CIPROFLOXACIN- ciprofloxacin hydrochloride tablet, film coated 
PD-Rx Pharmaceuticals, Inc.

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BOXED WARNING

WARNING:
Fluoroquinolones, including ciprofloxacin, 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 (SeeWARNINGS).


DESCRIPTION

Ciprofloxacin hydrochloride tablets are synthetic broad spectrum antimicrobial agents for oral administration. Ciprofloxacin hydrochloride, USP, a fluoroquinolone, is the monohydrochloride monohydrate salt of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. It is a faintly yellowish to light yellow crystalline substance with a molecular weight of 385.8. Its empirical formula is C17H18FN3O3HClH2O and its chemical structure is as follows:

MM1



Ciprofloxacin tablets are film-coated and white in color. Each tablet, for oral administration, contains ciprofloxacin hydrochloride equivalent to 100 mg, 250 mg, 500 mg or 750 mg ciprofloxacin. In addition, each tablet contains the following inactive ingredients: colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol 400, sodium starch glycolate, corn starch and titanium dioxide.

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.

DoseMaximum SerumArea Under Curve(mg)Concentration ((AUC) (2501.24.85002.411.67504.320.210005.430.8Maximum serum concentrations are attained 1 to 2 hours after oral dosing. Mean concentrations 12 hours after dosing with 250, 500, or 750 mg are 0.1, 0.2, and 0.4respectively. The serum elimination half-life in subjects with normal renal function is approximately 4 hours. Serum concentrations increase proportionately with doses up to 1000 mg.
A 500 mg oral dose given every 12 hours has been shown to produce an area under the serum concentration time curve (AUC) equivalent to that produced by an intravenous infusion of 400 mg ciprofloxacin given over 60 minutes every 12 hours. A 750 mg oral dose given every 12 hours has been shown to produce an AUC at steady-state equivalent to that produced by an intravenous infusion of 400 mg given over 60 minutes every 8 hours. A 750 mg oral dose results in a Cmax similar to that observed with a 400 mg I.V. dose. A 250 mg oral dose given every 12 hours produces an AUC equivalent to that produced by an infusion of 200 mg ciprofloxacin given every 12 hours.

Steady-state Pharmacokinetic Parameters Following Multiple Oral and I.V. Doses
Parameters500 mg400 mg750 mg400 mgq12h, P.Oq12h, I.V.q12h, P.Oq8h, I.V.* AUC0-12hAUC 24h=AUC0-12h2AUC 24h=AUC0-8h3AUC (13.7*12.7*31.632.9Cmax (2.974.563.594.07
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 WARNINGSPRECAUTIONS: Drug Interactions).

Excretion
The serum elimination half-life in subjects with normal renal function is approximately 4 hours. Approximately 40 to 50% of an orally administered dose is excreted in the urine as unchanged drug. After a 250 mg oral dose, urine concentrations of ciprofloxacin usually exceed 200during the first two hours and are approximately 30at 8 to 12 hours after dosing. The urinary excretion of ciprofloxacin is virtually complete within 24 hours after dosing. The renal clearance of ciprofloxacin, which is approximately 300 mL/minute, exceeds the normal glomerular filtration rate of 120 mL/minute. Thus, active tubular secretion would seem to play a significant role in its elimination. Co-administration of probenecid with ciprofloxacin results in about a 50% reduction in the ciprofloxacin renal clearance and a 50% increase in its concentration in the systemic circulation. Although bile concentrations of ciprofloxacin are several fold higher than serum concentrations after oral dosing, only a small amount of the dose administered is recovered from the bile as unchanged drug. An additional 1 to 2% of the dose is recovered from the bile in the form of metabolites. Approximately 20 to 35% of an oral dose is recovered from the feces within 5 days after dosing. This may arise from either biliary clearance or transintestinal elimination.

Drug-drug Interactions
When ciprofloxacin tablets are given concomitantly with food, there is a delay in the absorption of the drug, resulting in peak concentrations that occur closer to 2 hours after dosing rather than 1 hour. The overall absorption of ciprofloxacin 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%. (SeePRECAUTIONS.)
The serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs were given concomitantly.
Concomitant administration with tizanidine is contraindicated (SeeCONTRAINDICATIONS).
Concomitant administration of ciprofloxacin with theophylline decreases the clearance of theophylline resulting in elevated serum theophylline levels and increased risk of a patient developing CNS or other adverse reactions. Ciprofloxacin also decreases caffeine clearance and inhibits the formation of paraxanthine after caffeine administration. (SeeWARNINGS,PRECAUTIONS.)

Special Populations
Pharmacokinetic studies of the oral (single dose) and intravenous (single and multiple dose) forms 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 16-40%, 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. (SeePRECAUTIONS: Geriatric Use.)
In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged. Dosage adjustments may be required. (SeeDOSAGE AND ADMINISTRATION.)
In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in ciprofloxacin pharmacokinetics have been observed. The kinetics of ciprofloxacin in patients with acute hepatic insufficiency, however, have not been fully elucidated.

MICROBIOLOGY


Ciprofloxacin is slightly less active when tested at acidic pH. The inoculum size has little effect when tested in vitro. The minimal bactericidal concentration (MBC) generally does not exceed the minimal inhibitory concentration (MIC) by more than a factor of 2.
Ciprofloxacin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in theINDICATIONS AND USAGEsection of the package insert for ciprofloxacin hydrochloride tablets.
Aerobic gram-positive microorganisms
Enterococcus faecalis (Many strains are only moderately susceptible.)
Staphylococcus aureus (methicillin-susceptible strains only)
Staphylococcus epidermidis (methicillin-susceptible strains only)
Staphylococcus saprophyticus
Streptococcus pneumoniae (penicillin-susceptible strains only)
Streptococcus pyogenes
Aerobic gram-negative microorganisms
Campylobacter jejuniProteus mirabilisCitrobacter diversusProteus 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 a surrogate marker (seeINDICATIONS AND USAGEandINHALATIONAL ANTHRAX - ADDITIONAL INFORMATION.)
The following in vitro data are available, but their clinical significance is unknown.
Ciprofloxacin exhibits in vitro minimum inhibitory concentrations (MICs) of 1or less against most (
Aerobic gram-positive microorganisms
Staphylococcus haemolyticus
Staphylococcus hominis
Streptococcus pneumoniae (penicillin-resistant strains only)
Aerobic gram-negative microorganisms
Acinetobacter IwoffiPasteurella multocidaAeromonas hydrophilaSalmonella enteritidisEdwardsiella tardaVibrio choleraeEnterobacter aerogenesVibrio parahaemolyticusKlebsiella oxytocaVibrio vulnificusLegionella pneumophilaYersinia enterocoliticaMost strains of Burkholderia cepacia and some strains of Stenotrophomonas maltophilia are resistant to ciprofloxacin as are most anaerobic bacteria, including Bacteroides fragilis and Clostridium difficile.

Susceptibility Tests

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 a standardized procedure. Standardized procedures are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of ciprofloxacin powder. The MIC values should be interpreted according to the following criteria:
For testing Enterobacteriaceae, Enterococcus faecalis, methicillin-susceptible Staphylococcus species, penicillin-susceptible Streptococcus pneumoniae, Streptococcus pyogenes, and Pseudomonas aeruginosaa:
MIC (Interpretation1Susceptible (S)2Intermediate (I)4Resistant (R)a These interpretive standards are applicable only to broth microdilution susceptibility tests with streptococci using cation-adjusted Mueller-Hinton broth with 2-5% lysed horse blood.
For testing Haemophilus influenzae and Haemophilus parainfluenzae b:
MIC (Interpretation1Susceptible (S)b This interpretive standard is applicable only to broth microdilution susceptibility tests with Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium.1
The current absence of data on resistant strains precludes defining any results other than "Susceptible". Strains yielding MIC results suggestive of a "nonsusceptible" category should be submitted to a reference laboratory for further testing.
For testing Neisseria gonorrhoeae c:
MIC (Interpretation0.06Susceptible (S)0.120.5Intermediate (I)1Resistant (R)c This interpretive standard is applicable only to agar dilution test with GC agar base and 1% defined growth supplement.
A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A 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 a buffer zone, which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard ciprofloxacin powder should provide the following MIC values:
OrganismMIC (* This quality control range is applicable to only H. influenzae ATCC 49247 tested by a broth microdilution procedure using Haemophilus Test Medium (HTM)1.C. jejuni ATCC 33560 tested by broth microdilution procedure using cation adjusted Mueller Hinton broth with 2.5-5% lysed horse blood in a microaerophilic environment at 36-37for 48 hours and for 42at 24 hours2, respectively.N. gonorrhoeae ATCC 49226 tested by agar dilution procedure using GC agar and 1% defined growth supplement in a 5% CO2 environment at 35-37for 20-24 hours3.E. faecalisATCC 292120.25 - 2E. coliATCC 259220.004 - 0.015H. influenzae*ATCC 492470.004 - 0.03P. aeruginosaATCC 278530.25 - 1.0S. aureusATCC 292130.12 - 0.5C.jejuniATCC 335600.06 - 0.25 and 0.03-0.12N. gonorrhoeaeATCC 492260.001 - 0.008
Diffusion Techniques
Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure3 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 5-ciprofloxacin to test the susceptibility of microorganisms to ciprofloxacin.
Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5-ciprofloxacin disk should be interpreted according to the following criteria:
For testing Enterobacteriaceae, Enterococcus faecalis, methicillin-susceptible Staphylococcus species, penicillin-susceptible Streptococcus pneumoniae, Streptococcus pyogenes, and Pseudomonas aeruginosaa:
Zone Diameter (mm)Interpretation21Susceptible (S)1620Intermediate (I)15Resistant (R)a These zone diameter standards are applicable only to tests performed for streptococci using Mueller-Hinton agar supplemented with 5% sheep blood incubated in 5% CO2.
For testing Haemophilus influenzae and Haemophilus parainfluenzae b:
Zone Diameter (mm)Interpretation21Susceptible (S)b This zone diameter standard is applicable only to tests with Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium (HTM)3.
The current absence of data on resistant strains precludes defining any results other than "Susceptible". Strains yielding zone diameter results suggestive of a "nonsusceptible" category should be submitted to a reference laboratory for further testing.
For testing Neisseria gonnorhoeae c:
Zone Diameter (mm)Interpretation41Susceptible (S)2840Intermediate (I)27Resistant (R)c This zone diameter standard is applicable only to disk diffusion tests with GC agar base and 1% defined growth supplement.
Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for ciprofloxacin.
As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 5-ciprofloxacin disk should provide the following zone diameters in these laboratory test quality control strains:
OrganismZone Diameter (mm)* These quality control limits are applicable to only H. influenzae ATCC 49247 testing using Haemophilus Test Medium (HTM) 3.These quality control limits are applicable only to tests conducted with N. gonorrhoeae ATCC 49226 performed by disk diffusion using GC agar base and 1% defined growth supplement.E. coliATCC 2592230 - 40H. influenzae*ATCC 4924734 - 42N. gonorrhoeaeATCC 4922648 - 58P. aeruginosaATCC 2785325 - 33S. aureusATCC 259232230

INDICATIONS & USAGE

Ciprofloxacin tablets are indicated for the treatment of infections caused by susceptible strains of the designated microorganisms in the conditions and patient populations listed below. Please seeDOSAGE AND ADMINISTRATIONfor specific recommendations.

Adult Patients
Urinary Tract Infections caused by Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus mirabilis, Providencia rettgeri, Morganella morganii, Citrobacter diversus, Citrobacter freundii, Pseudomonas aeruginosa, methicillin-susceptible Staphylococcus epidermidis, Staphylococcus saprophyticus, or Enterococcus 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.
NOTE: Although effective in clinical trials, ciprofloxacin is not a 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 strains), Campylobacter jejuni, Shigella boydii1, Shigella dysenteriae, Shigella flexneri or Shigella sonnei1when antibacterial therapy is indicated.
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.

1
     Although treatment of infections due to this organism in this organ system demonstrated a clinically significant outcome, efficacy was studied in fewer than 10 patients.

Pediatric Patients (1 to 17 years of age)
Complicated Urinary Tract Infections and Pyelonephritis due to Escherichia coli.
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. (SeeWARNINGS,PRECAUTIONS, Pediatric Use,ADVERSE REACTIONSandCLINICAL STUDIES.) Ciprofloxacin, like other fluoroquinolones, is associated with arthropathy and histopathological changes in weight-bearing joints of juvenile animals. (SeeANIMAL PHARMACOLOGY.)

Adult and Pediatric Patients
Inhalational anthrax (post-exposure): To reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis.
Ciprofloxacin serum concentrations achieved in humans served as a surrogate endpoint reasonably likely to predict clinical benefit and provided the initial basis for approval of this indication.5 Supportive clinical information for ciprofloxacin for anthrax post-exposure prophylaxis was obtained during the anthrax bioterror attacks of October 2001. (See also,INHALATIONAL ANTHRAX - ADDITIONAL 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 hydrochloride may be initiated before results of these tests are known; once results become available appropriate therapy should be continued. As with other drugs, some strains 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 and other antibacterial drugs, ciprofloxacin tablets 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.

CONTRAINDICATIONS

Ciprofloxacin hydrochloride is contraindicated in persons with a history of hypersensitivity to ciprofloxacin, any member of the quinolone class of antimicrobial agents, or any of the product components.
Concomitant administration with tizanidine is contraindicated. (SeePRECAUTIONS, Drug Interactions.)

WARNINGS

Tendinopathy and Tendon Rupture:


Pregnant Women
THE SAFETY AND EFFECTIVENESS OF CIPROFLOXACIN IN PREGNANT AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED. (SeePRECAUTIONS: Pregnancy, andNursing Motherssubsections.)

Pediatrics
Ciprofloxacin should be used in pediatric patients (less than 18 years of age) only for infections listed in theINDICATIONS AND USAGEsection. An increased incidence of adverse events compared to controls, including events related to joints and/or surrounding tissues, has been observed. (SeeADVERSE 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. (SeeANIMAL PHARMACOLOGY.)

Cytochrome P450 (CYP450)
Ciprofloxacin is an inhibitor of the hepatic CYP1A2 enzyme pathway. Coadministration of ciprofloxacin and other drugs primarily metabolized by the CYP1A2 (e.g. theophylline, methylxanthines, tizanidine) results in increased plasma concentrations of the coadministered drug and could lead to clinically significant pharmacodynamic side effects of the coadministered drug.

Central Nervous System Disorders
Convulsions, increased intracranial pressure, and toxic psychosis have been reported in patients receiving quinolones, including ciprofloxacin. Ciprofloxacin may also cause central nervous system (CNS) events including: dizziness, confusion, tremors, hallucinations, depression, and, rarely, suicidal thoughts or acts. These reactions may occur following the first dose. If these reactions occur in patients receiving ciprofloxacin, the drug should be discontinued and appropriate measures instituted. As with all quinolones, ciprofloxacin should be used with caution in patients with known or suspected CNS disorders that may predispose to seizures or lower the seizure threshold (e.g. severe cerebral arteriosclerosis, epilepsy), or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold (e.g. certain drug therapy, renal dysfunction). (SeePRECAUTIONS: General,Information for Patients,Drug InteractionsandADVERSE 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.

Hypersensitivity Reactions
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving quinolone therapy. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria, and itching. Only a few patients had a history of hypersensitivity reactions. Serious anaphylactic reactions require immediate emergency treatment with epinephrine. Oxygen, intravenous steroids, and airway management, including intubation, should be administered as indicated.
Other serious and sometimes fatal 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:

     vasculitis; arthralgia; myalgia; serum sickness;
     allergic pneumonitis;
     interstitial nephritis; acute renal insufficiency or failure;
     hepatitis; jaundice; acute hepatic necrosis or failure;

The drug should be discontinued immediately at the first appearance of a skin rash, jaundice, or any other sign of hypersensitivity and supportive measures instituted (SeePRECAUTIONS: Information for PatientsandADVERSE REACTIONS).


Pseudomembranous Colitis
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including ciprofloxacin, 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 A and B which contribute to the development of CDAD. Hypertoxin producing strains 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
Rare cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving quinolones, including ciprofloxacin. Ciprofloxacin should be discontinued if the patient experiences symptoms of neuropathy including pain, burning, tingling, numbness, and/or weakness, or is found to have deficits in light touch, pain, temperature, position sense, vibratory sensation, and/or motor strength in order to prevent the development of an irreversible condition.

Syphilis
Ciprofloxacin has not been shown to be effective in the treatment of syphilis. Antimicrobial agents used in high dose for short periods of time to treat gonorrhea may mask or delay the symptoms of incubating syphilis. All patients with gonorrhea should have a serologic test for syphilis at the time of diagnosis. Patients treated with ciprofloxacin should have a follow-up serologic test for syphilis after three months.

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. (SeeANIMAL 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. (SeeWARNINGS, Information for Patients, andDrug Interactions.)

Renal Impairment
Alteration of the dosage regimen is necessary for patients with impairment of renal function. (SeeDOSAGE AND ADMINISTRATION.)

Photosensitivity/Phototoxicity
Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as exaggerated sunburn reactions (e.g., 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 (SeeADVERSE REACTIONSandADVERSE REACTIONS/ Post-Marketing Adverse Events).
As with any potent drug, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic function, is advisable during prolonged therapy.
Prescribing ciprofloxacin tablets in the absence of a proven or strongly suspected bacterial infection or a 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:

     that antibacterial drugs including ciprofloxacin tablets should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When ciprofloxacin tablets are prescribed to treat a 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 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, or sucralfate, 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 a meal that contains these products.
     that ciprofloxacin may be associated with hypersensitivity reactions, even following a single dose, and to discontinue the drug at the first sign of a 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 a sunburn-like reaction or skin eruption occurs, patients should contact their physician.
     that peripheral neuropathies have been associated with ciprofloxacin use. If symptoms of peripheral neuropathy including pain, burning, tingling, numbness and/or weakness develop, they should discontinue treatment and contact their physicians.
     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 increase the effects of tizanidine. Patients should not use ciprofloxacin if they are already taking tizanidine.
     that ciprofloxacin may increase the effects of theophylline and caffeine. There is a 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 a 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 child's physician if the child has a history of joint-related problems before taking this drug. Parents of pediatric patients should also notify their child's physician of any joint-related problems that occur during or following ciprofloxacin therapy. (See WARNINGS, PRECAUTIONS, Pediatric Useand ADVERSE REACTIONS.)
     that diarrhea is a 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

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. (SeeWARNINGS.) 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, 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. (SeeDOSAGE AND ADMINISTRATIONfor 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.

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 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 16-32 weeks in mice treated concomitantly with UVA and other quinolones4.
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 risk8.
A controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5% exposed to ciprofloxacin and 68% first trimester exposures) during gestation9. 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 1-5%). Rates of spontaneous abortions, prematurity and low birth weight did not differ between the groups and there were no clinically significant musculoskelatal 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 pregnancy8,9. 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. Ciprofloxacin should not be used during pregnancy unless the potential benefit justifies the potential risk to both fetus and mother. (SeeWARNINGS.)
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. (SeeWARNINGS.)

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. (SeeANIMAL 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), seeDOSAGE AND ADMINISTRATIONandINHALATIONAL 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 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 6.0% (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. (SeeADVERSE REACTIONSandCLINICAL 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 5-17 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 10-21 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 10-21 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 0-93 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 a 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 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

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 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. (SeeCLINICAL PHARMACOLOGYandDOSAGE 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 torsade 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 formulation, all dosages, all drug-therapy durations, and for all indications of ciprofloxacin therapy were nausea (2.5%), diarrhea (1.6%), liver function tests abnormal (1.3%), vomiting (1%), and rash (1%).
Additional medically important events that occurred in less than 1% of ciprofloxacin patients are listed below.
     Body as a Whole: headache, abdominal pain/discomfort, foot pain, pain, pain in extremities, injection site reaction (ciprofloxacin intravenous)
     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 - 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
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 64 years). The trial was conducted in the US, Canada, Argentina, Peru, Costa Rica, Mexico, South Africa, and Germany. The duration of therapy was 10 to 21 days (mean duration of treatment was 11 days with a range of 1 to 88 days). The primary objective of the study was to assess musculoskeletal and neurological safety within 6 weeks of therapy and through one year of follow-up in the 335 ciprofloxacin- and 349 comparator-treated patients enrolled.
An Independent Pediatric Safety Committee (IPSC) reviewed all cases of musculoskeletal adverse events as well as all patients with an abnormal gait or abnormal joint exam (baseline or treatment-emergent). These events were evaluated in a comprehensive fashion and included such conditions as arthralgia, abnormal gait, abnormal joint exam, joint sprains, leg pain, back pain, arthrosis, bone pain, pain, myalgia, arm pain, and decreased range of motion in a joint. The affected joints included: knee, elbow, ankle, hip, wrist, and shoulder. Within 6 weeks of treatment initiation, the rates of these events were 9.3% (31/335) in the ciprofloxacin-treated group versus 6 % (21/349) in comparator-treated patients. The majority of these events were mild or moderate in intensity. All musculoskeletal events occurring by 6 weeks resolved (clinical resolution of signs and symptoms), usually within 30 days of end of treatment. Radiological evaluations were not routinely used to confirm resolution of the events. The events occurred more frequently in ciprofloxacin-treated patients than control patients, regardless of whether they received 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 1 year, the rate of these events reported at any time during that period was 13.7% (46/335) in the ciprofloxacin-treated group versus 9.5% (33/349) comparator-treated patients.
An adolescent female discontinued ciprofloxacin for wrist pain that developed during treatment. An MRI performed 4 weeks later showed a tear in the right ulnar fibrocartilage. A diagnosis of overuse syndrome secondary to sports activity was made, but a contribution from ciprofloxacin cannot be excluded. The patient recovered by 4 months without surgical intervention.
Findings Involving Joint or Peri-articular Tissues as Assessed by the IPSC
CiprofloxacinComparator* 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.All Patients (within 6 weeks)31/335 (9.3%)21/349 (6%)95% Confidence Interval*(-0.8%, +7.2%)Age Group12 months < 24 months1/36 (2.8%)0/412 years < 6 years5/124 (4%)3/118 (2.5%)6 years < 12 years18/143 (12.6%)12/153 (7.8%)12 years to 17 years7/32 (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 versus 2% (7/349) in the comparator group and included dizziness, nervousness, insomnia, and somnolence.
In this trial, the overall incidence rates of adverse events regardless of relationship to study drug and within 6 weeks of treatment initiation were 41% (138/335) in the ciprofloxacin group versus 31% (109/349) in the comparator group. The most frequent events were gastrointestinal: 15% (50/335) of ciprofloxacin patients compared to 9% (31/349) of comparator patients. Serious adverse events were seen in 7.5% (25/335) of ciprofloxacin-treated patients compared to 5.7% (20/349) of control patients. Discontinuation of drug due to an adverse event was observed in 3% (10/335) of ciprofloxacin-treated patients versus 1.4% (5/349) of comparator patients. Other adverse events that occurred in at least 1% of ciprofloxacin patients were diarrhea 4.8%, vomiting 4.8%, abdominal pain 3.3%, accidental injury 3%, rhinitis 3%, dyspepsia 2.7%, nausea 2.7%, fever 2.1%, asthma 1.8% and rash 1.8%.
In addition to the events reported in pediatric patients in clinical trials, it should be expected that events reported in adults during clinical trials or 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 quinolones, 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, myasthenia gravis (possible exacerbation), 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 (SeePRECAUTIONS.)
Adverse events were also reported by persons who received ciprofloxacin for anthrax post-exposure prophylaxis following the anthrax bioterror attacks of October 2001. (See alsoINHALATIONAL 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 10-14 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 & 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, 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
InfectionSeverityDoseFrequencyUsual Durations** 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 metronidazoleDrug 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 benefit4. For a discussion of ciprofloxacin serum concentrations in various human populations, seeINHALATIONAL ANTHRAX - ADDITIONAL INFORMATION.Urinary TractAcute Uncomplicated250 mgq 12 h3 DaysMild/Moderate250 mgq 12 h7 to 14 DaysSevere/Complicated500 mgq 12 h7 to 14 DaysChronic Bacterial ProstatitisMild/Moderate500 mgq 12 h28 DaysLower Respiratory TractMild/Moderate500 mgq 12 h7 to 14 daysSevere/Complicated750 mgq 12 h7 to 14 daysAcute SinusitisMild/Moderate500 mgq 12 h10 daysSkin and Skin StructureMild/Moderate500 mgq 12 h7 to 14 DaysSevere/Complicated750 mgq 12 h7 to 14 DaysBone and JointMild/Moderate500 mgq 12 h4 to 6 weeksSevere/Complicated750 mgq 12 h4 to 6 weeksIntra-AbdominalComplicated500 mgq 12 h7 to 14 DaysInfectious DiarrheaMild/Moderate/Severe500 mgq 12 h5 to 7 DaysTyphoid FeverMild/Moderate500 mgq 12 h10 daysUrethral and Cervical Gonococcal InfectionsUncomplicated250 mgsingle dosesingle doseInhalational anthrax (post-exposure)500 mgq 12 h60 Days
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 (SeeCLINICAL PHARMACOLOGYand table below for the equivalent dosing regimens).
Equivalent AUC Dosing Regimens
Ciprofloxacin Oral DosageEquivalent Ciprofloxacin I.V. Dosage250 mg Tablet q 12 h200 mg I.V. q 12 h500 mg Tablet q 12 h400 mg I.V. q 12 h750 mg Tablet q 12 h400 mg I.V. q 8 h
Adults with Impaired Renal Function

RECOMMENDED STARTING AND MAINTENANCE DOSES FOR PATIENTS WITH IMPAIRED RENAL FUNCTION
Creatinine Clearance (mL/min)Dose> 50See Usual Dosage3050250500 mg q 12 h529250500 mg q 18 hPatients on hemodialysis or Peritoneal dialysis250500 mg q 24 h (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)72serum creatinine (mg/dL)Women: 0.85the value calculated for men.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.

DOSAGE AND ADMINISTRATIONPEDIATRICS
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. (SeeADVERSE REACTIONSandCLINICAL 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
InfectionRoute of AdministrationDose (mg/kg)FrequencyTotal Duration* 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 benefit5. For a discussion of ciprofloxacin serum concentrations in various human populations, seeINHALATIONAL ANTHRAXADDITIONAL INFORMATION.Complicated Urinary Tract or Pyelonephritis (patients from 1 to 17 years of age)IntravenousEvery 8 hours10-21 days*OralEvery 12 hoursInhalational Anthrax (Post-Exposure)Intravenous10 mg/kg (maximum 400 mg per dose)Every 12 hours60 daysOral15 mg/kg (maximum 500 mg per dose)Every 12 hoursPediatric 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 500 mg are white, oval shaped film-coated tablets embossed with "R" on one side and "127" on other side and are supplied in bottles of 50, 100, 500 and unit dose packages of 1010.
Bottles of 1, 3, 4, 6, 10, 14, 20, 28, 30, 40 and 50.
Store below 86(30

ANIMAL PHARMACOLOGY & OR TOXICOLOGY

Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most species tested. (SeeWARNINGS.) 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 nonsteroidal 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 PyelonephritisEfficacy 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 64 years). The trial was conducted in the US, Canada, Argentina, Peru, Costa Rica, Mexico, South Africa, and Germany. The duration of therapy was 10 to 21 days (mean duration of treatment was 11 days with a range of 1 to 88 days). The primary objective of the study was to assess musculoskeletal and neurological safety.
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)
CiprofloxacinComparator* 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.Randomized Patients337352Per Protocol Patients211231Clinical Response at 5 to 9 Days Post-Treatment95.7% (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-TreatmentEscherichia coli156/178 (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. (SeeDOSAGE 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 2.97and 4.56following 400 mg intravenously every 12 hours. The mean trough serum concentration at steady-state for both of these regimens is 0.2In a study of 10 pediatric patients between 6 and 16 years of age, the mean peak plasma concentration achieved is 8.3and trough concentrations range from 0.09 to 0.26following 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 3.6after 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, seePRECAUTIONS, 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 indication5.
A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 11 LD50 (~5.5105 spores (range 5-30 LD50) of B. anthracis was conducted. The minimal inhibitory concentration (MIC) of ciprofloxacin for the anthrax strain used in this study was 0.08In 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 1.69Mean steady-state trough concentrations at 12 hours post-dose ranged from 0.12 to 0.19Mortality due to anthrax for animals that received a 30-day regimen for 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 period7.
More than 9300 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 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 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

1. National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically - Fifth Edition. Approved Standard NCCLS Document M7-A5, Vol. 20, No. 2, NCCLS, Wayne, PA, January, 2000.
2. Clinical and Laboratory Standards Institute, Methods for Antimicrobial Dilution and Disk Susceptibility Testing of Infrequently Isolated or Fastidious Bacteria; Approved Guideline., CLSI Document M45-A, Vol. 26, No. 19, CLSI, Wayne, PA, 2006.
3. National Committee for Clinical Laboratory Standards, Performance Standards for Antimicrobial Disk Susceptibility Tests - Seventh Edition. Approved Standard NCCLS Document M2-A7, Vol. 20, No. 1, NCCLS, Wayne, PA, January, 2000.
4. Report presented at the FDA's Anti-Infective Drug and Dermatological Drug Product's 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.
5. 21 CFR 314.510 (Subpart H - Accelerated Approval of New Drugs for Life-Threatening Illnesses).
6. Kelly DJ, et al. Serum concentrations of penicillin, doxycycline, and ciprofloxacin during prolonged therapy in rhesus monkeys. J Infect Dis 1992; 166: 1184-7. 7. Friedlander AM, et al. Postexposure prophylaxis against experimental inhalational anthrax. J Infect Dis 1993; 167: 1239-42.
8. Friedman J, Polifka J. Teratogenic effects of drugs: a resource for clinicians (TERIS). Baltimore, Maryland: Johns Hopkins University Press, 2000:149-195.
9. Loebstein R, Addis A, Ho E, et al. Pregnancy outcome following gestational exposure to fluoroquinolones: a multicenter prospective controlled study. Antimicrob Agents Chemother. 1998;42(6): 1336-1339.
10. Schaefer C, Amoura-Elefant E, Vial T, et al. Pregnancy outcome after prenatal quinolone exposure. Evaluation of a case registry of the European network of teratology information services (ENTIS). Eur J Obstet Gynecol Reprod Biol. 1996;69: 83-89.

SPL MEDGUIDE

CIPROFLOXACIN TABLETS, USP
CIPROFLOXACIN EXTENDED-RELEASE TABLETS
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 belongs 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 tablet is 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). It is not known if ciprofloxacin extended-release tablets are safe and works in children under 18 years of age.
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?
SeeWhat is the most important information I should know aboutciprofloxacin tablets?
Tell your healthcare provider about all your medical conditions, including if you:

     have nerve problems
     have or anyone in your family has an irregular heartbeat, especially a condition calledQT prolongation
     have a history of seizures
     have kidney problems. You may need a 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.

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 ofciprofloxacin tablets?.
     a blood thinner (warfarin, CoumadinJantoven
     tizanidine (ZanaflexYou should not take ciprofloxacin tablets if you are already taking tizanidine. See Whoshould not takeciprofloxacin tablets?
     theophylline (Theo-24ElixophyllinTheochronUniphylTheolair
     glyburide (MicronaseGlynaseDiabetaGlucovanceSee What are the possible side effects ofciprofloxacin tablets?
     phenytoin(Fosphenytoin SodiumCerebyxDilantin-125DilantinExtended Phenytoin SodiumPrompt Penytoin SodiumPhenytek
     products that contain caffeine
     a medicine to control your heart rate or rhythm (antiarrhythmics) See Whatare the possible side effects ofciprofloxacin 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 I should knowabout ciprofloxacin tablets?
     methotrexate (Trexall
     Probenecid (ProbalanCol-probenecid
     Metoclopromide (ReglanReglan ODT
     Certain medicines may keep ciprofloxacin tablets from working correctly. Take ciprofloxacin tablets either 2 hours before or 6 hours after taking these products:
               an antacid, multivitamin, or other product that has magnesium, calcium, aluminum, iron, or zinc
               sucralfate (Carafate
               didanosine (VidexVidexEC).

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?
     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 a 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 I should know aboutciprofloxacin tablets?),
               you have a 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 a 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 miss a dose of ciprofloxacin extended-release tablets, take it as soon as you remember. Do not take more than one dose in one day.
     If you take too much, call your healthcare provider or get medical help immediately.

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

     Ciprofloxacin tablets has 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 I 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 affects 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 a sunscreen and wear a 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. SeeWhat is the most important information I should know aboutciprofloxacin tablets?
Other serious side effects of ciprofloxacin tablets include:

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:
o feel dizzy
o seizures
o hear voices, see things, or sense things that are not there (hallucinations)
o feel restless
o tremors
o feel anxious or nervous
o confusion
o depression

     Serious allergic reactions: Allergic reactions 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 a 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 a serious reaction to ciprofloxacin tablets (a liver problem).
     Skin rash: Skin rash may happen in people taking ciprofloxacin tablets, even after only one dose. Stop taking ciprofloxacin tablets at the first sign of a skin rash and call your healthcare provider. Skin rash may be a sign of a more serious reaction to ciprofloxacin tablets.
     Serious heart rhythm changes (QT prolongation and torsades de pointes): Tell your healthcare provider right away if you have a change in your heart beat (a fast or irregular heartbeat), or if you faint. Ciprofloxacin tablets may cause a 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 a family history of prolonged QT interval,
               with 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 a fever. Pseudomembranous colitis can happen 2 or more months after you have finished your antibiotic.
     Changes in sensation and possible nerve damage (Peripheral Neuropathy): Damage to the nerves in arms, hands, legs, or feet can happen in people who take fluoroquinolones, including ciprofloxacin tablets. 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

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

     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 I avoid while takingciprofloxacin tablets?
     Joint Problems: Increased chance of problems with joints and tissues around joints in children under 18 years old. Tell your child's 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
     headache
     diarrhea
     vomiting
     vaginal yeast infection
     changes in liver function tests
     pain or discomfort in the abdomen

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?
     Ciprofloxacin Tablets:

o Store ciprofloxacin tablets below 86(30

     Ciprofloxacin Extended-Release Tablets:

o Store ciprofloxacin extended-release tablets at 20(68(59[see USP Controlled Room Temperature].
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 1-888-375-3784.


What are the ingredients in ciprofloxacin tablets?
     Ciprofloxacin Tablets:

o Active ingredient: ciprofloxacin
o Inactive ingredients: colloidal silicon dioxide, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol 400, sodium starch glycolate, corn starch and titanium dioxide.

     Ciprofloxacin Extended-Release Tablets:

o Active ingredient: ciprofloxacin
o Inactive ingredients: crospovidone, colloidal silicon dioxide, ethylcellulose, hypromellose, magnesium stearate, polyethylene glycol, succinic acid and titanium dioxide


PACKAGE LABEL.PRINCIPAL DISPLAY PANEL SECTION

43063427 Label



CIPROFLOXACIN 
ciprofloxacin tablet, film coated
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:43063-427(NDC:55111-127)
Route of Administration ORAL DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
CIPROFLOXACIN HYDROCHLORIDE (UNII: 4BA73M5E37) (CIPROFLOXACIN - UNII:5E8K9I0O4U) CIPROFLOXACIN 500 mg
Inactive Ingredients
Ingredient Name Strength
silicon dioxide (UNII: ETJ7Z6XBU4)  
HYPROMELLOSE 2910 (5 MPA.S) (UNII: R75537T0T4)  
magnesium stearate (UNII: 70097M6I30)  
CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)  
polyethylene glycol 400 (UNII: B697894SGQ)  
SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2)  
STARCH, CORN (UNII: O8232NY3SJ)  
titanium dioxide (UNII: 15FIX9V2JP)  
Product Characteristics
Color white Score no score
Shape OVAL (TABLET, FILM COATED) Size 18mm
Flavor Imprint Code R;127
Contains     
Packaging
# Item Code Package Description Marketing Start Date Marketing End Date
1 NDC:43063-427-01 1 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product
2 NDC:43063-427-03 3 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product
3 NDC:43063-427-04 4 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product
4 NDC:43063-427-06 6 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product
5 NDC:43063-427-10 10 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product
6 NDC:43063-427-14 14 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product
7 NDC:43063-427-20 20 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product
8 NDC:43063-427-28 28 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product
9 NDC:43063-427-30 30 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product
10 NDC:43063-427-40 40 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product
11 NDC:43063-427-50 50 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product
12 NDC:43063-427-79 1 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA075593 05/24/2011
Labeler - PD-Rx Pharmaceuticals, Inc. (156893695)
Registrant - PD-Rx Pharmaceuticals, Inc. (156893695)
Establishment
Name Address ID/FEI Business Operations
PD-Rx Pharmaceuticals, Inc. 156893695 repack(43063-427)

Revised: 5/2011
Document Id: 27277f40-e119-425e-abe7-a4bd1383caa5
Set id: 9cda7abc-a9cb-45a8-8459-03f575857643
Version: 19
Effective Time: 20110524
 
PD-Rx Pharmaceuticals, Inc.