Professional Information — Cetraxal, Ciloxan, Cipro, Cipro Hc, Ciprodex, Otiprio, Otovel, Proquin

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

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

Acute Uncomplicated Pyelonephritis caused by Escherichia coli.

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.

Dosage and Administration

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

Patients whose therapy is started with ciprofloxacin 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 are 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 .)

Contraindications

Ciprofloxacin extended-release tablets are 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 .)

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 was 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 was 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/Hypersensivity: dry skin, maculopapular rash, photosensitivity/phototoxicity reactions, pruritus, rash, skin disorder, urticaria, vesiculobullous rash
• Special Senses: diplopia, taste perversion
• Urogenital: dysmenorrhea, hematuria, kidney function abnormal, vaginitis

Post-Marketing Adverse Event Reports: The following adverse events have been reported from worldwide marketing experience with fluoroquinolones, including ciprofloxacin. 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 (including fatal cases), 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, exacerbation of myasthenia gravis, 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, photosensitivity/phototoxicity reaction, 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.

Drug Interactions

In a pharmacokinetic study, systemic exposure of tizanidine (4 mg single dose) was significantly increased (C_max 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-release 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.

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.

Description

Ciprofloxacinas ciprofloxacin and ciprofloxacin hydrochloride extended-release tablets contains 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 matrix type controlled-release layer. The tablets contain a combination of two types of ciprofloxacin drug substance, ciprofloxacin hydrochloride, USP and ciprofloxacin, USP. Ciprofloxacin hydrochloride is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid hydrochloride. It is provided as monohydrate. The empirical formula of the monohydrate is C₁₇H₁₈FN₃O₃ • HCl • H₂O and its molecular weight is 385.8. The drug substance is a faintly yellowish to light yellow crystalline substance. The chemical structure of the monohydrate is as follows:

Ciprofloxacin, USP 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 pale yellowish to light yellow crystalline substance and its chemical structure is as follows:

Ciprofloxacin extended-release tablets are available in 500 mg and 1000 mg (ciprofloxacin equivalent) tablet strength. Ciprofloxacin extended-release tablets are white to off white, film coated, oblong shaped, biconvex tablets. Each ciprofloxacin extended-release 500 mg tablet contains 500 mg of ciprofloxacin as ciprofloxacin HCl (287.5 mg, calculated as ciprofloxacin on anhydrous 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 HCl (574.9 mg, calculated as ciprofloxacin on anhydrous basis) and ciprofloxacin (425.2 mg, calculated on the dried basis). The inactive ingredients are crospovidone, colloidal silicon dioxide, ethylcellulose, hypromellose, magnesium stearate, polyethylene glycol, succinic acid and titanium dioxide

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 C_max 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).

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 sulfociprofloxacin (M2), each accounting for roughly 3% to 8% of the total dose. Other minor metabolites are desethylene ciprofloxacin (M1), and formylciprofloxacin (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 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. C_max 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 C_max 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 was 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 C_max of ciprofloxacin were reduced by 20% and 23%, respectively. The clinical significance of this interaction has not been determined. (See PRECAUTIONS, Drug Interactions .)

Clinical Studies

Uncomplicated Urinary Tract Infections (acute cystitis)

Ciprofloxacin extended-release tablets was 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 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:

Complicated Urinary Tract Infections and Acute Uncomplicated Pyelonephritis

Ciprofloxacin extended-release tablets was 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% CIconfidence interval of the difference in rates (ciprofloxacin extended-release tablets minus control). (-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%)].

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:

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.

How Supplied / Storage and Handling

Ciprofloxacin extended-release tablets, 500 mg are white to off-white, film coated, oblong shaped, biconvex tablets, embossed with ‘RDY’ on one side and ‘422’ on other side. They are supplied in bottles of 30's, 100's, 500's and unit-dose package of 100 (10×10).

Ciprofloxacin extended-release tablets, 1000 mg are white to off-white, film coated, oblong shaped, biconvex tablets, embossed with ‘RDY’on one side and ‘423’ on other side. They are supplied in bottles of 30's, 100's, 500's and unit-dose packages of 100 (10×10).

Store at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].

Patient Counseling Information

Patients should be advised:

• to contact their healthcare provider if they experience pain, swelling, or inflammation of a tendon, or weakness or inability to use one of their joints; rest and refrain from exercise; and discontinue ciprofloxacin extended-release tablets treatment.The risk of severe tendon disorder with fluoroquinolones is higher in older patients usually over 60 years of age, in patients taking corticosteroid drugs,  and in patients with kidney, heart or lung transplants.
• that fluoroquinolones like ciprofloxacin extended-release tablets may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Patients should call their healthcare provider right away if they have any worsening muscle weakness or breathing problems.
• that antibacterial drugs including ciprofloxacin extended-release tablets should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When ciprofloxacin extended-release tablets is 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 extended-release tablets or other antibacterial drugs in the future.
• that ciprofloxacin extended-release tablets may be taken with or without meals and to drink fluids liberally. As with other quinolones, concurrent administration with magnesium/aluminum antacids, or sucralfate, VIDEX® (didanosine) chewable/buffered tablets or pediatric powder, other highly buffered drugs, or with other products containing calcium, iron, or zinc should be avoided. Ciprofloxacin extended-release tablets may be taken two hours before or six hours after taking these products. (See CLINICAL PHARMACOLOGY, Drug-drug Interactions, DOSAGE AND ADMINISTRATION, and PRECAUTIONS, Drug Interactions .) Ciprofloxacin extended-release tablets 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 extended-release tablets may be taken with a meal that contains these products. (See CLINICAL PHARMACOLOGY, Drug-drug Interactions, DOSAGE AND ADMINISTRATION, and PRECAUTIONS, Drug Interactions .)
• if the patient should forget to take ciprofloxacin extended-release tablets at the usual time, he/she may take the dose later in the day. Do not take more than one ciprofloxacin extended-release tablet per day even if a patient misses a dose. Swallow the ciprofloxacin extended-release tablet whole. DO NOT SPLIT, CRUSH, OR CHEW THE TABLET.
• that ciprofloxacin may be associated with hypersensitivity reactions, even following a single dose, and to discontinue ciprofloxacin extended-release tablets at the first sign of a skin rash or other allergic reaction.
• that photosensitivity/phototoxicity has been reported in patients receiving quinolones. Patients should minimize or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) while taking quinolones. If patients need to be outdoors while using quinolones, they should wear loose-fitting clothes that protect skin from sun exposure and discuss other sun protection measures with their physician. If a sunburn-like reaction or skin eruption occurs, patients should contact their physician.
• that peripheral neuropathies have been associated with ciprofloxacin use. If symptoms of peripheral neuropathy including pain, burning, tingling, numbness and/or weakness develop, they should discontinue treatment and contact their physicians.
• that ciprofloxacin extended-release tablets may cause dizziness and lightheadedness; therefore, patients should know how they react to this drug before they operate an automobile or machinery or engage in activities requiring mental alertness or coordination.
• that ciprofloxacin increases the effects of tizanidine (Zanaflex®). Patients should not use ciprofloxacin if they are already taking tizanidine.
• that ciprofloxacin extended-release tablets may increase the effects of theophylline and caffeine. There is a possibility of caffeine accumulation when products containing caffeine are consumed while taking quinolones.
• that convulsions have been reported in patients receiving quinolones, including ciprofloxacin, and to notify their physician before taking ciprofloxacin extended-release tablets if there is a history of this condition.
• that diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.