 |
 |
 |
 |
|
 |
|||||||||||||||||
 | |||||||||||||||||
 |
|||||||||||||||||
|
The complete prescribing information for Cipro XR 500 mg is reproduced below. Use the pull-down menu to navigate this information by topic.
You may also download a printable version of this Prescribing Information in PDF format. Download Prescribing Information
To view specific information, select a topic:
| 08756557M |
12/02
|
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:
Ciprofloxacin betaine is 1-cyclopropyl-6-fluoro-1, -dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. As a hydrate, its empirical formula is 17H18FN3O3 • 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:
CIPRO XR is available as a 500 mg (ciprofloxacin equivalent) tablet strength. 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). 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.
Back to topAbsorption
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 ciprofloxacin immediate-release BID treatment, which is approved for the treatment of uncomplicated urinary tract infections, the Cmax of CIPRO XR 500 mg once daily is higher, while the AUC over 24 hours is equivalent.
The following table compares the pharmacokinetic parameters obtained at steady state for these two treatment regimens (500 mg QD CIPRO XR versus 250 mg BID ciprofloxacin immediate-release tablets).
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 (e.g. high-fat and low-fat meals or under fasted conditions).
Distribution
The volume of distribution calculated for intravenous ciprofloxacin is approximately
2.1 - 2.7 L/kg. Studies with the oral and intravenous forms of ciprofloxacin
have demonstrated penetration of ciprofloxacin into a variety of tissues.
The binding of ciprofloxacin to serum proteins is 20% to 40%, which is not
likely to be high enough to cause significant protein binding interactions
with other drugs. Following administration of a single dose of CIPRO XR, ciprofloxacin concentrations in urine collected up to 4 hours after dosing averaged over 300 mg/L; in urine excreted from 12 to 24 hours after dosing, ciprofloxacin concentration averaged 27 mg/L.
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.
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.
Special Populations
Pharmacokinetic studies of the immediate-release oral tablet
(single dose) and intravenous (single and multiple dose) forms of
ciprofloxacin indicate that plasma concentrations of ciprofloxacin
are higher in elderly subjects (>65 years) as compared to young
adults. Cmax is increased 16% to 40%, and mean AUC is
increased approximately 30%, which can be at least partially
attributed to decreased renal clearance in the elderly. Elimination
half-life is only slightly (~20%) prolonged in the elderly. These
differences are not considered clinically significant. (See
PRECAUTIONS, Geriatric Use.)
In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged. No dose adjustment is required for patients with uncomplicated urinary tract infections receiving 500 mg CIPRO XR. The total drug exposure attained with 500 mg CIPRO XR is similar to or less than that achieved with a single dose of 500 mg immediate-release ciprofloxacin, which is approved for use in patients with severe renal impairment. (See DOSAGE AND ADMINISTRATION.)
In studies in patients with stable chronic cirrhosis, no significant changes in ciprofloxacin pharmacokinetics have been observed. The kinetics of ciprofloxacin in patients with acute hepatic insufficiency, however, have not been fully elucidated. (See DOSAGE AND ADMINISTRATION.)
Drug-drug Interactions
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 PRECAUTIONS, Drug
Interactions and Information for
Patients, and DOSAGE AND
ADMINISTRATION.)
Antacids: When CIPRO XR given as a single 1000 mg dose (twice the recommended daily 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, 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 (twice the recommended daily 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. These differences are not considered clinically significant. (See PRECAUTIONS, Drug Interactions.)
Back to topCiprofloxacin 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.
| Aerobic gram-positive
microorganisms Enterococcus faecalis (Many strains are only moderately susceptible.) Staphylococcus saprophyticus |
| Aerobic gram-negative
microorganisms Escherichia coli Proteus mirabilis |
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.
|
Aerobic gram-negative microorganisms
|
|
|
Citrobacter koseri
Citrobacter freundii Edwardsiella tarda Enterobacter aerogenes Enterobacter cloacae Klebsiella oxytoca |
Klebsiella pneumoniae
Morganella morganii Proteus vulgaris Providencia rettgeri Providencia stuartii Serratia marcescens |
Susceptibility Tests
Dilution Techniques: Quantitative methods are used to determine antimicrobial minimal inhibitory
concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs
should be determined using a standardized procedure. Standardized procedures are based on a dilution method1 (broth or
agar) or equivalent with standardized inoculum concentrations and standardized concentrations of ciprofloxacin. The MIC values should be interpreted according to the following criteria:
For testing Enterobacteriaceae, Enterococcus species, and Staphylococcus species:
|
MIC (µg/mL)
|
Interpretation
|
||
|
<= 1
2 >= 4 |
Susceptible (S)
Intermediate (I) 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
Escherichia coli Staphylococcus aureus |
ATCC 29212
ATCC 25922 ATCC 29213 |
0.25 -
2.0
0.004 - 0.015 0.12 - 0.5 |
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 species, and Staphylococcus species:
|
Zone Diameter (mm)
>= 21 16 - 20 <= 15 |
Interpretation
Susceptible (S) Intermediate (I) 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 Staphylococcus aureus |
ATCC 25922
ATCC 25923 |
30 - 40
22 - 30 |
CIPRO XR is indicated solely for the treatment of uncomplicated urinary tract infections (acute cystitis) 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 saprophyticusa.
a Treatment of infections due to this organism in this organ system was studied in fewer than 10 patients.
THE SAFETY AND EFFICACY OF CIPRO XR IN TREATING INFECTIONS OTHER THAN UNCOMPLICATED URINARY TRACT INFECTIONS HAVE 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.
Back to topCipro XR is contraindicated in persons with a history of hypersensitivity to ciprofloxacin or any member of the quinolone class of antimicrobial agents.
Back to topTHE 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.)
Convulsions, increased intracranial pressure, and toxic psychosis have been reported in patients receiving quinolones, including ciprofloxacin. Ciprofloxacin may also cause central nervous system (CNS) events including: dizziness, confusion, tremors, hallucinations, depression, and, rarely, suicidal thoughts or acts. These reactions may occur following the first dose. If these reactions occur in patients receiving ciprofloxacin, the drug should be discontinued and appropriate measures instituted. As with all quinolones, ciprofloxacin should be used with caution in patients with known or suspected CNS disorders that may predispose to seizures or lower the seizure threshold (e.g. severe cerebral arteriosclerosis, epilepsy), or in the presence of other risk factors that may predispose to seizures or lower the seizure threshold (e.g. certain drug therapy, renal dysfunction). (See PRECAUTIONS: General, Information for Patients, Drug Interactions and ADVERSE REACTIONS.)
SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED IN PATIENTS RECEIVING CONCURRENT ADMINISTRATION OF CIPROFLOXACIN AND THEOPHYLLINE. These reactions have included cardiac arrest, seizure, status epilepticus, and respiratory failure. Although similar serious adverse effects have been reported in patients receiving theophylline alone, the possibility that these reactions may be potentiated by ciprofloxacin cannot be eliminated. If concomitant use cannot be avoided, serum levels of theophylline should be monitored and dosage adjustments made as appropriate.
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving quinolone therapy. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria, and itching. Only a few patients had a history of hypersensitivity reactions. Serious anaphylactic reactions require immediate emergency treatment with epinephrine. Oxygen, intravenous steroids, and airway management, including intubation, should be administered as indicated.
Severe hypersensitivity reactions characterized by rash, fever, eosinophilia, jaundice, and hepatic necrosis with fatal outcome have also been rarely reported in patients receiving ciprofloxacin along with other drugs. The possibility that these reactions were related to ciprofloxacin cannot be excluded. Ciprofloxacin should be discontinued at the first appearance of a skin rash or any other sign of hypersensitivity.
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including ciprofloxacin, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.
Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of ldquo;antibiotic-associated colitis.”
If a diagnosis of pseudomembranous colitis is established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against C difficile colitis.
Achilles and other tendon ruptures that required surgical repair or resulted in prolonged disability have been reported with ciprofloxacin and other quinolones. Ciprofloxacin should be discontinued if the patient experiences pain, inflammation, or rupture of a tendon.
Back to topGeneral: Crystals of ciprofloxacin
have been observed rarely in the urine of human subjects but more
frequently in the urine of laboratory animals, which is usually
alkaline. (See ANIMAL PHARMACOLOGY.) Crystalluria related to ciprofloxacin has been reported only rarely in humans because human urine is usually acidic. Alkalinity of the urine should be avoided in patients receiving ciprofloxacin. Patients should be well hydrated to prevent the formation of highly concentrated urine.
Quinolones, including ciprofloxacin, may also cause central nervous system (CNS) events, including: nervousness, agitation, insomnia, anxiety, nightmares or paranoia. (See WARNINGS, Information for Patients, and Drug Interactions.)
Moderate to severe phototoxicity manifested as an exaggerated sunburn reaction has been observed in patients who are exposed to direct sunlight while receiving some members of the quinolone class of drugs. Excessive sunlight should be avoided. Therapy should be discontinued if phototoxicity occurs.
Information for Patients:
Patients should be advised:
Drug Interactions: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, or products containing calcium, iron, or zinc may ubstantially 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, metal cations such as iron, and multivitamin preparations with zinc. (See CLINICAL PHARMACOLOGY, Drug-drug Interactions, RECAUTIONS, 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. This difference is not considered clinically significant. (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 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.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Eight in vitro mutagenicity tests have been conducted with ciprofloxacin, and the test results are listed below:
| Salmonella/Microsome Test (Negative) E coli DNA Repair Assay (Negative) Mouse Lymphoma Cell Forward Mutation Assay (Positive) Chinese Hamster V79 Cell HGPRT Test (Negative) Syrian Hamster Embryo Cell Transformation Assay (Negative) Saccharomyces cerevisiae Point Mutation Assay (Negative) Saccharomyces cerevisiae Mitotic Crossover and Gene Conversion Assay (Negative) Rat Hepatocyte DNA Repair Assay (Positive) |
Thus, 2 of the 8 tests were positive, but results of the following 3 in vivo test systems gave negative results:
| Rat Hepatocyte DNA Repair Assay Micronucleus Test (Mice) Dominant Lethal Test (Mice) |
Ciprofloxacin was not carcinogenic or tumorigenic in 2-year carcinogenicity studies with rats and mice at daily oral dose levels of 250 and 750 mg/kg, respectively (approximately 4- and 6-fold greater than the 500 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 twice the maximum recommended daily human dose of 500 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 (1.9 times the highest recommended daily human dose of 500 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 (1.4 and 0.7 times the maximum daily human dose of 500 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 clinical studies with immediate-release ciprofloxacin, no differences in safety or effectiveness were observed between elderly and young patients. Ciprofloxacin is substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. However, no significant accumulation of ciprofloxacin is anticipated in elderly subjects with renal impairment who take CIPRO XR. The total drug exposure and maximum serum concentrations attained with CIPRO XR are similar to or less than the corresponding values achieved with 500 mg immediate-release ciprofloxacin, which is approved for use in renally impaired patients. Therefore, no reductions in dosage are required. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION.)
Back to topA clinical trial enrolled 905 ciprofloxacin treated patients, of whom 444 patients received the CIPRO XR 500 mg QD dose and 447 patients received the CIPRO 250 mg BID dose. Most adverse events reported (93.5%) were described as mild to moderate in severity and required no treatment. CIPRO XR was discontinued due to adverse reactions thought to be drug-related in 0.2% of patients.
Adverse reactions, judged by investigators to be at least possibly drug-related, occurring in greater than or equal to 1% of CIPRO XR treated patients were nausea (3%) and headache (2%).
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, photosensitivity reaction CARDIOVASCULAR: migraine DIGESTIVE: anorexia, constipation, diarrhea, dyspepsia, flatulence, thirst, vomiting CENTRAL NERVOUS SYSTEM: depersonalization, dizziness, hypertonia, incoordination, somnolence SKIN/APPENDAGES: maculopapular rash, pruritus, rash, skin disorder, vesiculobullous rash SPECIAL SENSES: taste perversion UROGENITAL: dysmenorrhea, vaginal candidiasis, vaginitis |
In the event of acute excessive overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage. The patient should be carefully observed and given supportive treatment. 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.
In uncomplicated urinary tract infections (acute cystitis), the recommended dosage of CIPRO XR is 500 mg once daily for 3 days.
CIPRO XR and ciprofloxacin immediate-release tablets are not interchangeable.
|
|
|||
|
|
|
|
|
|
|
|||
| Uncomplicated Urinary Tract Infection (Acute Cystitis) |
|
|
|
|
|
|||
CIPRO XR is available as nearly white to slightly yellowish, film-coated, oblong-shaped tablets containing 500 mg ciprofloxacin. The tablet is coded with the word “BAYER” on one side and “C500 QD” on the reverse side.
| NDC Code | |
| Bottles of 50 Bottles of 100 |
0026-8889-50 0026-8889-51 |
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].
Back to top
Back to top
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 redominate 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.
Uncomplicated Urinary Tract Infections (acute cystitis)
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 at Test of Cure (Day 4 - 11 Post-therapy).
The bacteriologic eradication and linical 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:
* n/N = patients with pathogen eradicated/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).
| 08756557M | 11490 |
 |
|||
|
|||
 |
|||
 |
|||
Physician Site
