CIPRO® XR
(ciprofloxacin*) Extended-Release Tablets
WARNING
Fluoroquinolones, including CIPRO® XR, are associated with an increased risk of tendinitis and tendon rupture in all ages. This risk 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 (See WARNINGS).
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 or prevent infections that are proven or strongly suspected to be caused by bacteria.
CIPRO XR (ciprofloxacin* extended-release tablets) contains ciprofloxacin, a synthetic broad-spectrum antimicrobial agent for oral administration. CIPRO XR tablets are coated, bilayer tablets consisting of an immediate-release layer and an erosion-matrix type controlled-release layer. The tablets contain a combination of two types of ciprofloxacin drug substance, ciprofloxacin hydrochloride and ciprofloxacin betaine (base). Ciprofloxacin hydrochloride is 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl)-3-quinolinecarboxylic acid hydrochloride. It is provided as a mixture of the monohydrate and the sesquihydrate. The empirical formula of the monohydrate is C17H18FN3O3 • HCl • H2O and its molecular weight is 385.8. The empirical formula of the sesquihydrate is C17H18FN3O3•HCl •1.5 H2O and its molecular weight is 394.8. The drug substance is a faintly yellowish to light yellow crystalline substance. The chemical structure of the monohydrate is as follows:
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Ciprofloxacin betaine is 1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. As a hydrate, its empirical formula is C17H18FN3O3 • 3.5 H2O and its molecular weight is 394.3. It is a pale yellowish to light yellow crystalline substance and its chemical structure is as follows:
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CIPRO XR is available in 500 mg and 1000 mg (ciprofloxacin equivalent) tablet strengths. CIPRO XR tablets are nearly white to slightly yellowish, film-coated, oblong-shaped tablets. Each CIPRO XR 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 CIPRO XR 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 crospovidone, hypromellose, magnesium stearate, polyethylene glycol, silica colloidal anhydrous, succinic acid, and titanium dioxide.
* as ciprofloxacin† and ciprofloxacin hydrochloride
†does not comply with the loss on drying test and residue
on ignition test of the USP monograph.
Last updated on RxList: 12/3/2008
CIPRO XR is indicated only for the treatment of urinary tract infections, including acute uncomplicated pyelonephritis, caused by susceptible strains of the designated microorganisms as listed below. CIPRO XR and ciprofloxacin immediate-release tablets are not interchangeable. Please see DOSAGE AND ADMINISTRATION for specific recommendations.
Uncomplicated Urinary Tract Infections (Acute Cystitis) caused by Escherichia coli, Proteus mirabilis, Enterococcus faecalis, or Staphylococcus saprophyticus a.
Complicated Urinary Tract Infections caused by Escherichia coli, Klebsiella pneumoniae, Enterococcus faecalis, Proteus mirabilis, or Pseudomonas aeruginosa a.
Acute Uncomplicated Pyelonephritis caused by Escherichia coli.
THE SAFETY AND EFFICACY OF CIPRO XR 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 CIPRO XR 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 CIPRO XR and other antibacterial drugs, CIPRO XR 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.
a Treatment of infections due to this organism in the organ system was studied in fewer than 10 patients.
CIPRO XR and ciprofloxacin immediate-release tablets are not interchangeable. Cipro XR should be administered orally once daily as described in the following Dosage Guidelines table:
DOSAGE GUIDELINES
| Indication | Unit Dose | Frequency | Usual Duration |
| Uncomplicated Urinary Tract Infection (Acute Cystitis) | 500 mg | Q24h | 3 Days |
| Complicated Urinary Tract Infection | 1000 mg | Q24h | 7-14 Days |
| Acute Uncomplicated Pyelonephritis | 1000 mg | Q24h | 7-14 Days |
Patients whose therapy is started with CIPRO I.V. for urinary tract infections may be switched to CIPRO XR when clinically indicated at the discretion of the physician.
CIPRO XR 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 CIPRO XR 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 CIPRO XR is recommended. CIPRO XR 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.)
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 CIPRO XR. In patients with complicated urinary tract infections and acute uncomplicated pyelonephritis, who have a creatinine clearance of < 30 mL/min, the dose of CIPRO XR should be reduced from 1000 mg to 500 mg daily. For patients on hemodialysis or peritoneal dialysis, administer CIPRO XR after the dialysis procedure is completed. (See CLINICAL PHARMACOLOGY, Special Populations, and PRECAUTIONS, Geriatric Use.)
No dosage adjustment is required with CIPRO XR 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.)
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.
| Strength | NDC Code | |
| Bottles of 50 | 500 mg | 0085-1775-02 |
| Bottles of 100 | 500 mg | 0085-1775-01 |
| Bottles of 50 | 1000 mg | 0085-1778-03 |
| Bottles of 100 | 1000 mg | 0085-1778-01 |
| Unit Dose Pack of 30 | 1000 mg | 0085-1778-02 |
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].
Manufactured by: Bayer HealthCare Pharmaceuticals Inc. Wayne, NJ 07470. Made in Germany. Distributed by: Schering Corporation, Kenilworth, NJ 07033. FDA Rev date: 10/3/2008.
Last updated on RxList: 12/3/2008
Clinical trials in patients with urinary tract infections enrolled 961 patients treated with 500 mg or 1000 mg CIPRO XR. 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 CIPRO XR. 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, 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 complicated urinary tract infection and acute uncomplicated pyelonephritis, 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, 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 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.
Additional uncommon events, judged by investigators to be at least possibly drug-related, that occurred in less than 1% of CIPRO XR treated patients were:
BODY AS A WHOLE: abdominal pain, asthenia, malaise, photosensitivity reaction
CARDIOVASCULAR: bradycardia, migraine, syncope
DIGESTIVE: anorexia, constipation, dry mouth, flatulence, liver function tests abnormal, thirst
HEMIC/LYMPHATIC: prothrombin decrease
CENTRAL NERVOUS SYSTEM: abnormal dreams, depersonalization, depression, hypertonia, incoordination, insomnia, somnolence, tremor, vertigo
METABOLIC: hyperglycemia
SKIN/HYPERSENSIVITY: dry skin, maculopapular rash, photosensitivity/phototoxicity reactions, pruritus, rash, skin disorder, urticaria, vesiculobullous rash
SPECIAL SENSES: diplopia, taste perversion
UROGENITAL: dysmenorrhea, hematuria, kidney function abnormal, vaginitis
The following additional adverse events, some of them life threatening, regardless of incidence or relationship to drug, have been reported during clinical trials and from worldwide post-marketing experience in patients given ciprofloxacin (includes all formulations, all dosages, all drug-therapy durations, and all indications). Because these reactions have been reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or a causal relationship to drug exposure. The events in alphabetical order are:
abnormal gait, achiness, acidosis, agitation, agranulocytosis, allergic reactions (ranging from urticaria to anaphylactic reactions and including life-threatening anaphylactic shock), amylase increase, anemia, angina pectoris, angioedema, anosmia, anxiety, arrhythmia, arthralgia, ataxia, atrial flutter, bleeding diathesis, blurred vision, bronchospasm, C. difficile associated diarrhea, candidiasis (cutaneous, oral), candiduria, cardiac murmur, cardiopulmonary arrest, cardiovascular collapse, cerebral thrombosis, chills, cholestatic jaundice, chromatopsia, confusion, convulsion, delirium, drowsiness, dysphagia, dysphasia, dyspnea, edema (conjunctivae, face, hands, laryngeal, lips, lower extremities, neck, pulmonary), epistaxis, erythema multiforme, erythema nodosum, exfoliative dermatitis, fever, fixed eruptions, flushing, gastrointestinal bleeding, gout (flare up), grand mal convulsion, gynecomastia, hallucinations, hearing loss, hemolytic anemia, hemoptysis, hemorrhagic cystitis, hepatic failure (including fatal cases), hepatic necrosis, hepatitis, hiccup, hyperesthesia, hyperpigmentation, hypertension, hypertonia, hypesthesia, hypotension, ileus, interstitial nephritis, intestinal perforation, jaundice, joint stiffness, lethargy, lightheadedness, lipase increase, lymphadenopathy, manic reaction, marrow depression, migraine, moniliasis (oral, gastrointestinal, vaginal), myalgia, myasthenia, myasthenia gravis (possible exacerbation), myocardial infarction, myoclonus, nephritis, nightmares, nystagmus, oral ulceration, pain (arm, back, breast, chest, epigastric, eye, extremities, foot, jaw, neck, oral mucosa), palpitation, pancreatitis, pancytopenia, paranoia, paresthesia, peripheral neuropathy, perspiration (increased), petechia, phlebitis, phobia, photosensitivity/phototoxicity reaction, pleural effusion, polyuria, postural hypotension, prothrombin time prolongation, pseudomembranous colitis (the onset of symptoms may occur during or after antimicrobial treatment), pulmonary embolism, purpura, renal calculi, renal failure, respiratory arrest, respiratory distress, restlessness, serum sickness-like reaction, Stevens-Johnson syndrome, sweating, tachycardia, taste loss, tendinitis, tendon rupture, tinnitus, torsade de pointes, toxic epidermal necrolysis (Lyell's syndrome), toxic psychosis, twitching, unresponsiveness, urethral bleeding, urinary retention, urination (frequent), vaginal pruritus, vasculitis, ventricular ectopy, vesicles, visual acuity (decreased), visual disturbances (flashing lights, change in color perception, overbrightness of lights).
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.
In a pharmacokinetic study, systemic exposure of tizanidine (4 mg single dose) was significantly increased (Cmax 7-fold, AUC 10-fold) when the drug was given concomitantly with ciprofloxacin (500 mg bid for 3 days). The hypotensive and sedative effects of tizanidine were also potentiated. Concomitant administration of tizanidine and ciprofloxacin is contraindicated.
As with some other quinolones, concurrent administration of ciprofloxacin with theophylline may lead to elevated serum concentrations of theophylline and prolongation of its elimination half-life. This may result in increased risk of theophylline-related adverse reactions. (See WARNINGS.) If concomitant use cannot be avoided, serum levels of theophylline should be monitored and dosage adjustments made as appropriate.
Some quinolones, including ciprofloxacin, have also been shown to interfere with the metabolism of caffeine. This may lead to reduced clearance of caffeine and a prolongation of its serum half-life.
Concurrent administration of a quinolone, including ciprofloxacin, with multivalent cation-containing products such as magnesium/aluminum antacids, sucralfate, VIDEX® (didanosine) chewable/buffered tablets or pediatric powder, other highly buffered drugs, or products containing calcium, iron, or zinc may substantially interfere with the absorption of the quinolone, resulting in serum and urine levels considerably lower than desired. CIPRO XR should be administered at least 2 hours before or 6 hours after antacids containing magnesium or aluminum, as well as sucralfate, VIDEX® (didanosine) chewable/buffered tablets or pediatric powder, other highly buffered drugs, metal cations such as iron, and multivitamin preparations with zinc. (See CLINICAL PHARMACOLOGY, Drug-drug Interactions, PRECAUTIONS, Information for Patients, and DOSAGE AND ADMINISTRATION.)
Histamine H2-receptor antagonists appear to have no significant effect on the bioavailability of ciprofloxacin.
Absorption of the CIPRO XR tablet was slightly diminished (20%) when given concomitantly with omeprazole. (See CLINICAL PHARMACOLOGY, Drug-drug Interactions.)
Altered serum levels of phenytoin (increased and decreased) have been reported in patients receiving concomitant ciprofloxacin.
The concomitant administration of ciprofloxacin with the sulfonylurea glyburide has, on rare occasions, resulted in severe hypoglycemia.
Some quinolones, including ciprofloxacin, have been associated with transient elevations in serum creatinine in patients receiving cyclosporine concomitantly.
Quinolones, including ciprofloxacin, have been reported to enhance the effects of the oral anticoagulant warfarin or its derivatives. When these products are administered concomitantly, prothrombin time or other suitable coagulation tests should be closely monitored.
Probenecid interferes with renal tubular secretion of ciprofloxacin and produces an increase in the level of ciprofloxacin in the serum. This should be considered if patients are receiving both drugs concomitantly.
Renal tubular transport of methotrexate may be inhibited by concomitant administration of ciprofloxacin potentially leading to increased plasma levels of methotrexate. This might increase the risk of methotrexate associated toxic reactions. Therefore, patients under methotrexate therapy should be carefully monitored when concomitant ciprofloxacin therapy is indicated. Metoclopramide significantly accelerates the absorption of oral ciprofloxacin resulting in a shorter time to reach maximum plasma concentrations. No significant effect was observed on the bioavailability of ciprofloxacin.
Non-steroidal anti-inflammatory drugs (but not acetyl salicylic acid) in combination of very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies.
Last updated on RxList: 12/3/2008
THE SAFETY AND EFFECTIVENESS OF CIPRO XR IN PEDIATRIC PATIENTS AND ADOLESCENTS (UNDER THE AGE OF 18 YEARS), PREGNANT WOMEN, AND NURSING WOMEN HAVE NOT BEEN ESTABLISHED. (See PRECAUTIONS: Pediatric Use, Pregnancy, and Nursing Mothers subsections.) The oral administration of ciprofloxacin caused lameness in immature dogs. Histopathological examination of the weight-bearing joints of these dogs revealed permanent lesions of the cartilage. Related quinolone-class drugs also produce erosions of cartilage of weight-bearing joints and other signs of arthropathy in immature animals of various species. (See ANIMAL PHARMACOLOGY.)
Cytochrome P450 (CYP450): Ciprofloxacin is an inhibitor of the hepatic CYP1A2 enzyme pathway. Coadministration of ciprofloxacin and other drugs primarily metabolized by CYP1A2 (e.g. theophylline, methylxanthines, tizanidine) results in increased plasma concentrations of the coadministered drug and could lead to clinically significant pharmacodynamic side effects of the coadministered drug.
Convulsions, increased intracranial pressure, and toxic psychosis have been reported in patients receiving quinolones, including ciprofloxacin. Ciprofloxacin may also cause central nervous system (CNS) events including: dizziness, confusion, tremors, hallucinations, depression, and, rarely, suicidal thoughts or acts. These reactions may occur following the first dose. If these reactions occur in patients receiving ciprofloxacin, the drug should be discontinued and appropriate measures instituted. As with all quinolones, ciprofloxacin should be used with caution in patients with known or suspected CNS disorders that may predispose to seizures or lower the seizure threshold (e.g. severe cerebral arteriosclerosis, epilepsy), or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold (e.g. certain drug therapy, renal dysfunction). (See PRECAUTIONS: General, INFORMATION FOR PATIENTS, DRUG INTERACTIONS and ADVERSE REACTIONS.)
SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED IN PATIENTS RECEIVING CONCURRENT ADMINISTRATION OF CIPROFLOXACIN AND THEOPHYLLINE. These reactions have included cardiac arrest, seizure, status epilepticus, and respiratory failure. Although similar serious adverse effects have been reported in patients receiving theophylline alone, the possibility that these reactions may be potentiated by ciprofloxacin cannot be eliminated. If concomitant use cannot be avoided, serum levels of theophylline should be monitored and dosage adjustments made as appropriate.
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving quinolone therapy. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria, and itching. Only a few patients had a history of hypersensitivity reactions. Serious anaphylactic reactions require immediate emergency treatment with epinephrine. Oxygen, intravenous steroids, and airway management, including intubation, should be administered as indicated.
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:
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).
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including CIPRO, 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 strains 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: Rare cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving quinolones, including ciprofloxacin. Ciprofloxacin should be discontinued if the patient experiences symptoms of neuropathy including pain, burning, tingling, numbness, and/or weakness, or is found to have deficits in light touch, pain, temperature, position sense, vibratory sensation, and/or motor strength in order to prevent the development of an irreversible condition.
Tendon Effects: Ruptures of the shoulder, hand, Achilles tendon or other tendons that required surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones, including ciprofloxacin. Post-marketing surveillance reports indicate that this risk may be increased in patients receiving concomitant corticosteroids, especially the elderly. Ciprofloxacin should be discontinued if the patient experiences pain, inflammation, or rupture of a tendon. Patients should rest and refrain from exercise until the diagnosis of tendonitis or tendon rupture has been excluded. Tendon rupture can occur during or after therapy with quinolones, including ciprofloxacin.
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 (e.g., 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 and ADVERSE REACTIONS/ Post-Marketing Adverse Events).
Prescribing CIPRO XR 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.
Patients should be advised
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. coliDNA 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 cerevisiaePoint Mutation Assay (Negative)
Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative)
Rat Hepatocyte DNA Repair Assay (Positive)
Thus, 2 of the 8 tests were positive, but results of the following 3 in vivo test systems gave negative results:
Rat Hepatocyte DNA Repair Assay
Micronucleus Test (Mice)
Dominant Lethal Test (Mice)
Ciprofloxacin was not carcinogenic or tumorigenic in 2-year carcinogenicity studies with rats and mice at daily oral dose levels of 250 and 750 mg/kg, respectively (approximately 2 and 3 -fold greater than the 1000 mg daily human dose based upon body surface area).
Results from photo co-carcinogenicity testing indicate that ciprofloxacin does not reduce the time to appearance of UV-induced skin tumors as compared to vehicle control. Hairless (Skh-1) mice were exposed to UVA light for 3.5 hours five times every two weeks for up to 78 weeks while concurrently being administered ciprofloxacin. The time to development of the first skin tumors was 50 weeks in mice treated concomitantly with UVA and ciprofloxacin (mouse dose approximately equal to the maximum recommended daily human dose of 1000 mg based upon mg/m²), as opposed to 34 weeks when animals were treated with both UVA and vehicle. The times to development of skin tumors ranged from 16-32 weeks in mice treated concomitantly with UVA and other quinolones.
In this model, mice treated with ciprofloxacin alone did not develop skin or systemic tumors. There are no data from similar models using pigmented mice and/or fully haired mice. The clinical significance of these findings to humans is unknown.
Fertility studies performed in rats at oral doses of ciprofloxacin up to 100 mg/kg (1.0 times the highest recommended daily human dose of 1000 mg based upon body surface area) revealed no evidence of impairment.
Pregnancy: Teratogenic Effects. Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. An expert review of published data on experiences with ciprofloxacin use during pregnancy by TERIS - the Teratogen Information System - concluded that therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk (quantity and quality of data=fair), but the data are insufficient to state there is no risk.
A controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5% exposed to ciprofloxacin and 68% first trimester exposures) during gestation. In utero exposure to fluoroquinolones during embryogenesis was not associated with increased risk of major malformations. The reported rates of major congenital malformations were 2.2% for the fluoroquinolone group and 2.6% for the control group (background incidence of major malformations is 1-5%). Rates of spontaneous abortions, prematurity and low birth weight did not differ between the groups and there were no clinically significant musculoskeletal dysfunctions up to one year of age in the ciprofloxacin exposed children.
Another prospective follow-up study reported on 549 pregnancies with fluoroquinolone exposure (93% first trimester exposures).There were 70 ciprofloxacin exposures, all within the first trimester. The malformation rates among live-born babies exposed to ciprofloxacin and to fluoroquinolones overall were both within background incidence ranges. No specific patterns of congenital abnormalities were found. The study did not reveal any clear adverse reactions due to in utero exposure to ciprofloxacin.
No differences in the rates of prematurity, spontaneous abortions, or birth weight were seen in women exposed to ciprofloxacin during pregnancy. However, these small postmarketing epidemiology studies, of which most experience is from short term, first trimester exposure, are insufficient to evaluate the risk for the less common defects or to permit reliable and definitive conclusions regarding the safety of ciprofloxacin in pregnant women and their developing fetuses. Ciprofloxacin should not be used during pregnancy unless potential benefit justifies the potential risk to both fetus and mother (see WARNINGS).
Reproduction studies have been performed in rats and mice using oral doses up to 100 mg/kg (0.7 and 0.4 times the maximum daily human dose of 1000 mg based upon body surface area, respectively) and have revealed no evidence of harm to the fetus due to ciprofloxacin. In rabbits, ciprofloxacin (30 and 100 mg/kg orally) produced gastrointestinal disturbances resulting in maternal weight loss and an increased incidence of abortion, but no teratogenicity was observed at either dose. After intravenous administration of doses up to 20 mg/kg, no maternal toxicity was produced in the rabbit, and no embryotoxicity or teratogenicity was observed.
Nursing Mothers: Ciprofloxacin is excreted in human milk. The amount of ciprofloxacin absorbed by the nursing infant is unknown. Because of the potential for serious adverse reactions in infants nursing from mothers taking ciprofloxacin, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use: Safety and effectiveness of CIPRO XR in pediatric patients and adolescents less than 18 years of age have not been established. Ciprofloxacin causes arthropathy in juvenile animals. (See WARNINGS.)
Geriatric Use: In a large, prospective, randomized CIPRO XR 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 CIPRO XR with concomitant drugs that can result in prolongation of the QT interval (e.g., class IA or class III antiarrhythmics) or in patients with risk factors for torsade de pointes (e.g., known QT prolongation, uncorrected hypokalemia).
Patients over 65 years of age 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. Tendon rupture usually involves the Achilles, hand, or shoulder tendons and can occur during therapy or up to a few months post completion of therapy. 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 therapy and inform their physicians if any tendon symptoms occur.
Last updated on RxList: 12/3/2008
In the event of acute excessive overdosage, reversible renal toxicity has been reported in some cases. The stomach should be emptied by inducing vomiting or by gastric lavage. The patient should be carefully observed and given supportive treatment, including monitoring of renal function and administration of magnesium or calcium containing antacids which can reduce the absorption of ciprofloxacin. Adequate hydration must be maintained. Only a small amount of ciprofloxacin ( < 10%) is removed from the body after hemodialysis or peritoneal dialysis.
In mice, rats, rabbits and dogs, significant toxicity including tonic/clonic convulsions was observed at intravenous doses of ciprofloxacin between 125 and 300 mg/kg.
Single doses of ciprofloxacin were relatively non-toxic via the oral route of administration in mice, rats, and dogs. No deaths occurred within a 14-day post treatment observation period at the highest oral doses tested; up to 5000 mg/kg in either rodent species, or up to 2500 mg/kg in the dog. Clinical signs observed included hypoactivity and cyanosis in both rodent species and severe vomiting in dogs. In rabbits, significant mortality was seen at doses of ciprofloxacin > 2500 mg/kg. Mortality was delayed in these animals, occurring 10-14 days after dosing.
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.)
Last updated on RxList: 12/3/2008
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 comparison to the 250 mg and 500 mg ciprofloxacin immediate-release 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 QD CIPRO XR versus 250 mg BID ciprofloxacin immediate-release tablets and 1000 mg QD CIPRO XR versus 500 mg BID ciprofloxacin immediate-release).
Ciprofloxacin Pharmacokinetics (Mean ± SD) Following
CIPRO® and CIPRO XR Administration
| Cmax (mg/L) | AUC0-24h (mg•h/L) | T½ (hr) | Tmax (hr) § | |
| CIPRO XR 500 mg QD | 1.59 ± 0.43 | 7.97 ± 1.87 | 6.6 ± 1.4 | 1.5 (1.0 - 2.5) |
| CIPRO 250 mg BID | 1.14 ± 0.23 | 8.25 ± 2.15 | 4.8 ± 0.6 | 1.0 (0.5 - 2.5) |
| CIPRO XR 1000 mg QD | 3.11 ± 1.08 | 16.83 ± 5.65 | 6.31 ± 0.72 | 2.0 (1 - 4) |
| CIPRO 500 mg BID | 2.06 ± 0.41 | 17.04 ± 4.79 | 5.66 ± 0.89 | 2.0 (0.5 - 3.5) |
| § median (range) | ||||
Results of the pharmacokinetic studies demonstrate that CIPRO XR may be administered with or without food (e.g. high-fat and low-fat meals or under fasted conditions).
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.
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).
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.
Pharmacokinetic studies of the immediate-release oral tablet (single dose) and intravenous (single and multiple dose) forms of ciprofloxacin indicate that plasma concentrations of ciprofloxacin are higher in elderly subjects ( > 65 years) as compared to young adults. Cmax is increased 16% to 40%, and mean AUC is increased approximately 30%, which can be at least partially attributed to decreased renal clearance in the elderly. Elimination half-life is only slightly (~20%) prolonged in the elderly. These differences are not considered clinically significant. (See PRECAUTIONS, Geriatric Use.)
In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged. No dose adjustment is required for patients with uncomplicated urinary tract infections receiving 500 mg CIPRO XR. For complicated urinary tract infection and acute uncomplicated pyelonephritis, where 1000 mg is the appropriate dose, the dosage of CIPRO XR should be reduced to CIPRO XR 500 mg q24h in patients with creatinine clearance below 30 mL/min. (See DOSAGE AND ADMINISTRATION.)
In studies in patients with stable chronic cirrhosis, no significant changes in ciprofloxacin pharmacokinetics have been observed. The kinetics of ciprofloxacin in patients with acute hepatic insufficiency, however, have not been fully elucidated. (See DOSAGE AND ADMINISTRATION.)
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 CIPRO XR given as a single 1000 mg dose was administered two hours before, or four hours after a magnesium/aluminum-containing antacid (900 mg aluminum hydroxide and 600 mg magnesium hydroxide as a single oral dose) to 18 healthy volunteers, there was a 4% and 19% reduction, respectively, in the mean Cmax of ciprofloxacin. The reduction in the mean AUC was 24% and 26%, respectively. CIPRO XR 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 CIPRO XR 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 CIPRO XR was administered as a single 1000 mg dose concomitantly with omeprazole (40 mg once daily for three days) to 18 healthy volunteers, the mean AUC and Cmax of ciprofloxacin were reduced by 20% and 23%, respectively. The clinical significance of this interaction has not been determined. (See PRECAUTIONS: DRUG INTERACTIONS.)
Ciprofloxacin has in vitro activity against a wide range of gram-negative and gram-positive organisms. The bactericidal action of ciprofloxacin results from inhibition of topoisomerase II (DNA gyrase) and topoisomerase IV (both Type II topoisomerases), which are required for bacterial DNA replication, transcription, repair, and recombination. The mechanism of action of quinolones, including ciprofloxacin, is different from that of other antimicrobial agents such as beta-lactams, macrolides, tetracyclines, or aminoglycosides; therefore, organisms resistant to these drugs may be susceptible to ciprofloxacin. There is no known cross-resistance between ciprofloxacin and other classes of antimicrobials. Resistance to ciprofloxacin in vitro develops slowly (multiple-step mutation). Resistance to ciprofloxacin due to spontaneous mutations occurs at a general frequency of between < 10-9 to 1x10-6.
Ciprofloxacin is slightly less active when tested at acidic pH. The inoculum size has little effect when tested in vitro. The minimal bactericidal concentration (MBC) generally does not exceed the minimal inhibitory concentration (MIC) by more than a factor of 2.
Ciprofloxacin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.
Enterococcus faecalis (Many strains are only moderately susceptible.)
Staphylococcus saprophyticus
Escherichia coli
Klebsiella pneumoniae
Proteus mirabilis
Pseudomonas aeruginosa
The following in vitro data are available, but their clinical significance is unknown.
Ciprofloxacin exhibits in vitro minimum inhibitory concentrations (MICs) of 1 μg/mL or less against most ( ≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of CIPRO XR in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.
| Citrobacter koseri | Morganella morganii |
| Citrobacter freundii | Proteus vulgaris |
| Edwardsiella tarda | Providencia rettgeri |
| Enterobacter aerogenes | Providencia stuartii |
| Enterobacter cloacae | Serratia marcescens |
| Klebsiella oxytoca |
Dilution Techniques: Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of ciprofloxacin. The MIC values should be interpreted according to the following criteria:
For testing Enterobacteriaceae, Enterococcus faecalis, Pseudomonas aeruginosa, and Staphylococcus saprophyticus:
| MIC (μg/mL) | Interpretation |
| ≤ 1 | Susceptible(S) |
| 2 | Intermediate(I) |
| ≥ 4 | Resistant(R) |
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of “Intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard ciprofloxacin powder should provide the following MIC values:
| Microorganism | MIC Range (μg/mL) | |
| Enterococcus faecalis | ATCC 29212 | 0.25 - 2.0 |
| Escherichia coli | ATCC 25922 | 0.004 - 0.015 |
| Staphylococcus aureus | ATCC 29213 | 0.12 - 0.5 |
| Pseudomonas aeruginosa | ATCC 27853 | 0.25 - 1 |
Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 5-μg ciprofloxacin to test the susceptibility of microorganisms to ciprofloxacin. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5-μg ciprofloxacin disk should be interpreted according to the following criteria:
For testing Enterobacteriaceae, Enterococcus faecalis, Pseudomonas aeruginosa, and Staphylococcus saprophyticus:
| Zone Diameter (mm) | Interpretation |
| ≥ 21 | Susceptible(S) |
| 16 - 20 | Intermediate(I) |
| ≤ 15 | Resistant(R) |
Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for ciprofloxacin.
As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 5-μg ciprofloxacin disk should provide the following zone diameters in these laboratory test quality control strains:
| Microorganism | Zone Diameter (mm) | |
| Escherichia coli | ATCC 25922 | 30 - 40 |
| Staphylococcus aureus | ATCC 25923 | 22 - 30 |
| Pseudomonas aeruginosa | ATCC 27853 | 25 - 33 |
Ciprofloxacin and other quinolones have been shown to cause arthropathy in immature animals of most species tested. (See WARNINGS.) Damage of weight bearing joints was observed in juvenile dogs and rats. In young beagles, 100 mg/kg ciprofloxacin, given daily for 4 weeks, caused degenerative articular changes of the knee joint. At 30 mg/kg, the effect on the joint was minimal. In a subsequent study in beagles, removal of weight bearing from the joint reduced the lesions but did not totally prevent them.
Crystalluria, sometimes associated with secondary nephropathy, occurs in laboratory animals dosed with ciprofloxacin. This is primarily related to the reduced solubility of ciprofloxacin under alkaline conditions, which predominate in the urine of test animals; in man, crystalluria is rare since human urine is typically acidic. In rhesus monkeys, crystalluria without nephropathy has been noted after single oral doses as low as 5 mg/kg. After 6 months of intravenous dosing at 10 mg/kg/day, no nephropathological changes were noted; however, nephropathy was observed after dosing at 20 mg/kg/day for the same duration.
In mice, concomitant administration of nonsteroidal anti-inflammatory drugs such as phenylbutazone and indomethacin with quinolones has been reported to enhance the CNS stimulatory effect of quinolones.
Ocular toxicity seen with some related drugs has not been observed in ciprofloxacin-treated animals.
CIPRO XR was evaluated for the treatment of uncomplicated urinary tract infections (acute cystitis) in a randomized, double-blind, controlled clinical trial conducted in the US. This study compared CIPRO XR (500 mg once daily for three days) with ciprofloxacin immediate-release tablets (CIPRO® 250 mg BID for three days). Of the 905 patients enrolled, 452 were randomly assigned to the CIPRO XR treatment group and 453 were randomly assigned to the control group. The primary efficacy variable was bacteriologic eradication of the baseline organism(s) with no new infection or superinfection at test-of-cure (Day 4 -11 Post-therapy).
The bacteriologic eradication and clinical success rates were similar between CIPRO XR and the control group. The eradication and clinical success rates and their corresponding 95% confidence intervals for the differences between rates (CIPRO XR minus control group) are given in the following table:
| CIPRO XR 500 mg QD x 3 Days | CIPRO 250 mg BID x 3 Days | |
| Randomized Patients | 452 | 453 |
| Per Protocol Patients† | 199 | 223 |
| Bacteriologic Eradication at TOC (n/N)* | 188/199 (94.5%) | 209/223 (93.7%) |
| CI [-3.5%,5.1%] | ||
| Bacteriologic Eradication (by organism) at TOC (n/N)** | ||
| E. coli | 156/160 (97.5%) | 176/181 (97.2%) |
| E. faecalis | 10/11 (90.9%) | 17/21 (81.0%) |
| P. mirabilis | 11/12 (91.7%) | 7/7 (100%) |
| S. saprophyticus | 6/7 (85.7%) | 9/9 (100%) |
| Clinical Response at TOC (n/N)*** | 189/199 (95.0%) | 204/223 (91.5%) |
| CI [-1.1%,8.1%] | ||
| * n/N = patients with baseline organism(s)
eradicated and no new infections or superinfections/ total number of patients
** n/N = patients with specified baseline organism eradicated/patients with specified baseline organism *** n/N = patients with clinical success /total number of patients † The presence of a pathogen at a level of ≥ 105 CFU/mL was required for microbiological evaluability criteria, except for S. saprophyticus ( ≥ 104 CFU/mL). |
||
CIPRO XR was evaluated for the treatment of complicated urinary tract infections (cUTI) and acute uncomplicated pyelonephritis (AUP) in a randomized, double-blind, controlled clinical trial conducted in the US and Canada. The study enrolled 1,042 patients (521 patients per treatment arm) and compared CIPRO XR (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 CIPRO XR 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 CIPRO XR arm and 324 patients in the control arm. Patients with missing responses were counted as failures in this analysis. In the MITT analysis of cUTI patients, bacteriologic eradication was 160/271 (59.0%) versus 156/248 (62.9%) in CIPRO XR and control arm, respectively [97.5% CI* (-13.5%, 5.7%)]. Clinical cure was 184/271 (67.9%) for CIPRO XR 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 CIPRO XR and control arm, respectively [97.5% CI* (-26.8%, 6.5%)]. Clinical cure at TOC was 50/71 (70.4%) for CIPRO XR and 58/76 (76.3%) for the control arm [97.5% CI* (-22.0%, 10.4%)].
* confidence interval of the difference in rates (CIPRO XR minus control).
In the Per Protocol population, the differences between CIPRO XR 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 CIPRO XR arm than in the control arm. For AUP patients, the bacteriologic eradication rate was lower in the CIPRO XR 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 CIPRO XR and the control arm, respectively.
The bacterial eradication and clinical cure rates by infection type for CIPRO XR and the control arm at the TOC visit and their corresponding 97.5% confidence intervals for the differences between rates (CIPRO XR minus control arm) are given below for the Per Protocol population analysis:
| CIPRO XR 1000 mg QD | CIPRO 500 mg BID | |
| Randomized Patients | 521 | 521 |
| Per Protocol Patients^ | 206 | 229 |
|
cUTI Patients
|
||
| Bacteriologic Eradication at TOC (n/N)* | 148/166 (89.2%) | 144/177 (81.4%) |
| CI [-0.7%,16.3%] | ||
| Bacteriologic Eradication (by organism) at TOC (n/N)** | ||
| E. coli | 91/94 (96.8%) | 90/92 (97.8%) |
| K. pneumoniae | 20/21 (95.2%) | 19/23 (82.6%) |
| E. faecalis | 17/17 (100%) | 14/21 (66.7%) |
| P. mirabilis | 11/12 (91.6%) | 10/10 (100%) |
| P. aeruginosa | 3/3 (100%) | 3/3 (100%) |
| Clinical Cure at TOC (n/N)*** | 159/166 (95.8%) | 161/177 (91.0%) |
| CI [-1.1%,10.8%] | ||
| AUP Patients | ||
| Bacteriologic Eradication at TOC (n/N)* | 35/40 (87.5%) | 51/52 (98.1%) |
| CI [-34.8%,6.2%] | ||
| Bacteriologic Eradication of E. coli at TOC (n/N)** | 35/36 (97.2%) | 41/41 (100%) |
| Clinical Cure at TOC (n/N)*** | 39/40 (97.5%) | 50/52 (96.2%) |
| CI [-15.3%,21.1%] | ||
| ^ Patients excluded from the Per Protocol
population were primarily those with no causative organism(s) at baseline
or no organism present at ≥ 105 CFU/mL at baseline, inclusion
criteria violation, no valid test-of-cure urine culture within the TOC
window, an organism resistant to study drug, premature discontinuation
due to an adverse event, lost to follow-up, or non-compliance with dosage
regimen (among other criteria). * n/N = patients with baseline organism(s) eradicated and no new infections or superinfections/total number of patients ** n/N = patients with specified baseline organism eradicated/patients with specified baseline organism ***n/N = patients with clinical success /total number of patients |
||
Of the 166 cUTI patients treated with CIPRO XR, 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 CIPRO XR, 35 (87.5%) had the causative organism(s) eradicated, 2 (5%) patients had persistence and 3 (7.5%) developed new infections. Of the 5 CIPRO XR AUP patients without eradication at TOC, 4 were considered clinical cures and did not receive alternative antibiotic therapy. Of the 52 patients with AUP treated in the control arm, 51 (98%) had the causative organism(s) eradicated. One patient (2%) had persistence.
REFERENCES
1. NCCLS, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically-Sixth Edition. Approved Standard NCCLS Document M7-A6, Vol. 23, No. 2, NCCLS, Wayne, PA, January, 2003.
2. NCCLS, Performance Standards for Antimicrobial Disk Susceptibility Tests-Eighth Edition. Approved Standard NCCLS Document M2-A8, Vol. 23, No. 1, NCCLS, Wayne, PA, January, 2003.
Last updated on RxList: 12/3/2008
MEDICATION GUIDE
CIPRO® (Sip-row)
(ciprofloxacin hydrochloride) TABLETS
CIPRO® (Sip-row)
(ciprofloxacin) ORAL SUSPENSION
CIPRO® XR (Sip-row)
(ciprofloxacin extended-release tablets)
CIPRO® I.V. (Sip-row)
(ciprofloxacin) For Intravenous Infusion
Read the Medication Guide that comes with CIPRO® 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 CIPRO?
CIPRO belongs to a class of antibiotics called fluoroquinolones. CIPRO 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 CIPRO.
What is CIPRO?
CIPRO is a fluoroquinolone antibiotic medicine used to treat certain infections caused by certain germs called bacteria.
Children less than 18 years of age have a higher chance of getting bone, joint, or tendon (musculoskeletal) problems such as pain or swelling while taking CIPRO. CIPRO should not be used as the first choice of antibiotic medicine in children under 18 years of age.
CIPRO Tablets, CIPRO Oral Suspension and CIPRO I.V. should not be used in children under 18 years old, except to treat specific serious infections, such as complicated urinary tract infections and to prevent anthrax disease after breathing the anthrax bacteria germ (inhalational exposure). It is not known if CIPRO XR is 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 CIPRO, do not kill viruses.
Call your healthcare provider if you think your condition is not getting better while you are taking CIPRO.
Who should not take CIPRO?
Do not take CIPRO if you:
What should I tell my healthcare provider before taking CIPRO?
See "What is the most important information I should know about CIPRO?"
Tell your healthcare provider about all your medical conditions, including if you:
Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal and dietary supplements. CIPRO and other medicines can affect each other causing side effects. Especially tell your healthcare provider if you take:
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 CIPRO?
If you have been prescribed CIPRO Tablets, CIPRO Oral Suspension or CIPRO I.V. after being exposed to anthrax:
What should I avoid while taking CIPRO?
What are the possible side effects of CIPRO?
Other serious side effects of CIPRO include:
Seizures have been reported in people who take fluoroquinolone antibiotics including CIPRO. Tell your healthcare provider if you have a history of seizures. Ask your healthcare provider whether taking CIPRO 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 CIPRO. Talk to your healthcare provider right away if you get any of these side effects, or other changes in mood or behavior:
Allergic reactions can happen in people taking fluoroquinolones, including CIPRO, even after only one dose. Stop taking CIPRO and get emergency medical help right away if you get any of the following symptoms of a severe allergic reaction:
These are not all the possible side effects of CIPRO. Tell your healthcare provider about any side effect that bothers you, or that does not go away. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store CIPRO?
Keep CIPRO and all medicines out of the reach of children.
General Information about CIPRO
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use CIPRO for a condition for which it is not prescribed. Do not give CIPRO 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 CIPRO. If you would like more information about CIPRO, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about CIPRO that is written for healthcare professionals. For more information go to www.CIPRO.com or call 1-800-526-4099.
What are the ingredients in CIPRO?
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Last updated on RxList: 12/3/2008
IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.
CIPROFLOXACIN SUSTAINED-RELEASE - ORAL
(sip-row-FLOX-ah-sin)
COMMON BRAND NAME(S): Cipro XR
WARNING: This medication may rarely cause tendon damage (e.g., tendinitis, tendon rupture) during or after treatment. Your risk for tendon problems is greater if you are over 60 years of age, if you are taking corticosteroids (such as prednisone), or if you have had a kidney, heart or lung transplant. Stop exercising, rest, and seek immediate medical attention if you develop joint/muscle/tendon pain or swelling.
USES: This medication is used to treat kidney or bladder (urinary tract) infections. Ciprofloxacin belongs to a class of drugs called quinolone antibiotics. It works by stopping the growth of bacteria.
This antibiotic treats only bacterial infections. It will not work for virus infections (e.g., common cold, flu). Unnecessary use or overuse of any antibiotic can lead to its decreased effectiveness
HOW TO USE: Read the Patient Information Leaflet provided by your pharmacist before you start using ciprofloxacin and each time you get a refill. If you have any questions, consult your doctor or pharmacist.
Take this medication by mouth with or without food, usually once daily or as directed by your doctor. Swallow this medication whole with a full glass of water. Do not break, crush, or chew the tablets.
The dosage and length of treatment is based on your medical condition and response to treatment. Drink plenty of fluids while taking this medication unless your doctor tells you otherwise.
Take this medication 2 hours before or 6 hours after taking any medications or antacids containing magnesium, aluminum, or calcium. Some examples include quinapril, certain forms of didanosine (chewable/dispersible buffered tablets or pediatric oral solution), vitamins/minerals, antacids, dairy products (e.g., milk, yogurt), calcium-enriched juice, and sucralfate. Other products include bismuth subsalicylate, iron, and zinc. These medications/products bind with ciprofloxacin and prevent its full absorption. However, this medication may be taken with dairy products or calcium-enriched juice as part of a meal because food helps prevent this effect.
Ask your doctor or pharmacist about safely using nutritional supplements/replacements with this medication.
Antibiotics work best when the amount of medicine in your body is kept at a constant level. It is important not to miss a dose. To help you remember and to keep the drug at a constant level, take it at the same time every day.
Continue to take this medication until the full prescribed amount is finished, even if symptoms disappear after a few days. Stopping the medication too early may allow bacteria to continue to grow, which may result in a return of the infection.
Tell your doctor if your condition persists or worsens.
Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.
Tell your doctor immediately if any of these unlikely but serious side effects occur: mental/mood changes (e.g., anxiety, confusion, hallucinations, depression, rare thoughts of suicide), shaking (tremors), skin that sunburns more easily (sun sensitivity).
Ciprofloxacin may rarely cause serious nerve problems that may be reversible if identified and treated early. Seek immediate medical attention if you develop any of the following symptoms: pain/numbness/burning/tingling/weakness in any part of the body, changes in how you sense touch/pain/temperature/body position/vibration.
Tell your doctor immediately if any of these rare but very serious side effects occur: unusual bruising/bleeding, severe/persistent headache, signs of a new infection (e.g., new/persistent fever, persistent sore throat), unusual change in the amount of urine, change in color of urine (red/pink urine), signs of liver problems (e.g., unusual tiredness, stomach/abdominal pain, persistent nausea/vomiting, yellowing eyes/skin, dark urine), vision changes.
Seek immediate medical attention if any of these rare but very serious side effects occur: severe dizziness, fainting, fast/irregular heartbeat, seizures.
This medication may rarely cause a severe intestinal condition (pseudomembranous colitis) due to a type of resistant bacteria. This condition may occur during treatment or weeks to months after treatment has stopped. Do not use anti-diarrhea products or narcotic pain medications if you have any of the following symptoms because these products may make them worse. Tell your doctor immediately if you develop: persistent diarrhea, abdominal or stomach pain/cramping, blood/mucus in your stool.
Use of this medication for prolonged or repeated periods may result in oral thrush or a new vaginal yeast infection. Contact your doctor if you notice white patches in your mouth, a change in vaginal discharge, or other new symptoms.
A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any of the following symptoms of a serious allergic reaction: rash, itching/swelling, severe dizziness, trouble breathing.
This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.
Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.
PRECAUTIONS: Before taking ciprofloxacin, tell your doctor or pharmacist if you are allergic to it; or to other quinolone antibiotics such as norfloxacin, gemifloxacin, levofloxacin, moxifloxacin, or ofloxacin; or if you have any other allergies.
Before using this medication, tell your doctor or pharmacist your medical history, especially of: diabetes, certain heart problem (QT prolongation in the EKG), family history of a certain heart problem (QT prolongation in the EKG), heart problems (e.g., slow/fast/irregular heartbeat, heart failure, recent heart attack), joint/tendon problems (e.g., tendonitis, bursitis), kidney disease, liver disease, nervous system disorder (e.g., peripheral neuropathy), seizure disorder, conditions that increase your risk of seizures (e.g., brain/head injury, brain tumors, cerebral atherosclerosis), untreated low levels of potassium or magnesium in the blood.
This medication may rarely cause serious changes in blood sugar levels, especially if you have diabetes. Watch for symptoms of high blood sugar including increased thirst and urination. Also watch for symptoms of low blood sugar such as nervousness, shakiness, fast heartbeat, sweating, or hunger. Check your blood sugar regularly as directed by your doctor and report any changes. If you experience symptoms of low blood sugar, you may raise your blood sugar by using glucose tablets/gel or eating a quick source of sugar such as table sugar, honey, or candy, or drink fruit juice or non-diet soda. Tell your doctor immediately about the reaction and the use of this product. To help prevent low blood sugar, eat meals on a regular schedule, and do not skip meals.
This drug may make you dizzy or lightheaded. Use caution while driving, using machinery, or taking part in any activity that requires alertness. Limit alcoholic beverages.
This medication may make you more sensitive to the sun. Avoid prolonged sun exposure, tanning booths, and sunlamps. Use a sunscreen and wear protective clothing when outdoors.
Caution is advised when using this drug in children because they may be more sensitive to its possible side effects (e.g., joint/tendon problems). Discuss the risks and benefits with the doctor.
Kidney function declines as you grow older. This medication is removed by the kidneys. Therefore, older adults may be more sensitive to its side effects such as tendon problems (especially if they are also taking corticosteroids such as prednisone or hydrocortisone) or heart problems. Discuss the risks and benefits with your doctor.
During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.
This medication passes into breast milk. Breastfeeding is not recommended while taking this drug. Consult your doctor before breast-feeding.
Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with them first.
This drug should not be used with the following medications because very serious interactions may occur: strontium, tizanidine, certain drugs that affect the heart rhythm (antiarrhythmics that may cause QT prolongation such as amiodarone, dofetilide, quinidine, procainamide, sotalol).
If you are currently using any of these medications listed above, tell your doctor or pharmacist before starting ciprofloxacin.
Other drugs besides ciprofloxacin and those listed above that may affect the heart rhythm (QT prolongation in the EKG) include certain macrolide antibiotics (e.g., erythromycin, clarithromycin), and certain antipsychotic medications (e.g., pimozide, thioridazine, ziprasidone), among others. QT prolongation can infrequently result in serious (rarely fatal) fast/irregular heartbeat and other symptoms (e.g., severe dizziness, fainting) that require immediate medical treatment. Ask your doctor or pharmacist for more details and for instructions on how you may reduce the risk of this effect.
Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: live bacterial vaccines (e.g., typhoid, BCG), "blood thinners" (e.g., warfarin), corticosteroids (e.g., prednisone, hydrocortisone), cyclosporine, drugs removed from your body by certain liver enzymes (such as clozapine, duloxetine, phenytoin, ropinirole, tacrine), drugs for diabetes (e.g., glyburide, insulin), methotrexate, nonsteroidal anti-inflammatory drugs (NSAIDs such as ibuprofen, naproxen), certain "water pills" (potassium-wasting diuretics such as furosemide, hydrochlorothiazide), probenecid, sevelamer, theophylline, urinary alkalinizers (e.g., potassium/sodium citrate).
Also report the use of drugs that might increase seizure risk when combined with this medication such as isoniazid (INH), phenothiazines (e.g., chlorpromazine), or tricyclic antidepressants (e.g., amitriptyline), among others. Consult your doctor or pharmacist for details.
Avoid drinking large amounts of beverages containing caffeine (coffee, tea, colas), eating large amounts of chocolate, or taking over-the-counter products that contain caffeine to keep you awake and alert. This drug may increase and/or prolong the effects of caffeine.
This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.
OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.
NOTES: Do not share this medication with others.
This medication has been prescribed for your current condition only. Do not use it later for another infection unless told to do so by your doctor. A different medication may be necessary in those cases.
Laboratory and/or medical tests (e.g., kidney function, blood counts, cultures) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.
Do not change brands of this medication without checking with your doctor or pharmacist. Not all brands have the same effects.
MISSED DOSE: If you miss a dose, take it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.
STORAGE: Store at room temperature at 77 degrees F (25 degrees C) away from light and moisture. Brief storage between 59-86 degrees F (15-30 degrees C) is permitted. Do not store in the bathroom. Keep all medicines away from children and pets.
Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.
Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.
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