PRECAUTIONS SECTION.


PRECAUTIONS General. Crystals of ciprofloxacin have been observed rarely in the urine of human subjects but more frequently in the urine of laboratory animals, which is usually alkaline. (See ANIMAL PHARMACOLOGY.) Crystalluria related to ciprofloxacin has been reported only rarely in humans because human urine is usually acidic. Alkalinity of the urine should be avoided in patients receiving ciprofloxacin. Patients should be well hydrated to prevent the formation of highly concentrated urine. Central Nervous System. Quinolones, including ciprofloxacin, may also cause central nervous system (CNS) events, including: nervousness, agitation, insomnia, anxiety, nightmares or paranoia. (See WARNINGS Information for Patients, and Drug Interactions.) Renal Impairment. Alteration of the dosage regimen is necessary for patients with impairment of renal function. (See DOSAGE AND ADMINISTRATION.). Photosensitivity/Phototoxicity. Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as exaggerated sunburn reactions (for example, burning, erythema, exudation, vesicles, blistering, edema) involving areas exposed to light (typically the face, V area of the neck, extensor surfaces of the forearms, dorsa of the hands), can be associated with the use of quinolones after sun or UV light exposure. Therefore, excessive exposure to these sources of light should be avoided. Drug therapy should be discontinued if phototoxicity occurs (See ADVERSE REACTIONS/Postmarketing Adverse Event Reports).As with any potent drug, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic function, is advisable during prolonged therapy. Prescribing ciprofloxacin hydrochloride tablets in the absence of proven or strongly suspected bacterial infection or prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Information for Patients. Patients should be advised:To contact their healthcare provider if they experience pain, swelling, or inflammation of tendon, or weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue ciprofloxacin hydrochloride treatment. The risk of severe tendon disorder with fluoroquinolones is higher in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. That fluoroquinolones like ciprofloxacin hydrochloride may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Patients should call their healthcare provider right away if they have any worsening muscle weakness or breathing problems. That antibacterial drugs including ciprofloxacin hydrochloride tablets should only be used to treat bacterial infections. They do not treat viral infections (for example, the common cold). When ciprofloxacin hydrochloride tablets are prescribed to treat bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by ciprofloxacin hydrochloride tablets or other antibacterial drugs in the future.That ciprofloxacin may be taken with or without meals and to drink fluids liberally. As with other quinolones, concurrent administration of ciprofloxacin with magnesium/aluminum antacids, polymeric phosphate binders (for example, sevelamer, lanthanum carbonate) or sucralfate, Videx(R) (didanosine) chewable/buffered tablets or pediatric powder, other highly buffered drugs, or with other products containing calcium, iron or zinc should be avoided. Ciprofloxacin may be taken two hours before or six hours after taking these products. Ciprofloxacin should not be taken with dairy products (like milk or yogurt) or calcium-fortified juices alone since absorption of ciprofloxacin may be significantly reduced; however, ciprofloxacin may be taken with meal that contains these products.That ciprofloxacin may be associated with hypersensitivity reactions, even following single dose, and to discontinue the drug at the first sign of skin rash or other allergic reaction. That photosensitivity/phototoxicity has been reported in patients receiving quinolones. Patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while taking quinolones. If patients need to be outdoors while using quinolones, they should wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician. If sunburn-like reaction or skin eruption occurs, patients should contact their physician.That peripheral neuropathies have been associated with ciprofloxacin use, that symptoms may occur soon after initiation of therapy and may be irreversible. If symptoms of peripheral neuropathy including pain, burning, tingling, numbness and/or weakness develop, patients should immediately discontinue ciprofloxacin hydrochloride and contact their physician.That ciprofloxacin may cause dizziness and lightheadedness; therefore, patients should know how they react to this drug before they operate an automobile or machinery or engage in activities requiring mental alertness or coordination.That ciprofloxacin increases the effects of tizanidine (Zanaflex(R)). Patients should not use ciprofloxacin if they are already taking tizanidine.That ciprofloxacin may increase the effects of theophylline and caffeine. There is possibility of caffeine accumulation when products containing caffeine are consumed while taking quinolones.That convulsions have been reported in patients receiving quinolones, including ciprofloxacin, and to notify their physician before taking this drug if there is history of this condition. That ciprofloxacin has been associated with an increased rate of adverse events involving joints and surrounding tissue structures (like tendons) in pediatric patients (less than 18 years of age). Parents should inform their childs physician if the child has history of joint-related problems before taking this drug. Parents of pediatric patients should also notify their childs physician of any joint-related problems that occur during or following ciprofloxacin therapy. (See WARNINGS, PRECAUTIONS, Pediatric Use and ADVERSE REACTIONS.) That diarrhea is common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.. To contact their healthcare provider if they experience pain, swelling, or inflammation of tendon, or weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue ciprofloxacin hydrochloride treatment. The risk of severe tendon disorder with fluoroquinolones is higher in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. That fluoroquinolones like ciprofloxacin hydrochloride may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Patients should call their healthcare provider right away if they have any worsening muscle weakness or breathing problems. That antibacterial drugs including ciprofloxacin hydrochloride tablets should only be used to treat bacterial infections. They do not treat viral infections (for example, the common cold). When ciprofloxacin hydrochloride tablets are prescribed to treat bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by ciprofloxacin hydrochloride tablets or other antibacterial drugs in the future.. That ciprofloxacin may be taken with or without meals and to drink fluids liberally. As with other quinolones, concurrent administration of ciprofloxacin with magnesium/aluminum antacids, polymeric phosphate binders (for example, sevelamer, lanthanum carbonate) or sucralfate, Videx(R) (didanosine) chewable/buffered tablets or pediatric powder, other highly buffered drugs, or with other products containing calcium, iron or zinc should be avoided. Ciprofloxacin may be taken two hours before or six hours after taking these products. Ciprofloxacin should not be taken with dairy products (like milk or yogurt) or calcium-fortified juices alone since absorption of ciprofloxacin may be significantly reduced; however, ciprofloxacin may be taken with meal that contains these products.. That ciprofloxacin may be associated with hypersensitivity reactions, even following single dose, and to discontinue the drug at the first sign of skin rash or other allergic reaction. That photosensitivity/phototoxicity has been reported in patients receiving quinolones. Patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while taking quinolones. If patients need to be outdoors while using quinolones, they should wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician. If sunburn-like reaction or skin eruption occurs, patients should contact their physician.. That peripheral neuropathies have been associated with ciprofloxacin use, that symptoms may occur soon after initiation of therapy and may be irreversible. If symptoms of peripheral neuropathy including pain, burning, tingling, numbness and/or weakness develop, patients should immediately discontinue ciprofloxacin hydrochloride and contact their physician.. That ciprofloxacin may cause dizziness and lightheadedness; therefore, patients should know how they react to this drug before they operate an automobile or machinery or engage in activities requiring mental alertness or coordination.. That ciprofloxacin increases the effects of tizanidine (Zanaflex(R)). Patients should not use ciprofloxacin if they are already taking tizanidine.. That ciprofloxacin may increase the effects of theophylline and caffeine. There is possibility of caffeine accumulation when products containing caffeine are consumed while taking quinolones.. That convulsions have been reported in patients receiving quinolones, including ciprofloxacin, and to notify their physician before taking this drug if there is history of this condition. That ciprofloxacin has been associated with an increased rate of adverse events involving joints and surrounding tissue structures (like tendons) in pediatric patients (less than 18 years of age). Parents should inform their childs physician if the child has history of joint-related problems before taking this drug. Parents of pediatric patients should also notify their childs physician of any joint-related problems that occur during or following ciprofloxacin therapy. (See WARNINGS, PRECAUTIONS, Pediatric Use and ADVERSE REACTIONS.) That diarrhea is common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.. Drug Interactions. TizanidineIn pharmacokinetic study, systemic exposure of tizanidine (4 mg single dose) was significantly increased (Cmax 7-fold, AUC 10-fold) when the drug was given concomitantly with ciprofloxacin (500 mg BID for days). The hypotensive and sedative effects of tizanidine were also potentiated. Concomitant administration of tizanidine and ciprofloxacin is contraindicated. (See CONTRAINDICATIONS.)Theophylline As with some other quinolones, concurrent administration of ciprofloxacin with theophylline may lead to elevated serum concentrations of theophylline and prolongation of its elimination half-life. This may result in increased risk of theophylline-related adverse reactions. (See WARNINGS.) If concomitant use cannot be avoided, serum levels of theophylline should be monitored and dosage adjustments made as appropriate. Other Xanthine DerivativesSome quinolones, including ciprofloxacin, have also been shown to interfere with the metabolism of caffeine. This may lead to reduced clearance of caffeine and prolongation of its serum half-life. On concurrent administration of ciprofloxacin and caffeine or pentoxifylline containing products, elevated serum concentrations of these xanthine derivatives were reported. Chelation Complex FormationConcurrent administration of quinolone, including ciprofloxacin, with multivalent cation-containing products such as magnesium/aluminum antacids, polymeric phosphate binders (for example. sevelamer, lanthanum carbonate) sucralfate, Videx(R) (didanosine) chewable/buffered tablets or pediatric powder, other highly buffered drugs, or products containing calcium, iron, or zinc may substantially decrease its absorption, resulting in serum and urine levels considerably lower than desired. (See DOSAGE AND ADMINISTRATION for concurrent administration of these agents with ciprofloxacin.) Histamine H2-receptor antagonists appear to have no significant effect on the bioavailability of ciprofloxacin. OmeprazoleConcomitant administration of single tablet dose of 500 mg ciprofloxacin and once-daily administration of 20 mg omeprazole pretreatment for days resulted in 16% reduction of mean Cmax and mean AUC of ciprofloxacin PhenytoinAltered serum levels of phenytoin (increased and decreased) have been reported in patients receiving concomitant ciprofloxacin. To avoid the loss of seizure control associated with decreased phenytoin levels, and to prevent phenytoin overdose-related undesirable effects when ciprofloxacin is discontinued in patients receiving both agents, monitoring of phenytoin therapy, including phenytoin serum concentration measurements, is recommended during and shortly after co-administration of ciprofloxacin with phenytoin.Oral Antidiabetic AgentsHypoglycemia 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 (see ADVERSE REACTIONS).The concomitant administration of ciprofloxacin with glyburide has, on rare occasions, resulted in severe hypoglycemia. Fatalities have been reported.MetronidazoleThe serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs were given concomitantly.CyclosporineSome quinolones, including ciprofloxacin, have been associated with transient elevations in serum creatinine in patients receiving cyclosporine concomitantly. Oral Anti-coagulantsSimultaneous administration of ciprofloxacin with an oral anticoagulant may augment the effect of the anticoagulant. 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. Prothrombin time and INR should be monitored frequently during and shortly after co-administration of ciprofloxacin with an oral anticoagulant (for example, warfarin).ProbenecidProbenecid interferes with renal tubular secretion of ciprofloxacin and produces an increase in the level of ciprofloxacin in the serum. This should be considered if patients are receiving both drugs concomitantly. MethotrexateRenal tubular transport of methotrexate may be inhibited by concomitant administration of ciprofloxacin potentially leading to increased plasma levels of methotrexate. This might increase the risk of methotrexate associated toxic reactions. Therefore, patients under methotrexate therapy should be carefully monitored when concomitant ciprofloxacin therapy is indicated.Metoclopramide Metoclopramide significantly accelerates the absorption of oral ciprofloxacin resulting in shorter time to reach maximum plasma concentrations. No significant effect was observed on the bioavailability of ciprofloxacin. DuloxetineIn clinical studies it was demonstrated that concomitant use of duloxetine with strong inhibitors of the CYP450 1A2 isozyme such as fluvoxamine, may result in 5-fold increase in mean AUC and 2.5-fold increase in mean Cmax of duloxetine. Although no clinical data are available on possible interaction with ciprofloxacin, similar effects can be expected upon concomitant administration.NSAIDsNon-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.RopiniroleIn study conducted in 12 patients with Parkinsons disease who were administered mg ropinirole once daily with 500 mg ciprofloxacin twice-daily, the mean Cmax and mean AUC of ropinirole were increased by 60% and 84%, respectively. Monitoring for ropinirole-related side effects and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin. (See WARNINGS, Cytochrome P450.)LidocaineIn study conducted in healthy volunteers, concomitant use of 1.5 mg/kg IV lidocaine with 500 mg ciprofloxacin twice daily, resulted in an increase of lidocaine Cmax and AUC by 12% and 26%, respectively. Although lidocaine treatment was well tolerated at this elevated exposure, possible interaction with ciprofloxacin and an increase in side effects related to lidocaine may occur upon concomitant administration.ClozapineFollowing concomitant administration of 250 mg ciprofloxacin with 304 mg clozapine for days, serum concentrations of clozapine and N-desmethylclozapine were increased by 29% and 31%, respectively. Careful monitoring of clozapine associated adverse effects and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised. (See WARNINGS.)SildenafilFollowing concomitant administration of single oral dose of 50 mg sildenafil with 500 mg ciprofloxacin to healthy subjects, the mean Cmax and mean AUC of sildenafil were both increased approximately two-fold. Therefore, sildenafil should be used with caution when co-administered with ciprofloxacin.Drugs known to prolong QT intervalPrecaution should be taken when using ciprofloxacin concomitantly with drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) as ciprofloxacin may have an additive effect on the QT interval (see WARNINGS, Prolongation of the QT Interval and PRECAUTIONS, Geriatric Use).. Carcinogenesis, Mutagenesis, Impairment of Fertility Eight in vitro mutagenicity tests have been conducted with ciprofloxacin, and the test results are listed below: Salmonella/Microsome Test (Negative) E. coli DNULL Repair Assay (Negative) Mouse Lymphoma Cell Forward Mutation Assay (Positive) Chinese Hamster V79 Cell HGPRT Test (Negative) Syrian Hamster Embryo Cell Transformation Assay (Negative) Saccharomyces cerevisiae Point Mutation Assay (Negative) Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative) Rat Hepatocyte DNULL Repair Assay (Positive) Thus, of the tests were positive, but results of the following in vivo test systems gave negative results: Rat Hepatocyte DNULL Repair Assay Micronucleus Test (Mice) Dominant Lethal Test (Mice) Long-term carcinogenicity studies in rats and mice resulted in no carcinogenic or tumorigenic effects due to ciprofloxacin at daily oral dose levels up to 250 and 750 mg/kg to rats and mice, respectively (approximately 1.7- and 2.5- times the highest recommended therapeutic dose based upon mg/m2). Results from photo co-carcinogenicity testing indicate that ciprofloxacin does not reduce the time to appearance of UV-induced skin tumors as compared to vehicle control. Hairless (Skh-1) mice were exposed to UVA light for 3.5 hours five times every two weeks for up to 78 weeks while concurrently being administered ciprofloxacin. The time to development of the first skin tumors was 50 weeks in mice treated concomitantly with UVA and ciprofloxacin (mouse dose approximately equal to maximum recommended human dose based upon mg/m2), as opposed to 34 weeks when animals were treated with both UVA and vehicle. The times to development of skin tumors ranged from 16 to 32 weeks in mice treated concomitantly with UVA and other quinolones.5 In this model, mice treated with ciprofloxacin alone did not develop skin or systemic tumors. There are no data from similar models using pigmented mice and/or fully haired mice. The clinical significance of these findings to humans is unknown. Fertility studies performed in rats at oral doses of ciprofloxacin up to 100 mg/kg (approximately 0.7-times the highest recommended therapeutic dose based upon mg/m2) revealed no evidence of impairment. Pregnancy. Teratogenic Effects. Pregnancy Category CThere 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 (see WARNINGS). 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 substantial teratogenic risk (quantity and quality of data=fair), but the data are insufficient to state that there is no risk.9 controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5% exposed to ciprofloxacin and 68% first trimester exposures) during gestation.10 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 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).11 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.9,10 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 mg/m2) 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 mg/m2) no maternal toxicity was produced and no embryotoxicity or teratogenicity was observed. (See WARNINGS.) 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, decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use. Ciprofloxacin, like other quinolones, causes arthropathy and histological changes in weight-bearing joints of juvenile animals resulting in lameness. (See ANIMAL PHARMACOLOGY.) Inhalational Anthrax (Post-Exposure)Ciprofloxacin is indicated in pediatric patients for inhalational anthrax (post-exposure). The risk-benefit assessment indicates that administration of ciprofloxacin to pediatric patients is appropriate. For information regarding pediatric dosing in inhalational anthrax (post-exposure), see DOSAGE AND ADMINISTRATIONand Inhalational Anthrax, Additional Information. Complicated Urinary Tract Infection and PyelonephritisCiprofloxacin is indicated for the treatment of complicated urinary tract infections and pyelonephritis due to Escherichia coli. Although effective in clinical trials, ciprofloxacin is not drug of first choice in the pediatric population due to an increased incidence of adverse events compared to the controls, including events related to joints and/or surrounding tissues. The rates of these events in pediatric patients with complicated urinary tract infection and pyelonephritis within six weeks of follow-up were 9.3% (31/335) versus 6% (21/349) for control agents. The rates of these events occurring at any time up to the one year follow-up were 13.7% (46/335) and 9.5% (33/349), respectively. The rate of all adverse events regardless of drug relationship at six weeks was 41% (138/335) in the ciprofloxacin arm compared to 31% (109/349) in the control arm. (See ADVERSE REACTIONS and CLINICAL STUDIES.) Cystic FibrosisShort-term safety data from single trial in pediatric cystic fibrosis patients are available. In randomized, double-blind clinical trial for the treatment of acute pulmonary exacerbations in cystic fibrosis patients (ages to 17 years), 67 patients received ciprofloxacin IV 10 mg/kg/dose q8h for one week followed by ciprofloxacin tablets 20 mg/kg/dose q12h to complete 10 to 21 days treatment and 62 patients received the combination of ceftazidime IV 50 mg/kg/dose q8h and tobramycin IV mg/kg/dose q8h for total of 10 to 21 days. Patients less than years of age were not studied. Safety monitoring in the study included periodic range of motion examinations and gait assessments by treatment-blinded examiners. Patients were followed for an average of 23 days after completing treatment (range to 93 days). This study was not designed to determine long term effects and the safety of repeated exposure to ciprofloxacin. Musculoskeletal adverse events in patients with cystic fibrosis were reported in 22% of the patients in the ciprofloxacin group and 21% in the comparison group. Decreased range of motion was reported in 12% of the subjects in the ciprofloxacin group and 16% in the comparison group. Arthralgia was reported in 10% of the patients in the ciprofloxacin group and 11% in the comparison group. Other adverse events were similar in nature and frequency between treatment arms. One of sixty-seven patients developed arthritis of the knee nine days after ten day course of treatment with ciprofloxacin. Clinical symptoms resolved, but an MRI showed knee effusion without other abnormalities eight months after treatment. However, the relationship of this event to the patients course of ciprofloxacin can not be definitively determined, particularly since patients with cystic fibrosis may develop arthralgias/arthritis as part of their underlying disease process. Geriatric Use. Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with fluoroquinolone such as ciprofloxacin hydrochloride. This risk is further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after fluoroquinolone treatment have been reported. Caution should be used when prescribing ciprofloxacin hydrochloride to elderly patients especially those on corticosteroids. Patients should be informed of this potential side effect and advised to discontinue ciprofloxacin hydrochloride and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur (See Boxed Warning WARNINGS and ADVERSE REACTIONS/Postmarketing Adverse Event Reports). In retrospective analysis of 23 multiple-dose controlled clinical trials of ciprofloxacin encompassing over 3500 ciprofloxacin treated patients, 25% of patients were greater than or equal to 65 years of age and 10% were greater than or equal to 75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals on any drug therapy cannot be ruled out. Ciprofloxacin is known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. No alteration of dosage is necessary for patients greater than 65 years of age with normal renal function. However, since 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. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.) In general, elderly patients may be more susceptible to drug-associated effects on the QT interval. Therefore, precaution should be taken when using ciprofloxacin hydrochloride with concomitant drugs that can result in prolongation of the QT interval (for example, class IA or class III antiarrhythmics) or in patients with risk factors for torsade de pointes (for example, known QT prolongation, uncorrected hypokalemia). (See WARNINGS.).

NURSING MOTHERS SECTION.


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, decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

ADVERSE REACTIONS SECTION.


ADVERSE REACTIONS 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 WHOLE: headache, abdominal pain/discomfort, foot pain, pain, pain in extremities, injection site reaction (ciprofloxacin intravenous) CARDIOVASCULAR: palpitation, atrial flutter, ventricular ectopy, syncope, hypertension, angina pectoris, myocardial infarction, cardiopulmonary arrest, cerebral thrombosis, phlebitis, tachycardia, migraine, hypotension CENTRAL NERVOUS SYSTEM: restlessness, dizziness, lightheadedness, insomnia, nightmares, hallucinations, manic reaction, irritability, tremor, ataxia, convulsive seizures (including status epilepticus), grand mal convulsion, lethargy, drowsiness, weakness, malaise, anorexia, phobia, depersonalization, depression (potentially culminating in self-injurious behavior, such as suicidal ideations/thoughts and attempted or completed suicide), paresthesia, abnormal gaitGASTROINTESTINULLL: painful oral mucosa, oral candidiasis, dysphagia, intestinal perforation, gastrointestinal bleeding, cholestatic jaundice, hepatitisHEMIC/LYMPHATIC: lymphadenopathy, petechia METABOLIC/NUTRITIONULLL: amylase increase, lipase increase, hyperglycemia, hypoglycemiaMUSCULOSKELETAL: arthralgia or back pain, joint stiffness, achiness, neck or chest pain, flare up of gout, muscle weakness RENULLL/UROGENITAL: interstitial nephritis, nephritis, renal failure, polyuria, urinary retention, urethral bleeding, vaginitis, acidosis, breast pain RESPIRATORY: dyspnea, epistaxis, laryngeal or pulmonary edema, hiccough, hemoptysis, bronchospasm, pulmonary embolism 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, sweatingSPECIAL 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 result of drug interaction with ciprofloxacin. In randomized, double-blind controlled clinical trials comparing ciprofloxacin tablets (500 mg BID) to cefuroxime axetil (250 mg to 500 mg BID) and to clarithromycin (500 mg BID) in patients with respiratory tract infections, ciprofloxacin demonstrated CNS adverse event profile comparable to the control drugs. Adverse Reactions in Pediatric Patients. Ciprofloxacin, administered IV and /or orally, was compared to cephalosporin for treatment of complicated urinary tract infections (cUTI) or pyelonephritis in pediatric patients to 17 years of age (mean age of +- 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 range of to 88 days). The primary objective of the study was to assess musculoskeletal and neurological safety within 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 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 joint. The affected joints included: knee, elbow, ankle, hip, wrist, and shoulder. Within 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 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 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 weeks later showed tear in the right ulnar fibrocartilage. diagnosis of overuse syndrome secondary to sports activity was made, but contribution from ciprofloxacin cannot be excluded. The patient recovered by months without surgical intervention. Findings Involving Joint or Peri-articular Tissues as Assessed by the IPSC Ciprofloxacin Comparator All Patients (within weeks) 31/335 (9.3%) 21/349 (6%) 95% Confidence Interval (-0.8%, +7.2%) Age Group >= 12 months 24 months 1/36 (2.8%) 0/41 >= years 6 years 5/124 (4%) 3/118 (2.5%) >= years 12 years 18/143 (12.6%) 12/153 (7.8%) >= 12 years to 17 years 7/32 (21.9%) 6/37 (16.2 %) All Patients (within year) 46/335 (13.7%) 33/349 (9.5%) 95% Confidence Interval (-0.6%, 9.1%) The study was designed to demonstrate that the arthropathy rate for the ciprofloxacin group did not exceed that of the control group by more than 6%. At both the week and year evaluations, the 95% confidence interval indicated that it could not be concluded that ciprofloxacin group had findings comparable to the control group. The incidence rates of neurological events within 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 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 Adverse Event Reports. The following adverse events have been reported from worldwide marketing experience with fluoroquinolones, including ciprofloxacin. Because these events are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish 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. Acute generalized exanthematous pustulosis (AGEP), 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 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 (Lyells Syndrome), triglyceride elevation (serum), twitching, vaginal candidiasis, vasculitis and ventricular arrhythmia. (See PRECAUTIONS .) Adverse events were also reported by persons who received ciprofloxacin for anthrax post-exposure prophylaxis following the anthrax bioterror attacks of October 2001. (See also INHALATION ANTHRAX -ADDITIONULLL INFORMATION.)Adverse Laboratory Changes: Changes in laboratory parameters listed as adverse events without regard to drug relationship are listed below: Hepatic Elevations of ALT (SGPT) (1.9%), AST (SGOT) (1.7%), alkaline phosphatase (0.8%), LDH (0.4%), serum bilirubin (0.3%). Hematologic Eosinophilia (0.6%), leukopenia (0.4%), decreased blood platelets (0.1%), elevated blood platelets (0.1%), pancytopenia (0.1%). Renal Elevations of serum creatinine (1.1%), BUN (0.9%), crystalluria, cylindruria, and hematuria have been reported. 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. To report SUSPECTED ADVERSE REACTIONS, contact Actavis at 1-800-272-5525 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

BOXED WARNING SECTION.


WARNING:. Fluoroquinolones, including ciprofloxacin hydrochloride, are associated with an increased risk of tendinitis and tendon rupture in all ages. This risk 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 (see WARNINGS).Fluoroquinolones, including ciprofloxacin hydrochloride, may exacerbate muscle weakness in persons with myasthenia gravis. Avoid ciprofloxacin hydrochloride in patients with known history of myasthenia gravis (see WARNINGS).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


Carcinogenesis, Mutagenesis, Impairment of Fertility Eight in vitro mutagenicity tests have been conducted with ciprofloxacin, and the test results are listed below: Salmonella/Microsome Test (Negative) E. coli DNULL Repair Assay (Negative) Mouse Lymphoma Cell Forward Mutation Assay (Positive) Chinese Hamster V79 Cell HGPRT Test (Negative) Syrian Hamster Embryo Cell Transformation Assay (Negative) Saccharomyces cerevisiae Point Mutation Assay (Negative) Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative) Rat Hepatocyte DNULL Repair Assay (Positive) Thus, of the tests were positive, but results of the following in vivo test systems gave negative results: Rat Hepatocyte DNULL Repair Assay Micronucleus Test (Mice) Dominant Lethal Test (Mice) Long-term carcinogenicity studies in rats and mice resulted in no carcinogenic or tumorigenic effects due to ciprofloxacin at daily oral dose levels up to 250 and 750 mg/kg to rats and mice, respectively (approximately 1.7- and 2.5- times the highest recommended therapeutic dose based upon mg/m2). Results from photo co-carcinogenicity testing indicate that ciprofloxacin does not reduce the time to appearance of UV-induced skin tumors as compared to vehicle control. Hairless (Skh-1) mice were exposed to UVA light for 3.5 hours five times every two weeks for up to 78 weeks while concurrently being administered ciprofloxacin. The time to development of the first skin tumors was 50 weeks in mice treated concomitantly with UVA and ciprofloxacin (mouse dose approximately equal to maximum recommended human dose based upon mg/m2), as opposed to 34 weeks when animals were treated with both UVA and vehicle. The times to development of skin tumors ranged from 16 to 32 weeks in mice treated concomitantly with UVA and other quinolones.5 In this model, mice treated with ciprofloxacin alone did not develop skin or systemic tumors. There are no data from similar models using pigmented mice and/or fully haired mice. The clinical significance of these findings to humans is unknown. Fertility studies performed in rats at oral doses of ciprofloxacin up to 100 mg/kg (approximately 0.7-times the highest recommended therapeutic dose based upon mg/m2) revealed no evidence of impairment.

CLINICAL PHARMACOLOGY SECTION.


CLINICAL PHARMACOLOGY 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. Dose(mg)Maximum Serum Concentration(mcg/mL)Area Under Curve (AUC) (mcgohr/mL) 250 1.2 4.8 500 2.4 11.6 750 4.3 20.2 1000 5.4 30.8Maximum serum concentrations are attained to 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 hours. Serum concentrations increase proportionately with doses up to 1000 mg. 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. 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 hours. 750 mg oral dose results in Cmax similar to that observed with 400 mg IV dose. 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. Steady-state Pharmacokinetic ParametersFollowing Multiple Oral and IV Doses Parameters 500 mgq12h, P.O. 400 mgq12h, IV 750 mgq12h, P.O. 400 mgq8h, IV AUC (mcghr/mL) 13.7a 12.7a 31.6b 32.9c Cmax (mcg/mL) 2.97 4.56 3.59 4.07aAUC0-12hbAUC 24h=AUC0-12h 2cAUC 24h=AUC0-8h 3. 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 (see CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, Drug Interactions).. Excretion. The serum elimination half-life in subjects with normal renal function is approximately hours. Approximately 40 to 50% of an orally administered dose is excreted in the urine as unchanged drug. After 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 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 significant role in its elimination. Co-administration of probenecid with ciprofloxacin results in about 50% reduction in the ciprofloxacin renal clearance and 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 small amount of the dose administered is recovered from the bile as unchanged drug. An additional 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 days after dosing. This may arise from either biliary clearance or transintestinal elimination. Drug-Drug Interactions. When ciprofloxacin hydrochloride tablets are given concomitantly with food, there is delay in the absorption of the drug, resulting in peak concentrations that occur closer to hours after dosing rather than hour. The overall absorption of ciprofloxacin hydrochloride tablets, however, is not substantially affected. Concurrent administration of antacids containing magnesium hydroxide or aluminum hydroxide may reduce the bioavailability of ciprofloxacin by as much as 90%. (See PRECAUTIONS.)The serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs were given concomitantly. Concomitant administration with tizanidine is contraindicated. (See CONTRAINDICATIONS).Concomitant administration of ciprofloxacin with theophylline decreases the clearance of theophylline resulting in elevated serum theophylline levels and increased risk of patient developing CNS or other adverse reactions. Ciprofloxacin also decreases caffeine clearance and inhibits the formation of paraxanthine after caffeine administration. (See WARNINGS PRECAUTIONS.) Special Populations. Pharmacokinetic studies of the oral (single dose) form of ciprofloxacin indicate that plasma concentrations of ciprofloxacin are higher in elderly subjects (> 65 years) as compared to young adults. Although the Cmax is increased 16 to 40%, the increase in mean AUC is approximately 30%, and can be at least partially attributed to decreased renal clearance in the elderly. Elimination half-life is only slightly (~20%) prolonged in the elderly. These differences are not considered clinically significant. (See PRECAUTIONS: Geriatric Use.) Patients with Renal ImpairmentIn patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged. Dosage adjustments may be required. (See DOSAGE AND ADMINISTRATION.) Patients with Hepatic ImpairmentIn 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. PediatricsFollowing single oral dose of 10 mg/kg ciprofloxacin suspension to 16 children ranging in age from months to years, the mean Cmax was 2.4 mcg/mL (range: 1.5 to 3.4 mcg/mL) and the mean AUC was 9.2 mcgh/mL (range: 5.8 to 14.9 mcgh/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 1-hour infusion), the mean Cmax was 6.1 mcg/mL (range: 4.6 to 8.3 mcg/mL) in 10 children less than year of age; and 7.2 mcg/mL (range: 4.7 to 11.8 mcg/mL) in 10 children between and years of age. The AUC values were 17.4 mcgh/mL (range: 11.8 to 32.0 mcgh/mL) and 16.5 mcgh/mL (range: 11.0 to 23.8 mcgh/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 to hours, and the bioavailability of the oral suspension is approximately 60%.

CLINICAL STUDIES SECTION.


CLINICAL STUDIES. Complicated Urinary Tract Infection and Pyelonephritis Efficacy in Pediatric Patients:. NOTE: Although effective in clinical trials, ciprofloxacin is not 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, administered IV and/or orally, was compared to cephalosporin for treatment of complicated urinary tract infections (cUTI) and pyelonephritis in pediatric patients to 17 years of age (mean age of +- 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 range of to 88 days). The primary objective of the study was to assess musculoskeletal and neurological safety. Patients were evaluated for clinical success and bacteriological eradication of the baseline organism(s) with no new infection or superinfection at to days post-therapy (Test of Cure or TOC). The Per Protocol population had causative organism(s) with protocol specified colony count(s) at baseline, no protocol violation, and no premature discontinuation or loss to follow-up (among other criteria). The clinical success and bacteriologic eradication rates in the Per Protocol population were similar between ciprofloxacin and the comparator group as shown below.Clinical Success and Bacteriologic Eradication at Test of Cure (5 to Days Post-Therapy)Ciprofloxacin Comparator Randomized Patients 337 352 Per Protocol Patients 211 231 Clinical Response at to Days Post-Treatment 95.7% (202/211) 92.6% (214/231) 95% CI [-1.3%, 7.3%] Bacteriologic Eradication by Patient at to Days Post-Treatment 84.4% (178/211) 78.3% (181/231) 95% CI -1.3%, 13.1%] Bacteriologic Eradication of the Baseline Pathogen at to Days Post-TreatmentEscherichia coli 156/178 (88%) 161/179 (90%) Patients with baseline pathogen(s) eradicated and no new infections or superinfections/total number of patients. There were 5.5% (6/211) ciprofloxacin and 9.5% (22/231) comparator patients with superinfections or new infections.. Inhalational Anthrax In Adults And Pediatrics. Additional InformationThe mean serum concentrations of ciprofloxacin associated with statistically significant improvement in survival in the rhesus monkey model of inhalational anthrax are reached or exceeded in adult and pediatric patients receiving oral regimens. (See DOSAGE AND ADMINISTRATION.) Ciprofloxacin pharmacokinetics have been evaluated in various human populations. The mean peak serum concentration achieved at steady-state in human adults receiving 500 mg orally every 12 hours is 2.97 mcg/mL, and 4.56 mcg/mL following 400 mg intravenously every 12 hours. The mean trough serum concentration at steady-state for both of these regimens is 0.2 mcg/mL. In study of 10 pediatric patients between and 16 years of age, the mean peak plasma concentration achieved is 8.3 mcg/mL and trough concentrations range from 0.09 to 0.26 mcg/mL, following two 30-minute intravenous infusions of 10 mg/kg administered 12 hours apart. After the second intravenous infusion patients switched to 15 mg/kg orally every 12 hours achieve mean peak concentration of 3.6 mcg/mL after the initial oral dose. Long-term safety data, including effects on cartilage, following the administration of ciprofloxacin to pediatric patients are limited. (For additional information, see PRECAUTIONS, Pediatric Use .) Ciprofloxacin serum concentrations achieved in humans serve as surrogate endpoint reasonably likely to predict clinical benefit and provide the basis for this indication.6 placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 11 LD50 (~5.5 105 spores (range to 30 LD50) of B. anthracis was conducted. The minimal inhibitory concentration (MIC) of ciprofloxacin for the anthrax strain used in this study was 0.08 mcg/mL. In the animals studied, mean serum concentrations of ciprofloxacin achieved at expected Tmax (1 hour post-dose) following oral dosing to steady-state ranged from 0.98 to 1.69 mcg/mL. Mean steady-state trough concentrations at 12 hours post-dose ranged from 0.12 to 0.19 mcg/mL.7 Mortality due to anthrax for animals that received 30-day regimen of oral ciprofloxacin beginning 24 hours post-exposure was significantly lower (1/9), compared to the placebo group (9/10) [p=0.001]. The one ciprofloxacin-treated animal that died of anthrax did so following the 30-day drug administration period.8 More than 9300 persons were recommended to complete minimum of 60 days of antibiotic prophylaxis against possible inhalational exposure to B. anthracis during 2001. Ciprofloxacin was recommended to most of those individuals for all or part of the prophylaxis regimen. Some persons were also given anthrax vaccine or were switched to alternative antibiotics. No one who received ciprofloxacin or other therapies as prophylactic treatment subsequently developed inhalational anthrax. The number of persons who received ciprofloxacin as all or part of their post-exposure prophylaxis regimen is unknown.Among the persons surveyed by the Centers for Disease Control and Prevention, over 1000 reported receiving ciprofloxacin as sole post-exposure prophylaxis for inhalational anthrax. Gastrointestinal adverse events (nausea, vomiting, diarrhea, or stomach pain), neurological adverse events (problems sleeping, nightmares, headache, dizziness or light headedness) and musculoskeletal adverse events (muscle or tendon pain and joint swelling or pain) were more frequent than had been previously reported in controlled clinical trials. This higher incidence, in the absence of control group, could be explained by reporting bias, concurrent medical conditions, other concomitant medications, emotional stress or other confounding factors, and/or longer treatment period with ciprofloxacin. Because of these factors and limitations in the data collection, it is difficult to evaluate whether the reported symptoms were drug-related.

CONTRAINDICATIONS SECTION.


CONTRAINDICATIONS Ciprofloxacin is contraindicated in persons with history of hypersensitivity to ciprofloxacin, any member of the quinolone class of antimicrobial agents, or any of the product components (see DESCRIPTION).Concomitant administration with tizanidine is contraindicated. (See PRECAUTIONS: Drug Interactions .).

DESCRIPTION SECTION.


DESCRIPTION Ciprofloxacin tablets, USP is synthetic broad spectrum antimicrobial agent for oral administration. Ciprofloxacin hydrochloride, USP, fluoroquinolone, is the monohydrochloride monohydrate salt of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. It is faintly yellowish to light yellow crystalline substance with molecular weight of 385.8. Its molecular formula is C17H18FN3O3YYHClYH2O and its chemical structure is as follows:Ciprofloxacin, USP is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. Its molecular formula is C17H18FN3O3 and its molecular weight is 331.4. It is faintly yellowish to light yellow crystalline substance and its chemical structure is as follows:Ciprofloxacin film-coated tablets are available in 250 mg, 500 mg and 750 mg (ciprofloxacin equivalent) strengths. Ciprofloxacin tablets, USP are white to off-white. The inactive ingredients are cornstarch, microcrystalline cellulose, silicon dioxide, crospovidone, magnesium stearate, polyvinyl alcohol, talc, titanium dioxide, polyethylene glycol and purified water.. Structure 1. Structure 2.

DOSAGE & ADMINISTRATION SECTION.


DOSAGE AND ADMINISTRATION. Adults. Ciprofloxacin tablets should be administered orally to adults as described in the Dosage Guidelines table. 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 patients 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 to 14 days; however, for severe and complicated infections more prolonged therapy may be required. Ciprofloxacin should be administered at least hours before or hours after magnesium/aluminum antacids, polymeric phosphate binders (for example, sevelamer, lanthanum carbonate) or sucralfate, Videx(R) (didanosine) chewable/buffered tablets or pediatric powder for oral solution, other highly buffered drugs, or other products containing calcium, iron or zinc. ADULT DOSAGE GUIDELINESInfectionSeverityDoseFrequencyUsual Durations+ Urinary Tract Acute Uncomplicated 250 mg 12 3 days Mild/Moderate 250 mg 12 7 to 14 days Severe/Complicated 500 mg 12 7 to 14 days Chronic Bacterial Prostatitis Mild/Moderate 500 mg 12 28 days Lower Respiratory Tract Mild/Moderate 500 mg 12 7 to 14 days Severe/Complicated 750 mg 12 7 to 14 daysAcute Sinusitis Mild/Moderate 500 mg 12 10 daysSkin andSkin Structure Mild/Moderate 500 mg 12 7 to 14 days Severe/Complicated 750 mg 12 7 to 14 days Bone and Joint Mild/Moderate 500 mg 12 >= to weeks Severe/Complicated 750 mg 12 >= to weeks Intra-Abdominal Complicated 500 mg 12 7 to 14 days Infectious Diarrhea Mild/Moderate/Severe 500 mg 12 5 to days Typhoid Fever Mild/Moderate 500 mg 12 10 days Urethral and Cervical Gonococcal Infections Uncomplicated 250 mg single dose single dose Inhalational anthrax (post-exposure) 500 mg h 12 60 days Used in conjunction with metronidazole Generally ciprofloxacin tablets should be continued for at least days after the signs and symptoms of infection have disappeared, except for inhalational anthrax (post-exposure). Drug administration should begin as soon as possible after suspected or confirmed exposure.This indication is based on surrogate endpoint, ciprofloxacin serum concentrations achieved in humans, reasonably likely to predict clinical benefit.6 For discussion of ciprofloxacin serum concentrations in various human populations, see Inhalational Anthrax, Additional Information. Conversion of IV to Oral Dosing in Adults: Patients whose therapy is started with ciprofloxacin hydrochloride I.V. may be switched to ciprofloxacin tablets when clinically indicated at the discretion of the physician (See CLINICAL PHARMACOLOGYand table below for the equivalent dosing regimens). Equivalent AUC Dosing RegimensCiprofloxacin Oral DosageEquivalent Ciprofloxacin IV Dosage 250 mg Tablet 12 200 mg IV 12 500 mg Tablet 12 400 mg IV 12 750 mg Tablet 12 400 mg IV 8 hAdults 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: RECOMMENDED STARTING AND MAINTENULLNCE DOSESFOR PATIENTS WITH IMPAIRED RENULLL FUNCTIONCreatinine Clearance (mL/min)Dose 50 See Usual Dosage. 30 to 50 250 to 500 mg 12 5 to 29 250 to 500 mg 18 Patients on hemodialysis or Peritoneal dialysis 250 to 500 mg 24 (after dialysis)When only the serum creatinine concentration is known, the following formula may be used to estimate creatinine clearance. Men: Creatinine clearance (mL/min) Weight (kg) (140 age) 72 serum creatinine (mg/dL) Women: 0.85 the value calculated for men.The serum creatinine should represent steady state of renal function. In patients with severe infections and severe renal impairment, unit dose of 750 mg may be administered at the intervals noted above. Patients should be carefully monitored. Pediatrics. Ciprofloxacin tablets 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. (See ADVERSE REACTIONS and CLINICAL STUDIES.) 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 to 10 mg/kg IV every hours and allowed to switch to oral therapy (10 to 20 mg/kg every 12 hours), at the discretion of the physician.PEDIATRIC DOSAGE GUIDELINESInfectionRoute of AdministrationDose (mg/kg)FrequencyTotal DurationComplicatedUrinary TractorPyelonephritis(patients from1 to 17 years ofage) Oral 10 mg/kg to 20 mg/kg(maximum 750 mg per dose; not to be exceeded even in patients weighing 51 kg) Every 12 hours 10 to 21 days Inhalational Anthrax (Post-Exposure) Oral 15 mg/kg(maximum 500 mg per dose) Every 12 hours 60 days The total duration of therapy for complicated urinary tract infection and pyelonephritis in the clinical trial was determined by the physician. The mean duration of treatment was 11 days (range 10 to 21 days). Drug administration should begin as soon as possible after suspected or confirmed exposure to Bacillus anthracis spores. This indication is based on surrogate endpoint, ciprofloxacin serum concentrations achieved in humans, reasonably likely to predict clinical benefit.6 For discussion of ciprofloxacin serum concentrations in various human populations, see Inhalational Anthrax In Adults and Pediatrics, Additional Information 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).

DRUG INTERACTIONS SECTION.


Drug Interactions. TizanidineIn pharmacokinetic study, systemic exposure of tizanidine (4 mg single dose) was significantly increased (Cmax 7-fold, AUC 10-fold) when the drug was given concomitantly with ciprofloxacin (500 mg BID for days). The hypotensive and sedative effects of tizanidine were also potentiated. Concomitant administration of tizanidine and ciprofloxacin is contraindicated. (See CONTRAINDICATIONS.)Theophylline As with some other quinolones, concurrent administration of ciprofloxacin with theophylline may lead to elevated serum concentrations of theophylline and prolongation of its elimination half-life. This may result in increased risk of theophylline-related adverse reactions. (See WARNINGS.) If concomitant use cannot be avoided, serum levels of theophylline should be monitored and dosage adjustments made as appropriate. Other Xanthine DerivativesSome quinolones, including ciprofloxacin, have also been shown to interfere with the metabolism of caffeine. This may lead to reduced clearance of caffeine and prolongation of its serum half-life. On concurrent administration of ciprofloxacin and caffeine or pentoxifylline containing products, elevated serum concentrations of these xanthine derivatives were reported. Chelation Complex FormationConcurrent administration of quinolone, including ciprofloxacin, with multivalent cation-containing products such as magnesium/aluminum antacids, polymeric phosphate binders (for example. sevelamer, lanthanum carbonate) sucralfate, Videx(R) (didanosine) chewable/buffered tablets or pediatric powder, other highly buffered drugs, or products containing calcium, iron, or zinc may substantially decrease its absorption, resulting in serum and urine levels considerably lower than desired. (See DOSAGE AND ADMINISTRATION for concurrent administration of these agents with ciprofloxacin.) Histamine H2-receptor antagonists appear to have no significant effect on the bioavailability of ciprofloxacin. OmeprazoleConcomitant administration of single tablet dose of 500 mg ciprofloxacin and once-daily administration of 20 mg omeprazole pretreatment for days resulted in 16% reduction of mean Cmax and mean AUC of ciprofloxacin PhenytoinAltered serum levels of phenytoin (increased and decreased) have been reported in patients receiving concomitant ciprofloxacin. To avoid the loss of seizure control associated with decreased phenytoin levels, and to prevent phenytoin overdose-related undesirable effects when ciprofloxacin is discontinued in patients receiving both agents, monitoring of phenytoin therapy, including phenytoin serum concentration measurements, is recommended during and shortly after co-administration of ciprofloxacin with phenytoin.Oral Antidiabetic AgentsHypoglycemia 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 (see ADVERSE REACTIONS).The concomitant administration of ciprofloxacin with glyburide has, on rare occasions, resulted in severe hypoglycemia. Fatalities have been reported.MetronidazoleThe serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs were given concomitantly.CyclosporineSome quinolones, including ciprofloxacin, have been associated with transient elevations in serum creatinine in patients receiving cyclosporine concomitantly. Oral Anti-coagulantsSimultaneous administration of ciprofloxacin with an oral anticoagulant may augment the effect of the anticoagulant. 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. Prothrombin time and INR should be monitored frequently during and shortly after co-administration of ciprofloxacin with an oral anticoagulant (for example, warfarin).ProbenecidProbenecid interferes with renal tubular secretion of ciprofloxacin and produces an increase in the level of ciprofloxacin in the serum. This should be considered if patients are receiving both drugs concomitantly. MethotrexateRenal tubular transport of methotrexate may be inhibited by concomitant administration of ciprofloxacin potentially leading to increased plasma levels of methotrexate. This might increase the risk of methotrexate associated toxic reactions. Therefore, patients under methotrexate therapy should be carefully monitored when concomitant ciprofloxacin therapy is indicated.Metoclopramide Metoclopramide significantly accelerates the absorption of oral ciprofloxacin resulting in shorter time to reach maximum plasma concentrations. No significant effect was observed on the bioavailability of ciprofloxacin. DuloxetineIn clinical studies it was demonstrated that concomitant use of duloxetine with strong inhibitors of the CYP450 1A2 isozyme such as fluvoxamine, may result in 5-fold increase in mean AUC and 2.5-fold increase in mean Cmax of duloxetine. Although no clinical data are available on possible interaction with ciprofloxacin, similar effects can be expected upon concomitant administration.NSAIDsNon-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.RopiniroleIn study conducted in 12 patients with Parkinsons disease who were administered mg ropinirole once daily with 500 mg ciprofloxacin twice-daily, the mean Cmax and mean AUC of ropinirole were increased by 60% and 84%, respectively. Monitoring for ropinirole-related side effects and appropriate dose adjustment of ropinirole is recommended during and shortly after co-administration with ciprofloxacin. (See WARNINGS, Cytochrome P450.)LidocaineIn study conducted in healthy volunteers, concomitant use of 1.5 mg/kg IV lidocaine with 500 mg ciprofloxacin twice daily, resulted in an increase of lidocaine Cmax and AUC by 12% and 26%, respectively. Although lidocaine treatment was well tolerated at this elevated exposure, possible interaction with ciprofloxacin and an increase in side effects related to lidocaine may occur upon concomitant administration.ClozapineFollowing concomitant administration of 250 mg ciprofloxacin with 304 mg clozapine for days, serum concentrations of clozapine and N-desmethylclozapine were increased by 29% and 31%, respectively. Careful monitoring of clozapine associated adverse effects and appropriate adjustment of clozapine dosage during and shortly after co-administration with ciprofloxacin are advised. (See WARNINGS.)SildenafilFollowing concomitant administration of single oral dose of 50 mg sildenafil with 500 mg ciprofloxacin to healthy subjects, the mean Cmax and mean AUC of sildenafil were both increased approximately two-fold. Therefore, sildenafil should be used with caution when co-administered with ciprofloxacin.Drugs known to prolong QT intervalPrecaution should be taken when using ciprofloxacin concomitantly with drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) as ciprofloxacin may have an additive effect on the QT interval (see WARNINGS, Prolongation of the QT Interval and PRECAUTIONS, Geriatric Use).

GENERAL PRECAUTIONS SECTION.


General. Crystals of ciprofloxacin have been observed rarely in the urine of human subjects but more frequently in the urine of laboratory animals, which is usually alkaline. (See ANIMAL PHARMACOLOGY.) Crystalluria related to ciprofloxacin has been reported only rarely in humans because human urine is usually acidic. Alkalinity of the urine should be avoided in patients receiving ciprofloxacin. Patients should be well hydrated to prevent the formation of highly concentrated urine.

GERIATRIC USE SECTION.


Geriatric Use. Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with fluoroquinolone such as ciprofloxacin hydrochloride. This risk is further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after fluoroquinolone treatment have been reported. Caution should be used when prescribing ciprofloxacin hydrochloride to elderly patients especially those on corticosteroids. Patients should be informed of this potential side effect and advised to discontinue ciprofloxacin hydrochloride and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur (See Boxed Warning WARNINGS and ADVERSE REACTIONS/Postmarketing Adverse Event Reports). In retrospective analysis of 23 multiple-dose controlled clinical trials of ciprofloxacin encompassing over 3500 ciprofloxacin treated patients, 25% of patients were greater than or equal to 65 years of age and 10% were greater than or equal to 75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals on any drug therapy cannot be ruled out. Ciprofloxacin is known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. No alteration of dosage is necessary for patients greater than 65 years of age with normal renal function. However, since 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. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.) In general, elderly patients may be more susceptible to drug-associated effects on the QT interval. Therefore, precaution should be taken when using ciprofloxacin hydrochloride with concomitant drugs that can result in prolongation of the QT interval (for example, class IA or class III antiarrhythmics) or in patients with risk factors for torsade de pointes (for example, known QT prolongation, uncorrected hypokalemia). (See WARNINGS.).

HOW SUPPLIED SECTION.


HOW SUPPLIED. Ciprofloxacin tablets, USP are available as round, white to off-white film-coated tablets containing 250 mg ciprofloxacin. The 250 mg tablet is coded with on one side and on the other side. Ciprofloxacin tablets, USP are also available as capsule shaped, white to off-white film-coated tablets containing 500 mg or 750 mg ciprofloxacin. The 500 mg tablet is coded with CR 500 on one side and on the reverse side. The 750 mg tablet is coded with CR 750 on one side and on the reverse side. Ciprofloxacin tablets, USP 250 mg, 500 mg, and 750 mg are available in the following pack types.StrengthNDC Code Bottles of 100 250 mg NDC 16252-514-01 500 mg NDC 16252-515-01 Bottles of 50 750 mg NDC 16252-516-05Store at 20o to 25oC (68o to 77oF); excursions permitted to 15o to 30oC (59o to 86oF) [see USP Controlled Room Temperature].. Imprint 1. Imprint 2. Imprint 3. Imprint 4.

INDICATIONS & USAGE SECTION.


INDICATIONS AND USAGE Ciprofloxacin tablets, USP are 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. Adult PatientsUrinary Tract Infections caused by Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus mirabilis, Providencia rettgeri, Morganella morganii, Citrobacter koseri diversus , Citrobacter freundii, Pseudomonas aeruginosa, methicillin-susceptible Staphylococcus epidermidis, Staphylococcus saprophyticus, or vancomycin-susceptible nterococcus faecalis. 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, Klebsiella pneumoniae, 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 drug of first choice in the treatment of presumed or confirmed pneumonia secondary to Streptococcus pneumoniae. Acute Sinusitis caused by Haemophilus influenzae, penicillin-susceptible Streptococcus pneumoniae, or Moraxella catarrhalis. Skin and Skin Structure Infections caused by Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Proteus mirabilis, Proteus vulgaris, Providencia stuartii, Morganella morganii, Citrobacter freundii, Pseudomonas aeruginosa, methicillin-susceptible Staphylococcus aureus, methicillin-susceptible Staphylococcus epidermidis, or Streptococcus pyogenes.Bone and Joint Infections caused by Enterobacter cloacae, Serratia marcescens, or Pseudomonas aeruginosa.Complicated Intra-Abdominal Infections (used in combination with metronidazole) caused by Escherichia coli, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, or Bacteroides fragilis.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 clinically significant outcome, efficacy was studied in fewer than 10 patients. Typhoid Fever (Enteric Fever) caused by Salmonella typhi.NOTE: 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.NOTE: Although effective in clinical trials, ciprofloxacin is not 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. (See WARNINGS PRECAUTIONS, Pediatric Use ADVERSE REACTIONS and CLINICAL STUDIES .) Ciprofloxacin, like other fluoroquinolones, is associated with arthropathy and histopathological changes in weight-bearing joints of juvenile animals. (See ANIMAL PHARMACOLOGY .) Adult and Pediatric PatientsInhalational 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 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. (See also, INHALATIONULLL ANTHRAX ADDITIONULLL INFORMATION). 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 ciprofloxacin tablets, USP 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 ciprofloxacin tablets, USP and other antibacterial drugs, ciprofloxacin tablets, USP 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.

INFORMATION FOR PATIENTS SECTION.


Information for Patients. Patients should be advised:To contact their healthcare provider if they experience pain, swelling, or inflammation of tendon, or weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue ciprofloxacin hydrochloride treatment. The risk of severe tendon disorder with fluoroquinolones is higher in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. That fluoroquinolones like ciprofloxacin hydrochloride may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Patients should call their healthcare provider right away if they have any worsening muscle weakness or breathing problems. That antibacterial drugs including ciprofloxacin hydrochloride tablets should only be used to treat bacterial infections. They do not treat viral infections (for example, the common cold). When ciprofloxacin hydrochloride tablets are prescribed to treat bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by ciprofloxacin hydrochloride tablets or other antibacterial drugs in the future.That ciprofloxacin may be taken with or without meals and to drink fluids liberally. As with other quinolones, concurrent administration of ciprofloxacin with magnesium/aluminum antacids, polymeric phosphate binders (for example, sevelamer, lanthanum carbonate) or sucralfate, Videx(R) (didanosine) chewable/buffered tablets or pediatric powder, other highly buffered drugs, or with other products containing calcium, iron or zinc should be avoided. Ciprofloxacin may be taken two hours before or six hours after taking these products. Ciprofloxacin should not be taken with dairy products (like milk or yogurt) or calcium-fortified juices alone since absorption of ciprofloxacin may be significantly reduced; however, ciprofloxacin may be taken with meal that contains these products.That ciprofloxacin may be associated with hypersensitivity reactions, even following single dose, and to discontinue the drug at the first sign of skin rash or other allergic reaction. That photosensitivity/phototoxicity has been reported in patients receiving quinolones. Patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while taking quinolones. If patients need to be outdoors while using quinolones, they should wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician. If sunburn-like reaction or skin eruption occurs, patients should contact their physician.That peripheral neuropathies have been associated with ciprofloxacin use, that symptoms may occur soon after initiation of therapy and may be irreversible. If symptoms of peripheral neuropathy including pain, burning, tingling, numbness and/or weakness develop, patients should immediately discontinue ciprofloxacin hydrochloride and contact their physician.That ciprofloxacin may cause dizziness and lightheadedness; therefore, patients should know how they react to this drug before they operate an automobile or machinery or engage in activities requiring mental alertness or coordination.That ciprofloxacin increases the effects of tizanidine (Zanaflex(R)). Patients should not use ciprofloxacin if they are already taking tizanidine.That ciprofloxacin may increase the effects of theophylline and caffeine. There is possibility of caffeine accumulation when products containing caffeine are consumed while taking quinolones.That convulsions have been reported in patients receiving quinolones, including ciprofloxacin, and to notify their physician before taking this drug if there is history of this condition. That ciprofloxacin has been associated with an increased rate of adverse events involving joints and surrounding tissue structures (like tendons) in pediatric patients (less than 18 years of age). Parents should inform their childs physician if the child has history of joint-related problems before taking this drug. Parents of pediatric patients should also notify their childs physician of any joint-related problems that occur during or following ciprofloxacin therapy. (See WARNINGS, PRECAUTIONS, Pediatric Use and ADVERSE REACTIONS.) That diarrhea is common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.. To contact their healthcare provider if they experience pain, swelling, or inflammation of tendon, or weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue ciprofloxacin hydrochloride treatment. The risk of severe tendon disorder with fluoroquinolones is higher in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. That fluoroquinolones like ciprofloxacin hydrochloride may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Patients should call their healthcare provider right away if they have any worsening muscle weakness or breathing problems. That antibacterial drugs including ciprofloxacin hydrochloride tablets should only be used to treat bacterial infections. They do not treat viral infections (for example, the common cold). When ciprofloxacin hydrochloride tablets are prescribed to treat bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by ciprofloxacin hydrochloride tablets or other antibacterial drugs in the future.. That ciprofloxacin may be taken with or without meals and to drink fluids liberally. As with other quinolones, concurrent administration of ciprofloxacin with magnesium/aluminum antacids, polymeric phosphate binders (for example, sevelamer, lanthanum carbonate) or sucralfate, Videx(R) (didanosine) chewable/buffered tablets or pediatric powder, other highly buffered drugs, or with other products containing calcium, iron or zinc should be avoided. Ciprofloxacin may be taken two hours before or six hours after taking these products. Ciprofloxacin should not be taken with dairy products (like milk or yogurt) or calcium-fortified juices alone since absorption of ciprofloxacin may be significantly reduced; however, ciprofloxacin may be taken with meal that contains these products.. That ciprofloxacin may be associated with hypersensitivity reactions, even following single dose, and to discontinue the drug at the first sign of skin rash or other allergic reaction. That photosensitivity/phototoxicity has been reported in patients receiving quinolones. Patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while taking quinolones. If patients need to be outdoors while using quinolones, they should wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician. If sunburn-like reaction or skin eruption occurs, patients should contact their physician.. That peripheral neuropathies have been associated with ciprofloxacin use, that symptoms may occur soon after initiation of therapy and may be irreversible. If symptoms of peripheral neuropathy including pain, burning, tingling, numbness and/or weakness develop, patients should immediately discontinue ciprofloxacin hydrochloride and contact their physician.. That ciprofloxacin may cause dizziness and lightheadedness; therefore, patients should know how they react to this drug before they operate an automobile or machinery or engage in activities requiring mental alertness or coordination.. That ciprofloxacin increases the effects of tizanidine (Zanaflex(R)). Patients should not use ciprofloxacin if they are already taking tizanidine.. That ciprofloxacin may increase the effects of theophylline and caffeine. There is possibility of caffeine accumulation when products containing caffeine are consumed while taking quinolones.. That convulsions have been reported in patients receiving quinolones, including ciprofloxacin, and to notify their physician before taking this drug if there is history of this condition. That ciprofloxacin has been associated with an increased rate of adverse events involving joints and surrounding tissue structures (like tendons) in pediatric patients (less than 18 years of age). Parents should inform their childs physician if the child has history of joint-related problems before taking this drug. Parents of pediatric patients should also notify their childs physician of any joint-related problems that occur during or following ciprofloxacin therapy. (See WARNINGS, PRECAUTIONS, Pediatric Use and ADVERSE REACTIONS.) That diarrhea is common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

MECHANISM OF ACTION SECTION.


Mechanism of Action. The bactericidal action of ciprofloxacin results from inhibition of the enzymes topoisomerase II (DNULL gyrase) and topoisomerase IV (both Type II topoisomerases), which are required for bacterial DNULL replication, transcription, repair, and recombination.

MICROBIOLOGY SECTION.


MICROBIOLOGY Mechanism of Action. The bactericidal action of ciprofloxacin results from inhibition of the enzymes topoisomerase II (DNULL gyrase) and topoisomerase IV (both Type II topoisomerases), which are required for bacterial DNULL replication, transcription, repair, and recombination. Mechanism of Resistance. The mechanism of action of fluoroquinolones, including ciprofloxacin, is different from that of penicillins, cephalosporins, aminoglycosides, macrolides, and tetracyclines; therefore, microorganisms resistant to these classes of drugs may be susceptible to ciprofloxacin. Resistance to fluoroquinolones occurs primarily by either mutations in the DNULL gyrases, decreased outer membrane permeability, or drug efflux. In vitro resistance to ciprofloxacin develops slowly by multiple step mutations. Resistance to ciprofloxacin due to spontaneous mutations occurs at general frequency of between 10-9 to 1x10-6.. Cross Resistance. There is no known cross-resistance between ciprofloxacin and other classes of antimicrobials. Ciprofloxacin has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section of the package insert for ciprofloxacin hydrochloride tablets. Gram-positive bacteriaEnterococcus faecalis(vancomycin-susceptible isolates only)Staphylococcus aureus (methicillin-susceptible isolates only)Staphylococcus epidermidis(methicillin-susceptible isolates only)Staphylococcus saprophyticusStreptococcus pneumoniae(penicillin-susceptible isolates only)Streptococcus pyogenesGram-negative bacteriaCampylobacter jejuniProteus mirabilisCitrobacter koseri (diversus)Proteus vulgarisCitrobacter freundiiProvidencia rettgeriEnterobacter cloacaeProvidencia stuartiiEscherichia coliPseudomonas aeruginosaHaemophilus influenzaeSalmonella typhiHaemophilus parainfluenzaeSerratia marcescensKlebsiella pneumoniaeShigella boydiiMoraxella catarrhalisShigella dysenteriaeMorganella morganiiShigella flexneriNeisseria gonorrhoeaeShigella sonneiCiprofloxacin has been shown to be active against Bacillus anthracis both in vitro and by use of serum levels as surrogate marker (see INDICATIONS AND USAGE and INHALATIONULLL ANTHRAX -ADDITIONULLL INFORMATION). The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for ciprofloxacin (<=1 mcg/mL). However, the efficacy of ciprofloxacin in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials. Gram-positive bacteriaStaphylococcus haemolyticus(methicillin-susceptible isolates only)Staphylococcus hominis(methicillin-susceptible isolates only)Bacillus anthracisGram-negative bacteriaAcinetobacter lwoffiPasteurella multocidaAeromonas hydrophilaSalmonella enteritidisEdwardsiella tardaVibrio choleraeEnterobacter aerogenesVibrio parahaemolyticusKlebsiella oxytocaVibrio vulnificusLegionella pneumophilaYersinia enterocolitica. Susceptibility Test Methods. When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment.Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using standardized test method (broth and/or agar).1 ,3,4 The MIC values should be interpreted according to criteria provided in Table 1. Diffusion Techniques: Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using standardized test method.2,3,4 This procedure uses paper disks impregnated with mcg ciprofloxacin to test the susceptibility of bacteria to ciprofloxacin. The disc diffusion interpretive criteria are provided in Table 1.Table 1: Susceptibility Test Interpretive Criteria for CiprofloxacinMIC (mcg/mL)Zone Diameter (mm)BacteriaSIRSIREnterobacteriaceae<=12>=4>=2116 to 20<=15Enterococcus faecalis<=12>=4>=2116 to 20<=15Staphylococcus aureus<=12>=4>=2116 to 20<=15Staphylococcus epidermidis<=12>=4>=2116 to 20<=15Staphylococcus saprophyticus<=12>=4>=2116 to 20<=15Pseudomonas aeruginosa<=12>=4>=2116 to 20<=15Haemophilus influenzaea<=1-->=21--Haemophilus parainfluenzaea<=1-->=21--Salmonella typhi<=0.060.12 to 0.5>1 >=3121 to 30 <=20 Streptococcus pneumoniae<=12>=4>=2116 to 20<=15Streptococcus pyogenes<=12>=4>=2116 to 20<=15Neisseria gonorrhoeae<=0.060.12 to 0.5>=1>=4128 to 40<=27Bacillus anthracisa<=0.25----- S=Susceptible, I=Intermediate, and R=Resistant.a The current absence of data on resistant isolates precludes defining any results other than Susceptible. If isolates yield MIC results other than susceptible, they should be submitted to reference laboratory for further testing.A report of Susceptible indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations at the site of infection necessary to inhibit growth of the pathogen. report of Intermediate indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. report of Resistant indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected. Quality Control: Standardized susceptibility test procedures require the use of laboratory controls to monitor the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test.1,2,3,4 Standard ciprofloxacin powder should provide the following range of MIC values noted in Table 2. For the diffusion technique using the ciprofloxacin mcg disk the criteria in Table should be achieved. Table 2: Acceptable Quality Control Ranges for CiprofloxacinBacteriaMIC range (mcg/mL)Zone Diameter (mm)Enterococcus faecalis ATCC 29212 0.25 to -Escherichia coli ATCC 25922 0.004 to 0.015 30 to 40 Haemophilus influenzae ATCC 49247 0.004 to 0.03 34 to 42Pseudomonas aeruginosa ATCC 27853 0.25 to 25 to 33Staphylococcus aureus ATCC29213 0.12 to 0.5 -Staphylococcus aureus ATCC25923 22 to 30Neisseria gonorrhoeae ATCC 49226 0.001 to 0.008 48 to 58Campylobacter jejuni ATCC 33560 0.06 to 0.25 and 0.03 to 0.12. Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using standardized test method (broth and/or agar).1 ,3,4 The MIC values should be interpreted according to criteria provided in Table 1. Diffusion Techniques: Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using standardized test method.2,3,4 This procedure uses paper disks impregnated with mcg ciprofloxacin to test the susceptibility of bacteria to ciprofloxacin. The disc diffusion interpretive criteria are provided in Table 1.. Quality Control: Standardized susceptibility test procedures require the use of laboratory controls to monitor the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test.1,2,3,4 Standard ciprofloxacin powder should provide the following range of MIC values noted in Table 2. For the diffusion technique using the ciprofloxacin mcg disk the criteria in Table should be achieved.

OVERDOSAGE SECTION.


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 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 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 to 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


Principal Display Panel. Ciprofloxacin Tablets, USP 250mg Tablets NDC 10544-147-06. 250mg 06ct.

PEDIATRIC USE SECTION.


Pediatric Use. Ciprofloxacin, like other quinolones, causes arthropathy and histological changes in weight-bearing joints of juvenile animals resulting in lameness. (See ANIMAL PHARMACOLOGY.) Inhalational Anthrax (Post-Exposure)Ciprofloxacin is indicated in pediatric patients for inhalational anthrax (post-exposure). The risk-benefit assessment indicates that administration of ciprofloxacin to pediatric patients is appropriate. For information regarding pediatric dosing in inhalational anthrax (post-exposure), see DOSAGE AND ADMINISTRATIONand Inhalational Anthrax, Additional Information. Complicated Urinary Tract Infection and PyelonephritisCiprofloxacin is indicated for the treatment of complicated urinary tract infections and pyelonephritis due to Escherichia coli. Although effective in clinical trials, ciprofloxacin is not drug of first choice in the pediatric population due to an increased incidence of adverse events compared to the controls, including events related to joints and/or surrounding tissues. The rates of these events in pediatric patients with complicated urinary tract infection and pyelonephritis within six weeks of follow-up were 9.3% (31/335) versus 6% (21/349) for control agents. The rates of these events occurring at any time up to the one year follow-up were 13.7% (46/335) and 9.5% (33/349), respectively. The rate of all adverse events regardless of drug relationship at six weeks was 41% (138/335) in the ciprofloxacin arm compared to 31% (109/349) in the control arm. (See ADVERSE REACTIONS and CLINICAL STUDIES.) Cystic FibrosisShort-term safety data from single trial in pediatric cystic fibrosis patients are available. In randomized, double-blind clinical trial for the treatment of acute pulmonary exacerbations in cystic fibrosis patients (ages to 17 years), 67 patients received ciprofloxacin IV 10 mg/kg/dose q8h for one week followed by ciprofloxacin tablets 20 mg/kg/dose q12h to complete 10 to 21 days treatment and 62 patients received the combination of ceftazidime IV 50 mg/kg/dose q8h and tobramycin IV mg/kg/dose q8h for total of 10 to 21 days. Patients less than years of age were not studied. Safety monitoring in the study included periodic range of motion examinations and gait assessments by treatment-blinded examiners. Patients were followed for an average of 23 days after completing treatment (range to 93 days). This study was not designed to determine long term effects and the safety of repeated exposure to ciprofloxacin. Musculoskeletal adverse events in patients with cystic fibrosis were reported in 22% of the patients in the ciprofloxacin group and 21% in the comparison group. Decreased range of motion was reported in 12% of the subjects in the ciprofloxacin group and 16% in the comparison group. Arthralgia was reported in 10% of the patients in the ciprofloxacin group and 11% in the comparison group. Other adverse events were similar in nature and frequency between treatment arms. One of sixty-seven patients developed arthritis of the knee nine days after ten day course of treatment with ciprofloxacin. Clinical symptoms resolved, but an MRI showed knee effusion without other abnormalities eight months after treatment. However, the relationship of this event to the patients course of ciprofloxacin can not be definitively determined, particularly since patients with cystic fibrosis may develop arthralgias/arthritis as part of their underlying disease process.

PREGNULLNCY SECTION.


Pregnancy. Teratogenic Effects. Pregnancy Category CThere 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 (see WARNINGS). 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 substantial teratogenic risk (quantity and quality of data=fair), but the data are insufficient to state that there is no risk.9 controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5% exposed to ciprofloxacin and 68% first trimester exposures) during gestation.10 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 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).11 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.9,10 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 mg/m2) 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 mg/m2) no maternal toxicity was produced and no embryotoxicity or teratogenicity was observed. (See WARNINGS.).

REFERENCES SECTION.


References: Clinical and Laboratory Standards Institute, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically Approved Standard 9th Edition. CLSI Document M7-A9, CLSI, 950 West Valley Rd., Suite 2500, Wayne, PA, January, 2012. CLSI, Performance Standards for Antimicrobial Disk Susceptibility Tests Approved Standard 11 th Edition CLSI Document M2-A11,CLSI, Wayne, PA, January, 2012. CLSI. Performance Standards for Antimicrobial Susceptibility Testing; 22nd Informational Supplement. CLSI Document M100 S22, January 2012.CLSI. Methods for Antimicrobial Dilution and Disk Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria; Approved Guideline 2nd Edition. CLSI Document M45 A2, January 2010.Report presented at the FDAs Anti-Infective Drug and Dermatological Drug Products Advisory Committee meeting, March 31, 1993, Silver Spring, MD. Report available from FDA, CDER, Advisors and Consultants Staff, HFD-21, 1901 Chapman Avenue, Room 200, Rockville, MD 20852, USA. 21 CFR 314.510 (Subpart - Accelerated Approval of New Drugs for Life-Threatening Illnesses). Kelly DJ, et al. Serum concentrations of penicillin, doxycycline, and ciprofloxacin during prolonged therapy in rhesus monkeys. Infect Dis 1992; 166:1184-7. Friedlander AM, et al. Postexposure prophylaxis against experimental inhalational anthrax. Infect Dis 1993; 167:1239-42. Friedman J, Polifka J. Teratogenic effects of drugs: resource for clinicians (TERIS). Baltimore, Maryland: Johns Hopkins University Press, 2000:149-195. Loebstein R, Addis A, Ho E, et al. Pregnancy outcome following gestational exposure to fluoroquinolones: multicenter prospective controlled study. Antimicrob Agents Chemother. 1998;42(6):1336-1339. Schaefer C, Amoura-Elefant E, Vial T, et al. Pregnancy outcome after prenatal quinolone exposure. Evaluation of case registry of the European network of teratology information services (ENTIS). Eur Obstet Gynecol Reprod Biol. 1996;69:83-89. Brands listed are the trademarks of their respective owners.Manufactured by:Watson Pharma Private LimitedVerna, Salcette Goa 403 722 INDIADistributed by:Actavis Pharma, Inc.Parsippany, NJ 07054 USARevised: November 2014. Clinical and Laboratory Standards Institute, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically Approved Standard 9th Edition. CLSI Document M7-A9, CLSI, 950 West Valley Rd., Suite 2500, Wayne, PA, January, 2012. CLSI, Performance Standards for Antimicrobial Disk Susceptibility Tests Approved Standard 11 th Edition CLSI Document M2-A11,CLSI, Wayne, PA, January, 2012. CLSI. Performance Standards for Antimicrobial Susceptibility Testing; 22nd Informational Supplement. CLSI Document M100 S22, January 2012.. CLSI. Methods for Antimicrobial Dilution and Disk Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria; Approved Guideline 2nd Edition. CLSI Document M45 A2, January 2010.. Report presented at the FDAs Anti-Infective Drug and Dermatological Drug Products Advisory Committee meeting, March 31, 1993, Silver Spring, MD. Report available from FDA, CDER, Advisors and Consultants Staff, HFD-21, 1901 Chapman Avenue, Room 200, Rockville, MD 20852, USA. 21 CFR 314.510 (Subpart - Accelerated Approval of New Drugs for Life-Threatening Illnesses). Kelly DJ, et al. Serum concentrations of penicillin, doxycycline, and ciprofloxacin during prolonged therapy in rhesus monkeys. Infect Dis 1992; 166:1184-7. Friedlander AM, et al. Postexposure prophylaxis against experimental inhalational anthrax. Infect Dis 1993; 167:1239-42. Friedman J, Polifka J. Teratogenic effects of drugs: resource for clinicians (TERIS). Baltimore, Maryland: Johns Hopkins University Press, 2000:149-195. Loebstein R, Addis A, Ho E, et al. Pregnancy outcome following gestational exposure to fluoroquinolones: multicenter prospective controlled study. Antimicrob Agents Chemother. 1998;42(6):1336-1339. Schaefer C, Amoura-Elefant E, Vial T, et al. Pregnancy outcome after prenatal quinolone exposure. Evaluation of case registry of the European network of teratology information services (ENTIS). Eur Obstet Gynecol Reprod Biol. 1996;69:83-89.

SPL MEDGUIDE SECTION.


MEDICATION GUIDE CIPROFLOXACIN (SIP-roe-FLOX-a-sin) TABLETS, USP Read the Medication Guide that comes with ciprofloxacin tablets before you start taking it and each time you get refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or your treatment. What is the most important information should know about ciprofloxacin tablets Ciprofloxacin tablets belong to class of antibiotics called fluoroquinolones. Ciprofloxacin tablets can cause side effects that may be serious or even cause death. If you get any of the following serious side effects, get medical help right away. Talk with your healthcare provider about whether you should continue to take ciprofloxacin tablets. 1. Tendon rupture or swelling of the tendon (tendinitis) Tendon problems can happen in people of all ages who take ciprofloxacin tablets. Tendons are tough cords of tissue that connect muscles to bones. Symptoms of tendon problems may include: Pain, swelling, tears and inflammation of tendons including the back of the ankle (Achilles), shoulder, hand, or other tendon sites. The risk of getting tendon problems while you take ciprofloxacin tablets is higher if you: Are over 60 years of age Are taking steroids (corticosteroids) Have had kidney, heart or lung transplantTendon problems can happen in people who do not have the above risk factors when they take ciprofloxacin tablets. Other reasons that can increase your risk of tendon problems can include: Physical activity or exercise Kidney failure Tendon problems in the past, such as in people with rheumatoid arthritis (RA) Call your healthcare provider right away at the first sign of tendon pain, swelling or inflammation. Stop taking ciprofloxacin tablets until tendinitis or tendon rupture has been ruled out by your healthcare provider. Avoid exercise and using the affected area. The most common area of pain and swelling is the Achilles tendon at the back of your ankle. This can also happen with other tendons. Talk to your healthcare provider about the risk of tendon rupture with continued use of ciprofloxacin tablets. You may need different antibiotic that is not fluoroquinolone to treat your infection. Tendon rupture can happen while you are taking or after you have finished taking ciprofloxacin tablets. Tendon ruptures have happened up to several months after patients have finished taking their fluoroquinolone. Get medical help right away if you get any of the following signs or symptoms of tendon rupture: Hear or feel snap or pop in tendon area Bruising right after an injury in tendon area Unable to move the affected area or bear weight 2. Worsening of myasthenia gravis (a disease which causes muscle weakness).Fluoroquinolones like ciprofloxacin may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Call your healthcare provider right away if you have any worsening muscle weakness or breathing problems.See the section What are the possible side effects of ciprofloxacin tablets for more information about side effects. What are ciprofloxacin tablets Ciprofloxacin tablets are fluoroquinolone antibiotic medicine used to treat certain infections caused by certain germs called bacteria. Children less than 18 years of age have higher chance of getting bone, joint, or tendon (musculoskeletal) problems such as pain or swelling while taking ciprofloxacin tablets. Ciprofloxacin tablets should not be used as the first choice of antibiotic medicine in children under 18 years of age. Ciprofloxacin tablets should not be used in children under 18 years old, except to treat specific serious infections, such as complicated urinary tract infections and to prevent anthrax disease after breathing the anthrax bacteria germ (inhalational exposure). Sometimes infections are caused by viruses rather than by bacteria. Examples include viral infections in the sinuses and lungs, such as the common cold or flu. Antibiotics, including ciprofloxacin tablets, do not kill viruses. Call your healthcare provider if you think your condition is not getting better while you are taking ciprofloxacin tablets. Who should not take ciprofloxacin tablets Do not take ciprofloxacin tablets if you: Have ever had severe allergic reaction to an antibiotic known as fluoroquinolone, or are allergic to any of the ingredients in ciprofloxacin tablets. Ask your healthcare provider if you are not sure. See the list of ingredients in ciprofloxacin tablets at the end of this Medication Guide. Also take medicine called tizanidine (Zanaflex(R)). Serious side effects from tizanidine are likely to happen. What should tell my healthcare provider before taking ciprofloxacin tabletsSee What is the most important information should know about ciprofloxacin tabletsTell your healthcare provider about all your medical conditions, including if you: Have tendon problems.Have disease that causes muscle weakness (myasthenia gravis). Have central nervous system problems (such as epilepsy). Have nerve problems. Have or anyone in your family has an irregular heartbeat, especially condition called QT prolongation. Have history of seizures. Have kidney problems. You may need lower dose of ciprofloxacin tablets if your kidneys do not work well. Have rheumatoid arthritis (RA) or other history of joint problems. Have trouble swallowing pills. Are pregnant or planning to become pregnant. It is not known if ciprofloxacin tablets will harm your unborn child. Are breast-feeding or planning to breast-feed. Ciprofloxacin passes into breast milk. You and your healthcare provider should decide whether you will take ciprofloxacin tablets or breast-feed. Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal and dietary supplements. Ciprofloxacin tablets and other medicines can affect each other causing side effects. Especially tell your healthcare provider if you take: An NSAID (Non-Steroidal Anti-Inflammatory Drug). Many common medicines for pain relief are NSAIDs. Taking an NSAID while you take ciprofloxacin tablets or other fluoroquinolones may increase your risk of central nervous system effects and seizures. See What are the possible side effects of iprofloxacin tablets .A blood thinner (such as warfarin, Coumadin(R), Jantoven(R)). Tizanidine (Zanaflex(R)). You should not take ciprofloxacin tablets if you are already taking tizanidine. See Who should not take iprofloxacin tablets . Theophylline (such as Theo-24(R), Elixophyllin(R), Theochron(R), Uniphyl(R), Theolair(R)). Glyburide (Micronase(R), Glynase(R), Diabeta(R), Glucovance(R)). See What are the possible side effects of iprofloxacin tablets . Phenytoin (Fosphenytoin Sodium(R), Cerebyx(R), Dilantin-125(R), Dilantin(R), Extended Phenytoin Sodium(R), Prompt Phenytoin Sodium(R), Phenytek(R)). Products that contain caffeine. medicine to control your heart rate or rhythm (antiarrhythmics) See What are the possible side effects of iprofloxacin tablets . An anti-psychotic medicine. tricyclic antidepressant. water pill (diuretic). steroid medicine. Corticosteroids taken by mouth or by injection may increase the chance of tendon injury. See What is the most important information should know about iprofloxacin tablets . Methotrexate (Trexall(R)) Probenecid (Probalan(R), Col-probenecid(R)). Metoclopromide (Reglan(R), Reglan ODT(R)). Ropinirole (Requip(R)).Lidocaine (Xylocaine(R) intravenous infusion).Clozapine (Clozaril(R), Fazaclo(R) ODT(R)).Pentoxifylline (Trental(R)).Sildenafil (Viagra(R), Revatio(R)).Cyclosporine (Gengraf(R), Neoral(R), Sandimmune(R), Sangcya(R)).Omeprazole.Certain medicines may keep ciprofloxacin tablets from working correctly. Take ciprofloxacin tablets either hours before or hours after taking these products: An antacid, multivitamin, or other product that has magnesium, calcium, aluminum, iron, or zinc. Sucralfate (Carafate(R)). Didanosine (Videx(R), Videx EC(R)). Ask your healthcare provider if you are not sure if any of your medicines are listed above. Know the medicines you take. Keep list of your medicines and show it to your healthcare provider and pharmacist when you get new medicine. How should take ciprofloxacin tablets Take ciprofloxacin tablets exactly as prescribed by your healthcare provider. Take ciprofloxacin tablets in the morning and evening at about the same time each day. Swallow the tablet whole. Do not split, crush or chew the tablet. Tell your healthcare provider if you can not swallow the tablet whole. Ciprofloxacin tablets can be taken with or without food. Ciprofloxacin tablets should not be taken with dairy products (like milk or yogurt) or calcium-fortified juices alone, but may be taken with meal that contains these products. Drink plenty of fluids while taking ciprofloxacin tablets. Do not skip any doses, or stop taking ciprofloxacin tablets even if you begin to feel better, until you finish your prescribed treatment, unless: You have tendon effects (see What is the most important information should know about ciprofloxacin tablets ), You have serious allergic reaction (see What are the possible side effects of ciprofloxacin tablets ), or Your healthcare provider tells you to stop. This will help make sure that all of the bacteria are killed and lower the chance that the bacteria will become resistant to ciprofloxacin tablets. If this happens, ciprofloxacin tablets and other antibiotic medicines may not work in the future. If you miss dose of ciprofloxacin tablets, take it as soon as you remember. Do not take two doses at the same time, and do not take more than two doses in one day. If you take too much, call your healthcare provider or get medical help immediately. If you have been prescribed ciprofloxacintablets after being exposed to anthrax: Ciprofloxacin tablets have been approved to lessen the chance of getting anthrax disease or worsening of the disease after you are exposed to the anthrax bacteria germ. Take ciprofloxacin tablets exactly as prescribed by your healthcare provider. Do not stop taking ciprofloxacin tablets without talking with your healthcare provider. If you stop taking ciprofloxacin tablets too soon, it may not keep you from getting the anthrax disease. Side effects may happen while you are taking ciprofloxacin tablets. When taking your ciprofloxacin tablets to prevent anthrax infection, you and your healthcare provider should talk about whether the risks of stopping ciprofloxacin tablets too soon are more important than the risks of side effects with ciprofloxacin tablets. If you are pregnant, or plan to become pregnant while taking ciprofloxacin tablets, you and your healthcare provider should decide whether the benefits of taking ciprofloxacin tablets for anthrax are more important than the risks. What should avoid while taking ciprofloxacin tablets Ciprofloxacin tablets can make you feel dizzy and lightheaded. Do not drive, operate machinery, or do other activities that require mental alertness or coordination until you know how ciprofloxacin tablets affect you. Avoid sunlamps, tanning beds, and try to limit your time in the sun. Ciprofloxacin tablets can make your skin sensitive to the sun (photosensitivity) and the light from sunlamps and tanning beds. You could get severe sunburn, blisters or swelling of your skin. If you get any of these symptoms while taking ciprofloxacin tablets, call your healthcare provider right away. You should use sunscreen and wear hat and clothes that cover your skin if you have to be in sunlight. What are the possible side effects of ciprofloxacin tablets Ciprofloxacin tablets can cause side effects that may be serious or even cause death. See What is the most important information should know about ciprofloxacin tabletsOther serious side effects of ciprofloxacin tablets include: TheophyllineYou may have serious seizure and breathing problems when you take theophylline with ciprofloxacin tablets. These problems may lead to death. Get emergency help right away if you have seizures or trouble breathing.Central Nervous System effects Seizures have been reported in people who take fluoroquinolone antibiotics including ciprofloxacin tablets. Tell your healthcare provider if you have history of seizures. Ask your healthcare provider whether taking ciprofloxacin tablets will change your risk of having seizure. Central Nervous System (CNS) side effects may happen as soon as after taking the first dose of ciprofloxacin tablets. Talk to your healthcare provider right away if you get any of these side effects, or other changes in mood or behavior: Feel dizzy Seizures Hear voices, see things, or sense things that are not there (hallucinations)Feel restless Tremors Feel anxious or nervous Confusion Depression Trouble sleeping Nightmares Feel more suspicious (paranoia) Suicidal thoughts or acts Serious allergic reactionsAllergic reactions, including death, can happen in people taking fluoroquinolones, including ciprofloxacin tablets, even after only one dose. Stop taking ciprofloxacin tablets and get emergency medical help right away if you get any of the following symptoms of severe allergic reaction: Hives. Trouble breathing or swallowing. Swelling of the lips, tongue, face. Throat tightness, hoarseness. Rapid heartbeat. Faint. Yellowing of the skin or eyes. Stop taking ciprofloxacin tablets and tell your healthcare provider right away if you get yellowing of your skin or white part of your eyes, or if you have dark urine. These can be signs of serious reaction to ciprofloxacin tablets (a liver problem). Skin rashSkin rash may happen in people taking ciprofloxacin tablets, even after only one dose. Stop taking ciprofloxacin tablets at the first sign of skin rash and call your healthcare provider. Skin rash may be sign of more serious reaction to ciprofloxacin tablets. Serious heart rhythm changes (QT prolongation and torsade de pointes) Tell your healthcare provider right away if you have change in your heart beat (a fast or irregular heartbeat), or if you faint. Ciprofloxacin tablets may cause rare heart problem known as prolongation of the QT interval. This condition can cause an abnormal heartbeat and can be very dangerous. The chances of this event are higher in people: Who are elderly With family history of prolonged QT intervalWith low blood potassium (hypokalemia)Who take certain medicines to control heart rhythm (antiarrhythmics)Intestine infection (Pseudomembranous colitis)Pseudomembranous colitis can happen with most antibiotics, including ciprofloxacin tablets. Call your healthcare provider right away if you get watery diarrhea, diarrhea that does not go away, or bloody stools. You may have stomach cramps and fever. Pseudomembranous colitis can happen or more months after you have finished your antibiotic. Changes in sensation and nerve damage (Peripheral Neuropathy)Damage to the nerves in arms, hands, legs, or feet can happen in people who take fluoroquinolones, including ciprofloxacin tablets. Stop ciprofloxacin tablets and talk with your healthcare provider right away if you get any of the following symptoms of peripheral neuropathy in your arms, hands, legs, or feet:Pain Burning Tingling Numbness Weakness The nerve damage may be permanent. Low blood sugar (hypoglycemia) People who take ciprofloxacin tablets and other fluoroquinolone medicines with the oral anti-diabetes medicine glyburide (Micronase, Glynase, Diabeta, Glucovance) can get low blood sugar (hypoglycemia) which can sometimes be severe. Tell your healthcare provider if you get low blood sugar with ciprofloxacin tablets. Your antibiotic medicine may need to be changed. Sensitivity to sunlight (photosensitivity). See What should avoid while taking ciprofloxacin tablets Joint ProblemsIncreased chance of problems with joints and tissues around joints in children under 18 years old. Tell your childs healthcare provider if your child has any joint problems during or after treatment with ciprofloxacin tablets. The most common side effects of ciprofloxacin tablets include: Nausea Diarrhea Changes in liver function tests Vomiting RashVaginal yeast infection Pain or discomfort in the abdomenHeadache These are not all the possible side effects of ciprofloxacin tablets. Tell your healthcare provider about any side effect that bothers you, or that does not go away. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should store ciprofloxacin tablets Ciprofloxacin tablets Store ciprofloxacin tablets at 20-25C (68-77F); excursions permitted to 15-30C (59-86F). Keep ciprofloxacin tablets and all medicines out of the reach of children. General Information about Ciprofloxacin TabletsMedicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use ciprofloxacin tablets for condition for which it is not prescribed. Do not give ciprofloxacin tablets to other people, even if they have the same symptoms that you have. It may harm them. This Medication Guide summarizes the most important information about ciprofloxacin tablets. If you would like more information about ciprofloxacin tablets, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about ciprofloxacin tablets that is written for healthcare professionals. For more information call 1-800-272-5525.What are the ingredients in ciprofloxacin tablets Ciprofloxacin tablets: Active ingredient: ciprofloxacin Inactive ingredients: cornstarch, microcrystalline cellulose, silicon dioxide, crospovidone, magnesium stearate, polyvinyl alcohol, talc, titanium dioxide, polyethylene glycol and purified water This Medication Guide has been approved by the U.S. Food and Drug Administration.Brands listed are the trademarks of their respective owners.Manufactured by: Watson Pharma Private Limited Verna, Salcette Goa 403 722 INDIADistributed by: Actavis Pharma, Inc.Parsippany, NJ 07054 USARevised: November 2014 Tendon problems can happen in people of all ages who take ciprofloxacin tablets. Tendons are tough cords of tissue that connect muscles to bones. Symptoms of tendon problems may include: Pain, swelling, tears and inflammation of tendons including the back of the ankle (Achilles), shoulder, hand, or other tendon sites. The risk of getting tendon problems while you take ciprofloxacin tablets is higher if you: Are over 60 years of age Are taking steroids (corticosteroids) Have had kidney, heart or lung transplant. Tendon problems can happen in people who do not have the above risk factors when they take ciprofloxacin tablets. Other reasons that can increase your risk of tendon problems can include: Physical activity or exercise Kidney failure Tendon problems in the past, such as in people with rheumatoid arthritis (RA) Call your healthcare provider right away at the first sign of tendon pain, swelling or inflammation. Stop taking ciprofloxacin tablets until tendinitis or tendon rupture has been ruled out by your healthcare provider. Avoid exercise and using the affected area. The most common area of pain and swelling is the Achilles tendon at the back of your ankle. This can also happen with other tendons. Talk to your healthcare provider about the risk of tendon rupture with continued use of ciprofloxacin tablets. You may need different antibiotic that is not fluoroquinolone to treat your infection. Tendon rupture can happen while you are taking or after you have finished taking ciprofloxacin tablets. Tendon ruptures have happened up to several months after patients have finished taking their fluoroquinolone. Get medical help right away if you get any of the following signs or symptoms of tendon rupture: Hear or feel snap or pop in tendon area Bruising right after an injury in tendon area Unable to move the affected area or bear weight Have ever had severe allergic reaction to an antibiotic known as fluoroquinolone, or are allergic to any of the ingredients in ciprofloxacin tablets. Ask your healthcare provider if you are not sure. See the list of ingredients in ciprofloxacin tablets at the end of this Medication Guide. Also take medicine called tizanidine (Zanaflex(R)). Serious side effects from tizanidine are likely to happen. Have tendon problems.. Have disease that causes muscle weakness (myasthenia gravis). Have central nervous system problems (such as epilepsy). Have nerve problems. Have or anyone in your family has an irregular heartbeat, especially condition called QT prolongation. Have history of seizures. Have kidney problems. You may need lower dose of ciprofloxacin tablets if your kidneys do not work well. Have rheumatoid arthritis (RA) or other history of joint problems. Have trouble swallowing pills. Are pregnant or planning to become pregnant. It is not known if ciprofloxacin tablets will harm your unborn child. Are breast-feeding or planning to breast-feed. Ciprofloxacin passes into breast milk. You and your healthcare provider should decide whether you will take ciprofloxacin tablets or breast-feed. An NSAID (Non-Steroidal Anti-Inflammatory Drug). Many common medicines for pain relief are NSAIDs. Taking an NSAID while you take ciprofloxacin tablets or other fluoroquinolones may increase your risk of central nervous system effects and seizures. See What are the possible side effects of iprofloxacin tablets .. blood thinner (such as warfarin, Coumadin(R), Jantoven(R)). Tizanidine (Zanaflex(R)). You should not take ciprofloxacin tablets if you are already taking tizanidine. See Who should not take iprofloxacin tablets . Theophylline (such as Theo-24(R), Elixophyllin(R), Theochron(R), Uniphyl(R), Theolair(R)). Glyburide (Micronase(R), Glynase(R), Diabeta(R), Glucovance(R)). See What are the possible side effects of iprofloxacin tablets . Phenytoin (Fosphenytoin Sodium(R), Cerebyx(R), Dilantin-125(R), Dilantin(R), Extended Phenytoin Sodium(R), Prompt Phenytoin Sodium(R), Phenytek(R)). Products that contain caffeine. A medicine to control your heart rate or rhythm (antiarrhythmics) See What are the possible side effects of iprofloxacin tablets . An anti-psychotic medicine. A tricyclic antidepressant. A water pill (diuretic). A steroid medicine. Corticosteroids taken by mouth or by injection may increase the chance of tendon injury. See What is the most important information should know about iprofloxacin tablets . Methotrexate (Trexall(R)) Probenecid (Probalan(R), Col-probenecid(R)). Metoclopromide (Reglan(R), Reglan ODT(R)). Ropinirole (Requip(R)).. Lidocaine (Xylocaine(R) intravenous infusion).. Clozapine (Clozaril(R), Fazaclo(R) ODT(R)).. Pentoxifylline (Trental(R)).. Sildenafil (Viagra(R), Revatio(R)).. Cyclosporine (Gengraf(R), Neoral(R), Sandimmune(R), Sangcya(R)).. Omeprazole.. Certain medicines may keep ciprofloxacin tablets from working correctly. Take ciprofloxacin tablets either hours before or hours after taking these products: An antacid, multivitamin, or other product that has magnesium, calcium, aluminum, iron, or zinc. Sucralfate (Carafate(R)). Didanosine (Videx(R), Videx EC(R)). Take ciprofloxacin tablets exactly as prescribed by your healthcare provider. Take ciprofloxacin tablets in the morning and evening at about the same time each day. Swallow the tablet whole. Do not split, crush or chew the tablet. Tell your healthcare provider if you can not swallow the tablet whole. Ciprofloxacin tablets can be taken with or without food. Ciprofloxacin tablets should not be taken with dairy products (like milk or yogurt) or calcium-fortified juices alone, but may be taken with meal that contains these products. Drink plenty of fluids while taking ciprofloxacin tablets. Do not skip any doses, or stop taking ciprofloxacin tablets even if you begin to feel better, until you finish your prescribed treatment, unless: You have tendon effects (see What is the most important information should know about ciprofloxacin tablets ), You have serious allergic reaction (see What are the possible side effects of ciprofloxacin tablets ), or Your healthcare provider tells you to stop. If you miss dose of ciprofloxacin tablets, take it as soon as you remember. Do not take two doses at the same time, and do not take more than two doses in one day. If you take too much, call your healthcare provider or get medical help immediately. Ciprofloxacin tablets have been approved to lessen the chance of getting anthrax disease or worsening of the disease after you are exposed to the anthrax bacteria germ. Take ciprofloxacin tablets exactly as prescribed by your healthcare provider. Do not stop taking ciprofloxacin tablets without talking with your healthcare provider. If you stop taking ciprofloxacin tablets too soon, it may not keep you from getting the anthrax disease. Side effects may happen while you are taking ciprofloxacin tablets. When taking your ciprofloxacin tablets to prevent anthrax infection, you and your healthcare provider should talk about whether the risks of stopping ciprofloxacin tablets too soon are more important than the risks of side effects with ciprofloxacin tablets. If you are pregnant, or plan to become pregnant while taking ciprofloxacin tablets, you and your healthcare provider should decide whether the benefits of taking ciprofloxacin tablets for anthrax are more important than the risks. Ciprofloxacin tablets can make you feel dizzy and lightheaded. Do not drive, operate machinery, or do other activities that require mental alertness or coordination until you know how ciprofloxacin tablets affect you. Avoid sunlamps, tanning beds, and try to limit your time in the sun. Ciprofloxacin tablets can make your skin sensitive to the sun (photosensitivity) and the light from sunlamps and tanning beds. You could get severe sunburn, blisters or swelling of your skin. If you get any of these symptoms while taking ciprofloxacin tablets, call your healthcare provider right away. You should use sunscreen and wear hat and clothes that cover your skin if you have to be in sunlight. Theophylline. Central Nervous System effects Feel dizzy Seizures Hear voices, see things, or sense things that are not there (hallucinations). Feel restless Tremors Feel anxious or nervous Confusion Depression Trouble sleeping Nightmares Feel more suspicious (paranoia) Suicidal thoughts or acts Serious allergic reactions. Hives. Trouble breathing or swallowing. Swelling of the lips, tongue, face. Throat tightness, hoarseness. Rapid heartbeat. Faint. Yellowing of the skin or eyes. Stop taking ciprofloxacin tablets and tell your healthcare provider right away if you get yellowing of your skin or white part of your eyes, or if you have dark urine. These can be signs of serious reaction to ciprofloxacin tablets (a liver problem). Skin rash. Serious heart rhythm changes (QT prolongation and torsade de pointes) Who are elderly With family history of prolonged QT interval. With low blood potassium (hypokalemia). Who take certain medicines to control heart rhythm (antiarrhythmics). Intestine infection (Pseudomembranous colitis). Changes in sensation and nerve damage (Peripheral Neuropathy). Pain Burning Tingling Numbness Weakness Low blood sugar (hypoglycemia) Sensitivity to sunlight (photosensitivity). See What should avoid while taking ciprofloxacin tablets Joint Problems. Nausea Diarrhea Changes in liver function tests Vomiting Rash. Vaginal yeast infection Pain or discomfort in the abdomen. Headache Ciprofloxacin tablets Store ciprofloxacin tablets at 20-25C (68-77F); excursions permitted to 15-30C (59-86F). Ciprofloxacin tablets: Active ingredient: ciprofloxacin Inactive ingredients: cornstarch, microcrystalline cellulose, silicon dioxide, crospovidone, magnesium stearate, polyvinyl alcohol, talc, titanium dioxide, polyethylene glycol and purified water.

SPL UNCLASSIFIED SECTION.


CIPROFLOXACIN TABLETS, USPRx Only.

USE IN SPECIFIC POPULATIONS SECTION.


Special Populations. Pharmacokinetic studies of the oral (single dose) form of ciprofloxacin indicate that plasma concentrations of ciprofloxacin are higher in elderly subjects (> 65 years) as compared to young adults. Although the Cmax is increased 16 to 40%, the increase in mean AUC is approximately 30%, and can be at least partially attributed to decreased renal clearance in the elderly. Elimination half-life is only slightly (~20%) prolonged in the elderly. These differences are not considered clinically significant. (See PRECAUTIONS: Geriatric Use.) Patients with Renal ImpairmentIn patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged. Dosage adjustments may be required. (See DOSAGE AND ADMINISTRATION.) Patients with Hepatic ImpairmentIn 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. PediatricsFollowing single oral dose of 10 mg/kg ciprofloxacin suspension to 16 children ranging in age from months to years, the mean Cmax was 2.4 mcg/mL (range: 1.5 to 3.4 mcg/mL) and the mean AUC was 9.2 mcgh/mL (range: 5.8 to 14.9 mcgh/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 1-hour infusion), the mean Cmax was 6.1 mcg/mL (range: 4.6 to 8.3 mcg/mL) in 10 children less than year of age; and 7.2 mcg/mL (range: 4.7 to 11.8 mcg/mL) in 10 children between and years of age. The AUC values were 17.4 mcgh/mL (range: 11.8 to 32.0 mcgh/mL) and 16.5 mcgh/mL (range: 11.0 to 23.8 mcgh/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 to hours, and the bioavailability of the oral suspension is approximately 60%.

WARNINGS SECTION.


WARNINGS Tendinopathy and Tendon Rupture. Fluoroquinolones, including ciprofloxacin hydrochloride, 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. Ciprofloxacin hydrochloride should be used with caution in patients with history of tendon disorders. Ciprofloxacin hydrochloride should be discontinued if the patient experiences pain, swelling, inflammation or rupture of 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 non-quinolone antimicrobial drug. Exacerbation of Myasthenia Gravis. Fluoroquinolones, including ciprofloxacin hydrochloride, 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 ciprofloxacin hydrochloride in patients with known history of myasthenia gravis. (See PRECAUTIONS: Information for Patients and ADVERSE REACTIONS: Postmarketing Adverse Event Reports .) Pregnant Women. THE SAFETY AND EFFECTIVENESS OF CIPROFLOXACIN IN PREGNULLNT AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED. (See PRECAUTIONS: Pregnancy, and Nursing Motherssubsections.) 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 few patients had 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 skin rash, jaundice, or any other sign of hypersensitivity and supportive measures instituted (see PRECAUTIONS: Information for Patients and ADVERSE REACTIONS).. 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.. Hepatobiliary System. Cases of severe hepatotoxicity, including hepatic necrosis, life-threatening hepatic failure, and fatal events, have been reported with ciprofloxacin. Acute liver injury is rapid in onset (range to 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 (see ADVERSE REACTIONS).There can be temporary increase in transaminases, alkaline phosphatase, or cholestatic jaundice, especially in patients with previous liver damage, who are treated with ciprofloxacin (see ADVERSE REACTIONS).. Theophylline. SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED IN PATIENTS RECEIVING CONCURRENT 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. Ciprofloxacin hydrochloride, 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). Ciprofloxacin hydrochloride 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. (See PRECAUTIONS: General Information for Patients Drug Interactions and ADVERSE REACTIONS.) Clostridium Difficile-Associated Diarrhea. Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including ciprofloxacin hydrochloride, 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. difficile produces toxins and which contribute to the development of CDAD. Hypertoxin producing isolates of C. difficile cause 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. difficile may 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. 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 fluoroquinolones, including ciprofloxacin. Symptoms may occur soon after initiation of ciprofloxacin hydrochloride and may be irreversible. Ciprofloxacin should be discontinued immediately if the patient experiences symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness, other alterations in sensations including light touch, pain, temperature, position sense and vibratory sensation.. Musculoskeletal Disorders in Pediatric Patients and Arthropathic Effects in Animals. Ciprofloxacin should be used in pediatric patients (less than 18 years of age) only for infections listed in the INDICATIONS AND USAGE section. An increased incidence of adverse events compared to controls, including events related to joints and/or surrounding tissues, has been observed. (See ADVERSE REACTIONS.) 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. (See ANIMAL PHARMACOLOGY.) 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 antiarrhythmic agents (amiodarone, sotalol), tricyclic antidepressants, macrolides, and antipsychotics. Elderly patients may also be more susceptible to drug-associated effects on the QT interval. (See PRECAUTIONS, Drug Interactions and Geriatric Use .) 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 (See PRECAUTIONS, Drug Interactions).. 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 serologic test for syphilis at the time of diagnosis. Patients treated with ciprofloxacin should have follow-up serologic test for syphilis after three months.