CIPROFLOXACIN - ciprofloxacin tablet 
Sandoz Inc.

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Ciprofloxacin Tablets, USP

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Ciprofloxacin Tablets, USP and other antibacterial drugs, Ciprofloxacin Tablets, USP should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

DESCRIPTION

Ciprofloxacin Tablets is a synthetic broad spectrum antimicrobial agent for oral administration. Ciprofloxacin Hydrochloride, USP, a fluoroquinolone, is a 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 C17H18FN3O3•HCl•H2O and its chemical structure is as follows:

Ciprofloxacin is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. Its empirical formula is C17H18FN3O3 and its molecular weight is 331.4. It is a faintly yellowish to light yellow crystalline substance and its chemical structure is as follows:

Ciprofloxacin film-coated tablets are available in 250 mg, 500 mg and 750 mg (ciprofloxacin equivalent) strengths. Ciprofloxacin tablets are white to slightly yellowish. The inactive ingredients are pregelatinized starch 1500, sodium starch glycolate, magnesium stearate, colloidal silicon dioxide, polyvinyl alcohol (partially hydrolyzed), titanium dioxide, polyethylene glycol 3350 and talc.

CLINICAL PHARMACOLOGY

Absorption: Ciprofloxacin given as an oral tablet is rapidly and well absorbed from the gastrointestinal tract after oral administration. The absolute bioavailability is approximately 70% with no substantial loss by first pass metabolism. Ciprofloxacin maximum serum concentrations and area under the curve are shown in the chart for the 250 mg to 1000 mg dose range.

Dose (mg)	Maximum Serum Concentration (µg/mL)	Area under Curve (AUC) (µg•hr/mL)
250	1.2	4.8
500	2.4	11.6
750	4.3	20.2
1000	5.4	30.8

Maximum serum concentrations are attained 1 to 2 hours after oral dosing. Mean concentrations 12 hours after dosing with 250, 500, or 750 mg are 0.1, 0.2, and 0.4 µg/mL, respectively. The serum elimination half-life in subjects with normal renal function is approximately 4 hours. Serum concentrations increase proportionately with doses up to 1000 mg.

A 500 mg oral dose given every 12 hours has been shown to produce an area under the serum concentration time curve (AUC) equivalent to that produced by an intravenous infusion of 400 mg ciprofloxacin given over 60 minutes every 12 hours. A 750 mg oral dose given every 12 hours has been shown to produce an AUC at steady-state equivalent to that produced by an intravenous infusion of 400 mg given over 60 minutes every 8 hours. A 750 mg oral dose results in a Cmax similar to that observed with a 400 mg 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 Parameter Following Multiple Oral and I.V. Doses

* AUC0-12h † AUC 24h=AUC0-12h x 2 ‡ AUC 24h=AUC0-8h x 3
Parameters	500 mg	400 mg	750 mg	400 mg
	q12h, P.O.	q12h, I.V.	q12h, P.O.	q8h, I.V.
AUC (µg•hr/mL)	13.7*	12.7*	31.6†	32.9‡
Cmax (µg/mL)	2.9	4.56	3.59	4.07

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.

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

Drug-drug Interactions: When Ciprofloxacin Tablet is given concomitantly with food, there is a delay in the absorption of the drug, resulting in peak concentrations that occur closer to 2 hours after dosing rather than 1 hour. The overall absorption of Ciprofloxacin Tablet, however, is not substantially affected. Concurrent administration of antacids containing magnesium hydroxide or aluminum hydroxide may reduce the bioavailability of ciprofloxacin by as much as 90%. (See PRECAUTIONS.) The serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs were given concomitantly.

Concomitant administration 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. (See 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 to 40%, the increase in mean AUC is approximately 30%, and can be at least partially attributed to decreased renal clearance in the elderly. Elimination half-life is only slightly (~20%) prolonged in the elderly. These differences are not considered clinically significant. (See PRECAUTIONS: Geriatric Use.) In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged. Dosage adjustments may be required. (See DOSAGE 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.

Information related to pharmacokinetics in pediatric patients is approved for Bayer Pharmaceutical Corporation’s ciprofloxacin drug products. However, due to Bayer’s marketing exclusivity rights, this drug product is not labeled for pediatric use, except for inhalational anthrax (post-exposure).

Microbiology: Ciprofloxacin has in vitro activity against a wide range of gram-negative and gram-positive microorganisms. The bactericidal action of ciprofloxacin results from inhibition of the enzymes topoisomerase II (DNA gyrase) and topoisomerase IV, which are required for bacterial DNA replication, transcription, repair, and recombination. The mechanism of action of fluoroquinolones, including ciprofloxacin, is different from that of penicillins, cephalosporins, aminoglycosides, macrolides, and tetracyclines; therefore, microorganisms resistant to these classes of drugs may be susceptible to ciprofloxacin and other quinolones. There is no known cross-resistance between ciprofloxacin and other classes of antimicrobials. In vitro resistance to ciprofloxacin develops slowly by multiple step mutations.

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 the INDICATIONS AND USAGEsection of the package insert for Ciprofloxacin 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 jejuni Proteus mirabilis

Campylobacter jejuni	Proteus mirabilis
Citrobacter diversus	Proteus vulgaris
Citrobacter freundii	Providencia rettgeri
Enterobacter cloacae	Providencia stuartii
Escherichia coli	Pseudomonas aeruginosa
Haemophilus influenzae	Salmonella typhi
Haemophilus parainfluenzae	Serratia marcescens
Klebsiella pneumoniae	Shigella boydii
Moraxella catarrhalis	Shigella dysenteriae
Morganella morganii	Shigella flexneri
Neisseria gonorrhoeae	Shigella sonnei

 Ciprofloxacin has been shown to be active against Bacillus anthracisboth in vitroand by use of serum levels as a surrogate marker (see INDICATIONS AND USAGEand INHALATIONAL 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 1 µg/mL or less against most (≥90%) strains of the following microorganisms; however, the safety and effectiveness of ciprofloxacin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Aerobic gram-positive microorganisms

Staphylococcus haemolyticus

Staphylococcus hominis

Streptococcus pneumoniae (penicillin-resistant strains only)

Aerobic gram -negative microorganisms

Acinetobacter lwoffi	Pasteurella multocida
Aeromonas hydrophila	Salmonella enteritidis
Edwardsiella tarda	Vibrio cholerae
Enterobacter aerogenes	Vibrio parahaemolyticus
Klebsiella oxytoc	Vibrio vulnificus
Legionella pneumophila	Yersinia enterocolitica

 

Most strains of Burkholderia cepaciaand 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 aerobic microorganisms other than Haemophilus influenzae, Haemophilus parainfluenzae, and Neisseria gonorrhoeaea:

MIC (µg/mL)	Interpretation
≤1	Susceptible (S)
2	Intermediate (I)
≥4	Resistant (R)

a These interpretive standards are applicable only to broth microdilution susceptibility tests with streptococci using cation-adjusting Mueller-Hinton broth with 2 to 5% lysed horse blood.

For testing Haemophilus influenzae and Haemophilus parainfluenzaeb:

MIC (µg/mL)	Interpretation
≤1	Susceptible (S)

b This interpretive standard is applicable only to broth microdilution susceptibility tests with Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium1.

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 gonorrhoeaec:

MIC (µg/mL)	Interpretation
≤0.06	Susceptible (S)
0.12 - 0.5	Intermediate (I)
≥1	Resistant (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:

* This quality control range is applicable to only H. influenzae ATCC 49427 tested by a broth microdilution procedure using Haemophilus Test Medium (HTM)1. † This quality control range is applicable to only N. gonorrhoeae ATCC 49226 tested by an agar dilution procedure using GC agar base and 1% defined growth supplement.
Organism		MIC (µg/mL)
E. faecalis	ATCC 29212	0.25 - 2.0
E. coli	ATCC 25922	0.004 - 0.015
H. influenzae*	ATCC 49247	0.004 - 0.03
N. gonorrhoeae†	ATCC 49226	0.001 - 0.008
P. aeruginosa	ATCC 27853	0.25 - 1.0
S. aureus	ATCC 29213	0.12 - 0.5

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 procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 5-µg 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-µg ciprofloxacin disk should be interpreted according to the following criteria:

For testing aerobic microorganisms other than Haemophilus influenzae, Haemophilus parainfluenzae, and Neisseria gonorrhoeaea:

Zone Diameter (mm)	Interpretation
≥21	Susceptible (S)
16-20	Intermediate (I)
≤15	Resistant (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 parinfluenzaeb:

Zone Diameter (mm)	Interpretation
≥21	Susceptible (S)

b This zone diameter standard is applicable only to tests with Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium (HTM)2.

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 gonorrhoeaec:

Zone Diameter (mm)	Interpretation
≥41	Susceptible (S)
28 – 40	Intermediate (I)
≤27	Resistant (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-µg ciprofloxacin disk should provide the following zone diameters in these laboratory test quality control strains:

* These quality control limits are applicable to only H. influenzae ATCC 49247 testing using Haemophilus Test Medium (HTM)2. † 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.
Organism		Zone Diameter (mm)
E. coli	ATCC 25922	30 - 40
H. influenzae*	ATCC 49247	34 - 42
N. gonorrhoeae†	ATCC 49226	48 - 58
P. aeruginosa	ATCC 27853	25 - 33
S. aureus	ATCC 25923	22 - 30

INDICATIONS AND USAGE

Ciprofloxacin Tablets, USP are indicated for the treatment of infections caused by susceptible strains of the designated microorganisms in the conditions and patient populations listed below. Please see DOSAGE 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, 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 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, 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, 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 boydii*, Shigella dysenteriae, Shigella flexneri or Shigella sonnei* when 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.

Pediatric patients (1 to 17 years of age):

Information related to the treatment of pediatric patients for complicated urinary tract infections and pyelonephritis is approved for Bayer Pharmaceutical Corporation’s ciprofloxacin drug products.

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. (See WARNINGS, PRECAUTIONS, Pediatric Use, and ADVERSE REACTIONS). Ciprofloxacin, like other fluoroquinolones, is associated with arthropathy and histopathological changes in weight-bearing joints of juvenile animals. (SeeANIMAL PHARMACOLOGY.)

Due to Bayer’s marketing exclusivity rights, this drug product is not labeled for pediatric use, except for inhalational anthrax (post-exposure).

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 serve as a surrogate endpoint reasonably likely to predict clinical benefit and provide the basis for this indication.4 (See also, INHALATIONAL ANTHRAX ADDITIONAL INFORMATION).

*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.

If anaerobic organisms are suspected of contributing to the infection, appropriate therapy should be administered. Appropriate culture and susceptibility tests should be performed before treatment in order to isolate and identify organisms causing infection and to determine their susceptibility to ciprofloxacin. Therapy with Ciprofloxacin Tablets 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 is contraindicated in persons with a history of hypersensitivity to ciprofloxacin or any member of the quinolone class of antimicrobial agents.

WARNINGS

Pregnant Women

THE SAFETY AND EFFECTIVENESS OF CIPROFLOXACIN IN PREGNANT AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED. (See PRECAUTIONS: Pregnancy, and Nursing Mothers subsections.)

Pediatrics

 Ciprofloxacin should be used in pediatric patients (less than 18 years of age) only for inhalational anthrax (post-exposure). Information related to an additional use of ciprofloxacin in the pediatric population is approved for Bayer Pharmaceutical Corporation’s ciprofloxacin drug products. An increased incidence of adverse events compared to controls, including events related to joints and/or surrounding tissues, has been observed. (See  ADVERSE REACTIONS.) Due to Bayer’s marketing exclusivity rights, this drug product is not labeled for pediatric use, except for inhalational anthrax (post-exposure).

In pre-clinical studies, oral administration of ciprofloxacin caused lameness in immature dogs. Histopathological examination of the weight-bearing joints of these dogs revealed permanent lesions of the cartilage. Related quinolone-class drugs also produce erosions of cartilage of weight-bearing joints and other signs of arthropathy in immature animals of various species. (See ANIMAL PHARMACOLOGY.)

Cytochrome P450

 Ciproflozacin is a moderate inhibitor of the CYP 450 1A2 isoenzymes. Coadministration of ciprofloxacin and other drugs primarily metabolized by the cytochrome P450 1A2 enzyme pathway (e.g. theophylline, methylxanthines) may result in increased plasma concentrations of the coadministered drug and could lead to clinically significant pharmacodynamic side effects.

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).

(See PRECAUTIONS: 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.

Severe hypersensitivity reactions characterized by rash, fever, eosinophilia, jaundice, and hepatic necrosis with fatal outcome have also been rarely reported in patients receiving ciprofloxacin along with other drugs. The possibility that these reactions were related to ciprofloxacin cannot be excluded. Ciprofloxacin should be discontinued at the first appearance of a skin rash or any other sign of hypersensitivity.

Pseudomembranous Colitis: Pseudomembranous colitis has been reported with nearly all antibacterial agents, including ciprofloxacin, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of “antibiotic-associated colitis.”

After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against C. difficile colitis. Drugs that inhibit peristalsis should be avoided.

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, positions sense, vibratory sensation, and/or motor strength in order to prevent the development of an irreversible condition.

Tendon Effects: Ruptures of the shoulder, hand, and Achilles and other tendon ruptures that required surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones, including ciprofloxacin. Post-marketing surveillance reports indicate that the risk may be increased in patients receiving concomitant corticosteroids, especially in the elderly. Ciprofloxacin should be discontinued if the patient experiences pain, inflammation, or rupture of a tendon. Patients should rest and refrain from exercise until the diagnosis of tendonitis or tendon rupture has been excluded. Tendon rupture can occur during or after therapy with quinolones, including ciprofloxacin.

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. (See ANIMAL PHARMACOLOGY.) Crystalluria related to ciprofloxacin has been reported only rarely in humans because human urine is usually acidic. Alkalinity of the urine should be avoided in patients receiving ciprofloxacin. Patients should be well hydrated to prevent the formation of highly concentrated urine.

Central Nervous System: Quinolones, including ciprofloxacin, may also cause central nervous system (CNS) events, including: nervousness, agitation, insomnia, anxiety, nightmares or paranoia. (See WARNINGS, Information for Patients, andDrug Interactions.)

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

Phototoxicity: Moderate to severe phototoxicity manifested as an exaggerated sunburn reaction has been observed in patients who are exposed to direct sunlight while receiving some members of the quinolone class of drugs. Excessive sunlight should be avoided. Therapy should be discontinued if phototoxicity occurs.

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, Videx® (didanosine) chewable/buffered tablets or pediatric powder, 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.
• to avoid excessive sunlight or artificial ultraviolet light while receiving ciprofloxacin and to discontinue therapy if phototoxicity occurs.
• 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.
• to discontinue treatment; rest and refrain from exercise; and inform their physician if they experience pain, inflammation, or rupture of a tendon.
• 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 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 taking quinolones, including ciprofloxacin, and to notify their physician before taking the 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 Use and ADVERSE REACTIONS.)

Drug Interactions

In a pharmacokinetic study, tizanidine serum concentrations were significantly increased (Cmax 7-fold, AUC 10-fold) when the drug was given concomitantly with ciprofloxacin. Potentiated hypotensive and sedative effects were observed. Coadministration of tizanidine and ciprofloxacin must be avoided.

As with some other quinolones, concurrent administration of ciprofloxacin with theophylline may lead to elevated serum concentrations of theophylline and prolongation of its elimination half-life. This may result in increased risk of theophylline-related adverse reactions. (See WARNINGS.) If concomitant use cannot be avoided, serum levels of theophylline should be monitored and dosage adjustments made as appropriate.

Some quinolones, including ciprofloxacin, have also been shown to interfere with the metabolism of caffeine. This may lead to reduced clearance of caffeine and a prolongation of its serum half-life. Concurrent administration of a quinolone, including ciprofloxacin, with multivalent cation-containing products such as magnesium/aluminum antacids, sucralfate, Videx® (didanosine) chewable/buffered tablets or pediatric powder, or products containing calcium, iron or zinc may substantially decrease its absorption, resulting in serum and urine levels considerably lower than desired. (See DOSAGE AND 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.

Animal studies have shown that the combination of very high doses of quinolones and certain nonsteroidal anti-inflammatory agents (but not acetylsalicylic acid) can provoke convulsions.

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 quinolones.3

In this model, mice treated with ciprofloxacin alone did not develop skin or systemic tumors. There are no data from similar models using pigmented mice and/or fully haired mice. The clinical significance of these findings to humans is unknown.

Fertility studies performed in rats at oral doses of ciprofloxacin up to 100 mg/kg (approximately 0.7-times the highest recommended therapeutic dose based upon mg/m2) revealed no evidence of impairment.

Pregnancy

Teratogenic Effects

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. An expert review of published data on experiences with ciprofloxacin use during pregnancy by TERIS - the Teratogen Information System - concluded that therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk (quantity and quality of data=fair), but the data are insufficient to state that there is no risk.7 A controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5% exposed to ciprofloxacin and 68% first trimester exposures) during gestation.8 In utero exposure to fluoroquinolones during embryogenesis was not associated with increased risk of major malformations. The reported rates of major congenital malformations were 2.2% for the fluoroquinolone group and 2.6% for the control group (background incidence of major malformations is 1 to 5%). Rates of spontaneous absorptions, prematurity and low birth weight did not differ between the groups and there were no clinically significant musculoskeletal dysfunctions up to one year of age in the ciprofloxacin exposed children.

Another prospective follow-up study reported on 549 pregnancies with fluoroquinolone exposure (93% first trimester exposures)9 There were 70 ciprofloxacin exposures, all within the first trimester. The malformation rates among live-born babies exposed to ciprofloxacin and to fluoroquinolones overall were both within background incidence ranges. No specific patterns of congenital abnormalities were found. The study did not reveal any clear adverse reactions due to in utero exposure to ciprofloxacin. No differences in the rates of prematurity, spontaneous abortions, or birth weight were seen in women exposed to ciprofloxacin during pregnancy.7,8 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 (see WARNINGS).

Reproduction studies have been performed in rats and mice using oral doses up to 100 mg/kg (0.6 and 0.3 times the maximum daily human dose based upon body surface area, respectively) and have revealed no evidence of harm to the fetus due to ciprofloxacin. In rabbits, oral ciprofloxacin dose levels of 30 and 100 mg/kg (approximately 0.4- and 1.3-times the highest recommended therapeutic dose based upon mg/m2) produced gastrointestinal toxicity resulting in maternal weight loss and an increased incidence of abortion, but no teratogenicity was observed at either dose level. After intravenous administration of doses up to 20 mg/kg (approximately 0.3-times the highest recommended therapeutic dose based upon mg/m2) no maternal toxicity was produced and no embryotoxicity or teratogenicity was observed. (See WARNINGS.)

Nursing Mothers

Ciprofloxacin is excreted in human milk. The amount of ciprofloxacin absorbed by the nursing infant is unknown. Because of the potential for serious adverse reactions in infants nursing from mothers taking ciprofloxacin, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Ciprofloxacin, like other quinolones, causes arthropathy and histological changes in weight-bearing joints of juvenile animals resulting in lameness. (See ANIMAL PHARMACOLOGY.)

Inhalational Anthrax (Post-Exposure)

Ciprofloxacin is indicated in pediatric patients for inhalational anthrax (post-exposure). The risk-benefit assessment indicates that administration of ciprofloxacin to pediatric patients is appropriate. For information regarding pediatric dosing in inhalational anthrax (post-exposure), see DOSAGE AND ADMINISTRATION and INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION.

Complicated Urinary Tract Infection and Pyelonephritis

Information related to the safety and efficacy of ciprofloxacin in pediatric patients for the treatment of complicated urinary tract infections and pyelonephritis is approved for Bayer Pharmaceutical Corporation’s ciprofloxacin drug products. 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. (See  ADVERSE REACTIONS. ) Due to Bayer’s marketing exclusivity rights, this drug product is not labeled for pediatric use, except for inhalational anthrax (post-exposure).

Cystic Fibrosis

Short-term safety data from a single trial in pediatric cystic fibrosis patients are available. In a randomized, double-blind clinical trial for the treatment of acute pulmonary exacerbations in cystic fibrosis patients (ages 5 to 17 years), 67 patients received ciprofloxacin I.V. 10 mg/kg/dose q8h for one week followed by ciprofloxacin tablets 20 mg/kg/dose q12h to complete 10 to 21 days treatment and 62 patients received the combination of ceftazidime I.V. 50 mg/kg/dose q8h and tobramycin I.V. 3 mg/kg/dose q8h for a total of 10 to 21 days. Patients less than 5 years of age were not studied. Safety monitoring in the study included periodic range of motion examinations and gait assessments by treatment-blinded examiners. Patients were followed for an average of 23 days after completing treatment (range 0 to 93 days). This study was not designed to determine long term effects and the safety of repeated exposure to ciprofloxacin.

Musculoskeletal adverse events in patients with cystic fibrosis were reported in 22% of the patients in the ciprofloxacin group and 21% in the comparison group. Decreased range of motion was reported in 12% of the subjects in the ciprofloxacin group and 16% in the comparison group. Arthralgia was reported in 10% of the patients in the ciprofloxacin group and 11% in the comparison group. Other adverse events were similar in nature and frequency between treatment arms. One of 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

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 risk of adverse reactions may be greater in patients with impaired renal functions. No alteration of dosage is necessary for patients greater than 65 years of age with normal renal function. However, since some older individuals experience reduced renal function by virtue of their advanced age, care should be taken in dose selection for elderly patients, and renal function monitoring may be useful in these patients. (See CLINICAL PHARMACOLOGYand DOSAGE AND ADMINISTRATION.)

ADVERSE REACTIONS

Adverse Reactions in Adult Patients

 During clinical investigation 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 1.0% of orally treated patients.

The most frequently reported drug related events, from clinical trials of all formulations, all dosages, all drug-therapy durations, and for all indications of ciprofloxacin therapy were nausea (2.5%), diarrhea (1.6%), liver function tests abnormal (1.3%), vomiting (1.0%), and rash (1.0%).

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, 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

Information related to the adverse reactions of ciprofloxacin in pediatric patients is approved for Bayer Pharmaceutical Corporation’s ciprofloxacin drug products. However, due to Bayer’s marketing exclusivity rights, this drug product is not labeled for pediatric use, except for inhalational anthrax (post-exposure).

Post-Marketing Adverse Events

 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, hepatic necrosis, hyperesthesia, hypertonia, hypesthesia, hypotension (postural), jaundice, marrow depression (life threatening), methemoglobinemia, monoliasis (oral, gastrointestinal, vaginal) myalgia, myasthenia, myasthenia gravis (possible exacerbation), myoclonus, nystagmus, pancreatitis, pancytopenia (life threatening or fatal outcome), peripheral neuropathy, phenytoin alteration (serum), potassium elevation (serum), prothrombin time prolongation or decrease, pseudomembranous colitis (The onset of pseudomembranous colitis symptoms may occur during or after antimicrobial treatment.), psychosis (toxic), renal calculi, serum sickness like reaction, Stevens-Johnson syndrome, taste loss, tendinitis, tendon rupture, torsade de pointes, toxic epidermal necrolysis (Lyell’s Syndrome), triglyceride elevation (serum), twitching, vaginal candidiasis, and vasculitis. (See PRECAUTIONS.)

Adverse events were also reported by persons who received ciprofloxacin for anthrax post-exposure prophylaxis following the anthrax bioterror attacks of October 2001. (See also INHALATIONAL ANTHRAX – ADDITIONAL INFORMATION.)

Adverse Laboratory Changes

 Changes in laboratory parameters listed as adverse events without regard to drug relationship are listed below:

Hepatic - Elevations of ALT (SGPT) (1.9%), AST (SGOT) (1.7%), alkaline hosphatase (0.8%), LDH (0.4%), serum bilirubin (0.3%).

Hematologic - Eosinophilia (0.6%), leukopenia (0.4%), decreased blood platelets (0.1%), elevated blood platelets (0.1%), pancytopenia (0.1%).

Renal - Elevations of serum creatinine (1.1%), BUN (0.9%), CRYSTALLURIA,

CYLINDRURIA, AND HEMATURIA HAVE BEEN REPORTED.

Other changes occurring in less than 0.1% of courses were: elevation of serum gammaglutamyl transferase, elevation of serum amylase, reduction in blood glucose, elevated uric acid, decrease in hemoglobin, anemia, bleeding diathesis, increase in blood monocytes, leukocytosis.

OVERDOSAGE

In the event of acute overdosage, reversible renal toxicity has been reported in some cases. The stomach should be emptied by inducing vomiting or by gastric lavage. The patient should be carefully observed and given supportive treatment, including monitoring of renal function and administration of magnesium, aluminum, or calcium containing antacids which can reduce the absorption of ciprofloxacin. Adequate hydration must be maintained. Only a small amount of ciprofloxacin (<10%) is removed from the body after hemodialysis or peritoneal dialysis.

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

In mice, rats, rabbits and dogs, significant toxicity including tonic/clonic convulsions was observed at intravenous doses of ciprofloxacin between 125 and 300 mg/kg.

DOSAGE AND ADMINISTRATION

ADULTS

Ciprofloxacin Tablets should be administered orally to adults as described in the Dosage Guidelines table.

The determination of dosage for any particular patient must take into consideration the severity and nature of the infection, the susceptibility of the causative organism, the integrity of the patient’s host defense mechanisms, and the status of renal function and hepatic function.

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

ADULT DOSAGE GUIDELINES

* Generally ciprofloxacin should be continued for at least 2 days after the signs and symptoms of infection have disappeared, except for inhalational anthrax (post-exposure). † Used in conjunction with metronidazole ‡ Drug administration should begin as soon as possible after suspected or confirmed exposure.
Infection	Type or Severity	Unit Dose	Frequency	Usual Durations*
Urinary Tract	Acute Uncomplicated Mild/Moderate Severe/Complicated	100 mg or 250 mg 250 mg 500 mg	q 12 h q 12 h q 12 h	3 Days 7 to 14 Days 7 to 14 Days
Chronic Bacterial Prostatitis	Mild/Moderate	500 mg	q 12 h	28 Days
Lower Respiratory Tract	Mild/Moderate Severe/Complicated	500 mg 750 mg	q 12 h q 12 h	7 to 14 Days 7 to 14 Days
Acute Sinusitis	Mild/Moderate	500 mg	q 12 h	10 Days
Skin and Skin Structure	Mild/Moderate Severe/Complicated	500 mg 750 mg	q 12 h q 12 h	7 to 14 Days 7 to 14 Days
Bone and Joint	Mild/Moderate Severe/Complicated	500 mg 750 mg	q 12 h q 12 h	≥4 to 6 weeks ≥4 to 6 weeks
Intra-Abdominal†	Complicated	500 mg	q 12 h	7 to 14 Days
Infectious Diarrhea	Mild/Moderate/Severe	500 mg	q 12 h	5 to 7 Days
Typhoid Fever	Mild/Moderate	500 mg	q 12 h	10 Days
Urethral and Cervical Gonococcal Infections	Uncomplicated	250 mg	single dose	single dose
Inhalation anthrax (post exposure)‡	Adult	500 mg	q 12 h	60 days

 

This indication is based on a surrogate endpoint, ciprofloxacin serum concentrations achieved in humans, reasonably likely to predict clinical benefit.4 For a discussion of ciprofloxacin serum concentrations in various human populations, see INHALATIONAL ANTHRAX - ADDITIONAL INFORMATION.

Conversion of I.V. to Oral Dosing in Adults: Patients whose therapy is started with CIPRO I.V. may be switched to CIPRO Tablets when clinically indicated at the discretion of the physician (See CLINICAL PHARMACOLOGYand table below for the equivalent dosing regimens).

Equivalent AUC Dosing Regimens

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

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

RECOMMENDED STARTING AND MAINTENANCE DOSES

FOR PATIENTS WITH IMPAIRED RENAL FUNCTION

Creatinine Clearance (mL/min)	Dose
>50	See Usual Dosage.
30 – 50	250 - 500 mg q 12 h
5 – 29	250 - 500 mg q 18 h
Patients on hemodialysis or Peritoneal dialysis	250 - 500 mg q 24 h (after dialysis)

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

Men:	Creatinine clearance (mL/min) = Weight (kg) x (140 - age)
		72 x serum creatinine (mg/dL)
Women:	0.85 x the 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 ADMINISTRATION - PEDIATRICS

Ciprofloxacin Tablets, USP should be administered orally as described in the Dosage Guidelines table.

Information related to dosing ciprofloxacin in pediatric patients for the treatment of complicated urinary tract infections and pyelonephritis is approved for Bayer Pharmaceutical Corporation’s ciprofloxacin drug products. An increased incidence of adverse events compared to controls, including events related to joints and/or surrounding tissues, has been observed. (See  ADVERSE REACTIONS.) Due to Bayer’s marketing exclusivity rights, this drug product is not labeled for pediatric use, except for inhalational anthrax (post-exposure).

PEDIATRIC DOSAGE GUIDELINES

* Drug administration should begin as soon as possible after suspected or confirmed exposure to Bacillus anthracis spores. This indication is based on a surrogate endpoint, ciprofloxacin serum concentrations achieved in humans, reasonably likely to predict clinical benefit.4 For a discussion of ciprofloxacin serum concentrations in various human populations, see INHALATION ANTHRAX – ADDITIONAL INFORMATION.
Infection	Route of Administration	Dose (mg/kg)	Frequency	Total Duration
Inhalational Anthrax (Post-Exposure)*	Intravenous	10 mg/kg (maximum 400 mg per dose)	Every 12 hours	60 days
	Oral	15 mg/kg (maximum 500 mg per dose)	Every 12 hours

HOW SUPPLIED

Ciprofloxacin Tablets, USP are available as 250 mg, 500 mg and 750 mg tablets for oral administration.

Ciprofloxacin Tablets, USP, 250 mg are white to off-white, round, film-coated, debossed "E" over “442” on one side and plain on the other side and are available in bottles of 100, 1000 and in unit dose package of 100.

Ciprofloxacin Tablets, USP, 500 mg are white to off-white, capsule-shaped, film-coated, debossed "E" over “451” on one side and plain on the other side and are available in bottles of 100, 500 and 1000 and in unit dose package of 100.

Ciprofloxacin Tablets, USP, 750 mg are white to off-white, capsule-shaped, film-coated, debossed "E" over “470” on one side and plain on the other side and are available in bottles of 50 and 100 and in unit dose package of 100.

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

ANIMAL PHARMACOLOGY

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

Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory animals dosed with ciprofloxacin. This is primarily related to the reduced solubility of ciprofloxacin under alkaline conditions, which predominate in the urine of test animals; in man, crystalluria is rare since human urine is typically acidic. In rhesus monkeys, crystalluria without nephropathy has been 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 Pyelonephritis - Efficacy in Pediatric Patients:

Information related to the efficacy of ciprofloxacin in pediatric patients for the treatment of complicated urinary tract infections and pyelonephritis is approved for Bayer Pharmaceutical Corporation’s ciprofloxacin drug products. 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. Due to Bayer’s marketing exclusivity rights, this drug product, produced by Eon Labs Inc., is not labeled for pediatric use, except for inhalation anthrax (post-exposure).

INHALATIONAL ANTHRAX IN ADULTS AND PEDIATRICS- ADDITIONAL INFORMATION

The mean serum concentrations of ciprofloxacin associated with a statistically significant improvement in survival in the rhesus monkey model of inhalational anthrax are reached or exceeded in adult and pediatric patients receiving oral and intravenous regimens. (See DOSAGE AND ADMINISTRATION). Ciprofloxacin pharmacokinetics have been evaluated in various human populations. The mean peak serum concentration achieved at steady state in human adults receiving 500 mg orally every 12 hours is 2.97 µg/mL, and 4.56 µg/mL following 400 mg intravenously every 12 hours. The mean trough serum concentration at steady-state for both of these regimens is 0.2 µg/mL. In a study of 10 pediatric patients between 6 and 16 years of age, the mean peak plasma concentration achieved is 8.3 µg/mL and trough concentrations range from 0.09 to 0.26 µg/mL, following two 30-minute intravenous infusions of 10 mg/kg administered 12 hours apart. After the second intravenous infusion patients switched to 15 mg/kg orally every 12 hours achieve a mean peak concentration of 3.6 µg/mL after the initial oral dose. Long-term safety data, including effects on cartilage, following the administration of ciprofloxacin to pediatric patients are limited. (For additional information, see PRECAUTIONS, Pediatric Use.)

Ciprofloxacin serum concentrations achieved in humans serve as a surrogate endpoint reasonably likely to predict clinical benefit and provide the basis for this indication.4

A placebo-controlled animal study in rhesus monkeys exposed to an inhaled mean dose of 11 LD50 (~5.5 x 105 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 0.08 µg/mL. In the animals studied, mean serum concentrations of ciprofloxacin achieved at expected Tmax (1 hour post-dose) following oral dosing to steady state ranged from 0.98 to 1.69 µg/mL. Mean steady-state trough concentrations at 12 hours post-dose ranged from 0.12 to 0.19 µg/mL5. Mortality due to anthrax for animals that received a 30-day regimen of oral ciprofloxacin beginning 24 hours post-exposure was significantly lower (1/9), compared to the placebo group (9/10)[p=0.001]. The one ciprofloxacin-treated animal that died of anthrax did so following the 30-day drug administration period.6

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. 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.

3. 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.

4. 21 CFR 314.510 (Subpart H - Accelerated Approval of New Drugs for Life-Threatening Illnesses).

5. Kelly DJ, et al. Serum concentrations of penicillin, doxycycline, and ciprofloxacin during prolonged therapy in rhesus monkeys. J Infect Dis 1992; 166: 1184-7.

6. Friedlander AM, et al. postexposure prophylaxis against experimental inhalational anthrax. J Infect Dis 1993; 167: 1239-42.

7. Friedman j, Polifka J. teratogenic effects of drugs: a resource for clinicians (TERIS). Baltimore, Maryland: Johns Hopkins University Press, 2000: 149-195.

8. 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.

9. 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.

PATIENT INFORMATION ABOUT

Ciprofloxacin Tablets

This section contains important patient information about Ciprofloxacin Tablets and should be read completely before you begin treatment. This section does not take the place of discussion with your doctor or health care professional about your medical condition or your treatment. This section does not list all benefits and risks of Ciprofloxacin Tablets. If you have any concerns about your condition or your medicine, ask your doctor. Only your doctor can determine if Ciprofloxacin is right for you.

What is Ciprofloxacin?

Ciprofloxacin is an antibiotic used to treat bladder, kidney, prostate, cervix, stomach, intestine, lung, sinus, bone, and skin infections caused by certain germs called bacteria. Ciprofloxacin kills many types of bacteria that can infect these areas of the body. Ciprofloxacin has been shown in a large number of clinical trials to be safe and effective for the treatment of bacterial infections.

Sometimes viruses rather than bacteria may infect the lungs and sinuses (for example the common cold). Ciprofloxacin, like all other antibiotics, does not kill viruses. You should contact your doctor if your condition is not improving while taking Ciprofloxacin.

Ciprofloxacin Tablets are white to off-white in color and are available in 250 mg, 500 mg and 750 mg strengths.

How and when should I take Ciprofloxacin?

Ciprofloxacin Tablets:

Unless directed otherwise by your physician, Ciprofloxacin Tablets should be taken twice a day at approximately the same time, in the morning and in the evening. Ciprofloxacin Tablets can be taken with food or on an empty stomach. Ciprofloxacin Tablets should not be taken with dairy products (like milk or yogurt) or calcium-fortified juices alone; however, Ciprofloxacin Tablets may be taken with a meal that contains these products.

You should take Ciprofloxacin Tablets for as long as your doctor prescribes it, even after you start to feel better. Stopping an antibiotic too early may result in failure to cure your infection. Do not take a double dose of Ciprofloxacin Tablets even if you miss a dose by mistake.

Who should not take Ciprofloxacin Tablets?

You should not take Ciprofloxacin Tablets if you have ever had a severe reaction to any of the group of antibiotics known as “quinolones”.

Ciprofloxacin Tablets are not recommended during pregnancy or nursing, as the effects of Ciprofloxacin Tablets on the unborn child or nursing infant are unknown. If you are pregnant or plan to become pregnant while taking Ciprofloxacin Tablets talk to your doctor before taking this medication. Due to possible side effects, Ciprofloxacin Tablets are not recommended for persons less than 18 years of age except for specific serious infections.

What are the possible side effects of Ciprofloxacin Tablets?

Ciprofloxacin Tablets are generally well tolerated. The most common side effects, which are usually mild, include nausea, diarrhea, vomiting, and abdominal pain/discomfort. If diarrhea persists, call your health care professional.

Rare cases of allergic reactions have been reported in patients receiving quinolones, including Ciprofloxacin Tablets, even after just one dose. If you develop hives, difficulty breathing, or other symptoms of a severe allergic reaction, seek emergency treatment right away. If you develop a skin rash, you should stop taking Ciprofloxacin Tablets and call your health care professional. Some patients taking quinolone antibiotics may become more sensitive to sunlight or ultraviolet light such as that used in tanning salons. You should avoid excessive exposure to sunlight or ultraviolet light while you are taking Ciprofloxacin.

You should be careful about driving or operating machinery until you are sure Ciprofloxacin Tablets are not causing dizziness. Convulsions have been reported in patients receiving quinolone antibiotics including ciprofloxacin. Be sure to let your physician know if you have a history of convulsions. Quinolones, including ciprofloxacin, have been rarely associated with other central nervous system events including confusion, tremors, hallucinations, and depression.

Ciprofloxacin has been rarely associated with inflammation of tendons. If you experience pain, swelling or rupture of a tendon, you should stop taking Ciprofloxacin Tablets and call your health care professional.

Ciprofloxacin has been associated with an increased rate of side effects with joints and surrounding 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.

If you notice any side effects not mentioned in this section, or if you have any concerns about side effects you may be experiencing, please inform your health care professional.

What about other medications I am taking?

Ciprofloxacin can affect how other medicines work. Tell your doctor about all other prescription and non-prescription medicines or supplements you are taking. This is especially important if you are taking theophylline. Other medications including warfarin, glyburide, and phenytoin may also interact with Ciprofloxacin.

Many antacids, multivitamins, and other dietary supplements containing magnesium, calcium, aluminum, iron or zinc can interfere with the absorption of Ciprofloxacin and may prevent it from working. Other medications such as sucralfate and Videx® (didanosine) chewable/buffered tablets or pediatric powder may also stop Ciprofloxacin from working. You should take Ciprofloxacin either 2 hours before or 6 hours after taking these products.

What if I have been prescribed Ciprofloxacin tablets for possible anthrax exposure?

Ciprofloxacin Tablets has been approved to reduce the chance of developing anthrax infection following exposure to the anthrax bacteria. In general, Ciprofloxacin is not recommended for children; however, it is approved for use in patients younger than 18 years old for anthrax exposure. If you are pregnant, or plan to become pregnant while taking Ciprofloxacin, you and your doctor should discuss if the benefits of taking Ciprofloxacin for anthrax outweigh the risks.

Ciprofloxacin is generally well tolerated. Side effects that may occur during treatment to prevent anthrax might be acceptable due to the seriousness of the disease. You and your doctor should discuss the risks of not taking your medicine against the risks of experiencing side effects.

Ciprofloxacin can cause dizziness, confusion, or other similar side effects in some people. Therefore, it is important to know how Ciprofloxacin affects you before driving a car or performing other activities that require you to be alert and coordinated such as operating machinery.

Your doctor has prescribed Ciprofloxacin only for you. Do not give it to other people. Do not use it for a condition for which it was not prescribed. You should take your Ciprofloxacin for as long as your doctor prescribes it; stopping Ciprofloxacin too early may result in failure to prevent anthrax.

Remember:

Do not give Ciprofloxacin to anyone other than the person for whom it was prescribed.

Take your dose of Ciprofloxacin in the morning and in the evening.

Complete the course of Ciprofloxacin even if you are feeling better.

Keep Ciprofloxacin and all medications out of reach of children.

Manufactured by:

Eon Labs, Inc.

Laurelton, NY 11413

Rev. 09/04

MF0440REV09/04

OS8002

MG #18894

Ciprofloxacin Tablets, USP, 250 mg x 100 Tablets - Label

NDC 0185-0442-01

Ciprofloxacin Tablets, USP

250 mg*

Rx only

100 Tablets

Eon Labs

Ciprofloxacin Tablets, USP, 500 mg x 100 Tablets - Label

NDC 0185-0451-01

Ciprofloxacin Tablets, USP

500 mg*

Rx only

100 Tablets

Eon Labs

Ciprofloxacin Tablets, USP, 750 mg x 50 Tablets - Label

NDC 0185-0470-53

Ciprofloxacin Tablets, USP

750 mg*

Rx only

50 Tablets

Eon Labs

CIPROFLOXACIN  ciprofloxacin   tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0185-0442 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CIPROFLOXACIN (CIPROFLOXACIN) CIPROFLOXACIN 250 mg

Inactive Ingredients Ingredient Name Strength STARCH, CORN   SODIUM STARCH GLYCOLATE TYPE A POTATO   MAGNESIUM STEARATE   SILICON DIOXIDE   POLYVINYL ALCOHOL   TITANIUM DIOXIDE   POLYETHYLENE GLYCOL 3350   TALC

Product Characteristics Color WHITE (OFF-WHITE) Score no score Shape ROUND Size 11mm Flavor Imprint Code E;442 Contains

Packaging # NDC Package Description Multilevel Packaging 1 0185-0442-01 100 TABLET In 1 BOTTLE None 2 0185-0442-10 1000 TABLET In 1 BOTTLE None 3 0185-0442-87 10 BLISTER PACK In 1 CARTON contains a BLISTER PACK (0185-0442-88) 3 0185-0442-88 10 TABLET In 1 BLISTER PACK This package is contained within the CARTON (0185-0442-87)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA076593	06/09/2004	06/01/2009

CIPROFLOXACIN  ciprofloxacin   tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0185-0451 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CIPROFLOXACIN (CIPROFLOXACIN) CIPROFLOXACIN 500 mg

Inactive Ingredients Ingredient Name Strength STARCH, CORN   SODIUM STARCH GLYCOLATE TYPE A POTATO   MAGNESIUM STEARATE   SILICON DIOXIDE   POLYVINYL ALCOHOL   TITANIUM DIOXIDE   POLYETHYLENE GLYCOL 3350   TALC

Product Characteristics Color WHITE (OFF-WHITE) Score no score Shape CAPSULE Size 8mm Flavor Imprint Code E;451 Contains

Packaging # NDC Package Description Multilevel Packaging 1 0185-0451-01 100 TABLET In 1 BOTTLE None 2 0185-0451-05 500 TABLET In 1 BOTTLE None 3 0185-0451-10 1000 TABLET In 1 BOTTLE None 4 0185-0451-87 10 BLISTER PACK In 1 CARTON contains a BLISTER PACK (0185-0451-88) 4 0185-0451-88 10 TABLET In 1 BLISTER PACK This package is contained within the CARTON (0185-0451-87)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA076593	06/09/2004	06/01/2009

CIPROFLOXACIN  ciprofloxacin   tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0185-0470 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength CIPROFLOXACIN (CIPROFLOXACIN) CIPROFLOXACIN 750 mg

Inactive Ingredients Ingredient Name Strength STARCH, CORN   SODIUM STARCH GLYCOLATE TYPE A POTATO   MAGNESIUM STEARATE   SILICON DIOXIDE   POLYVINYL ALCOHOL   TITANIUM DIOXIDE   POLYETHYLENE GLYCOL 3350   TALC

Product Characteristics Color WHITE (OFF-WHITE) Score no score Shape CAPSULE Size 9mm Flavor Imprint Code E;470 Contains

Packaging # NDC Package Description Multilevel Packaging 1 0185-0470-53 50 TABLET In 1 BOTTLE None 2 0185-0470-01 100 TABLET In 1 BOTTLE None 3 0185-0470-87 10 BLISTER PACK In 1 CARTON contains a BLISTER PACK (0185-0470-88) 3 0185-0470-88 10 TABLET In 1 BLISTER PACK This package is contained within the CARTON (0185-0470-87)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA076593	06/09/2004	06/01/2009

Labeler - Sandoz Inc. (614842560)

Establishment
Name	Address	ID/FEI	Operations
Sandoz Inc		614842560	MANUFACTURE, ANALYSIS, RELABEL, REPACK

Revised: 06/2010Sandoz Inc.