CIPROFLOXACIN* EXTENDED-RELEASE TABLETS

ciprofloxacin (Ciprofloxacintablet, film coated, extended release 
[Andrx Pharmaceuticals, Inc.]

Rx Only

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

DESCRIPTION

Ciprofloxacin* extended-release tablets contain ciprofloxacin, a synthetic broad-spectrum antimicrobial agent for oral administration. Ciprofloxacin extended-release tablets are coated, bilayer tablets consisting of an immediate-release layer and an erosion-matrix type controlled-release layer. The tablets contain a combination of two types of ciprofloxacin drug substance, ciprofloxacin hydrochloride and ciprofloxacin betaine (base). Ciprofloxacin hydrochloride is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid hydrochloride. It is provided as a monohydrate form. The empirical formula of the monohydrate is C17H18FN3O3• HCI • H2O and its molecular weight is 385.8. The drug substance is a white to pale yellow crystalline substance. The chemical structure of the monohydrate is as follows:

Image from Drug Label Content

Ciprofloxacin betaine is 1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. As the anhydrous form, its empirical formula is C17H18FN3O3 and its molecular weight is 331.34. It is a white to pale yellow crystalline substance and its chemical structure is as follows:

Image from Drug Label Content

Ciprofloxacin extended-reIease tablets are available in 500 mg and 1000 mg (ciprofloxacin equivalent) tablet strengths. Ciprofloxacin extended-release tablets are white capsule shaped film-coated tablets. Each Ciprofloxacin extended-release 500 mg tablet contains 500 mg of ciprofloxacin as ciprofloxacin HCI (287.5 mg, calculated as ciprofloxacin on the dried basis) and ciprofloxacin (212.6 mg, calculated on the dried basis). Each Ciprofloxacin extended-release 1000 mg tablet contains 1000 mg of ciprofloxacin as ciprofloxacin HCI (574.9 mg, calculated as ciprofloxacin on the dried basis) and ciprofloxacin (425.2 mg, calculated on the dried basis). The inactive ingredients are colloidal silicon dioxide, confectioner's sugar, crospovidone, hypromellose 2910, iron oxide black, lactose monohydrate, magnesium stearate, polydextrose, polyethylene glycol 400, polyethylene glycol 8000, polysorbate 80, propylene glycol, succinic acid, titanium dioxide and triacetin.

* as ciprofloxacin and ciprofloxacin hydrochloride

CLINICAL PHARMACOLOGY

Absorption

Ciprofloxacin extended-release tablets are formulated to release drug at a slower rate compared to immediate-release tablets. Approximately 35% of the dose is contained within an immediate-release component, while the remaining 65% is contained in a slow-release matrix.

Maximum plasma ciprofloxacin concentrations are attained between 1 and 4 hours after dosing with Ciprofloxacin extended-release tablets. In comparison to the 250 mg and 500 mg ciprofloxacin immediate-release BID treatment, the Cmax of Ciprofloxacin extended-release tablets 500 mg and 1000 mg once daily are higher than the corresponding BID doses, while the AUCs over 24 hours are equivalent.

The following table compares the pharmacokinetic parameters obtained at steady state for these four treatment regimens (500 mg QD Ciprofloxacin extended-release tablets versus 250 mg BID ciprofloxacin immediate-release tablets and 1000 mg QD Ciprofloxacin extended-release tablets versus 500 mg BID ciprofloxacin immediate-release).

Ciprofloxacin Pharmacokinetics (Mean ± SD) Following Ciprofloxacin Immediate-release Tablets and Ciprofloxacin Extended-release Tablets Administration

§ median (range)

Cmax (mg/L) AUC0-24h (mg•h/L) T1/2(hr) Tmax (hr) §
Ciprofloxacin extended-release tablets 500 mg QD 1.59 ± 0.43 7.97 ± 1.87 6.6 ± 1.4 1.5 (1.0 - 2.5)
Ciprofloxacin Immediate-release tablets 250 mg BID 1.14 ± 0.23 8.25 ± 2.15 4.8 ± 0.6 1.0 (0.5 - 2.5)
Ciprofloxacin extended-release tablets 1000 mg QD 3.11 ± 1.08 16.83 ± 5.65 6.31 ± 0.72 2.0 (1 - 4)
 
Ciprofloxacin Immediate-release Tablets 500 mg BID 2.06 ± 0.41 17.04 ± 4.79 5.66 ± 0.89 2.0 (0.5 - 3.5)

Results of the pharmacokinetic studies demonstrate that Ciprofloxacin extended-release tablets may be administered with or without food (e.g. high-fat and low-fat meals or under fasted conditions).

Distribution

The volume of distribution calculated for intravenous ciprofloxacin is approximately 2.1 - 2.7 L/kg. Studies with the oral and intravenous forms of ciprofloxacin have demonstrated penetration of ciprofloxacin into a variety of tissues. 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. Following administration of a single dose of Ciprofloxacin extended-release tablets, ciprofloxacin concentrations in urine collected up to 4 hours after dosing averaged over 300 mg/L for both the 500 mg and 1000 mg tablets; in urine excreted from 12 to 24 hours after dosing, ciprofloxacin concentration averaged 27 mg/L for the 500 mg tablet, and 58 mg/L for the 1000 mg tablet.

Metabolism

Four metabolites of ciprofloxacin were identified in human urine. The metabolites have antimicrobial activity, but are less active than unchanged ciprofloxacin. The primary metabolites are oxociprofloxacin (M3) and sulfo-ciprofloxacin (M2), each accounting for roughly 3% to 8% of the total dose. Other minor metabolites are desethylene ciprofloxacin (M1), and formyl-ciprofloxacin (M4). The relative proportion of drug and metabolite in serum corresponds to the composition found in urine. Excretion of these metabolites was essentially complete by 24 hours after dosing. Ciprofloxacin is an inhibitor of human cytochrome P450 1A2 (CYP1A2) mediated metabolism. Coadministration of ciprofloxacin with other drugs primarily metabolized by CYP1A2 results in increased plasma concentrations of these drugs and could lead to clinically significant adverse events of the coadministered drug (see CONTRAINDICATIONS; WARNINGS; PRECAUTIONS: Drug Interactions).

Elimination

The elimination kinetics of ciprofloxacin are similar for the immediate-release and the Ciprofloxacin extended-release tablet. In studies comparing the Ciprofloxacin extended-release tablets and immediate-release ciprofloxacin, approximately 35% of an orally administered dose was excreted in the urine as unchanged drug for both formulations. 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 immediate-release 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 with the immediate-release tablet, 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 of immediate-release ciprofloxacin is recovered from the feces within 5 days after dosing. This may arise from either biliary clearance or transintestinal elimination.

Special Populations

Pharmacokinetic studies of the immediate-release oral tablet (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. Cmax is increased 16% to 40%, and mean AUC is increased approximately 30%, which 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. No dose adjustment is required for patients with uncomplicated urinary tract infections receiving 500 mg Ciprofloxacin extended-release tablets. For complicated urinary tract infection and acute uncomplicated pyelonephritis, where 1000 mg is the appropriate dose, the dosage of Ciprofloxacin extended-release tablets should be reduced to Ciprofloxacin extended-release tablets 500 mg q24h in patients with creatinine clearance below 30 mL/min. (See DOSAGE AND ADMINISTRATION.)

In studies in patients with stable chronic 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. (See DOSAGE AND ADMINISTRATION.)

Drug-drug Interactions

Concomitant administration with tizanidine is contraindicated. (See CONTRAINDICATIONS). Previous studies with immediate-release ciprofloxacin have shown that 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. Absorption of ciprofloxacin is significantly reduced by concomitant administration of 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. (See WARNINGS: PRECAUTIONS, Drug Interactions and Information for Patients, and DOSAGE AND ADMINISTRATION.)

Antacids: When Ciprofloxacin extended-release tablets given as a single 1000 mg dose was administered two hours before, or four hours after a magnesium/aluminum-containing antacid (900 mg aluminum hydroxide and 600 mg magnesium hydroxide as a single oral dose) to 18 healthy volunteers, there was a 4% and 19% reduction, respectively, in the mean Cmax of ciprofloxacin. The reduction in the mean AUC was 24% and 26%, respectively. Ciprofloxacin extended-release tablets should be administered at least 2 hours before or 6 hours after antacids containing magnesium or aluminum, as well as sucralfate, VIDEX® (didanosine) chewable/buffered tablets or pediatric powder, other highly buffered drugs, metal cations such as iron, and multivitamin preparations with zinc. Although Ciprofloxacin extended-release tablets may be taken with meals that include milk, concomitant administration with dairy products or with calcium-fortified juices alone should be avoided, since decreased absorption is possible. (See PRECAUTIONS, Information for Patients and Drug Interactions, and DOSAGE AND ADMINISTRATION.)

Omeprazole: When Ciprofloxacin extended-release tablets were administered as a single 1000 mg dose concomitantly with omeprazole (40 mg once daily for three days) to 18 healthy volunteers, the mean AUC and Cmax of ciprofloxacin were reduced by 20% and 23%, respectively. The clinical significance of this interaction has not been determined. (See PRECAUTIONS, Drug Interactions.)

MICROBIOLOGY

Ciprofloxacin has in vitro activity against a wide range of gram-negative and gram-positive organisms. The bactericidal action of ciprofloxacin results from inhibition of topoisomerase II (DNA gyrase) and topoisomerase IV (both Type II topoisomerases), which are required for bacterial DNA replication, transcription, repair, and recombination. The mechanism of action of quinolones, including ciprofloxacin, is different from that of other antimicrobial agents such as betalactams, macrolides, tetracyclines, or aminoglycosides; therefore, organisms resistant to these drugs may be susceptible to ciprofloxacin. There is no known cross-resistance between ciprofloxacin and other classes of antimicrobials. Resistance to ciprofloxacin in vitro develops slowly (multiple-step mutation). Resistance to ciprofloxacin due to spontaneous mutations occurs at a general frequency of between < 10-9 to 1x10-6.

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 USAGE section.

 
Aerobic gram-positive microorganisms
 
Enterococcus faecalis (Many strains are only moderately susceptible.)
 
Staphylococcus saprophyticus
 
Aerobic gram-negative microorganisms
 
Escherichia coli
 
Klebsiella pneumoniae
 
Proteus mirabilis
 
Pseudomonas aeruginosa

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 extended-release tablets in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

   Aerobic gram-negative microorganisms

Citrobacter koseri             Morganella morganii

Citrobacter freundii            Proteus vulgaris

Edwardsiella tarda            Providencia rettgeri

Enterobacter aerogenes       Providencia stuartii

Enterobacter cloacae        Serratia marcescens

Klebsiella oxytoca

Susceptibility Tests

Dilution Techniques: Quantitative methods are used to determine antimicrobial minimal 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. The MIC values should be interpreted according to the following criteria:

For testing Enterobacteriaceae, Enterococcus faecalis, Pseudomonas aeruginosa, and Staphylococcus saprophyticus:

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

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:

Microorganism MIC Range (μg/mL)
Enterococcus faecalis ATCC 29212 0.25 - 2.0
Escherichia coii ATCC 25922 0.004 - 0.015
Staphylococcus aureus ATCC 29213 0.12 - 0.5
Pseudomonas aeruginosa ATCC 27853 0.25 - 1

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 Enterobacteriaceae, Enterococcus faecalis, Pseudomonas aeruginosa, and Staphylococcus saprophyticus:

Zone Diameter (mm) Interpretation
≥ 21 Susceptible (S)
16 – 20 Intermediate (I)
≤ 15 Resistant (R)

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:

Microorganism Zone Diameter (mm)
Escherichia coli ATCC 25922 30 - 40
Staphylococcus aureus ATCC 25923 22 - 30
Pseudomonas aeruginosa ATCC 27853 25 - 33

INDICATIONS AND USAGE

Ciprofloxacin extended-release tablets are indicated only for the treatment of urinary tract infections, including acute uncomplicated pyelonephritis, caused by susceptible strains of the designated microorganisms as listed below. Ciprofloxacin extended-release tablets and ciprofloxacin immediate-release tablets are not interchangeable. Please see DOSAGE AND ADMINISTRATION for specific recommendations.

Uncomplicated Urinary Tract Infections (Acute Cystitis) caused by Escherichia coli, Proteus mirabilis, Enterococcus faecalis, or Staphylococcus saprophyticusa

Complicated Urinary Tract Infections caused by Escherichia coli, Klebsiella pneumoniae, Enterococcus faecalis, Proteus mirabilis, or Pseudomonas aeruginosaa

Acute Uncomplicated Pyelonephritis caused by Escherichia coli.

a Treatment of infections due to this organism in the organ system was studied in fewer than 10 patients.

THE SAFETY AND EFFICACY OF CIPROFLOXACIN EXTENDED-RELEASE TABLETS IN TREATING INFECTIONS OTHER THAN URINARY TRACT INFECTIONS HAS NOT BEEN DEMONSTRATED. 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 extended-release tablets may be initiated before results of these tests are known; once results become available appropriate therapy should be continued. 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 extended-release tablets and other antibacterial drugs, Ciprofloxacin extended-release 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, any member of the quinolone class of antimicrobial agents, or any of the product components. Concomitant administration with tizanidine is contraindicated. (See PRECAUTIONS, Drug Interactions.)

WARNINGS

THE SAFETY AND EFFECTIVENESS OF CIPROFLOXACIN EXTENDED-RELEASE TABLETS IN PEDIATRIC PATIENTS AND ADOLESCENTS (UNDER THE AGE OF 18 YEARS), PREGNANT WOMEN, AND NURSING WOMEN HAVE NOT BEEN ESTABLISHED.(See PRECAUTIONS: Pediatric Use, Pregnancy,and Nursing Motherssubsections.) The 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 (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.

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 Interactions and ADVERSE REACTIONS.)

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.

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 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."

If a diagnosis of pseudomembranous colitis is 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, position sense, vibratory sensation, and/or motor strength in order to prevent the development of an irreversible condition.

Tendon Effects: Ruptures of the shoulder, hand, Achilles tendon or other tendons that required surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones, including ciprofloxacin. Post-marketing surveillance reports indicate that this risk may be increased in patients receiving concomitant corticosteroids, especially 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.

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

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. Prescribing Ciprofloxacin extended-release 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:

Drug Interactions: In a pharmacokinetic study, systemic exposure of tizanidine (4 mg single dose) was significantly increased (Cmax 7-fold, AUC 10-fold) when the drug was given concomitantly with ciprofloxacin (500 mg bid for 3 days). The hypotensive and sedative effects of tizanidine were also potentiated. Concomitant administration of tizanidine and ciprofloxacin is contraindicated.

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

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

Concurrent administration of a quinolone, including ciprofloxacin, with multivalent cation-containing products such as magnesium/aluminum antacids, sucralfate, VIDEX® (didanosine) chewable/buffered tablets or pediatric powder, other highly buffered drugs, or products containing calcium, iron, or zinc may substantially interfere with the absorption of the quinolone, resulting in serum and urine levels considerably lower than desired. Ciprofloxacin extended-release tablets should be administered at least 2 hours before or 6 hours after antacids containing magnesium or aluminum, as well as sucralfate, VIDEX® (didanosine) chewable/buffered tablets or pediatric powder, other highly buffered drugs, metal cations such as iron, and multivitamin preparations with zinc. (See CLINICAL PHARMACOLOGY, Drug-drug Interactions, PRECAUTIONS, Information for Patients, and DOSAGE AND ADMINISTRATION.)

Histamine H2-receptor antagonists appear to have no significant effect on the bioavailability of ciprofloxacin.

Absorption of the Ciprofloxacin extended-reIease tablet was slightly diminished (20%) when given concomitantly with omeprazole. (See CLINICAL PHARMACOLOGY, Drug-drug Interactions.)

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 a 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)

Ciprofloxacin was not carcinogenic or tumorigenic in 2-year carcinogenicity studies with rats and mice at daily oral dose levels of 250 and 750 mg/kg, respectively (approximately 2 and 3 -fold greater than the 1000 mg daily human dose based upon body surface area).

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 the maximum recommended daily human dose of 1000 mg 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.

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 (1.0 times the highest recommended daily human dose of 1000 mg based upon body surface area) 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 there is no risk.

A controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5% exposed to ciprofloxacin and 68% first trimester exposures) during gestation. 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 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). 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. However, these small postmarketing epidemiology studies, of which most experience is from short term, first trimester exposure, are insufficient to evaluate the risk for the 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 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 (0.7 and 0.4 times the maximum daily human dose of 1000 mg based upon body surface area, respectively) and have revealed no evidence of harm to the fetus due to ciprofloxacin. In rabbits, ciprofloxacin (30 and 100 mg/kg orally) produced gastrointestinal disturbances resulting in maternal weight loss and an increased incidence of abortion, but no teratogenicity was observed at either dose. After intravenous administration of doses up to 20 mg/kg, no maternal toxicity was produced in the rabbit, and no embryotoxicity or teratogenicity was observed.

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: Safety and effectiveness of Ciprofloxacin extended-release tablets in pediatric patients and adolescents less than 18 years of age have not been established. Ciprofloxacin causes arthropathy in juvenile animals. (See WARNINGS.)

Geriatric Use: In a large, prospective, randomized Ciprofloxacin extended-release tablets clinical trial in complicated urinary tract infections, 49% (509/1035) of the patients were 65 and over, while 30% (308/1035) were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and clinical experience with other formulations of ciprofloxacin has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Ciprofloxacin is known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. No alteration of dosage is necessary for patients greater than 65 years of age with normal renal function. However, since some older individuals experience reduced renal function by virtue of their advanced age, care should be taken in dose selection for elderly patients, and renal function monitoring may be useful in these patients. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.)

ADVERSE REACTIONS

Clinical trials in patients with urinary tract infections enrolled 961 patients treated with 500 mg or 1000 mg Ciprofloxacin extended-release tablets. Most adverse events reported were described as mild to moderate in severity and required no treatment. The overall incidence, type and distribution of adverse events were similar in patients receiving both 500 mg and 1000 mg of Ciprofloxacin extended-release tablets. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates observed in clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

In the clinical trial of uncomplicated urinary tract infection, Ciprofloxacin extended-release tablets (500 mg once daily) in 444 patients were compared to ciprofloxacin immediate-release tablets (250 mg twice daily) in 447 patients for 3 days. Discontinuations due to adverse reactions thought to be drug-related occurred in 0.2% (1/444) of patients in the Ciprofloxacin extended-release tablets arm and in 0% (0/447) of patients in the control arm.

In the clinical trial of complicated urinary tract infection and acute uncomplicated pyelonephritis, Ciprofloxacin extended-release tablets (1000 mg once daily) in 517 patients were compared to ciprofloxacin immediate-release tablets (500 mg twice daily) in 518 patients for 7 to 14 days. Discontinuations due to adverse reactions thought to be drug-related occurred in 3.1% (16/517) of patients in the Ciprofloxacin extended-release tablets arm and in 2.3% (12/518) of patients in the control arm. The most common reasons for discontinuation in the Ciprofloxacin extended-release tablets arm were nausea/vomiting (4 patients) and dizziness (3 patients). In the control arm the most common reason for discontinuation was nausea/vomiting (3 patients).

In these clinical trials, the following events occurred in ≥ 2% of all Ciprofloxacin extended-release tablets patients, regardless of drug relationship: nausea (4%), headache (3%), dizziness (2%), diarrhea (2%), vomiting (2%) and vaginal moniliasis (2%).

Adverse events, judged by investigators to be at least possibly drug-related, occurring in greater than or equal to 1% of all Ciprofloxacin extended-release tablets treated patients were: nausea (3%), diarrhea (2%), headache (1%), dyspepsia (1%), dizziness (1%), and vaginal moniliasis (1%). Vomiting (1%) occurred in the 1000 mg group.

Additional uncommon events, judged by investigators to be at least possibly drug-related, that occurred in less than 1% of Ciprofloxacin extended-release tablets treated patients were:

 
BODY AS A WHOLE: abdominal pain, asthenia, malaise, photosensitivity reaction
 
CARDIOVASCULAR: bradycardia, migraine, syncope
 
DIGESTIVE: anorexia, constipation, dry mouth, flatulence, liver function tests abnormal, thirst
 
HEMIC/LYMPHATIC: prothrombin decrease
 
CENTRAL NERVOUS SYSTEM: abnormal dreams, depersonalization, depression, hypertonia, incoordination, insomnia, somnolence, tremor, vertigo
 
METABOLIC: hyperglycemia
 
SKIN/APPENDAGES: dry skin, maculopapular rash, pruritus, rash, skin disorder, urticaria, vesiculobullous rash
 
SPECIAL SENSES: diplopia, taste perversion
 
UROGENITAL: dysmenorrhea, hematuria, kidney function abnormal, vaginitis

The following additional adverse events, some of them life threatening, regardless of incidence or relationship to drug, have been reported during clinical trials and from worldwide post-marketing experience in patients given ciprofloxacin (includes all formulations, all dosages, all drug-therapy durations, and all indications). Because these reactions have been reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or a causal relationship to drug exposure. The events in alphabetical order are:

abnormal gait, achiness, acidosis, agitation, agranulocytosis, allergic reactions (ranging from urticaria to anaphylactic reactions and including life-threatening anaphylactic shock), amylase increase, anemia, angina pectoris, angioedema, anosmia, anxiety, arrhythmia, arthralgia, ataxia, atrial flutter, bleeding diathesis, blurred vision, bronchospasm, C. difficile associated diarrhea, candidiasis (cutaneous, oral), candiduria, cardiac murmur, cardiopulmonary arrest, cardiovascular collapse, cerebral thrombosis, chills, cholestatic jaundice, chromatopsia, confusion, convulsion, delirium, drowsiness, dysphagia, dysphasia, dyspnea, edema (conjunctivae, face, hands, laryngeal, lips, lower extremities, neck, pulmonary), epistaxis, erythema multiforme, erythema nodosum, exfoliative dermatitis, fever, fixed eruptions, flushing, gastrointestinal bleeding, gout (flare up), grand mal convulsion, gynecomastia, hallucinations, hearing loss, hemolytic anemia, hemoptysis, hemorrhagic cystitis, hepatic failure, hepatic necrosis, hepatitis, hiccup, hyperesthesia, hyperpigmentation, hypertension, hypertonia, hypesthesia, hypotension, ileus, interstitial nephritis, intestinal perforation, jaundice, joint stiffness, lethargy, lightheadedness, lipase increase, lymphadenopathy, manic reaction, marrow depression, migraine, moniliasis (oral, gastrointestinal, vaginal), myalgia, myasthenia, myasthenia gravis (possible exacerbation), myocardial infarction, myoclonus, nephritis, nightmares, nystagmus, oral ulceration, pain (arm, back, breast, chest, epigastric, eye, extremities, foot, jaw, neck, oral mucosa), palpitation, pancreatitis, pancytopenia, paranoia, paresthesia, peripheral neuropathy, perspiration (increased), petechia, phlebitis, phobia, pleural effusion, polyuria, postural hypotension, prothrombin time prolongation, pseudomembranous colitis (the onset of symptoms may occur during or after antimicrobial treatment), pulmonary embolism, purpura, renal calculi, renal failure, respiratory arrest, respiratory distress, restlessness, serum sickness-like reaction, Stevens-Johnson syndrome, sweating, tachycardia, taste loss, tendinitis, tendon rupture, tinnitus, torsade de pointes, toxic epidermal necrolysis (Lyell's syndrome), toxic psychosis, twitching, unresponsiveness, urethral bleeding, urinary retention, urination (frequent), vaginal pruritus, vasculitis, ventricular ectopy, vesicles, visual acuity (decreased), visual disturbances (flashing lights, change in color perception, overbrightness of lights).

Laboratory Changes:

The following adverse laboratory changes, in alphabetical order, regardless of incidence or relationship to drug, have been reported in patients given ciprofloxacin (includes all formulations, all dosages, all drug-therapy durations, and all indications):

Decreases in blood glucose, BUN, hematocrit, hemoglobin, leukocyte counts, platelet counts, prothrombin time, serum albumin, serum potassium, total serum protein, uric acid.

Increases in alkaline phosphatase, ALT (SGPT), AST (SGOT), atypical lymphocyte counts, blood glucose, blood monocytes, BUN, cholesterol, eosinophil counts, LDH, platelet counts, prothrombin time, sedimentation rate, serum amylase, serum bilirubin, serum calcium, serum cholesterol, serum creatine phosphokinase, serum creatinine, serum gamma-glutamyl transpeptidase (GGT), serum potassium, serum theophylline (in patients receiving theophylline concomitantly), serum triglycerides, uric acid.

Others: albuminuria, change in serum phenytoin, crystalluria, cylindruria, immature WBCs, leukocytosis, methemoglobinemia, pancytopenia.

OVERDOSAGE

In the event of acute excessive 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 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.

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.

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.

DOSAGE AND ADMINISTRATION

Ciprofloxacin extended-release tablets and ciprofloxacin immediate-release tablets are not interchangeable. Cipro XR should be administered orally once daily as described in the following Dosage Guidelines table:

DOSAGE GUIDELINES
Indication Unit Dose Frequency Usual Duration
Uncomplicated Urinary Tract Infection 500 mg Q24h 3 Days
(Acute Cystitis)
Complicated Urinary Tract Infection 1000 mg Q24h 7-14 Days
Acute Uncomplicated Pyelonephritis 1000 mg Q24h 7-14 Days

Patients whose therapy is started with CIPRO I.V. for urinary tract infections may be switched to Ciprofloxacin extended-release tablets when clinically indicated at the discretion of the physician.

Ciprofloxacin extended-release tablets should be administered at least 2 hours before or 6 hours after antacids containing magnesium or aluminum, as well as sucralfate, VIDEX® (didanosine) chewable/buffered tablets or pediatric powder, other highly buffered drugs, metal cations such as iron, and multivitamin preparations with zinc. Although Ciprofloxacin extended-release tablets may be taken with meals that include milk, concomitant administration with dairy products alone, or with calcium-fortified products should be avoided, since decreased absorption is possible. A 2-hour window between substantial calcium intake (> 800 mg) and dosing with Ciprofloxacin extended-release tablets is recommended. Ciprofloxacin extended-release tablets should be swallowed whole. DO NOT SPLIT, CRUSH, OR CHEW THE TABLET. (See CLINICAL PHARMACOLOGY, Drug-drug Interactions, PRECAUTIONS, Drug Interactions and Information for Patients.)

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. No dosage adjustment is required for patients with uncomplicated urinary tract infections receiving 500 mg Ciprofloxacin extended-release tablets. In patients with complicated urinary tract infections and acute uncomplicated pyelonephritis, who have a creatinine clearance of < 30 mL/min, the dose of Ciprofloxacin extended-release tablets should be reduced from 1000 mg to 500 mg daily. For patients on hemodialysis or peritoneal dialysis, administer Ciprofloxacin extended-release tablets after the dialysis procedure is completed. (See CLINICAL PHARMACOLOGY, Special Populations, and PRECAUTIONS, Geriatric Use.)

Impaired Hepatic Function:

No dosage adjustment is required with Ciprofloxacin extended-release tablets in patients with stable chronic cirrhosis. The kinetics of ciprofloxacin in patients with acute hepatic insufficiency, however, have not been fully elucidated. (See CLINICAL PHARMACOLOGY, Special Populations.)

HOW SUPPLIED

Ciprofloxacin extended-release tablets are available as white, capsule shaped, film coated tablets containing 500 mg or 1000 mg ciprofloxacin. The 500 mg tablet is marked with Andrx Logo "Image from Drug Label Content" and "942" on one side. The 1000 mg tablet is marked with Andrx Logo "Image from Drug Label Content" and "938" on one side.

Strength NDC Code
Bottles of 30 500 mg 62037-942-30
Bottles of 50 500 mg 62037-942-06
Bottles of 100 500 mg 62037-942-01
Bottles of 1000 500 mg 62037-942-10
Bottles of 50 1000 mg 62037-938-06
Bottles of 100 1000 mg 62037-938-01
Bottles of 500 1000 mg 62037-938-05

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°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 beagles, 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. 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.

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

Uncomplicated Urinary Tract Infections (acute cystitis)

Ciprofloxacin extended-release tablets were evaluated for the treatment of uncomplicated urinary tract infections (acute cystitis) in a randomized, double-blind, controlled clinical trial conducted in the US. This study compared Ciprofloxacin extended-release tablets (500 mg once daily for three days) with ciprofloxacin immediate-release tablets (Ciprofloxacin immediate-release tablets 250 mg BID for three days). Of the 905 patients enrolled, 452 were randomly assigned to the Ciprofloxacin extended-release tablets treatment group and 453 were randomly assigned to the control group. The primary efficacy variable was bacteriologic eradication of the baseline organism(s) with no new infection or superinfection at test-of-cure (Day 4 -11 Post-therapy).

The bacteriologic eradication and clinical success rates were similar between Ciprofloxacin extended-release tablets and the control group. The eradication and clinical success rates and their corresponding 95% confidence intervals for the differences between rates (Ciprofloxacin extended-release tablets minus control group) are given in the following table:

* n/N = patients with baseline organism(s) eradicated and no new infections

or superinfections/total number of patients

** n/N = patients with specified baseline organism eradicated/patients with

specified baseline organism

*** n/N = patients with clinical success / total number of patients

† The presence of a pathogen at a level of ≥ 105 CFU/mL was required for microbiological evaluability criteria, except for S. saprophyticus (≥ 104 CFU/mL).

Ciprofloxacin
extended-release
tablets 500 mg
QD x 3 Days
Ciprofloxacin
immediate-release
tablets
250 mg
BID x 3 Days
Randomized Patients 452 453
Per Protocol Patients † 199 223
Bacteriologic Eradication at TOC (n/N)* 188/199 (94.5%) 209/223 (93.7%)
CI [-3.5%, 5.1%]
Bacteriologic Eradication (by organism) at TOC (n/N)**
E. coli 156/160 (97.5%) 176/181 (97.2%)
E. faecalis 10/11 (90.9%) 17/21 (81.0%)
P. mirabilis 11/12 (91.7%) 7/7 (100%)
S. saprophyticus 6/7 (85.7%) 9/9 (100%)
Clinical Response at TOC (n/N)*** 189/199 (95.0%) 204/223 (91.5%)
CI [-1.1%, 8.1%]

Complicated Urinary Tract Infections and Acute Uncomplicated Pyelonephritis

Ciprofloxacin extended-release tablets were evaluated for the treatment of complicated urinary tract infections (cUTI) and acute uncomplicated pyelonephritis (AUP) in a randomized, double-blind, controlled clinical trial conducted in the US and Canada. The study enrolled 1,042 patients (521 patients per treatment arm) and compared Ciprofloxacin extended-release tablets (1000 mg once daily for 7 to 14 days) with immediate-release ciprofloxacin (500 mg BID for 7 to 14 days). The primary efficacy endpoint for this trial was bacteriologic eradication of the baseline organism(s) with no new infection or superinfection at 5 to 11 days post-therapy (test-of-cure or TOC) for the Per Protocol and Modified Intent-To-Treat (MITT) populations.

The Per Protocol population was defined as patients with a diagnosis of cUTI or AUP, a causative organism(s) at baseline present at ≥ 105 CFU/mL, no inclusion criteria violation, a valid test-of-cure urine culture within the TOC window, an organism susceptible to study drug, no premature discontinuation or loss to follow-up, and compliance with the dosage regimen (among other criteria). More patients in the Ciprofloxacin extended-release tablets arm than in the control arm were excluded from the Per Protocol population and this should be considered in the interpretation of the study results. Reasons for exclusion with the greatest discrepancy between the two arms were no valid test-of-cure urine culture, an organism resistant to the study drug, and premature discontinuation due to adverse events.

An analysis of all patients with a causative organism(s) isolated at baseline and who received study medication, defined as the MITT population, included 342 patients in the Ciprofloxacin extended-release tablets arm and 324 patients in the control arm. Patients with missing responses were counted as failures in this analysis. In the MITT analysis of cUTI patients, bacteriologic eradication was 160/271 (59.0%) versus 156/248 (62.9%) in Ciprofloxacin extended-release tablets and control arm, respectively [97.5% CI* (-13.5%, 5.7%)]. Clinical cure was 184/271 (67.9%) for Ciprofloxacin extended-release tablets and 182/248 (73.4%) for control arm, respectively [97.5% CI* (-14.4%, 3.5%)]. Bacterial eradication in the MITT analysis of patients with AUP at TOC was 47/71 (66.2%) and 58/76 (76.3%) for Ciprofloxacin extended-release tablets and control arm, respectively [97.5% CI* (-26.8%, 6.5%)]. Clinical cure at TOC was 50/71 (70.4%) for Ciprofloxacin extended-release tablets and 58/76 (76.3%) for the control arm [97.5% CI* (-22.0%, 10.4%)].

* confidence interval of the difference in rates (Ciprofloxacin extended-release tablets minus control).

In the Per Protocol population, the differences between Ciprofloxacin extended-release tablets and the control arm in bacteriologic eradication rates at the TOC visit were not consistent between AUP and cUTI patients. The bacteriologic eradication rate for cUTI patients was higher in the Ciprofloxacin extended-release tablets arm than in the control arm. For AUP patients, the bacteriologic eradication rate was lower in the Ciprofloxacin extended-release tablets arm than in the control arm. This inconsistency was not observed between the two treatment groups for clinical cure rates. Clinical cure rates were 96.1% (198/206) and 92.1% (211/229) for Ciprofloxacin extended-release tablets and the control arm, respectively.

The bacterial eradication and clinical cure rates by infection type for Ciprofloxacin extended-release tablets and the control arm at the TOC visit and their corresponding 97.5% confidence intervals for the differences between rates (Ciprofloxacin extended-release tablets minus control arm) are given below for the Per Protocol population analysis:

^ Patients excluded from the Per Protocol population were primarily those with no causative organism(s) at baseline or no organism present at ≥ 105 CFU/mL at baseline, inclusion criteria violation, no valid test-of-cure urine culture within the TOC window, an organism resistant to study drug, premature discontinuation due to an adverse event, lost to follow-up, or non-compliance with dosage regimen (among other criteria).

* n/N = patients with baseline organism(s) eradicated and no new infections or superinfections/total number of patients

** n/N = patients with specified baseline organism eradicated/patients with specified baseline organism

*** n/N = patients with clinical success / total number of patients

Ciprofloxacin
extended-release
tablets 1000 mg QD
Ciprofloxacin
immediate-release
tablets 500 mg BID
Randomized Patients 521 521
Per Protocol Patients^ 206 229
cUTI Patients
Bacteriologic Eradication at TOC (n/N)* 148/166 (89.2%) 144/177 (81.4%)
CI [-0.7%, 16.3%]
Bacteriologic Eradication (by organism) at TOC (n/N)**
E. coli 91/94 (96.8%) 90/92 (97.8%)
K. pneumoniae 20/21 (95.2%) 19/23 (82.6%)
E. faecalis 17/17 (100%) 14/21 (66.7%)
P. mirabilis 11/12 (91.6%) 10/10 (100%)
P. aeruginosa 3/3 (100%) 3/3 (100%)
Clinical Cure at TOC (n/N)*** 159/166 (95.8%) 161/177 (91.0%)
CI [-1.1%, 10.8%]
AUP Patients
Bacteriologic Eradication at TOC
(n/N)*
35/40 (87.5%) 51/52 (98.1%)
CI [-34.8%, 6.2%]
Bacteriologic Eradication of E. coli at TOC (n/N)** 35/36 (97.2%) 41/41 (100%)
Clinical Cure at TOC (n/N)*** 39/40 (97.5%) 50/52 (96.2%)
CI [-15.3%, 21.1%]

Of the 166 cUTI patients treated with Ciprofloxacin extended-release tablets, 148 (89%) had the causative organism(s) eradicated, 8 (5%) had persistence, 5 (3%) patients developed superinfections and 5 (3%) developed new infections. Of the 177 cUTI patients treated in the control arm, 144 (81%) had the causative organism(s) eradicated, 16 (9%) patients had persistence, 3 (2%) developed superinfections and 14 (8%) developed new infections. Of the 40 patients with AUP treated with Ciprofloxacin extended-release tablets, 35 (87.5%) had the causative organism(s) eradicated, 2 (5%) patients had persistence and 3 (7.5%) developed new infections. Of the 5 Ciprofloxacin extended-release tablets AUP patients without eradication at TOC, 4 were considered clinical cures and did not receive alternative antibiotic therapy. Of the 52 patients with AUP treated in the control arm, 51 (98%) had the causative organism(s) eradicated. One patient (2%) had persistence.

References

1. NCCLS, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically-Sixth Edition. Approved Standard NCCLS Document M7-A6, Vol. 23, No. 2, NCCLS, Wayne, PA, January, 2003.

2. NCCLS, Performance Standards for Antimicrobial Disk Susceptibility Tests-Eighth Edition. Approved Standard NCCLS Document M2-A8, Vol. 23, No. 1. NCCLS, Wayne, PA, January, 2003.

Manufactured by:
Andrx Pharmaceuticals, Inc.
Ft. Lauderdale, FL 33314

Rev. date: 08/06
Label Code


Ciprofloxacin (Ciprofloxacin)
PRODUCT INFO
Product Code 62037-942 Dosage Form TABLET, FILM COATED, EXTENDED RELEASE
Route Of Administration ORAL DEA Schedule
INGREDIENTS
Name (Active Moiety) Type Strength
Ciprofloxacin (Ciprofloxacin) Active 500 MILLIGRAM  In 1 TABLET
Colloidal silicion dioxide Inactive  
confectioner's sugar Inactive  
crospovidone Inactive  
hypromellose 2910 Inactive  
iron oxide black Inactive  
lactose monohydrate Inactive  
magnesium stearate Inactive  
polydextrose Inactive  
polyethylene glycol 400 Inactive  
polyethylene glycol 8000 Inactive  
polysorbate 80 Inactive  
propylene glycol Inactive  
succinic acid Inactive  
titanium dioxide Inactive  
triacetin Inactive  
IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color WHITE (WHITE) Score 1
Shape OVAL (CAPSULE-SHAPED) Symbol true
Imprint Code 942 Coating true
Size 16mm
PACKAGING
# NDC Package Description Multilevel Packaging
1 62037-942-30 30 TABLET In 1 BOTTLE, PLASTIC None
2 62037-942-06 50 TABLET In 1 BOTTLE, PLASTIC None
3 62037-942-01 100 TABLET In 1 BOTTLE, PLASTIC None
4 62037-942-10 1000 TABLET In 1 BOTTLE, PLASTIC None

Ciprofloxacin (Ciprofloxacin)
PRODUCT INFO
Product Code 62037-938 Dosage Form TABLET, FILM COATED, EXTENDED RELEASE
Route Of Administration ORAL DEA Schedule
INGREDIENTS
Name (Active Moiety) Type Strength
Ciprofloxacin (Ciprofloxacin) Active 1000 MILLIGRAM  In 1 TABLET
Colloidal silicion dioxide Inactive  
confectioner's sugar Inactive  
crospovidone Inactive  
hypromellose 2910 Inactive  
iron oxide black Inactive  
lactose monohydrate Inactive  
magnesium stearate Inactive  
polydextrose Inactive  
polyethylene glycol 400 Inactive  
polyethylene glycol 8000 Inactive  
polysorbate 80 Inactive  
propylene glycol Inactive  
succinic acid Inactive  
titanium dioxide Inactive  
triacetin Inactive  
IMPRINT INFORMATION
Characteristic Appearance Characteristic Appearance
Color WHITE (WHITE) Score 1
Shape OVAL (CAPSULE-SHAPED) Symbol true
Imprint Code 938 Coating true
Size 20mm
PACKAGING
# NDC Package Description Multilevel Packaging
1 62037-938-06 50 TABLET In 1 BOTTLE, PLASTIC None
2 62037-938-01 100 TABLET In 1 BOTTLE, PLASTIC None
3 62037-938-10 1000 TABLET In 1 BOTTLE, PLASTIC None

Revised: 01/2007Andrx Pharmaceuticals, Inc.