylline levels and increased risk of a patient developing CNS or other adverse reactions. Ciprofloxacin also decreases caffeine clearance and inhibits the formation of paraxanthine after caffeine administration.
Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ciprofloxacin (oral) in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Ciprofloxacin (oral) during labor and delivery.
Nursing Mothers
There is no FDA guidance on the use of Ciprofloxacin (oral) with respect to nursing mothers.
Pediatric Use
Following a single oral dose of 10 mg/kg ciprofloxacin suspension to 16 children ranging in age from 4 months to 7 years, the mean Cmax was 2.4 mcg/mL (range: 1.5 – 3.4 mcg/mL) and the mean AUC was 9.2 mcg*h/mL (range: 5.8 – 14.9 mcg*h/mL). There was no apparent age-dependence, and no notable increase in Cmax or AUC upon multiple dosing (10 mg/kg TID).
In children with severe sepsis who were given intravenous ciprofloxacin (10 mg/kg as a 1-hour infusion), the mean Cmax was 6.1 mcg/mL (range: 4.6 – 8.3 mcg/mL) in 10 children less than 1 year of age; and 7.2 mcg/mL (range: 4.7 – 11.8 mcg/mL) in 10 children between 1 and 5 years of age. The AUC values were 17.4 mcg*h/mL (range: 11.8 – 32 mcg*h/mL) and 16.5 mcg*h/mL (range: 11 – 23.8 mcg*h/mL) in the respective age groups. These values are within the range reported for adults at therapeutic doses.
Based on population pharmacokinetic analysis of pediatric patients with various infections, the predicted mean half-life in children is approximately 4 - 5 hours, and the bioavailability of the oral suspension is approximately 60%.
Geriatic Use
There is no FDA guidance on the use of Ciprofloxacin (oral) with respect to geriatric patients.
Gender
There is no FDA guidance on the use of Ciprofloxacin (oral) with respect to specific gender populations.
Race
There is no FDA guidance on the use of Ciprofloxacin (oral) with respect to specific racial populations.
Renal Impairment
In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged. Dosage adjustments may be required.
Hepatic Impairment
In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in ciprofloxacin pharmacokinetics have been observed. The kinetics of ciprofloxacin in patients with acute hepatic insufficiency, however, have not been fully elucidated.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ciprofloxacin (oral) in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Ciprofloxacin (oral) in patients who are immunocompromised.
Administration and Monitoring
Administration
Oral
Monitoring
If concomitant use of theophylline, serum levels of theophylline should be monitored and dosage adjustments made as appropriate.
In some older individuals experience reduced renal function by virtue of their advanced age, care should be taken in dose selection for elderly patients, and renal function monitoring may be useful in these patients.
IV Compatibility
There is limited information regarding IV Compatibility of Ciprofloxacin (oral) in the drug label.
Overdosage
In the event of acute overdosage, reversible renal toxicity has been reported in some cases. The stomach should be emptied by inducing vomiting or by gastric lavage.
The patient should be carefully observed and given supportive treatment, including monitoring of renal function, urinary pH and acidify, if required, to prevent crystalluria and administration of magnesium, aluminum, or calcium containing antacids which can reduce the absorption of ciprofloxacin.
Adequate hydration must be maintained. Only a small amount of ciprofloxacin (< 10%) is removed from the body after hemodialysis or peritoneal dialysis.
Single doses of ciprofloxacin were relatively non-toxic via the oral route of administration in mice, rats, and dogs. No deaths occurred within a 14-day post treatment observation period at the highest oral doses tested; up to 5000 mg/kg in either rodent species, or up to 2500 mg/kg in the dog.
Clinical signs observed included hypoactivity and cyanosis in both rodent species and severe vomiting in dogs. In rabbits, significant mortality was seen at doses of ciprofloxacin > 2500 mg/kg. Mortality was delayed in these animals, occurring 10-14 days after dosing.
In mice, rats, rabbits and dogs, significant toxicity including tonic/clonic convulsions was observed at intravenous doses of ciprofloxacin between 125 and 300 mg/kg.
There is limited information regarding Pharmacodynamics of Ciprofloxacin (oral) in the drug label.
Pharmacokinetics
Absorption
Ciprofloxacin given as an oral tablet is rapidly and well absorbed from the gastrointestinal tract after oral administration. The absolute bioavailability is approximately 70% with no substantial loss by first pass metabolism. Ciprofloxacin maximum serum concentrations and area under the curve are shown in the chart for the 250 mg to 1000 mg dose range.
This image is provided by the National Library of Medicine.
Maximum serum concentrations are attained 1 to 2 hours after oral dosing. Mean concentrations 12 hours after dosing with 250, 500, or 750 mg are 0.1, 0.2, and 0.4 mcg/mL, respectively. The serum elimination half-life in subjects with normal renal function is approximately 4 hours.
Serum concentrations increase proportionately with doses up to 1000 mg.
A 500 mg oral dose given every 12 hours has been shown to produce an area under the serum concentration time curve (AUC) equivalent to that produced by an intravenous infusion of 400 mg ciprofloxacin given over 60 minutes every 12 hours.
A 750 mg oral dose given every 12 hours has been shown to produce an AUC at steady-state equivalent to that produced by an intravenous infusion of 400 mg given over 60 minutes every 8 hours. * A 750 mg oral dose results in a Cmax similar to that observed with a 400 mg IV dose. A 250 mg oral dose given every 12 hours produces an AUC equivalent to that produced by an infusion of 200 mg ciprofloxacin given every 12 hours.
This image is provided by the National Library of Medicine.
Distribution
The binding of ciprofloxacin to serum proteins is 20 to 40% which is not likely to be high enough to cause significant protein binding interactions with other drugs.
After oral administration, ciprofloxacin is widely distributed throughout the body. Tissue concentrations often exceed serum concentrations in both men and women, particularly in genital tissue including the prostate. Ciprofloxacin is present in active form in the saliva, nasal and bronchial secretions, mucosa of the sinuses, sputum, skin blister fluid, lymph, peritoneal fluid, bile, and prostatic secretions.
Ciprofloxacin has also been detected in lung, skin, fat, muscle, cartilage, and bone. The drug diffuses into the cerebrospinal fluid (CSF); however, CSF concentrations are generally less than 10% of peak serum concentrations. Low levels of the drug have been detected in the aqueous and vitreous humors of the eye.
Metabolism
Four metabolites have been identified in human urine which together account for approximately 15% of an oral dose. The metabolites have antimicrobial activity, but are less active than unchanged ciprofloxacin.
Ciprofloxacin is an inhibitor of human cytochrome P450 1A2 (CYP1A2) mediated metabolism. Coadministration of ciprofloxacin with other drugs primarily metabolized by CYP1A2 results in increased plasma concentrations of these drugs and could lead to clinically significant adverse events of the coadministered drug.
Excretion
The serum elimination half-life in subjects with normal renal function is approximately 4 hours.
Approximately 40 to 50% of an orally administered dose is excreted in the urine as unchanged drug. After a 250 mg oral dose, urine concentrations of ciprofloxacin usually exceed 200 mcg/mL during the first two hours and are approximately 30 mcg/mL at 8 to 12 hours after dosing.
The urinary excretion of ciprofloxacin is virtually complete within 24 hours after dosing. The renal clearance of ciprofloxacin, which is approximately 300 mL/minute, exceeds the normal glomerular filtration rate of 120 mL/minute. Thus, active tubular secretion would seem to play a significant role in its elimination. Co-administration of probenecid with ciprofloxacin results in about a 50% reduction in the ciprofloxacin renal clearance and a 50% increase in its concentration in the systemic circulation. Although bile concentrations of ciprofloxacin are several fold higher than serum concentrations after oral dosing, only a small amount of the dose administered is recovered from the bile as unchanged drug. An additional 1 to 2% of the dose is recovered from the bile in the form of metabolites.
Approximately 20 to 35% of an oral dose is recovered from the feces within 5 days after dosing. This may arise from either biliary clearance or transintestinal elimination.
With oral administration, a 500 mg dose, given as 10 mL of the 5% CIPRO Suspension (containing 250 mg ciprofloxacin/5mL) is bioequivalent to the 500 mg tablet. A 10 mL volume of the 5% CIPRO Suspension (containing 250 mg ciprofloxacin/5mL) is bioequivalent to a 5 mL volume of the 10% CIPRO Suspension (containing 500 mg ciprofloxacin/5mL).
Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Ciprofloxacin (oral) in the drug label.
Clinical Studies
There is limited information regarding Clinical Studies of Ciprofloxacin (oral) in the drug label.
How Supplied
Storage
There is limited information regarding Ciprofloxacin (oral) Storage in the drug label.
Images
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