Ciprofloxacin: Package Insert and Label Information (Page 4 of 8)

6.2 Postmarketing Experience

The following adverse reactions have been reported from worldwide marketing experience with fluoroquinolones, including ciprofloxacin. Because these 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 (Table 10).

Table 10: Postmarketing Reports of Adverse Drug Reactions
System Organ Class Adverse Reactions
Cardiovascular QT prolongation Torsade de Pointes Vasculitis and ventricular arrhythmia
Central Nervous System Hypertonia Myasthenia Exacerbation of myasthenia gravis Peripheral neuropathy Polyneuropathy Twitching
Eye Disorders Nystagmus
Gastrointestinal Pseudomembranous colitis
Hemic/Lymphatic Pancytopenia (life threatening or fatal outcome) Methemoglobinemia
Hepatobiliary Hepatic failure (including fatal cases)
Infections and Infestations Candidiasis (oral, gastrointestinal, vaginal)
Investigations Prothrombin time prolongation or decrease Cholesterol elevation (serum) Potassium elevation (serum)
Musculoskeletal Myalgia Myoclonus Tendinitis Tendon rupture
Psychiatric Disorders Agitation Confusion Delirium
Skin/Hypersensitivity Acute generalize exanthematous pustulosis (AGEP) Fixed eruption Serum sickness-like reaction
Special Senses Anosmia Hyperesthesia Hypesthesia Taste loss

6.3 Adverse Laboratory Changes

Changes in laboratory parameters while on ciprofloxacin are listed below:

Hepatic — Elevations of ALT (SGPT), AST (SGOT), alkaline phosphatase, LDH, serum bilirubin.

Hematologic — Eosinophilia, leukopenia, decreased blood platelets, elevated blood platelets, pancytopenia.

Renal — Elevations of serum creatinine, BUN, crystalluria, cylindruria, and hematuria have been reported.

Other changes occurring 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.

7 DRUG INTERACTIONS

Ciprofloxacin is an inhibitor of human cytochrome P450 1A2 (CYP1A2) mediated metabolism. Co­-administration 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 co-­administered drug.

Table 11: Drugs That are Affected by and Affecting Ciprofloxacin
Drugs That are Affected by Ciprofloxacin
Drug(s) Recommendation Comments
Tizanidine Contraindicated Concomitant administration of tizanidine and ciprofloxacin is contraindicated due to the potentiation of hypotensive and sedative effects of tizanidine [see Contraindications (4.2)].
Theophylline Avoid Use (Plasma Exposure Likely to be Increased and Prolonged) Concurrent administration of ciprofloxacin with theophylline may result in increased risk of a patient developing central nervous system (CNS) or other adverse reactions. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate [see Warnings and Precautions (5.9)].
Drugs Known to Prolong QT Interval Avoid Use Ciprofloxacin may further prolong the QT interval in patients receiving drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) [see Warnings and Precautions (5.11) and Use in Specific Populations (8.5)].
Oral antidiabetic drugs Use with caution Glucose-lowering effect potentiated Hypoglycemia sometimes severe has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were co-administered, presumably by intensifying the action of the oral antidiabetic agent. Fatalities have been reported . Monitor blood glucose when ciprofloxacin is co-administered with oral antidiabetic drugs [see Adverse Reactions (6.1)].
Phenytoin Use with caution Altered serum levels of phenytoin (increased and decreased) To avoid the loss of seizure control associated with decreased phenytoin levels and to prevent phenytoin overdose-related adverse reactions upon ciprofloxacin discontinuation in patients receiving both agents, monitor phenytoin therapy, including phenytoin serum concentration during and shortly after co-administration of ciprofloxacin with phenytoin.
Cyclosporine Use with caution (transient elevations in serum creatinine) Monitor renal function (in particular serum creatinine) when ciprofloxacin is co-administered with cyclosporine.
Anti-coagulant drugs Use with caution (Increase in anticoagulant effect) The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Monitor prothrombin time and INR frequently during and shortly after co-administration of ciprofloxacin with an oral anti-coagulant (for example, warfarin).
Methotrexate Use with caution Inhibition of methotrexate renal tubular transport potentially leading to increased methotrexate plasma levels Potential increase in the risk of methotrexate associated toxic reactions. Therefore, carefully monitor patients under methotrexate therapy when concomitant ciprofloxacin therapy is indicated.
Ropinirole Use with caution Monitoring for ropinirole-related adverse reactions and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin [see Warnings and Precautions (5.16)].
Clozapine Use with caution Careful monitoring of clozapine associated adverse reactions and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised.
NSAIDs Use with caution Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies and in postmarketing.
Sildenafil Use with caution Two-fold increase in exposure Monitor for sildenafil toxicity [see Clinical Pharmacology (12.3)].
Duloxetine Avoid Use Five-fold increase in duloxetine exposure If unavoidable, monitor for duloxetine toxicity
Caffeine/Xanthine Derivatives Use with caution Reduced clearance resulting in elevated levels and prolongation of serum half-life Ciprofloxacin inhibits the formation of paraxanthine after caffeine administration (or pentoxifylline containing products). Monitor for xanthine toxicity and adjust dose as necessary.
Zolpidem Avoid Use Co-administration with ciprofloxacin may increase blood levels of zolpidem, concurrent use is not recommended
Drug(s) Affecting Pharmacokinetics of Ciprofloxacin
Antacids, Sucralfate, Multivitamins and Other Products Containing Multivalent Cations (magnesium/aluminum antacids; polymeric phosphate binders (for example, sevelamer, lanthanum carbonate); sucralfate; Videx ® (didanosine) chewable/ buffered tablets or pediatric powder; other highly buffered drugs; or products containing calcium, iron, or zinc and dairy products) Ciprofloxacin should be taken at least two hours before or six hours after Multivalent cation-containing products administration [see Dosage and Administration (2.4)]. Decrease ciprofloxacin absorption, resulting in lower serum and urine levels
Probenecid Use with caution (interferes with renal tubular secretion of ciprofloxacin and increases ciprofloxacin serum levels) Potentiation of ciprofloxacin toxicity may occur.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. Ciprofloxacin should not be used during pregnancy unless the potential benefit justifies the potential risk to both fetus and mother. An expert review of published data on experiences with ciprofloxacin use during pregnancy by TERIS–the Teratogen Information System–concluded that therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk (quantity and quality of data=fair), but the data are insufficient to state that there is no risk. 2

A controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5% exposed to ciprofloxacin and 68% first trimester exposures) during gestation. 3 In utero exposure to fluoroquinolones during embryogenesis was not associated with increased risk of major malformations. The reported rates of major congenital malformations were 2.2% for the fluoroquinolone group and 2.6% for the control group (background incidence of major malformations is 1 to 5%). Rates of spontaneous abortions, prematurity and low birth weight did not differ between the groups and there were no clinically significant musculoskeletal dysfunctions up to one year of age in the ciprofloxacin exposed children.

Another prospective follow-up study reported on 549 pregnancies with fluoroquinolone exposure (93% first trimester exposures). 4 There were 70 ciprofloxacin exposures, all within the first trimester. The malformation rates among live-born babies exposed to ciprofloxacin and to fluoroquinolones overall were both within background incidence ranges. No specific patterns of congenital abnormalities were found. The study did not reveal any clear adverse reactions due to in utero exposure to ciprofloxacin.

No differences in the rates of prematurity, spontaneous abortions, or birth weight were seen in women exposed to ciprofloxacin during pregnancy. 2, 3 However, these small postmarketing epidemiology studies, of which most experience is from short term, first trimester exposure, are insufficient to evaluate the risk for less common defects or to permit reliable and definitive conclusions regarding the safety of ciprofloxacin in pregnant women and their developing fetuses.

Reproduction studies have been performed in rats and mice using oral doses up to 100 mg/kg (0.6 and 0.3 times the maximum daily human dose based upon body surface area, respectively) and have revealed no evidence of harm to the fetus due to ciprofloxacin. In rabbits, oral ciprofloxacin dose levels of 30 and 100 mg/kg (approximately 0.4- and 1.3-times the highest recommended therapeutic dose based upon body surface area) produced gastrointestinal toxicity resulting in maternal weight loss and an increased incidence of abortion, but no teratogenicity was observed at either dose level. After intravenous administration of doses up to 20 mg/kg (approximately 0.3-times the highest recommended therapeutic dose based upon body surface area), no maternal toxicity was produced and no embryotoxicity or teratogenicity was observed.

8.3 Nursing Mothers


Ciprofloxacin is excreted in human milk. The amount of ciprofloxacin absorbed by the nursing infant is unknown. Because of the potential risk of serious adverse reactions (including articular damage) in infants nursing from mothers taking ciprofloxacin, 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.

8.4 Pediatric Use

Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the pediatric population due to an increased incidence of adverse reactions compared to controls. Quinolones, including ciprofloxacin, cause arthropathy (arthralgia, arthritis), in juvenile animals [see Warnings and Precautions (5.12) and Nonclinical Toxicology (13.2)] .

Complicated Urinary Tract Infection and Pyelonephritis

Ciprofloxacin is indicated for the treatment of cUTI and pyelonephritis due to Escherichia coli in pediatric patients 1 to 17 years of age . Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the pediatric population due to an increased incidence of adverse reactions compared to the controls, including events related to joints and/or surrounding tissues [see Adverse Reactions (6.1) and Clinical Studies (14.1)].

Inhalational Anthrax (Post-Exposure)

Ciprofloxacin is indicated in pediatric patients from birth to 17 years of age, for inhalational anthrax (post-exposure). The risk-benefit assessment indicates that administration of ciprofloxacin to pediatric patients is appropriate [see Dosage and Administration (2.2) and Clinical Studies (14.2)].

Plague

Ciprofloxacin is indicated in pediatric patients from birth to 17 years of age, for treatment of plague, including pneumonic and septicemic plague due to Yersinia pestis (Y. pestis) and prophylaxis for plague. Efficacy studies of ciprofloxacin could not be conducted in humans with pneumonic plague for feasibility reasons. Therefore, approval of this indication was based on an efficacy study conducted in animals. The risk-benefit assessment indicates that administration of ciprofloxacin to pediatric patients is appropriate [see Indications and Usage (1.8), Dosage and Administration (2.2) and Clinical Studies (14.3)].

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