Ciprofloxacin

Ciprofloxacin extended-release tablets are available in 500 mg and 1000 mg (ciprofloxacin equivalent) tablet strengths. Ciprofloxacin extended-release tablets are white, film-coated, oval-shaped tablets. Each ciprofloxacin extended-release 500 mg tablet contains 500 mg of ciprofloxacin* as ciprofloxacin HCl (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 HCl (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, crospovidine, D&C Yellow #10, hydrogenated vegetable oil, lactitol, magnesium stearate, microcrystalline cellulose, and succinic acid. The coating contains: hypromellose, maltodextrin, polydextrose, polyethylene glycol, 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 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).

§ median (range)
Results of the pharmacokinetic studies demonstrate that ciprofloxacin extended-release tablets may be administered with or without food (for example, 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 tablets. 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. Coadministration 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 .)

Patients with Renal Impairment

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 equal to or below 30 mL/min. (See DOSAGE AND ADMINISTRATION.)

Patients with Hepatic Impairment

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 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 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 .)

MICROBIOLOGY

Mechanism of Action

The bactericidal action of ciprofloxacin results from inhibition of the enzymes topoisomerase II (DNA gyrase) and topoisomerase IV (both Type II topoisomerases), which are required for bacterial DNA replication, transcription, repair, and recombination.

Mechanism of Resistance

The mechanism of action of fluoroquinolones, including ciprofloxacin, is different from that of other antimicrobial agents such as beta-lactams, macrolides, tetracyclines, or aminoglycosides; therefore, microorganisms resistant to these classes of drugs may be susceptible to ciprofloxacin. Resistance to fluoroquinolones occurs primarily by either mutations in the DNA gyrases, decreased outer membrane permeability, or drug efflux. In vitro resistance to ciprofloxacin develops slowly by multiple step mutations. Resistance to ciprofloxacin due to spontaneous mutations occurs at a general frequency of between < 10^-9 to 1x10^-6.

There is no known cross-resistance between ciprofloxacin and other classes of antimicrobials.

Ciprofloxacin has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section of the package insert for ciprofloxacin extended-release tablets.

Gram-positive bacteria

Enterococcus faecalis (vancomycin-susceptible isolates only)

Staphylococcus saprophyticus

Gram-negative bacteria

Escherichia coli

Klebsiella pneumoniae

Proteus mirabilis

Pseudomonas aeruginosa

The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for ciprofloxacin (≤1 mcg/mL). However, the efficacy of ciprofloxacin in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials.

Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment.

• • Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method (broth and/or agar).^{1, 3} The MIC values should be interpreted according to criteria provided in Table 1.
• • Diffusion Techniques: Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method.^{2, 3} This procedure uses paper disks impregnated with 5 mcg ciprofloxacin to test the susceptibility of bacteria to ciprofloxacin. The disc diffusion interpretive criteria are provided in Table 1.

A report of “Susceptible” indicates that antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations at the site of infection necessary to inhibit growth of the pathogen. 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 that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected.

• • Quality Control: Standardized susceptibility test procedures require the use of laboratory controls to monitor the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test.^{1, 2} Standard ciprofloxacin powder should provide the following range of MIC values noted in Table 2. For the diffusion technique using the ciprofloxacin 5 mcg disk the criteria in Table 2 should be achieved.

CIPROFLOXACIN INDICATIONS AND USAGE

Ciprofloxacin extended-release tablets are indicated only for the treatment of urinary tract infections, including acute uncomplicated pyelonephritis, caused by susceptible isolates 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, vancomycin-susceptible Enterococcus faecalis, or Staphylococcus saprophyticus.

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

Acute Uncomplicated Pyelonephritis caused by Escherichia coli.

^*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.

CIPROFLOXACIN 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

Tendinopathy and Tendon Rupture

Fluoroquinolones, including ciprofloxacin extended-release tablets, are associated with an increased risk of tendinitis and tendon rupture in all ages. This adverse reaction most frequently involves the Achilles tendon, and rupture of the Achilles tendon may require surgical repair. Tendinitis and tendon rupture in the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendon sites have also been reported. The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is further increased in older patients usually over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. Factors, in addition to age and corticosteroid use, that may independently increase the risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disorders such as rheumatoid arthritis. Tendinitis and tendon rupture have also occurred in patients taking fluoroquinolones who do not have the above risk factors. Inflammation and tendon rupture can occur, sometimes bilaterally, even within the first 48 hours, during or after completion of therapy; cases occurring up to several months after completion of therapy have been reported. Ciprofloxacin extended-release tablets should be used with caution in patients with a history of tendon disorders. Ciprofloxacin extended-release tablets should be discontinued if the patient experiences pain, swelling, inflammation or rupture of a tendon. Patients should be advised to rest at the first sign of tendinitis or tendon rupture, and to contact their healthcare provider regarding changing to a non-quinolone antimicrobial drug.

Exacerbation of Myasthenia Gravis

Fluoroquinolones, including ciprofloxacin extended-release tablets, have neuromuscular blocking activity and may exacerbate muscle weakness in persons with myasthenia gravis. Postmarketing serious adverse events, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in persons with myasthenia gravis. Avoid ciprofloxacin extended-release tablets in patients with known history of myasthenia gravis. (See PRECAUTIONS: Information for Patients and ADVERSE REACTIONS: Post-Marketing Adverse Event Reports ).

Pregnant Women

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

Hypersensitivity Reactions:

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

Other Serious and Sometimes Fatal Reactions

Other serious and sometimes fatal events, some due to hypersensitivity, and some due to uncertain etiology, have been reported rarely in patients receiving therapy with quinolones, including ciprofloxacin. These events may be severe and generally occur following the administration of multiple doses. Clinical manifestations may include one or more of the following:

• •Fever, rash, or severe dermatologic reactions (for example, toxic epidermal necrolysis, Stevens-Johnson syndrome);
• •Vasculitis; arthralgia; myalgia; serum sickness;
• •Allergic pneumonitis;
• •Interstitial nephritis; acute renal insufficiency or failure;
• •Hepatitis; jaundice; acute hepatic necrosis or failure;
• •Anemia, including hemolytic and aplastic; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; agranulocytosis; pancytopenia; and/or other hematologic abnormalities.

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

Hepatobiliary System

Cases of sever hepatotoxicity, including hepatic necrosis, life-threatening hepatic failure, and fatal events, have been reported with ciprofloxacin. Acute liver injury is rapid in onset (range 1 to 39 days), and is often associated with hypersensitivity. The pattern of injury can be hepatocellular, cholestatic or mixed. Most patients with fatal outcomes were older than 55 years old. In the event of any signs and symptoms of hepatitis (such as anorexia, jaundice, dark urine, pruritus, or tender abdomen), treatment should be discontinued immediately (see ADVERSE REACTIONS ).

There can be a temporary increase in transaminases, alkaline phosphatase, or cholestatic jaundice, especially in patients with previous liver damage, who are treated with ciprofloxacin (see ADVERSE REACTIONS ).

Theophylline

SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED IN PATIENTS RECEIVING CONCURRENT ADMINISTRATION OF INTRAVENOUS CIPROFLOXACIN AND THEOPHYLLINE. These reactions have included cardiac arrest, seizure, status epilepticus, and respiratory failure. Although similar serious adverse events 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.

Central Nervous System Effects

Convulsions, increased intracranial pressure (including pseudotumor cerebri), and toxic psychosis have been reported in patients receiving fluoroquinolones, including ciprofloxacin. Ciprofloxacin may also cause central nervous system (CNS) events including: dizziness, confusion, tremors, hallucinations, depression, and, rarely, psychotic reactions have progressed to suicidal ideations/thoughts and self-injurious behavior such as attempted or completed suicide. These reactions may occur following the first dose. If these reactions occur in patients receiving ciprofloxacin, the drug should be discontinued, patients should be advised to inform their healthcare provider immediately and appropriate measures instituted. As with all fluoroquinolones, ciprofloxacin should be used with caution in epileptic patients and patients with known or suspected CNS disorders that may predispose to seizures or lower the seizure threshold (e.g., severe cerebral arteriosclerosis, previous history of convulsion, reduced cerebral blood flow, altered brain structure, or stroke), 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). Ciprofloxacin extended-release tablets should only be used where the benefits of treatment exceed the risks, since these patients are endangered because of possible undesirable CNS side effects. Cases of status epilepticus have been reported. If seizures occur, ciprofloxacin should be discontinued. (See PRECAUTIONS: General, Information for Patients, Drug Interactions and ADVERSE REACTIONS .)

Clostridium Difficile Associated Diarrhea

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including ciprofloxacin immediate-release tablets, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing isolates of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Peripheral Neuropathy

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 fluoroquinolones, including ciprofloxacin. Symptoms may occur soon after initiation of ciprofloxacin and may be irreversible. Ciprofloxacin should be discontinued immediately if the patient experiences symptoms of peripheral neuropathy including pain, burning, tingling, numbness, and/or weakness, or other alterations in sensations including light touch, pain, temperature, position sense or vibratory sensation.

Musculoskeletal Disorders in Pediatric Patients and Arthropathic Effects in Animals

Ciprofloxacin should be used in pediatric patients (less than 18 years of age) only for infections listed in the INDICATIONS AND USAGE section. An increased incidence of adverse events compared to controls, including events related to joints and/or surrounding tissues, has been observed. (See ADVERSE REACTIONS .)

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 .)

Prolongation of the QT Interval

Some fluoroquinolones, including ciprofloxacin, have been associated with prolongation of the QT interval on the electrocardiogram and infrequent cases of arrhythmia. Rare cases of torsade de pointes have been spontaneously reported during postmarketing surveillance in patients receiving fluoroquinolones, including ciprofloxacin. Ciprofloxacin should be avoided in patients with known prolongation of the QT interval, risk factors for QT prolongation or torsade de pointes (for example, congenital long QT syndrome , uncorrected electrolyte imbalance, such as hypokalemia or hypomagnesemia and cardiac disease, such as heart failure, myocardial infarction, or bradycardia), and patients receiving Class IA antiarrhythmic agents (quinidine, procainamide), or Class III antiarrhythmic agents (amiodarone, sotalol) , tricyclic antidepressants, macrolides, and antipsychotics. Elderly patients may also be more susceptible to drug-associated effects on the QT interval. (See PRECAUTIONS, Drug Interactions and Geriatric Use ).

Cytochrome P450 (CYP450)

Ciprofloxacin is an inhibitor of the hepatic CYP1A2 enzyme pathway. Coadministration of ciprofloxacin and other drugs primarily metabolized by CYP1A2 (for example, theophylline, methylxanthines, caffeine, tizanidine, ropinirole, clozapine, olanzapine) results in increased plasma concentrations of the coadministered drug and could lead to clinically significant pharmacodynamic side effects of the coadministered drug. (See PRECAUTIONS, Drug Interactions .)

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 .)

Photosensitivity/Phototoxicity

Moderate to severe photosensitivity/phototoxicity reactions, the latter of which may manifest as exaggerated sunburn reactions (for example, burning, erythema, exudation, vesicles, blistering, edema) involving areas exposed to light (typically the face, “V” area of the neck, extensor surfaces of the forearms, dorsa of the hands), can be associated with the use of quinolones after sun or UV light exposure. Therefore, excessive exposure to these sources of light should be avoided. Drug therapy should be discontinued if phototoxicity occurs(see ADVERSE REACTIONS ).

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:

• •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 are prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by ciprofloxacin 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, polymeric phosphate binders (for example, sevelamer, lanthanum carbonate) 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, that symptoms may occur soon after initiation of therapy and may be irreversible. If symptoms of peripheral neuropathy including pain, burning, tingling, numbness and/or weakness develop, they should immediately discontinue ciprofloxacin and contact their physician.
• •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.

Drug Interactions

Tizanidine

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. (See CONTRAINDICATIONS .)

Theophylline

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.

Other Xanthine Derivatives

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. On concurrent administration of ciprofloxacin and caffeine or pentoxifylline (oxpentifylline) containing products, elevated serum concentrations of these xanthine derivatives were reported.

Chelation Complex Formation

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.

Omeprazole

Concomitant administration of a single tablet dose of 500 mg ciprofloxacin and once-daily administration of 20 mg omeprazole pretreatment for 4 days resulted in a 16% reduction of mean C_max and mean AUC of ciprofloxacin (See CLINICAL PHARMACOLOGY, Drug-drug Interactions .)

Phenytoin

Altered serum levels of phenytoin (increased and decreased) have been reported in patients receiving concomitant ciprofloxacin. To avoid the loss of seizure control associated with decreased phenytoin levels, and to prevent phenytoin overdose-related undesirable effects when ciprofloxacin is discontinued in patients receiving both agents, monitoring of phenytoin therapy, including phenytoin serum concentration measurements, is recommended during and shortly after coadministration of ciprofloxacin extended-release tablets with phenytoin.

Oral Antidiabetic Agents

Hypoglycemia has been reported when ciprofloxacin and oral antidiabetic agents, mainly sulfonylureas (for example, glyburide, glimepiride), were coadministered, presumably by intensifying the action of the oral antidiabetic agent (see ADVERSE REACTIONS ). The concomitant administration of ciprofloxacin with glyburide has, on rare occasions, resulted in severe hypoglycemia.

Metronidazole

The serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs were given concomitantly.

Cyclosporine

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

Oral Anticoagulants

Simultaneous administration of ciprofloxacin with an oral anticoagulantmay augment the effect of the anticoagulant. The risk may vary with the underlying infection, age and general status of the patient so that the contribution of ciprofloxacin to the increase in INR (international normalized ratio) is difficult to assess. Prothrombin time and INR should be monitored frequently during and shortly after coadministration of ciprofloxacin with an oral anticoagulant (for example, warfarin).

Probenecid

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.

Methotrexate

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

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.

Duloxetine

In clinical studies it was demonstrated that concomitant use of duloxetine with strong inhibitors of the CYP450 1A2 isozyme such as fluvoxamine, may result in a 5-fold increase of mean AUC and a 2.5-fold increase in mean C_max of duloxetine. Although no clinical data are available on a possible interaction with ciprofloxacin, similar effects can be expected upon concomitant administration.

NSAIDs

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.

Ropinirole

In a study conducted in 12 patients with Parkinson’s disease who were administered 6 mg ropinirole once daily with 500 mg ciprofloxacin twice-daily, the mean C_max and mean AUC of ropinirole were increased by 60% and 84%, respectively. Monitoring for ropinirole-related side effects and appropriate dose adjustment of ropinirole is recommended during and shortly after coadministration with ciprofloxacin. (See WARNINGS, Cytochrome P450 .)

Lidocaine

In a study conducted in 9 healthy volunteers, concomitant use of 1.5 mg/kg IV lidocaine with 500 mg ciprofloxacin twice daily, resulted in an increase of lidocaine C_max and AUC by 12% and 26%, respectively. Although lidocaine treatment was well tolerated at this elevated exposure, a possible interaction with ciprofloxacin and an increase in side effects related to lidocaine may occur upon concomitant administration.

Clozapine

Following concomitant administration of 250 mg ciprofloxacin with 304 mg clozapine for 7 days, serum concentrations of clozapine and N-desmethylclozapine were increased by 29% and 31%, respectively. Careful monitoring of clozapine associated adverse effects and appropriate adjustment of clozapine dosage during and shortly after coadministration with ciprofloxacin are advised. (See WARNINGS.)

Sildenafil

Following concomitant administration of a single oral dose of 50 mg sildenafil with 500 mg ciprofloxacin to healthy subjects, the mean C_max and mean AUC of sildenafil were both increased approximately two-fold. Therefore, sildenafil should be used with caution when coadministered with ciprofloxacin.

Drugs known to prolong QT interval

Precaution should be taken when using ciprofloxacin concomitantly with drugs known to prolong the QT interval (for example, class IA or III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics) as ciprofloxacin may have an additive effect on the QT interval (see WARNINGS and PRECAUTIONS, Geriatric Use ).

Carcinogenesis, Mutagenesis, Impairment of Fertility:

Eight in vitro mutagenicity tests have been conducted with ciprofloxacin, and the test results are listed below:

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

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 to 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 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 to 5%). Rates of spontaneous abortions, prematurity and low birth weight did not differ between the groups and there were no clinically significant musculoskeletal dysfunctions up to one year of age in the ciprofloxacin exposed children.

Another prospective follow-up study reported on 549 pregnancies with fluoroquinolone exposure (93% first trimester exposures). 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 risk of serious adverse reactions (including articular damage) 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

Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as ciprofloxacin extended-release tablets. This risk is further increased in patients receiving concomitant corticosteroid therapy. Tendinitis or tendon rupture can involve the Achilles, hand, shoulder, or other tendon sites and can occur during or after completion of therapy; cases occurring up to several months after fluoroquinolone treatment have been reported. Caution should be used when prescribing ciprofloxacin extended-release tablets to elderly patients especially those on corticosteroids. Patients should be informed of this potential side effect and advised to discontinue ciprofloxacin extended-release tablets and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur (See BOXED WARNING, WARNINGS, and ADVERSE REACTIONS ).

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 .)

In general, elderly patients may be more susceptible to drug-associated effects on the QT interval. Therefore, precaution should be taken when using ciprofloxacin extended-release tablets with concomitant drugs that can result in prolongation of the QT interval (for example, class IA or class III antiarrhythmics) or in patients with risk factors for torsade de pointes (for example, known QT prolongation, uncorrected hypokalemia).

CIPROFLOXACIN 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 tablet 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 tablet arm and in 2.3% (12/518) of patients in the control arm. The most common reasons for discontinuation in the ciprofloxacin extended-release tablet 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 tablet 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 tablet 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: convulsive seizures (including status epilepticus) abnormal dreams, depersonalization, depression (potentially culminating in self-injurious behavior, such as suicidal ideations/thoughts and attempted or completed suicide), hypertonia, incoordination, insomnia, somnolence, tremor, vertigo

METABOLIC: hyperglycemia, hypoglycemia

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, acute generalized exanthematous pustulosis (AGEP), 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, International Normalized Ratio (INR) increased (in patients treated with Vitamin K antagonists), 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 that may be irreversible, 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, QT prolongation, twitching, unresponsiveness, urethral bleeding, urinary retention, urination (frequent), uveitis, 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, urinary pH and acidify, if required, to prevent crystalluria 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 to 14 days after dosing.

CIPROFLOXACIN 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, polymeric phosphate binders (for example, sevelamer, lanthanum carbonate), 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. The use of ciprofloxacin 1000 mg extended-release tablets are not recommended in this patient population.

For patients on hemodialysis or peritoneal dialysis, administer ciprofloxacin extended-release tablets after the dialysis procedure is completed (maximum dose should be ciprofloxacin 500 mg extended-release tablets q 24 h). The use of ciprofloxacin 1000 mg extended-release tablets are not recommended in this patient population. (See CLINICAL PHARMACOLOGY, Special Populations, and PRECAUTIONS, Geriatric Use .)

For patients on continuous ambulatory peritoneal dialysis (CAPD), the maximum dose should be 500 mg q 24h.

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 .)

Children and Adolescents

Dosing in children (less than 18 years of age) with impaired renal or hepatic function has not been studied.

HOW SUPPLIED

Ciprofloxacin Extended-Release Tablets are available as white film-coated, oval-shaped tablets containing 500 mg or 1000 mg ciprofloxacin. The 500 mg tablet is engraved with “ANCHEN 107” on one side and plain on the other side. The 1000 mg tablet is engraved with “ANCHEN 108” on one side and plain on the other side. They are available as follow:

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

ANIMAL PHARMACOLOGY

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

Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory animals dosed with ciprofloxacin. This is primarily related to the reduced solubility of ciprofloxacin under alkaline conditions, which predominate in the urine of test animals; in man, crystalluria is rare since human urine is typically acidic. In rhesus monkeys, crystalluria without nephropathy has been noted after single oral doses as low as 5 mg/kg (approximately 0.1-times the highest recommended therapeutic dose based upon mg/m². After 6 months of intravenous dosing at 10 mg/kg/day, no nephropathological changes were noted; however, nephropathy was observed after dosing at 20 mg/kg/day for the same duration (approximately 0.4 times the highest recommended therapeutic dose based upon mg/m²).

In dogs, ciprofloxacin administered at 3 and 10 mg/kg by rapid infusion injection (15 sec.) produces hypotensive effects. These effects are considered to be related to histamine release because they are partially antagonized by pyrilamine, an antihistamine. In rhesus monkeys, rapid infusion injection also produces hypotension, but the effect in this species is inconsistent and less pronounced. In mice, concomitant administration of nonsteroidal anti-inflammatory drugs such as phenylbutazone and indomethacin with quinolones has been reported to enhance the CNS stimulatory effect of quinolones.

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

CLINICAL STUDIES

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 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 to 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 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 tablet 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 tablet 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%) versus 156/248 (62.9%) in ciprofloxacin extended-release tablet and control arm, respectively [97.5% CI* (-13.5%, 5.7%)]. Clinical cure was 184/271 (67.9%) for ciprofloxacin extended-release tablet 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 tablet and control arm, respectively [97.5% CI* (-26.8%, 6.5%)]. Clinical cure at TOC was 50/71 (70.4%) for ciprofloxacin extended-release tablet 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 tablet minus control).

In the Per Protocol population, the differences between ciprofloxacin extended-release tablet 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 tablet arm than in the control arm. For AUP patients, the bacteriologic eradication rate was lower in the ciprofloxacin extended-release tablet 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 tablet and the control arm, respectively.

The bacterial eradication and clinical cure rates by infection type for ciprofloxacin extended-release tablet and the control arm at the TOC visit and their corresponding 97.5% confidence intervals for the differences between rates (ciprofloxacin extended-release tablet 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 tablet 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. Clinical Laboratory Standards, Methods for Dilution Antimicrobial Susceptibility Tests for Bactera That Grow Aerobically; Approved Standard - 9^th Edition. CLSI Document M7-A7, CLSI, 950 West Valley Rd., Suite 2500, Wayne, PA, January, 2010.

2. CLSI. Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard - 11^th Edition. CLSI Document M2-A11, CLSI, Wayne, PA, January, 2012.

3. CLSI. Performance Standards for Antimicrobial Susceptibility Testing; 22^nd Informational Supplement CLSI Document M100 S22, January, 2012.

MEDICATION GUIDE

Ciprofloxacin Extended-Release Tablets

Read the Medication Guide that comes with ciprofloxacin extended-release tablets before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or your treatment.

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

Ciprofloxacin belongs to a class of antibiotics called fluoroquinolones. Ciprofloxacin can cause side effects that may be serious or even cause death. If you get any of the following serious side effects, get medical help right away. Talk with your healthcare provider about whether you should continue to take ciprofloxacin extended-release tablets.

1.Tendon rupture or swelling of the tendon (tendinitis)

• • Tendon problems can happen in people of all ages who take ciprofloxacin. Tendons are tough cords of tissue that connect muscles to bones. Symptoms of tendon problems may include:
• •Pain, swelling, tears and inflammation of tendons including the back of the ankle (Achilles), shoulder, hand, or other tendon sites.
• •The risk of getting tendon problems while you take ciprofloxacin extended-release tablets is higher if you:
• •Are over 60 years of age
• •Are taking steroids (corticosteroids)
• •Have had a kidney, heart or lung transplant
• • Tendon problems can happen in people who do not have the above risk factors when they take ciprofloxacin. Other reasons that can increase your risk of tendon problems can include:
• •Physical activity or exercise
• •Kidney failure
• •Tendon problems in the past, such as in people with rheumatoid arthritis (RA)
• • Call your healthcare provider right away at the first sign of tendon pain, swelling or inflammation. Stop taking ciprofloxacin extended-release tablets until tendinitis or tendon rupture has been ruled out by your healthcare provider. Avoid exercise and using the affected area. The most common area of pain and swelling is the Achilles tendon at the back of your ankle. This can also happen with other tendons.
• • Talk to your healthcare provider about the risk of tendon rupture with continued use of ciprofloxacin extended-release tablets. You may need a different antibiotic that is not a fluoroquinolone to treat your infection.
• • Tendon rupture can happen while you are taking or after you have finished taking ciprofloxacin extended-release tablets. Tendon ruptures have happened up to several months after patients have finished taking their fluoroquinolone.
• • Get medical help right away if you get any of the following signs or symptoms of a tendon rupture:
• •Hear or feel a snap or pop in a tendon area
• •Bruising right after an injury in a tendon area
• •Unable to move the affected area or bear weight

2.Worsening of myasthenia gravis (a disease which causes muscle weakness). Fluoroquinolones like ciprofloxacin extended-release tablets may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Call your healthcare provider right away if you have any worsening muscle weakness or breathing problems.

See the section “What are the possible side effects of ciprofloxacin extended-release tablets?” for more information about side effects.

What are ciprofloxacin extended-release tablets?

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

It is not known if ciprofloxacin extended-release tablets are safe and works in children under 18 years of age.

Sometimes infections are caused by viruses rather than by bacteria. Examples include viral infections in the sinuses and lungs, such as the common cold or flu. Antibiotics, including ciprofloxacin, do not kill viruses.

Call your healthcare provider if you think your condition is not getting better while you are taking ciprofloxacin extended-release tablets.

Who should not take ciprofloxacin extended-release tablets?

Do not take ciprofloxacin extended-release tablets if you:

• •Have ever had a severe allergic reaction to an antibiotic known as a fluoroquinolone, or are allergic to any of the ingredients in ciprofloxacin extended-release tablets. Ask your healthcare provider if you are not sure. See the list of ingredients in ciprofloxacin extended-release tablets at the end of this Medication Guide.
• •Also take a medicine called tizanidine (Zanaflex^®). Serious side effects from tizanidine are likely to happen.

What should I tell my healthcare provider before taking ciprofloxacin extended-release tablets?
See “What is the most important information I should know about ciprofloxacin?”

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

• •Have tendon problems.
• •Have a disease that causes muscle weakness (myasthenia gravis).
• •Have central nervous system problems (such as epilepsy).
• •Have nerve problems.
• •Have or anyone in your family has an irregular heartbeat, especially a condition called “QT prolongation”.
• •Have a history of seizures.
• •Have kidney problems. You may need a lower dose of ciprofloxacin extended-release tablets if your kidneys do not work well.
• •Have rheumatoid arthritis (RA) or other history of joint problems.
• •Have trouble swallowing pills.
• •Are pregnant or planning to become pregnant. It is not known if ciprofloxacin extended-release tablets will harm your unborn child.
• •Are breast-feeding or planning to breast-feed. Ciprofloxacin passes into breast milk. You and your healthcare provider should decide whether you will take ciprofloxacin extended-release tablets or breast-feed.

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal and dietary supplements. Ciprofloxacin extended-release tablets and other medicines can affect each other causing side effects. Especially tell your healthcare provider if you take:

• •An NSAID (Non-Steroidal Anti-Inflammatory Drug). Many common medicines for pain relief are NSAIDs. Taking an NSAID while you take ciprofloxacin extended-release tablets or other fluoroquinolones may increase your risk of central nervous system effects and seizures. See “What are the possible side effects of ciprofloxacin extended-release tablets?”
• •A blood thinner (such as warfarin, Coumadin^®, Jantoven^®).
• •Tizanidine (Zanaflex^®). You should not take ciprofloxacin extended-release tablets if you are already taking tizanidine. See “Who should not take ciprofloxacin extended-release tablets?”
• •Theophylline (such as Theo-24^®, Elixophyllin^®, Theochron^®, Uniphyl^®, Theolair^®).
• •Glyburide (Micronase^®, Glynase^®, Diabeta^®, Glucovance^®). See “What are the possible side effects of ciprofloxacin extended-release tablets?”
• •Phenytoin (Fosphenytoin Sodium^®, Cerebyx^®, Dilantin-125^®, Dilantin^®, Extended Phenytoin Sodium^®, Prompt Phenytoin Sodium^®, Phenytek^®).
• •Products that contain caffeine.
• •A medicine to control your heart rate or rhythm (antiarrhythmics) See “What are the possible side effects of ciprofloxacin extended-release tablets?”
• •An anti-psychotic medicine.
• •A tricyclic antidepressant.
• •A water pill (diuretic).
• •A steroid medicine. Corticosteroids taken by mouth or by injection may increase the chance of tendon injury. See “What is the most important information I should know about ciprofloxacin?”
• •Methotrexate (Trexall^®).
• •Probenecid (Probalan^®, Col-probenecid^®).
• •Metoclopromide (Reglan^®, Reglan ODT^®).
• •Ropinirole (Requip^®).
• •Lidocaine (Xylocaine^® intravenous infusion).
• •Clozapine (Clozaril^®, Fazaclo^® ODT^®).
• •Pentoxifylline (Trental^®).
• •Sildenafil (Viagra^®, Revatio^®).
• •Cyclosporine (Gengraf^®, Neoral^®, Sandimmune^®, Sangcya^®).
• •Omeprazole.
• •Certain medicines may keep Ciprofloxacin Tablets, Ciprofloxacin Oral Suspension from working correctly. Take Ciprofloxacin Tablets and Oral Suspension either 2 hours before or 6 hours after taking these products:
• •An antacid, multivitamin, or other product that has magnesium, calcium, aluminum, iron, or zinc.
• •Sucralfate (Carafate^®).
• •Didanosine (Videx^®, Videx EC^®).

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

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

How should I take ciprofloxacin extended-release tablets?

• •Take ciprofloxacin extended-release tablets exactly as prescribed by your healthcare provider.
• •Take ciprofloxacin extended-release tablets one time each day at about the same time each day. Swallow the tablet whole. Do not split, crush or chew the tablet. Tell your healthcare provider if you cannot swallow the tablet whole.
• •Ciprofloxacin extended-release tablets can be taken with or without food.
• •Ciprofloxacin extended-release tablets should not be taken with dairy products (like milk or yogurt) or calcium-fortified juices alone, but may be taken with a meal that contains these products.
• •Drink plenty of fluids while taking ciprofloxacin extended-release tablets.
• •Do not skip any doses, or stop taking ciprofloxacin extended-release tablets even if you begin to feel better, until you finish your prescribed treatment, unless:
• •You have tendon effects (see “What is the most important information I should know about ciprofloxacin extended-release tablets?”),
• •You have a serious allergic reaction (see “What are the possible side effects of ciprofloxacin extended-release tablets?”), or
• •Your healthcare provider tells you to stop.

This will help make sure that all of the bacteria are killed and lower the chance that the bacteria will become resistant to ciprofloxacin. If this happens, ciprofloxacin extended-release tablets and other antibiotic medicines may not work in the future.

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

What should I avoid while taking ciprofloxacin extended-release tablets?

• •Ciprofloxacin extended-release tablets can make you feel dizzy and lightheaded. Do not drive, operate machinery, or do other activities that require mental alertness or coordination until you know how ciprofloxacin extended-release tablets affect you.
• •Avoid sunlamps, tanning beds, and try to limit your time in the sun. Ciprofloxacin extended-release tablets can make your skin sensitive to the sun (photosensitivity) and the light from sunlamps and tanning beds. You could get severe sunburn, blisters or swelling of your skin. If you get any of these symptoms while taking ciprofloxacin extended-release tablets, call your healthcare provider right away. You should use a sunscreen and wear a hat and clothes that cover your skin if you have to be in sunlight.

What are the possible side effects of ciprofloxacin extended-release tablets?

Ciprofloxacin extended-release tablets can cause side effects that may be serious or even cause death. See “What is the most important information I should know about ciprofloxacin extended-release tablets?”

Other serious side effects of ciprofloxacin extended-release tablets include:

• • Theophylline

You may have serious seizure and breathing problems when you take theophylline with ciprofloxacin extended-release tablets. These problems may lead to death. Get emergency help right away if you have seizures or trouble breathing.

• • Central Nervous System Effects

Seizures have been reported in people who take fluoroquinolone antibiotics including ciprofloxacin. Tell your healthcare provider if you have a history of seizures. Ask your healthcare provider whether taking ciprofloxacin extended-release tablets will change your risk of having a seizure.

Central Nervous System (CNS) side effects may happen as soon as after taking the first dose of ciprofloxacin extended-release tablets. Talk to your healthcare provider right away if you get any of these side effects, or other changes in mood or behavior:

• •Feel dizzy
• •Seizures
• •Hear voices, see things, or sense things that are not there (hallucinations)
• •Feel restless
• •Tremors
• •Feel anxious or nervous
• •Confusion
• •Depression
• •Trouble sleeping
• •Nightmares
• •Feel more suspicious (paranoia)
• •Suicidal thoughts or acts
• •Serious allergic reactions

Allergic reactions, including death, can happen in people taking fluoroquinolones, including ciprofloxacin extended-release tablets, even after only one dose. Stop taking ciprofloxacin extended-release tablets and get emergency medical help right away if you get any of the following symptoms of a severe allergic reaction:

• •Hives.
• •Trouble breathing or swallowing.
• •Swelling of the lips, tongue, face.
• •Throat tightness, hoarseness.
• •Rapid heartbeat.
• •Faint.
• •Yellowing of the skin or eyes. Stop taking ciprofloxacin extended-release tablets and tell your healthcare provider right away if you get yellowing of your skin or white part of your eyes, or if you have dark urine. These can be signs of a serious reaction to ciprofloxacin (a liver problem).
• • Skin rash

Skin rash may happen in people taking ciprofloxacin extended-release tablets, even after only one dose. Stop taking ciprofloxacin extended-release tablets at the first sign of a skin rash and call your healthcare provider. Skin rash may be a sign of a more serious reaction to ciprofloxacin.

• • Serious heart rhythm changes (QT prolongation and torsade de pointes)

Tell your healthcare provider right away if you have a change in your heart beat (a fast or irregular heartbeat), or if you faint. Ciprofloxacin may cause a rare heart problem known as prolongation of the QT interval. This condition can cause an abnormal heartbeat and can be very dangerous. The chances of this event are higher in people:

• •Who are elderly
• •With a family history of prolonged QT interval
• •With low blood potassium (hypokalemia)
• •Who take certain medicines to control heart rhythm (antiarrhythmics)
• • Intestine infection (Pseudomembranous colitis)

Pseudomembranous colitis can happen with most antibiotics, including ciprofloxacin. Call your healthcare provider right away if you get watery diarrhea, diarrhea that does not go away, or bloody stools. You may have stomach cramps and a fever. Pseudomembranous colitis can happen 2 or more months after you have finished your antibiotic.

• • Changes in sensation and nerve damage (Peripheral Neuropathy)

Damage to the nerves in arms, hands, legs, or feet can happen in people who take fluoroquinolones, including ciprofloxacin. Stop ciprofloxacin and talk with your healthcare provider right away if you get any of the following symptoms of peripheral neuropathy in your arms, hands, legs, or feet: pain, burning, tingling, numbness, weakness. The nerve damage may be permanent.

• • Low blood sugar (hypoglycemia)

People who take ciprofloxacin extended-release tablets and other fluoroquinolone medicines with the oral anti-diabetes medicine glyburide (Micronase, Glynase, Diabeta, Glucovance) can get low blood sugar (hypoglycemia) which can sometimes be severe. Tell your healthcare provider if you get low blood sugar with ciprofloxacin. Your antibiotic medicine may need to be changed.

• • Sensitivity to sunlight (photosensitivity). See “What should I avoid while taking ciprofloxacin extended-release tablets?”
• • Joint Problems

Increased chance of problems with joints and tissues around joints in children under 18 years old. Tell your child’s healthcare provider if your child has any joint problems during or after treatment with ciprofloxacin extended-release tablets.

The most common side effects of ciprofloxacin extended-release tablets include:

• •Nausea
• •Diarrhea
• •Changes in liver function tests
• •Vomiting
• •Rash
• •Vaginal yeast infection
• •Pain or discomfort in the abdomen
• •Headache

These are not all the possible side effects of ciprofloxacin extended-release tablets. Tell your healthcare provider about any side effect that bothers you, or that does not go away.

To report SUSPECTED ADVERSE REACTIONS, contact Par Pharmaceutical, Inc. at 1-800-828-9393 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

How should I store ciprofloxacin extended-release tablets?

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

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

General Information about ciprofloxacin extended-release tablets

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ciprofloxacin extended-release tablets for a condition for which it is not prescribed. Do not give ciprofloxacin extended-release tablets to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about ciprofloxacin extended-release tablets. If you would like more information about ciprofloxacin extended-release tablets, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about ciprofloxacin extended-release tablets that is written for healthcare professionals.

What are the ingredients in ciprofloxacin extended-release tablets?

• • Active ingredient: ciprofloxacin
• • Inactive ingredients: colloidal silicon dioxide, crospovidine, D&C Yellow #10, hydrogenated vegetable oil, lactitol, magnesium stearate, microcrystalline cellulose, and succinic acid. The coating contains: hypromellose, maltodextrin, polydextrose, polyethylene glycol, titanium dioxide, and triacetin.

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

Rx Only

Manufactured by:

Par Pharmaceutical Companies, Inc.

Spring Valley, NY 10977

Issued: 07/13 OS107A-01-1-01

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL

NDC 10370-107-05
Ciprofloxacin
Extended-Release Tablets
500 mg
50-count, 100-count and 500-count