Cipro XR

Dosage Forms And Strengths

• 500 mg white to slightly yellowish, film-coated, oblong-shaped tablets imprinted with the word “BAYER” on one side and “C500 QD” on the other
• 1000 mg white to slightly yellowish, film-coated, oblong-shaped tablets imprinted the word “BAYER” on one side and “C1000 QD” on the other

Storage And Handling

CIPRO XR is available as nearly white to slightly yellowish, film-coated, oblong-shaped tablets containing 500 mg or 1000 mg ciprofloxacin. The 500 mg tablet is coded with the word “BAYER” on one side and “C500 QD” on the reverse side. The 1000 mg tablet is coded with the word “BAYER” on one side and “C1000 QD” on the reverse side.

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

Manufactured for: Bayer HealthCare Pharmaceuticals Inc. Whippany, NJ 07981. Manufactured in Germany. Revised: July 2016

CIPRO XR is indicated for the treatment of infections caused by susceptible isolates of the designated microorganisms in the conditions and patient populations listed below.

Uncomplicated Urinary Tract Infections (Acute Cystitis)

CIPRO XR is indicated for the treatment of uncomplicated urinary tract infections (UTIs) caused by Escherichia coli, Proteus mirabilis, Enterococcus faecalis, or Staphylococcus saprophyticus.

Because fluoroquinolones, including CIPRO XR, have been associated with serious adverse reactions and for some patients uncomplicated UTI (acute cystitis) is self-limiting, reserve CIPRO XR for treatment of uncomplicated UTIs (acute cystitis) in patients who have no alternative treatment options.

Complicated Urinary Tract Infections, And Acute Uncomplicated Pyelonephritis

CIPRO XR is indicated for the treatment of complicated urinary tract infections (cUTI) caused by Escherichia coli, Klebsiella pneumoniae, Enterococcus faecalis, Proteus mirabilis, or Pseudomonas aeruginosa and acute uncomplicated pyelonephritis (AUP) caused by Escherichia coli.

Limitations Of Use

• The safety and efficacy of CIPRO XR in treating infections other than urinary tract infections has not been demonstrated.
• CIPRO XR is not indicated for pediatric patients.

Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of CIPRO XR and other antibacterial drugs, CIPRO XR should be used only to treat 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.

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 CIPRO XR may be initiated before results of these tests are known; once results become available appropriate therapy should be continued.

As with other drugs, some isolates of Pseudomonas aeruginosa may develop resistance fairly rapidly during treatment with ciprofloxacin. Culture and susceptibility testing performed periodically during therapy will provide information not only on the therapeutic effect of the antimicrobial agent but also on the possible emergence of bacterial resistance.

Dosage

CIPRO XR and ciprofloxacin immediate-release tablets are not interchangeable. Cipro XR should beadministered orally once daily (Table 1).

Table 1: Dosage Guidelines

Patients whose therapy is started with CIPRO IV for UTIs may be switched to CIPRO XR when clinically indicated at the discretion of the physician.

Administration

• CIPRO XR tablets should be taken whole and not split, crushed, or chewed.
• CIPRO XR 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.
• Concomitant administration of Cipro XR with dairy products (like milk or yogurt) or with calcium-fortified products alone should be avoided since decreased absorption is possible. A 2-hour window between substantial calcium intake (greater than 800 mg) and dosing with CIPRO XR is recommended.
• Adequate hydration of patients receiving CIPRO XR should be maintained to prevent the formation of highly concentrated urine. Crystalluria has been reported with quinolones.

Impaired Renal Function

• In patients with cUTI and acute uncomplicated pyelonephritis with a creatinine clearance of ≤ 30 mL/min, the dose of CIPRO XR should be reduced from 1000 mg to 500 mg daily. The use of Ciprofloxacin 1000 mg XR tablets is not recommended in this patient population.
• For patients on hemodialysis or peritoneal dialysis, administer CIPRO XR after the dialysis procedure is completed (maximum dose should be Ciprofloxacin 500 mg XR every 24 hours). The use of Ciprofloxacin 1000 mg XR is not recommended in this patient population.
• For patients on continuous ambulatory peritoneal dialysis (CAPD), the maximum dose should be 500 mg every 24 hours.

Hypersensitivity

CIPRO XR is contraindicated in persons with a history of hypersensitivity to ciprofloxacin, any member of the quinolone class of antibacterials, or any of the product components.

Tizanidine

Concomitant administration with tizanidine is contraindicated.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Disabling And Potentially Irreversible Serious Adverse Reactions Including Tendinitis And Tendon Rupture, Peripheral Neuropathy, And Central Nervous System Effects

Fluoroquinolones, including CIPRO XR, have been associated with disabling and potentially irreversible serious adverse reactions from different body systems that can occur together in the same patient. Commonly seen adverse reactions include tendinitis, tendon rupture, arthralgia, myalgia, peripheral neuropathy, and central nervous system effects (hallucinations, anxiety, depression, insomnia, severe headaches, and confusion). These reactions can occur within hours to weeks after starting CIPRO XR. Patients of any age or without pre-existing risk factors have experienced these adverse reactions.

Discontinue CIPRO XR immediately at the first signs or symptoms of any serious adverse reaction. In addition, avoid the use of fluoroquinolones, including CIPRO XR, in patients who have experienced any of these serious adverse reactions associated with fluoroquinolones.

Tendinitis And Tendon Rupture

Fluoroquinolones, including CIPRO XR, have been associated with an increased risk of tendinitis and tendon rupture in all ages. This adverse reaction most frequently involves the Achilles tendon, and also been reported in the rotator cuff (the shoulder), the hand, the biceps, the thumb, and other tendons. Tendinitis and tendon rupture can occur within hours or days of starting CIPRO XR, or as long as several months after completion of fluoroquinolone therapy. Tendinitis and tendon rupture can occur bilaterally.

The risk of developing fluoroquinolone-associated tendinitis and tendon rupture is further increased in patients over 60 years of age, in patients taking corticosteroid drugs, and in patients with kidney, heart or lung transplants. Other factors 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.

Discontinue CIPRO XR immediately if the patient experiences pain, swelling, inflammation or rupture of a tendon. Avoid fluoroquinolones, including CIPRO XR, in patients who have a history of tendon disorders or have experienced tendinitis or tendon rupture.

Peripheral Neuropathy

Fluoroquinolones, including CIPRO XR, have been associated with an increased risk of 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 CIPRO XR. Symptoms may occur soon after initiation of CIPRO XR and may be irreversible in some patients.

Discontinue CIPRO XR 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 and vibratory sensation and/or motor strength in order to minimize the development of an irreversible condition. Avoid fluoroquinolones, including CIPRO, in patients who have previously experienced peripheral neuropathy

Central Nervous System Effects

Fluoroquinolones, including CIPRO XR, have been associated with an increased risk of central nervous system (CNS) effects, including convulsions, increased intracranial pressure (including pseudotumor cerebri), and toxic psychosis. CIPRO XR may also cause central nervous system (CNS) events including: nervousness, agitation, insomnia, anxiety, nightmares, paranoia, dizziness, confusion, tremors, hallucinations, depression, and psychotic reactions that have progressed to suicidal ideations/thoughts and self-injurious behavior such as attempted or completed suicide. These reactions may occur following the first dose. Advise patients receiving ciprofloxacin to inform their healthcare provider immediately if these reactions occur, discontinue the drug, and institute appropriate care. CIPRO XR, like other fluoroquinolones, is known to trigger seizures or lower the seizure threshold. As with all fluoroquinolones, use CIPRO XR with caution in epileptic patients and patients with known or suspected CNS disorders that may predispose to seizures or lower the seizure threshold (for example, 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 (for example., certain drug therapy, renal dysfunction). Use CIPRO XR when 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, discontinue CIPRO XR.

Exacerbation Of Myasthenia Gravis

Fluoroquinolones, including CIPRO XR, have neuromuscular blocking activity and may exacerbate muscle weakness in patients with myasthenia gravis. Postmarketing serious adverse reactions, including deaths and requirement for ventilatory support, have been associated with fluoroquinolone use in patients with myasthenia gravis. Avoid CIPRO XR in patients with known history of myasthenia gravis.

Other Serious And Sometimes Fatal Adverse Reactions

Other serious and sometimes fatal adverse reactions, some due to hypersensitivity, and some due to uncertain etiology, have been reported 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.

Discontinue CIPRO XR immediately at the first appearance of a skin rash, jaundice, or any other sign of hypersensitivity and supportive measures instituted.

Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving quinolone therapy, including CIPRO XR. 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 and other resuscitation measures, including oxygen, intravenous fluids, intravenous antihistamines, corticosteroids, pressor amines, and airway management, including intubation, as indicated.

Hepatotoxicity

Cases of severe hepatotoxicity, including hepatic necrosis, life-threatening hepatic failure, and fatal events, have been reported with CIPRO XR. Acute liver injury is rapid in onset (range 1–39 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), discontinue treatment immediately.

There can be a temporary increase in transaminases, alkaline phosphatase, or cholestatic jaundice, especially in patients with previous liver damage, who are treated with CIPRO XR.

Serious Adverse Reactions With Concomitant Theophylline Use

Serious and fatal reactions have been reported in patients receiving concurrent administration of CIPRO XR and theophylline. These reactions have included cardiac arrest, seizure, status epilepticus, and respiratory failure. Instances of nausea, vomiting, tremor, irritability, or palpitation have also occurred.

Although similar serious adverse reactions have been reported in patients receiving theophylline alone, the possibility that these reactions may be potentiated by CIPRO XR cannot be eliminated. If concomitant use cannot be avoided, monitor serum levels of theophylline and adjust dosage as appropriate.

Clostridium Difficile - Associated Diarrhea

Clostridium difficile (C. difficile)-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including CIPRO XR, 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 antibacterial 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 antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and institute surgical evaluation as clinically indicated.

Prolongation Of The QT Interval

Some fluoroquinolones, including CIPRO XR have been associated with prolongation of the QT interval on the electrocardiogram and cases of arrhythmia. Cases of torsade de pointes have been reported during postmarketing surveillance in patients receiving fluoroquinolones, including CIPRO XR.

Avoid CIPRO XR 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.

Musculoskeletal Disorders In Pediatric Patients And Arthropathic Effects in Animals

An increased incidence of adverse reactions compared to controls, including reactions related to joints and/or surrounding tissues, has been observed.

In pre-clinical studies, oral administration of CIPRO XR 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.

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 including CIPRO XR after sun or UV light exposure. Therefore, avoid excessive exposure to these sources of light. Discontinue CIPRO XR if phototoxicity occurs.

Development Of Drug Resistant Bacteria

Prescribing CIPRO XR 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.

Potential Risks With Concomitant Use Of Drugs Metabolized By Cytochrome P450 1A2 Enzymes

Ciprofloxacin is an inhibitor of the hepatic CYP1A2 enzyme pathway. Co-administration 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 co- administered drug and could lead to clinically significant pharmacodynamic adverse reactions of the co-administered drug.

Interference With Timely Diagnosis Of Syphilis

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

Crystalluria

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. Crystalluria related to ciprofloxacin has been reported only rarely in humans because human urine is usually acidic. Avoid alkalinity of the urine in patients receiving CIPRO XR. Hydrate patients well to prevent the formation of highly concentrated urine.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Serious Adverse Reactions

Advise patients to stop taking CIPRO XR if they experience an adverse reaction and to call their healthcare provider for advice on completing the full course of treatment with another antibacterial drug.

Inform patients of the following serious adverse reactions that have been associated with CIPRO XR or other fluoroquinolone use:

• Disabling and potentially irreversible serious adverse reactions that may occur together: Inform patients that disabling and potentially irreversible serious adverse reactions, including tendinitis and tendon rupture, peripheral neuropathies, and central nervous system effects, have been associated with use of CIPRO XR and may occur together in the same patient. Inform patients to stop taking CIPRO XR immediately if they experience an adverse reaction and to call their healthcare provider.
• Tendinitis and Tendon Rupture: Instruct patients 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 CIPRO XR treatment. Symptoms may be irreversible. 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.
• Peripheral Neuropathies: Inform patients that peripheral neuropathies have been associated with ciprofloxacin use, 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, immediately discontinue CIPRO XR and tell them to contact their physician.
• Central Nervous System Effects (for example, convulsions, dizziness, lightheadedness, increased intracranial pressure): Inform patients that convulsions have been reported in patients receiving fluoroquinolones, including ciprofloxacin. Instruct patients to notify their physician before taking this drug if they have a history of convulsions. Inform patients that they should know how they react to CIPRO XR before they operate an automobile or machinery or engage in other activities requiring mental alertness and coordination. Instruct patients to notify their physician if persistent headache with or without blurred vision occurs.
• Exacerbation of Myasthenia Gravis: Instruct patients to inform their physician of any history of myasthenia gravis. Instruct patients to notify their physician if they experience any symptoms of muscle weakness, including respiratory difficulties.
• Hypersensitivity Reactions: Inform patients that ciprofloxacin can cause hypersensitivity reactions, even following a single dose, and to discontinue the drug at the first sign of a skin rash, hives or other skin reactions, a rapid heartbeat, difficulty in swallowing or breathing, any swelling suggesting angioedema (for example, swelling of the lips, tongue, face, tightness of the throat, hoarseness), or other symptoms of an allergic reaction.
• Hepatotoxicity: Inform patients that severe hepatotoxicity (including acute hepatitis and fatal events) has been reported in patients taking CIPRO XR. Instruct patients to inform their physician if they experience any signs or symptoms of liver injury including: loss of appetite, nausea, vomiting, fever, weakness, tiredness, right upper quadrant tenderness, itching, yellowing of the skin and eyes, light colored bowel movements or dark colored urine.
• Diarrhea: 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, instruct patients to contact their physician as soon as possible.
• Prolongation of the QT Interval: Instruct patients to inform their physician of any personal or family history of QT prolongation or proarrhythmic conditions such as hypokalemia, bradycardia, or recent myocardial ischemia; if they are taking any Class IA (quinidine, procainamide), or Class III (amiodarone, sotalol) antiarrhythmic agents. Instruct patients to notify their physician if they have any symptoms of prolongation of the QT interval, including prolonged heart palpitations or a loss of consciousness.
• Musculoskeletal Disorders in Pediatric Patients: Instruct parents to inform their child’s physician if the child has a history of joint-related problems before taking this drug. Inform parents of pediatric patients to notify their child’s physician of any joint-related problems that occur during or following ciprofloxacin therapy.
• Tizanidine: Instruct patients not to use ciprofloxacin if they are already taking tizanidine. CIPRO XR increases the effects of tizanidine (Zanaflex®).
• Theophylline: Inform patients that ciprofloxacin CIPRO XR may increase the effects of theophylline. Life-threatening CNS effects and arrhythmias can occur. Advise the patients to immediately seek medical help if they experience seizures, palpitations, or difficulty breathing.
• Caffeine: Inform patients that CIPRO XR may increase the effects of caffeine. There is a possibility of caffeine accumulation when products containing caffeine are consumed while taking quinolones.
• Photosensitivity/Phototoxicity: Inform patients that photosensitivity/phototoxicity has been reported in patients receiving fluoroquinolones. Inform patients to 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, instruct them to 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, instruct patients to contact their physician.

Antibacterial Resistance

Inform patients that antibacterial drugs including CIPRO XR, CIPRO Tablets, and CIPRO Oral Suspension should only be used to treat bacterial infections. They do not treat viral infections (for example, the common cold). When CIPRO XR, CIPRO Tablets, and CIPRO Oral Suspension 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 CIPRO XR, CIPRO Tablets, and CIPRO Oral Suspension or other antibacterial drugs in the future.

Administration With Food, Fluids, And Concomitant Medications

Inform patients that CIPRO XR may be taken with or without food.

Inform patients to drink fluids liberally while taking CIPRO XR to avoid formation of a highly concentrated urine and crystal formation in the urine.

Inform patients that antacids containing magnesium, or aluminum, as well as sucralfate, metal cations such as iron, and multivitamin preparations with zinc or didanosine should be taken at least two hours before or six hours after CIPRO XR administration. CIPRO XR 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, CIPRO XR may be taken with a meal that contains these products

Drug Interactions Oral Antidiabetic Agents

Inform patients that hypoglycemia has been reported when ciprofloxacin and oral antidiabetic agents were co-administered; if low blood sugar occurs with CIPRO XR, instruct them to consult their physician and that their antibacterial medicine may need to be changed.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

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

• Salmonella/Microsome Test (Negative)
• E. coli DNA Repair Assay (Negative)
• Mouse Lymphoma Cell Forward Mutation Assay (Positive)
• Chinese Hamster V79 Cell HGPRT Test (Negative)
• Syrian Hamster Embryo Cell Transformation Assay (Negative)
• Saccharomyces cerevisiae Point Mutation Assay (Negative)
• Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative)
• Rat Hepatocyte DNA Repair Assay (Positive)

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

• Rat Hepatocyte DNA Repair Assay
• Micronucleus Test (Mice)
• Dominant Lethal Test (Mice)

Ciprofloxacin was not carcinogenic or tumorigenic in 2-year carcinogenicity studies with rats and mice at daily oral dose levels of 250 mg/kg 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 body surface area), as opposed to 34 weeks when animals were treated with both UVA and vehicle. The times to development of skin tumors ranged from 16–32 weeks in mice treated concomitantly with UVA and other quinolones.

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

Fertility studies performed in rats at oral doses of ciprofloxacin up to 100 mg/kg (1 times the highest recommended daily human dose of 1000 mg based upon body surface area) revealed no evidence ofimpairment.

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. CIPRO XR should not be used during pregnancy unless the potential benefit justifies the potential risk to both fetus and mother. An expert review of published data on experiences with ciprofloxacin use during pregnancy by TERIS–the Teratogen Information System concluded that therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk (quantity and quality of data=fair), but the data are insufficient to state that there is no risk.

A controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5% exposed to ciprofloxacin and 68% first trimester exposures) during gestation. In utero exposure to fluoroquinolones during embryogenesis was not associated with increased risk of major malformations. The reported rates of major congenital malformations were 2.2% for the fluoroquinolone group and 2.6% for the control group (background incidence of major malformations is 1–5%). Rates of spontaneous abortions, prematurity and low birth weight did not differ between the groups and there were no clinically significant musculoskeletal dysfunctions up to one year of age in the ciprofloxacin exposed children.

Another prospective follow-up study reported on 549 pregnancies with fluoroquinolone exposure (93% first trimester exposures). There were 70 ciprofloxacin exposures, all within the first trimester. The malformation rates among live-born babies exposed to ciprofloxacin and to fluoroquinolones overall were both within background incidence ranges. No specific patterns of congenital abnormalities were found. The study did not reveal any clear adverse reactions due to in utero exposure to ciprofloxacin.

No differences in the rates of prematurity, spontaneous abortions, or birth weight were seen in women exposed to ciprofloxacin during pregnancy. However, these small postmarketing epidemiology studies, of which most experience is from short term, first trimester exposure, are insufficient to evaluate the risk for the less common defects or to permit reliable and definitive conclusions regarding the safety of ciprofloxacin in pregnant women and their developing fetuses.

Reproduction studies have been performed in rats and mice using oral doses up to 100 mg/kg (0.6 and 0.3 times the maximum daily human dose of 1000 mg based upon body surface area, respectively) and have revealed no evidence of harm to the fetus due to ciprofloxacin. In rabbits, oral ciprofloxacin dose levels of 30 and 100 mg/kg (approximately 0.4-and 1.3-times the highest recommended therapeutic dose based upon body surface area) produced gastrointestinal toxicity resulting in maternal weight loss and an increased incidence of abortion, but no teratogenicity was observed at either dose level. After intravenous administration of doses up to 20 mg/kg (approximately 0.3-times the highest recommended therapeutic dose based upon body surface area), 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 CIPRO XR, 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 CIPRO XR in pediatric patients and adolescents less than 18 years of age have not been established. Ciprofloxacin causes arthropathy in juvenile animals. CIPRO XR is not indicated for pediatric patients.

Geriatric Use

Geriatric patients are at increased risk for developing severe tendon disorders including tendon rupture when being treated with a fluoroquinolone such as CIPRO XR. 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 CIPRO XR to elderly patients especially those on corticosteroids. Patients should be informed of this potential side effect and advised to discontinue CIPRO XR and contact their healthcare provider if any symptoms of tendinitis or tendon rupture occur.

In a large, prospective, randomized CIPRO XR clinical trial in cUTI, 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 other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals on any drug therapy cannot be ruled out. Ciprofloxacin is known to be substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. No alteration of dosage is necessary for patients greater than 65 years of age with normal renal function. However, since some older individuals experience reduced renal function by virtue of their advanced age, care should be taken in dose selection for elderly patients, and renal function monitoring may be useful in these patients .

In general, elderly patients may be more susceptible to drug-associated effects on the QT interval. Therefore, precaution should be taken when using CIPRO XR 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).

Renal Impairment

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 UTIs receiving 500 mg CIPRO XR. Dosing in children (less than 18 years of age) with impaired renal function has not been studied.

Hepatic Impairment

In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in ciprofloxacin pharmacokinetics have been observed.

SIDE EFFECTS

The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling:

• Disabling and Potentially Irreversible Serious Adverse Reactions
• Tenditits and Tendon Rupture
• Peripheral Neuropathy
• Central Nervous System Effects
• Exacerbation of Myasthenia Gravis
• Other Serious and Sometimes Fatal Adverse Reactions
• Hypersensitivity Reactions
• Hepatotoxicity
• Serious Adverse Reactions with Concomitant Theophylline
• Clostridium difficile-Associated Diarrhea
• Prolongation of the QT Interval
• Musculoskeletal Disorders in Pediatric Patients
• Photosensitivity/Phototoxicity
• Development of Drug Resistant Bacteria

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical trials in patients with urinary tract infections enrolled 961 patients treated with 500 mg or 1000 mg CIPRO XR. The overall incidence, type and distribution of adverse reactions were similar in patients receiving both 500 mg and 1000 mg of CIPRO XR. 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 UTIs, CIPRO XR (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 CIPRO XR arm and in 0% (0/447) of patients in the control arm.

In the clinical trial of cUTI and acute uncomplicated pyelonephritis (AUP) defined as infections occurring in premenopausal, non-pregnant women with no known urological abnormalities or comorbidities, CIPRO XR (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 CIPRO XR arm and in 2.3% (12/518) of patients in the control arm. The most common reasons for discontinuation in the CIPRO XR 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 CIPRO XR patients: nausea (4%), headache (3%), dizziness (2%), diarrhea (2%), vomiting (2%) and vaginal moniliasis (2%).

Adverse reactions, judged by investigators to be at least possibly drug-related, occurring in greater than or equal to 1% of all CIPRO XR 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.

Table 2: Medically Important Adverse Reactions That Occurred In < 1% of CIPRO XR Patients

Postmarketing Experience

The following adverse reactions have been reported from worldwide marketing experience with fluoroquinolones, including CIPRO XR. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure (Table 3).

Table 3: Postmarketing Reports of Adverse Drug Reactions

Adverse Laboratory Changes

Changes in laboratory parameters while on CIPRO are listed below:

Hepatic–Elevations of ALT (SGPT), AST (SGOT), alkaline phosphatase, LDH, serum bilirubin.

Hematologic–Eosinophilia, leukopenia, decreased blood platelets, elevated blood platelets, pancytopenia.

Renal–Elevations of serum creatinine, BUN, crystalluria, cylindruria, and hematuria have been reported.

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

DRUG INTERACTIONS

Ciprofloxacin is an inhibitor of human cytochrome P450 1A2 (CYP1A2) mediated metabolism. Co-administration of CIPRO XR 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 co-administered drug.

Table 4: Drugs That are Affected by and Affecting CIPRO

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. CIPRO XR should not be used during pregnancy unless the potential benefit justifies the potential risk to both fetus and mother. An expert review of published data on experiences with ciprofloxacin use during pregnancy by TERIS–the Teratogen Information System concluded that therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk (quantity and quality of data=fair), but the data are insufficient to state that there is no risk.

A controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5% exposed to ciprofloxacin and 68% first trimester exposures) during gestation. In utero exposure to fluoroquinolones during embryogenesis was not associated with increased risk of major malformations. The reported rates of major congenital malformations were 2.2% for the fluoroquinolone group and 2.6% for the control group (background incidence of major malformations is 1–5%). Rates of spontaneous abortions, prematurity and low birth weight did not differ between the groups and there were no clinically significant musculoskeletal dysfunctions up to one year of age in the ciprofloxacin exposed children.

Another prospective follow-up study reported on 549 pregnancies with fluoroquinolone exposure (93% first trimester exposures). There were 70 ciprofloxacin exposures, all within the first trimester. The malformation rates among live-born babies exposed to ciprofloxacin and to fluoroquinolones overall were both within background incidence ranges. No specific patterns of congenital abnormalities were found. The study did not reveal any clear adverse reactions due to in utero exposure to ciprofloxacin.

No differences in the rates of prematurity, spontaneous abortions, or birth weight were seen in women exposed to ciprofloxacin during pregnancy. However, these small postmarketing epidemiology studies, of which most experience is from short term, first trimester exposure, are insufficient to evaluate the risk for the less common defects or to permit reliable and definitive conclusions regarding the safety of ciprofloxacin in pregnant women and their developing fetuses.

Reproduction studies have been performed in rats and mice using oral doses up to 100 mg/kg (0.6 and 0.3 times the maximum daily human dose of 1000 mg based upon body surface area, respectively) and have revealed no evidence of harm to the fetus due to ciprofloxacin. In rabbits, oral ciprofloxacin dose levels of 30 and 100 mg/kg (approximately 0.4-and 1.3-times the highest recommended therapeutic dose based upon body surface area) produced gastrointestinal toxicity resulting in maternal weight loss and an increased incidence of abortion, but no teratogenicity was observed at either dose level. After intravenous administration of doses up to 20 mg/kg (approximately 0.3-times the highest recommended therapeutic dose based upon body surface area), no maternal toxicity was produced in the rabbit, and no embryotoxicity or teratogenicity was observed.

The following serious and otherwise important adverse drug reactions are discussed in greater detail in other sections of labeling:

• Disabling and Potentially Irreversible Serious Adverse Reactions
• Tenditits and Tendon Rupture
• Peripheral Neuropathy
• Central Nervous System Effects
• Exacerbation of Myasthenia Gravis
• Other Serious and Sometimes Fatal Adverse Reactions
• Hypersensitivity Reactions
• Hepatotoxicity
• Serious Adverse Reactions with Concomitant Theophylline
• Clostridium difficile-Associated Diarrhea
• Prolongation of the QT Interval
• Musculoskeletal Disorders in Pediatric Patients
• Photosensitivity/Phototoxicity
• Development of Drug Resistant Bacteria

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical trials in patients with urinary tract infections enrolled 961 patients treated with 500 mg or 1000 mg CIPRO XR. The overall incidence, type and distribution of adverse reactions were similar in patients receiving both 500 mg and 1000 mg of CIPRO XR. 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 UTIs, CIPRO XR (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 CIPRO XR arm and in 0% (0/447) of patients in the control arm.

In the clinical trial of cUTI and acute uncomplicated pyelonephritis (AUP) defined as infections occurring in premenopausal, non-pregnant women with no known urological abnormalities or comorbidities, CIPRO XR (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 CIPRO XR arm and in 2.3% (12/518) of patients in the control arm. The most common reasons for discontinuation in the CIPRO XR 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 CIPRO XR patients: nausea (4%), headache (3%), dizziness (2%), diarrhea (2%), vomiting (2%) and vaginal moniliasis (2%).

Adverse reactions, judged by investigators to be at least possibly drug-related, occurring in greater than or equal to 1% of all CIPRO XR 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.

Table 2: Medically Important Adverse Reactions That Occurred In < 1% of CIPRO XR Patients

Postmarketing Experience

The following adverse reactions have been reported from worldwide marketing experience with fluoroquinolones, including CIPRO XR. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure (Table 3).

Table 3: Postmarketing Reports of Adverse Drug Reactions

Adverse Laboratory Changes

Changes in laboratory parameters while on CIPRO are listed below:

Hepatic–Elevations of ALT (SGPT), AST (SGOT), alkaline phosphatase, LDH, serum bilirubin.

Hematologic–Eosinophilia, leukopenia, decreased blood platelets, elevated blood platelets, pancytopenia.

Renal–Elevations of serum creatinine, BUN, crystalluria, cylindruria, and hematuria have been reported.

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

In the event of acute overdosage, reversible renal toxicity has been reported in some cases. Empty the stomach by inducing vomiting or by gastric lavage. Observe the patient carefully and give supportive treatment, including monitoring of renal function, urinary pH and acidify, if required, to prevent crystalluria and administration of magnesium, aluminum or calcium containing antacids, which can reduce the absorption of ciprofloxacin. Adequate hydration must be maintained. Only a small amount of ciprofloxacin (less than 10%) is removed from the body after hemodialysis or peritoneal dialysis.

Absorption

CIPRO XR 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 CIPRO XR. In comparisontothe 250 mg and 500 mg ciprofloxacinimmediate-releasetwice a day (BID) treatment,the Cmax of CIPRO XR 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 once a day (QD) CIPRO XR versus 250 mg BID ciprofloxacin immediate-release tablets and 1000 mg QD CIPRO XR versus 500 mg BID ciprofloxacin immediate-release).

Table 5: Ciprofloxacin Pharmacokinetics (Mean ± SD) Following CIPRO and CIPRO XR Administration

Results of the pharmacokinetic studies demonstrate that CIPRO XR 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 CIPRO XR, 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 CYP1A2 mediated metabolism. Co-administration 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 co-administered drug.

Elimination

The elimination kinetics of ciprofloxacin are similar for the immediate-release and the CIPRO XR tablet. In studies comparing the CIPRO XR 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.