CIPROFLOXACIN tablet, film coated

Ciprofloxacin by

Drug Labeling and Warnings

Ciprofloxacin by is a Prescription medication manufactured, distributed, or labeled by Legacy Pharmaceutical Packaging. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

Drug Interactions

In a 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 3 days). The hypotensive and sedative effects of tizanidine were also potentiated. Concomitant administration of tizanidine and ciprofloxacin is contraindicated.

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.

Some quinolones, including ciprofloxacin, have also been shown to interfere with the metabolism of caffeine. This may lead to reduced clearance of caffeine and a prolongation of its serum half-life.

Concurrent administration of a quinolone, including ciprofloxacin, with multivalent cation-containing products such as magnesium/aluminum antacids, sucralfate, Videx®3(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.

Altered serum levels of phenytoin (increased and decreased) have been reported in patients receiving concomitant ciprofloxacin.

The concomitant administration of ciprofloxacin with the sulfonylurea glyburide has, on rare occasions, resulted in severe hypoglycemia.

Some quinolones, including ciprofloxacin, have been associated with transient elevations in serum creatinine in patients receiving cyclosporine concomitantly.

Quinolones, including ciprofloxacin, have been reported to enhance the effects of the oral anticoagulant warfarin or its derivatives. When these products are administered concomitantly, prothrombin time or other suitable coagulation tests should be closely monitored.

Probenecid 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.

Renal 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 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.

Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies.


  • 3

    Videx® (didanosine) is a registered trademark of Bristol Myers Squibb.

  • 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 DNA 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 DNA Repair Assay (Positive)

    Thus, 2 of the 8 tests were positive, but results of the following 3 in vivo test systems gave negative results:

    Rat Hepatocyte DNA 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 2 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.4

    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 C

    There are no adequate and well controlled studies in pregnant women. An expert review of published data on experiences with ciprofloxacin use during pregnancy by TERIS - the Teratogen Information System - concluded that therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk (quantity and quality of data=fair), but the data are insufficient to state that there is no risk.8

    A controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5% exposed to ciprofloxacin and 68% first trimester exposures) during gestation.9 In utero exposure to fluoroquinolones during embryogenesis was not associated with increased risk of major malformations. The reported rates of major congenital malformations were 2.2% for the fluoroquinolone group and 2.6% for the control group (background incidence of major malformations is 1% to 5%). Rates of spontaneous abortions, prematurity and low birth weight did not differ between the groups and there were no clinically significant musculoskeletal dysfunctions up to one year of age in the ciprofloxacin exposed children.

    Another prospective follow-up study reported on 549 pregnancies with fluoroquinolone exposure (93% first trimester exposures).10 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.8,9 However, these small post-marketing 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. Ciprofloxacin should not be used during pregnancy unless the potential benefit justifies the potential risk to both fetus and mother (see WARNINGS).

    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 for serious adverse reactions in infants nursing from mothers taking ciprofloxacin, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

    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 ADMINISTRATION and INHALATIONAL ANTHRAX: Additional Information.

    Complicated Urinary Tract Infection and Pyelonephritis

    Ciprofloxacin is indicated for the treatment of complicated urinary tract infections and pyelonephritis due to Escherichia coli. Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the pediatric population due to an increased incidence of adverse events compared to 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 6 weeks of follow-up were 9.3% (31/335) vs. 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 6 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 Fibrosis

    Short-term safety data from a single trial in pediatric cystic fibrosis patients are available. In a randomized, double-blind clinical trial for the treatment of acute pulmonary exacerbations in cystic fibrosis patients (ages 5 to 17 years), 67 patients received ciprofloxacin I.V. 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 I.V. 50 mg/kg/dose q8h and tobramycin I.V. 3 mg/kg/dose q8h for a total of 10 to 21 days. Patients less than 5 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 0 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 67 patients developed arthritis of the knee 9 days after a 10 day course of treatment with ciprofloxacin. Clinical symptoms resolved, but an MRI showed knee effusion without other abnormalities 8 months after treatment. However, the relationship of this event to the patient's 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 a fluoroquinolone such as ciprofloxacin. 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 to elderly patients especially those on corticosteroids. Patients should be informed of this potential side effect and advised to discontinue ciprofloxacin and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur (See Boxed Warning, WARNINGS, and ADVERSE REACTIONS: Post-Marketing Adverse Event Reports).

    In a retrospective analysis of 23 multiple-dose controlled clinical trials of ciprofloxacin encompassing over 3,500 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 with concomitant drugs that can result in prolongation of the QT interval (e.g., class IA or class III antiarrhythmics) or in patients with risk factors for Torsades de pointes (e.g., known QT prolongation, uncorrected hypokalemia).

  • 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 a Whole: headache, abdominal pain/discomfort, foot pain, pain, pain in extremities

    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, lethargy, drowsiness, weakness, malaise, anorexia, phobia, depersonalization, depression, paresthesia, abnormal gait, grand mal convulsion

    Gastrointestinal: painful oral mucosa, oral candidiasis, dysphagia, intestinal perforation, gastrointestinal bleeding, cholestatic jaundice, hepatitis

    Hemic/Lymphatic: lymphadenopathy, petechia

    Metabolic/Nutritional: amylase increase, lipase increase

    Musculoskeletal: arthralgia or back pain, joint stiffness, achiness, neck or chest pain, flare up of gout

    Renal/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, sweating

    Special Senses: blurred vision, disturbed vision (change in color perception, overbrightness of lights), decreased visual acuity, diplopia, eye pain, tinnitus, hearing loss, bad taste, chromatopsia

    In several instances nausea, vomiting, tremor, irritability, or palpitation were judged by investigators to be related to elevated serum levels of theophylline possibly as a result of drug interaction with ciprofloxacin.

    In randomized, double-blind controlled clinical trials comparing ciprofloxacin tablets (500 mg BID) to cefuroxime axetil (250 mg to 500 mg BID) and to clarithromycin (500 mg BID) in patients with respiratory tract infections, ciprofloxacin demonstrated a CNS adverse event profile comparable to the control drugs.

    Adverse Reactions in Pediatric Patients

    Ciprofloxacin, administered I.V. and /or orally, was compared to a cephalosporin for treatment of complicated urinary tract infections (cUTI) or pyelonephritis in pediatric patients 1 to 17 years of age (mean age of 6 ± 4 years). The trial was conducted in the U.S., Canada, Argentina, Peru, Costa Rica, Mexico, South Africa, and Germany. The duration of therapy was 10 to 21 days (mean duration of treatment was 11 days with a range of 1 to 88 days). The primary objective of the study was to assess musculoskeletal and neurological safety within 6 weeks of therapy and through one year of follow-up in the 335 ciprofloxacin- and 349 comparator-treated patients enrolled.

    An Independent Pediatric Safety Committee (IPSC) reviewed all cases of musculoskeletal adverse events as well as all patients with an abnormal gait or abnormal joint exam (baseline or treatment-emergent). These events were evaluated in a comprehensive fashion and included such conditions as arthralgia, abnormal gait, abnormal joint exam, joint sprains, leg pain, back pain, arthrosis, bone pain, pain, myalgia, arm pain, and decreased range of motion in a joint. The affected joints included: knee, elbow, ankle, hip, wrist, and shoulder. Within 6 weeks of treatment initiation, the rates of these events were 9.3% (31/335) in the ciprofloxacin-treated group vs. 6% (21/349) in comparator-treated patients. The majority of these events were mild or moderate in intensity. All musculoskeletal events occurring by 6 weeks resolved (clinical resolution of signs and symptoms), usually within 30 days of end of treatment. Radiological evaluations were not routinely used to confirm resolution of the events. The events occurred more frequently in ciprofloxacin-treated patients than control patients, regardless of whether they received I.V. 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 one year, the rate of these events reported at any time during that period was 13.7% (46/335) in the ciprofloxacin-treated group vs. 9.5% (33/349) comparator-treated patients.

    An adolescent female discontinued ciprofloxacin for wrist pain that developed during treatment. An MRI performed 4 weeks later showed a tear in the right ulnar fibrocartilage. A diagnosis of overuse syndrome secondary to sports activity was made, but a contribution from ciprofloxacin cannot be excluded. The patient recovered by 4 months without surgical intervention.

    Findings Involving Joint or Peri-articular Tissues as Assessed by the IPSC
  • * 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 6 week and 1 year evaluations, the 95% confidence interval indicated that it could not be concluded that ciprofloxacin group had findings comparable to the control group.
  •    Ciprofloxacin Comparator
     All Patients (within 6 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
     ≥ 2 years < 6 years 5/124 (4%) 3/118 (2.5%)
     ≥ 6 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 1 year) 46/335 (13.7%) 33/349 (9.5%)
     95% Confidence Interval* (-0.6%, +9.1%)

    The incidence rates of neurological events within 6 weeks of treatment initiation were 3% (9/335) in the ciprofloxacin group vs. 2% (7/349) in the comparator group and included dizziness, nervousness, insomnia, and somnolence.

    In this trial, the overall incidence rates of adverse events regardless of relationship to study drug and within 6 weeks of treatment initiation were 41% (138/335) in the ciprofloxacin group vs. 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 vs. 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 post-marketing experience may also occur in pediatric patients.

    Post-Marketing 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 a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these events in labeling are typically based on one or more of the following factors: (1) seriousness of the event, (2) frequency of the reporting, or (3) strength of causal connection to the drug.

    Agitation, agranulocytosis, albuminuria, anaphylactic reactions (including life-threatening anaphylactic shock), anosmia, candiduria, cholesterol elevation (serum), confusion, constipation, delirium, dyspepsia, dysphagia, erythema multiforme, exfoliative dermatitis, fixed eruption, flatulence, glucose elevation (blood), hemolytic anemia, hepatic failure (including fatal cases), hepatic necrosis, hyperesthesia, hypertonia, hypesthesia, hypotension (postural), 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, phenytoin alteration (serum), photosensitivity/phototoxicity reaction, 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), renal calculi, serum sickness like reaction, Stevens-Johnson Syndrome, taste loss, tendinitis, tendon rupture, torsade de pointes, toxic epidermal necrolysis (Lyell’s Syndrome), triglyceride elevation (serum), twitching, vaginal candidiasis, and vasculitis. (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 INHALATIONAL ANTHRAX: Additional 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, leukocytosis.

  • 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 and administration of magnesium, aluminum, or calcium containing antacids which can reduce the absorption of ciprofloxacin. Adequate hydration must be maintained. Only a small amount of ciprofloxacin (< 10%) is removed from the body after hemodialysis or peritoneal dialysis.

    Single doses of ciprofloxacin were relatively non-toxic via the oral route of administration in mice, rats, and dogs. No deaths occurred within a 14-day post treatment observation period at the highest oral doses tested; up to 5000 mg/kg in either rodent species, or up to 2500 mg/kg in the dog. Clinical signs observed included hypoactivity and cyanosis in both rodent species and severe vomiting in dogs. In rabbits, significant mortality was seen at doses of ciprofloxacin > 2500 mg/kg. Mortality was delayed in these animals, occurring 10 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.

  • 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 patient’s host-defense mechanisms, and the status of renal function and hepatic function.

    The duration of treatment depends upon the severity of infection. The usual duration is 7 to 14 days; however, for severe and complicated infections more prolonged therapy may be required. Ciprofloxacin should be administered at least 2 hours before or 6 hours after magnesium/aluminum antacids, or sucralfate, Videx®4 (didanosine) chewable/buffered tablets or pediatric powder for oral solution, other highly buffered drugs,or other products containing calcium, iron or zinc.

    ADULT DOSAGE GUIDELINES
  • * Generally ciprofloxacin should be continued for at least 2 days after the signs and symptoms of infection have disappeared, except for inhalational anthrax (post-exposure).
  • used in conjunction with metronidazole
  • Drug administration should begin as soon as possible after suspected or confirmed exposure. This indication is based on a surrogate endpoint, ciprofloxacin serum concentrations achieved in humans, reasonably likely to predict clinical benefit.5 For a discussion of ciprofloxacin serum concentrations in various human populations, see INHALATIONAL ANTHRAX: Additional Information.
  •  Infection Severity Dose Frequency Usual Durations*
     Urinary Tract Acute Uncomplicated 250 mg q 12 h 3 Days
      Mild/Moderate 250 mg q 12 h 7 to 14 Days
      Severe/Complicated 500 mg q 12 h 7 to 14 Days
     Chronic Bacterial Prostatitis Mild/Moderate 500 mg q 12 h 28 Days
     Lower Respiratory Tract Mild/Moderate 500 mg q 12 h 7 to 14 Days
      Severe/Complicated 750 mg q 12 h 7 to 14 Days
     Acute Sinusitis Mild/Moderate 500 mg q 12 h 10 Days
     Skin and Skin Structure Mild/Moderate 500 mg q 12 h 7 to 14 Days
      Severe/Complicated 750 mg q 12 h 7 to 14 Days
     Bone and Joint Mild/Moderate 500 mg q 12 h ≥ 4 to 6 Weeks
      Severe/Complicated 750 mg q 12 h ≥ 4 to 6 Weeks
     Intra-Abdominal Complicated 500 mg q 12 h 7 to 14 Days
     Infectious Diarrhea Mild/Moderate/Severe 500 mg q 12 h 5 to 7 Days
     Typhoid Fever Mild/Moderate 500 mg q 12 h 10 Days
     Urethral and Cervical Gonococcal Infections Uncomplicated 250 mg Single Dose Single Dose
     Inhalational Anthrax (post-exposure)  500 mg q 12 h 60 Days

  • 4

    Videx® (didanosine) is a registered trademark of Bristol Myers Squibb.

  • Conversion of I.V. to Oral Dosing in Adults

    Patients whose therapy is started with ciprofloxacin I.V. may be switched to ciprofloxacin tablets when clinically indicated at the discretion of the physician. (See CLINICAL PHARMACOLOGY and table below for the equivalent dosing regimens.)

    Equivalent AUC Dosing Regimens
     Ciprofloxacin Oral Dosage  Equivalent Ciprofloxacin I.V. Dosage
     250 mg Tablet q 12 h 200 mg I.V. q 12 h
     500 mg Tablet q 12 h 400 mg I.V. q 12 h
     750 mg Tablet q 12 h 400 mg I.V. q 8 h  

    Adults with Impaired Renal Function

    Ciprofloxacin is eliminated primarily by renal excretion; however, the drug is also metabolized and partially cleared through the biliary system of the liver and through the intestine. These alternative pathways of drug elimination appear to compensate for the reduced renal excretion in patients with renal impairment. Nonetheless, some modification of dosage is recommended, particularly for patients with severe renal dysfunction. The following table provides dosage guidelines for use in patients with renal impairment:

    RECOMMENDED STARTING AND MAINTENANCE DOSES FOR PATIENTS WITH IMPAIRED RENAL FUNCTION
     Creatinine Clearance (mL/min)  Dose
     > 50 See Usual Dosage.
     30 to 50 250 to 500 mg q 12 h
     5 to 29 250 to 500 mg q 18 h
     Patients on hemodialysis or
    Peritoneal dialysis
     250 to 500 mg q 24 h
    (after dialysis)

    When only the serum creatinine concentration is known, the following formula may be used to estimate creatinine clearance.

    Creatinine Clearance Calculation

    The serum creatinine should represent a steady-state of renal function.

    In patients with severe infections and severe renal impairment, a unit dose of 750 mg may be administered at the intervals noted above. Patients should be carefully monitored.

    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 (i.e., I.V. or oral) for complicated urinary tract infection or pyelonephritis should be determined by the severity of the infection. In the clinical trial, pediatric patients with moderate to severe infection were initiated on 6 to 10 mg/kg I.V. every 8 hours and allowed to switch to oral therapy (10 to 20 mg/kg every 12 hours), at the discretion of the physician.

    PEDIATRIC DOSAGE GUIDELINES
  • * 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 a surrogate endpoint, ciprofloxacin serum concentrations achieved in humans, reasonably likely to predict clinical benefit.4 For a discussion of ciprofloxacin serum concentrations in various human populations, see INHALATIONAL ANTHRAX: Additional Information.
  •  Infection Route of Administration Dose (mg/kg) Frequency Total Duration
     Complicated Urinary Tract or Pyelonephritis Intravenous 6 to 10 mg/kg (maximum 400 mg per dose; not to be exceeded even in patients weighing > 51 kg) Every 8 hours 10 to 21 days*
     (patients from 1 to 17 years of age) Oral 10 mg/kg to 20 mg/kg (maximum 750 mg per dose; not to be exceded even in patients weighing > 51 kg) Every 12 hours
     Inhalational Anthrax (Post-Exposure) Intravenous 10 mg/kg (maximum 400 mg per dose) Every 12 hours 60 days
     Oral 15 mg/kg (maximum 500 mg per dose) Every 12 hours

    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 (i.e., creatinine clearance of < 50 mL/min/1.73m2).

  • HOW SUPPLIED

    Ciprofloxacin Tablets, USP are available containing 500 mg of ciprofloxacin as the hydrochloride salt.

    The 500 mg tablets are white film-coated, modified capsule-shaped, unscored tablets debossed with G on one side of the tablet and CF 500 on the other side. They are available as follows:

    NDC: 68645-060-20 bottles of 20 tablets

    Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

    Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

    PHARMACIST: Dispense a Medication Guide with each prescription.

    Manufactured by:
    Mylan Pharmaceuticals
    Morgantown, WV 26505

    Packaged by:
    Legacy Pharmaceutical Packaging
    Earth City, MO 63045

  • ANIMAL PHARMACOLOGY

    Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most species tested. (See WARNINGS.) Damage of weight-bearing joints was observed in juvenile dogs and rats. In young beagles, 100 mg/kg ciprofloxacin, given daily for 4 weeks, caused degenerative articular changes of the knee joint. At 30 mg/kg, the effect on the joint was minimal. In a subsequent study in young beagle dogs, oral ciprofloxacin doses of 30 mg/kg and 90 mg/kg ciprofloxacin (approximately 1.3 and 3.5 times the pediatric dose based upon comparative plasma AUCs) given daily for 2 weeks caused articular changes which were still observed by histopathology after a treatment-free period of 5 months. At 10 mg/kg (approximately 0.6 times the pediatric dose based upon comparative plasma AUCs), no effects on joints were observed. This dose was also not associated with arthrotoxicity after an additional treatment-free period of 5 months. In another study, removal of weight-bearing from the joint reduced the lesions but did not totally prevent them.

    Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory animals dosed with ciprofloxacin. This is primarily related to the reduced solubility of ciprofloxacin under alkaline conditions, which predominate in the urine of test animals; in man, crystalluria is rare since human urine is typically acidic. In rhesus monkeys, crystalluria without nephropathy was noted after single oral doses as low as 5 mg/kg (approximately 0.07 times the highest recommended therapeutic dose based upon mg/m2). After 6 months of intravenous dosing at 10 mg/kg/day, no nephropathological changes were noted; however, nephropathy was observed after dosing at 20 mg/kg/day for the same duration (approximately 0.2 times the highest recommended therapeutic dose based upon mg/m2).

    In dogs, ciprofloxacin at 3 and 10 mg/kg by rapid I.V. injection (15 sec.) produces pronounced hypotensive effects. These effects are considered to be related to histamine release, since they are partially antagonized by pyrilamine, an antihistamine. In rhesus monkeys, rapid I.V. injection also produces hypotension but the effect in this species is inconsistent and less pronounced.

    In mice, concomitant administration of non-steroidal anti-inflammatory drugs such as phenylbutazone and indomethacin with quinolones has been reported to enhance the CNS stimulatory effect of quinolones.

    Ocular toxicity seen with some related drugs has not been observed in ciprofloxacin-treated animals.

  • CLINICAL STUDIES

    Complicated Urinary Tract Infection and Pyelonephritis

    Efficacy in Pediatric Patients

    NOTE: Although effective in clinical trials, ciprofloxacin is not a drug of first choice in the pediatric population due to an increased incidence of adverse events compared to controls, including events related to joints and/or surrounding tissues.

    Ciprofloxacin, administered I.V. and/or orally, was compared to a cephalosporin for treatment of complicated urinary tract infections (cUTI) and pyelonephritis in pediatric patients 1 to 17 years of age (mean age of 6 ± 4 years). The trial was conducted in the U.S., Canada, Argentina, Peru, Costa Rica, Mexico, South Africa, and Germany. The duration of therapy was 10 to 21 days (mean duration of treatment was 11 days with a range of 1 to 88 days). The primary objective of the study was to assess musculoskeletal and neurological safety.

    Patients were evaluated for clinical success and bacteriological eradication of the baseline organism(s) with no new infection or superinfection at 5 to 9 days post-therapy (Test of Cure or TOC). The Per Protocol population had a 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 9 Days Post-Therapy)
  • * 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.
  •    Ciprofloxacin Comparator
     Randomized Patients 337 352
     Per Protocol Patients 211 231
     Clinical Response at 5 to 9 Days
    Post-Treatment
     95.7% (202/211) 92.6% (214/231)
      95% CI [-1.3%, 7.3%]
     Bacteriologic Eradication by
    Patient at 5 to 9 Days
    Post-Treatment*
     84.4% (178/211) 78.3% (181/231)
      95% CI [-1.3%, 13.1%]
     Bacteriologic Eradication of the
    Baseline Pathogen at 5 to 9 Days
    Post-Treatment
      
     Escherichia coli 156/178 (88%) 161/179 (90%)
  • INHALATIONAL ANTHRAX IN ADULTS AND PEDIATRICS

    Additional Information

    The mean serum concentrations of ciprofloxacin associated with a statistically significant improvement in survival in the rhesus monkey model of inhalational anthrax are reached or exceeded in adult and pediatric patients receiving oral and intravenous 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 a study of 10 pediatric patients between 6 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 a 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 a surrogate endpoint reasonably likely to predict clinical benefit and provide the basis for this indication.5

    A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 11 LD50 (~5.5 x 105) spores (range 5 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.6  Mortality due to anthrax for animals that received a 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.7

    More than 9,300 persons were recommended to complete a 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 1,000 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 lightheadedness) 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 a control group, could be explained by a reporting bias, concurrent medical conditions, other concomitant medications, emotional stress or other confounding factors, and/or a 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.

  • REFERENCES

  • MEDICATION GUIDE CIPROFLOXACIN TABLETS, USP (sip" roe flox' a sin)

    Read the Medication Guide that comes with ciprofloxacin tablets before you start taking it and each time you get a 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 I should know about ciprofloxacin tablets?

    Ciprofloxacin tablets belong to a 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.

    Tendon rupture or swelling of the tendon (tendinitis)

    What are ciprofloxacin tablets?

    Ciprofloxacin tablets are a fluoroquinolone antibiotic medicine used to treat certain infections caused by certain germs called bacteria.

    Children less than 18 years of age have a 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:

    What should I tell my healthcare provider before taking ciprofloxacin tablets?

    See “What is the most important information I should know about ciprofloxacin tablets?

    Tell your healthcare provider about all your medical conditions, including if you:

    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:

    Ask your healthcare provider if you are not sure if any of your medicines are listed above.

    Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.

    How should I take ciprofloxacin tablets?

    If you have been prescribed ciprofloxacin tablets after being exposed to anthrax:

    What should I avoid while taking ciprofloxacin tablets?

    What are the possible side effects of ciprofloxacin tablets?

    Other serious side effects of ciprofloxacin tablets include:

    Ciprofloxacin tablets may need to be stopped to prevent permanent nerve damage.

    The most common side effects of ciprofloxacin tablets include:

    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 I store ciprofloxacin tablets?

    Store ciprofloxacin tablets at 20° to 25°C (68° to 77°F)

    Keep ciprofloxacin tablets and all medicines out of the reach of children.

    General Information about ciprofloxacin tablets

    Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ciprofloxacin tablets for a 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 Mylan Pharmaceuticals Inc. toll free at 1-877-446-3679 (1-877-4-INFO-RX).

    What are the ingredients in ciprofloxacin tablets, USP?

    The brand names mentioned in this Medication Guide are registered trademarks of their respective manufacturers.

    This Medication Guide has been approved by the U.S. Food and Drug Administration.

    REVISED MARCH 2011
    CIPF:R6mpbmt/MG:CIPF:R3

  • PRINCIPAL DISPLAY PANEL

    NDC: 68645-060-20
    Ciprofloxacin 500mg
    20 Tablets
    Rx Only

    NDC: <a href=/NDC/68645-060-20>68645-060-20</a> Ciprofloxacin 500mg 20 Tablets Rx Only

  • INGREDIENTS AND APPEARANCE
    CIPROFLOXACIN 
    ciprofloxacin tablet, film coated
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 68645-060(NDC:0378-7098)
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    CIPROFLOXACIN HYDROCHLORIDE (UNII: 4BA73M5E37) (CIPROFLOXACIN - UNII:5E8K9I0O4U) CIPROFLOXACIN500 mg
    Inactive Ingredients
    Ingredient NameStrength
    SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
    STARCH, CORN (UNII: O8232NY3SJ)  
    CROSPOVIDONE (UNII: 68401960MK)  
    HYPROMELLOSES (UNII: 3NXW29V3WO)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)  
    POLYDEXTROSE (UNII: VH2XOU12IE)  
    POLYETHYLENE GLYCOL (UNII: 3WJQ0SDW1A)  
    STARCH, CORN (UNII: O8232NY3SJ)  
    TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
    TRIACETIN (UNII: XHX3C3X673)  
    Product Characteristics
    ColorWHITEScoreno score
    ShapeOVAL (modified capsule-shaped) Size18mm
    FlavorImprint Code G;CF;500
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 68645-060-2020 in 1 BOTTLE, PLASTIC
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA07581704/12/2011
    Labeler - Legacy Pharmaceutical Packaging (143213275)
    Establishment
    NameAddressID/FEIBusiness Operations
    Legacy Pharmaceutical Packaging143213275RELABEL, REPACK

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