WARNINGS
THE SAFETY AND EFFECTIVENESS OF PROQUIN XR IN PEDIATRIC PATIENTS AND ADOLESCENTS (LESS THAN 18 YEARS OF AGE), PREGNANT WOMEN, AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED. ( See PRECAUTIONS:Pediatric Use, Pregnancy, and Nursing Mothers subsections. )
Ciprofloxacin, as with other members of the quinolone class, causes arthropathy and/or chondroplasia in immature dogs. Related quinolone-class drugs also produce erosions of cartilage of weight-bearing joints and other signs of arthropathy in immature animals of various species. The relevance of these findings to the clinical use of ciprofloxacin is unknown. (See ANIMAL PHARMACOLOGY)
Central Nervous System: Convulsions, increased intracranial pressure, and toxic psychosis have been reported in patients receiving quinolones, including ciprofloxacin. Ciprofloxacin may also cause CNS events including: dizziness, confusion, tremors, hallucinations, depression, and, rarely, suicidal thoughts or acts. The 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)
Theophylline: SERIOUS AND FATAL REACTIONS HAVE BEEN REPORTED IN PATIENTS RECEIVING CONCURRENT ADMINISTRATION OF FLUOROQUINOLONES, INCLUDING CIPROFLOXACIN, AND THEOPHYLLINE. These reactions have included cardiac arrest, seizure, status epilepticus, and respiratory failure. Although similar adverse effects have been reported in patients receiving theophylline alone, the possibility that these reactions may be potentiated by ProQuin XR cannot be eliminated. If concomitant use cannot be avoided, serum levels of theophylline should be monitored and dosage adjustments made as appropriate.
Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving quinolone therapy. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, tingling, pharyngeal or facial edema, dyspnea, urticaria, and itching. Only a few patients had a history of hypersensitivity reactions. Serious anaphylactic reactions may 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 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: 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 “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 fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against C. difficile colitis. Drugs that inhibit peristalsis should be avoided.
Peripheral Neuropathy: Rare cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paresthesias, hypoesthesias, dyesthesias, 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, hands, Achilles 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 elderly patients. 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 ruptures can occur during or after therapy with quinolones, including ciprofloxacin.
PRECAUTIONS
General
Crystals of ciprofloxacin have been observed rarely in the urine of human subjects but more frequently in the urine of laboratory animals, which is usually alkaline. (See ANIMAL PHARMACOLOGY) Crystalluria related to ciprofloxacin has been reported only rarely in humans because human urine is usually acidic. Alkalinity of the urine should be avoided in patients receiving ciprofloxacin. Patients should be well hydrated to prevent the formation of highly concentrated urine.
Quinolones, including ciprofloxacin, may also cause CNS events, including nervousness, agitation, insomnia, anxiety, nightmares, or paranoia. (See WARNINGS)
Moderate to severe phototoxicity manifested as an exaggerated sunburn reaction has been observed in patients who are exposed to direct sunlight while being treated with some members of the quinolones class of drugs. Excessive sunlight should be avoided. Therapy with ciprofloxacin should be discontinued if phototoxicity occurs.
Prescribing ProQuin XR in the absence of a strongly suspected bacterial infection is unlikely to benefit the patient and increases the risk of the development of drug-resistant bacteria.
Information for Patients
Patients should be advised:
- that antibacterial drugs, including ProQuin XR, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When ProQuin XR is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by ProQuin XR or other antibacterial drugs in the future.
- that ProQuin XR should only be used to treat uncomplicated urinary tract infections (also known as bladder infections). The safety and efficacy of ProQuin XR to treat other urinary tract or non-urinary tract infections have not been studied.
- that ProQuin XR should be taken with a main meal of the day, preferably the evening meal. The patient should not take more than one ProQuin XR tablet per day, even if the patient misses a dose
- that ProQuin XR tablets should be taken whole and never split, crushed, or chewed.
- that concomitant administration of ProQuin XR with aluminum or magnesium-containing antacids, sucralfate, VIDEX®(didanosine) chewable buffered tablets or pediatric powder, metal cations such as iron and calcium, and multivitamin preparations containing zinc should be avoided. ProQuin XR should be administered at least 4 hours before or 2 hours after these products. (See CLINICAL PHARMACOLOGY: Drug Interactions, DOSAGE AND ADMINISTRATION, and PRECAUTIONS: Drug Interactions)
- that ProQuin XR should not be taken with dairy products (like milk or yogurt) or calcium-fortified juices alone, since the absorption of ciprofloxacin may be significantly reduced. However, ProQuin XR may be taken with a meal that contains these products. (See CLINICAL PHARMACOLOGY: Drug Interactions and PRECAUTIONS: Drug Interactions)
- that ciprofloxacin may be associated with hypersensitivity reactions, even following a single dose, and to discontinue ProQuin XR at the first sign of a skin rash or other allergic reaction and contact their physician.
- to avoid excessive sunlight or artificial ultraviolet (UV) light while receiving ProQuin XR and to discontinue therapy if phototoxicity occurs.
- that peripheral neuropathies have been associated with ciprofloxacin use. If symptoms of peripheral neuropathy including pain, burning, tingling, numbness and/or weakness develop, patients should discontinue treatment and contact their physician.
- that if they experience pain, inflammation, or rupture of a tendon to discontinue treatment, to inform their physician, and to rest and refrain from exercise.
- to contact their doctor if they do not feel better or if they develop fever and back pain while or after taking ProQuin XR.
- that ProQuin XR may cause dizziness and lightheadedness; therefore, patients should know how they react to this drug before they operate an automobile or machinery or engage in activities requiring mental alertness or coordination.
- that ProQuin XR may increase the effects of theophylline and caffeine. There is a possibility of caffeine accumulation when products containing caffeine are consumed while taking quinolones.
- that convulsions have been reported in patients receiving quinolones, including ciprofloxacin, and to notify their physician before taking this drug if there is a history of this condition.
Drug Interactions
Caffeine: 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.
Cyclosporine: Some quinolones, including ciprofloxacin, have been associated with transient elevations in serum creatinine in patients receiving cyclosporine concomitantly.
Glyburide: The concomitant administration of ciprofloxacin with the sulfonylurea glyburide has, on rare occasions, resulted in severe hypoglycemia.
Histamine H2 antagonists: Histamine H2 antagonists appear to have no significant effect on the bioavailability of ciprofloxacin.
Methotrexate: Renal tubular transport of methotrexate may be inhibited by concomitant administration of ciprofloxacin, potentially leading to increased plasma levels of methotrexate. This might increase the risk of methotrexate toxic reactions. Therefore, patients under methotrexate therapy should be carefully monitored when concomitant ciprofloxacin therapy is indicated.
Multivalent cation-containing products: Concurrent administration of a quinolone, including ciprofloxacin, with multivalent cation-containing products such as magnesium or aluminum antacids, sucralfate, VIDEX® chewable/buffered tablets or pediatric powder, or products containing calcium, iron, or zinc may substantially decrease the absorption of ciprofloxacin, resulting in serum and urine levels considerably lower than desired. ProQuin XR should be administered at least 4 hours before or 2 hours after these products. This time window is different than for other oral formulations of ciprofloxacin, which are usually administered 2 hours before or 6 hours after antacids. (See CLINICAL PHARMACOLOGY: Drug Interactions, PRECAUTIONS: Information for Patients, and DOSAGE AND ADMINISTRATION)
Non-steroidal anti-inflammatory drugs (but not aspirin): These drugs in combination with very high doses of quinolones have been shown to provoke convulsions in pre-clinical studies.
Omeprazole: The rate and extent of absorption of ciprofloxacin was bioequivalent when ProQuin XR was given alone or when ProQuin XR was given 2 hours after omeprazole at the dose that maximally suppresses gastric acid secretion. Omeprazole should be taken as directed and ProQuin XR should be taken with a main meal of the day, preferably the evening meal. (See CLINICAL PHARMACOLOGY: Drug Interactions and Information for Patients).
Phenytoin: Altered serum levels of phenytoin (increased and decreased) have been reported in patients receiving concomitant ciprofloxacin.
Probenecid: Probenecid interferes with renal tubular secretion of ciprofloxacin and produces an increase in the level of ciprofloxacin in serum.
Theophylline: As with some other quinolones, concurrent administration of ciprofloxacin with theophylline may lead to elevated serum concentrations of theophylline and prolongation of its elimination half-life. This may result in increased risk of theophylline-related adverse reactions. (See WARNINGS) If concomitant use cannot be avoided, serum levels of theophylline should be monitored and dosage adjustments made as appropriate.
Warfarin: 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 monitored.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Rodent carcinogenicity studies were not required. Two in in vitro mutagenicity tests were conducted with ciprofloxacin:
- Bacterial Reverse Mutation Assay; negative for mutagenicity in the presence and absence of an S-9 metabolic activation system.
- Chinese Hamster Ovary (CHO) Chromosomal Aberration Assay; positive for inducing chromosomal aberrations.
In addition to the in vitro genotoxicity assays, an in vivo rat micronucleus study with ciprofloxacin was negative.
Fertility studies performed with male and female rats at oral doses of ciprofloxacin up to 600 mg/kg/day (approximately 10-fold the recommended 500 mg therapeutic dose based upon body surface area) revealed no evidence of impairment.
Pregnancy: Teratogenic Effects. Pregnancy Category C
There are no adequate and well-controlled studies of ProQuin XR 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 that there is no risk.
A controlled prospective observational study followed 200 women exposed to fluoroquinolones (52.5% exposed to ciprofloxacin and 68% first trimester exposures) during gestation. In utero exposure to fluoroquinolones during embryogenesis was not associated with increased risk of major malformations. The reported rates of major congenital malformations were 2.2% for the fluoroquinolone group and 2.6% for the control group (background incidence of major malformations is 1-5%). Rates of spontaneous abortions, prematurity and low birth weight did not differ between the groups and there were no clinically significant musculoskeletal dysfunctions up to one year of age in the ciprofloxacin-exposed children.
Another prospective follow up study reported on 549 pregnancies with fluoroquinolone exposure (93% first trimester exposures). There were 70 ciprofloxacin exposures, all within the first trimester. The malformation rates among live-born babies exposed to ciprofloxacin and to fluoroquinolones overall were both within background incidence ranges. No specific patterns of congenital abnormalities were found. The study did not reveal any clear adverse reactions due to in utero exposure to ciprofloxacin.
No differences in the rates of prematurity, spontaneous abortions, or birth weight were seen in women exposed to ciprofloxacin during pregnancy. However, these small postmarketing epidemiology studies, of which most experience is from short term first semester exposure, are insufficient to evaluate the risk for 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 the potential benefit justifies the potential risk to both fetus and mother (see WARNINGS).
Embryo/fetal developmental toxicity studies were conducted in pregnant rats and rabbits using oral doses up to 600 mg/kg/day in rats and 30 mg/kg/day in rabbits. Fetal development (skeletal variation) was affected in rats at the maternally toxic dose of 600 mg/kg/day (approximately 1.8-fold the recommended 500 mg therapeutic dose based upon plasma AUC measure of systemic exposure). The maternally toxic 30 mg/kg/day dose to pregnant rabbits resulted in abortions and body weight gain depression; embryo/fetal lethality and skeletal developmental effects were observed at this dose level (approximately 1.2-fold the recommended therapeutic dose based upon body surface area). The 10 mg/kg/day dose level, although maternally toxic, did not induce embryo/fetal developmental effects. A peri/postnatal developmental toxicity study with pregnant/lactating female rats exhibited no developmental effects to the F1 pups at the highest dose level of 600 mg/kg/day; the 300 and 600 mg/kg/day dose levels were maternally toxic to the pregnant dams based upon slight body weight gain reduction. No evidence of compound-related fetal malformation was observed in any of the reproductive toxicity studies.
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 ciprofloxacin taking into account the importance of the drug to the mother.
Pediatric Use
The safety and effectiveness of ProQuin XR in pediatric patients and adolescents less than 18 years of age have not been established. Quinolones, including ciprofloxacin, cause arthropathy in juvenile animals. (See WARNINGS)
Geriatric Use
Clinical experience with ProQuin XR did not include sufficient number of subjects 65 years of age or older to determine whether they respond differently than younger subjects. Reported clinical experience with other formulations of ciprofloxacin has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals on any drug therapy cannot be ruled out. Ciprofloxacin is 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. (See CLINICAL PHARMACOLOGY and DOSAGE and ADMINISTRATION)
|
