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THE SAFETY AND EFFICACY OF GREPAFLOXACIN IN CHILDREN, ADOLESCENTS (LESS T.A. 18 YEARS OF AGE), PREGNANT WOMEN, AND LACTATING WOMEN HAVE NOT BEEN ESTABLISHED (SEE
PRECAUTIONS - PEDIATRIC USE, PREGNANCY, AND NURSING MOTHERS SUBSECTIONS). Histopathological examination of the weight bearing joints of juvenile 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 CLINICAL PHARMACOLOGY: ANIMAL PHARMACOLOGY subsection).
Convulsions, increased intracranial pressure, and toxic psychosis have been reported in patients receiving quinolones. Quinolones may also cause central nervous system stimulation which may lead to tremors, restlessness, lightheadedness, confusion, or hallucinations. If these reactions occur in patients receiving grepafloxacin, the drug should be discontinued and appropriate treatment measures instituted. As with other quinolones, RAXAR (grepafloxacin) should be used with caution in patients with known or suspected CNS disorders such as severe cerebral arteriosclerosis, epilepsy, and other factors that predispose to seizures (see ADVERSE REACTIONS).
In healthy male and female volunteers who received RAXAR (grepafloxacin) , prolongation of the QTc interval was observed Because of a potential risk of cardiac arrhythmias including torsade de pointes, patients receiving RAXAR (grepafloxacin) should avoid concomitant treatment with medications known to prolong the QTc interval, e.g., class I antiarrhythmic agents (e.g., quinidine, procainamide), class III antiarrhythmic agents (e.g., amiodarone, sotalol), and bepridil, as well as erythromycin, terfenadine, astemizole, cisapride, pentamidine, tricyclic antidepressants, and some antipsychotics, including phenothiazines, when appropriate cardiac monitoring cannot be assured, e.g., during outpatient therapy (see CONTRAINDICATIONS). RAXAR (grepafloxacin) is not recommended for use in patients with ongoing pro-arrhythmic conditions, (e.g., hypokalemia, significant bradycardia, congestive heart failure, myocardial ischemia, and atrial fibrillation).
Serious and occasionally fatal hypersensitivity (anaphylactoid or anaphylactic) reactions have been reported in patients receiving therapy with quinolones, often following the first dose. Some reactions have been accompanied by cardiovascular collapse, hypotension, shock, seizure, loss of consciousness, tingling, angioedema, (including tongue, laryngeal, throat, or facial edema/swelling, etc.), airway obstruction (including bronchospasm, shortness of breath, and acute respiratory distress), dyspnea, urticaria/hives, itching, and other serious skin reactions. Only a few of these patients had a history of prior hypersensitivity reactions. Allergic reactions of varying severity, including anaphylactic shock and anaphylactoid reactions, have occurred in patients receiving grepafloxacin. Grepafloxacin should be discontinued if an allergic reaction or any other sign of hypersensitivity appears. Serious acute hypersensitivity reactions require immediate treatment.
Serious and sometimes fatal events of uncertain etiology have been reported in patients receiving therapy with quinolones. Serious events are extremely rare and generally occur following administration of multiple doses. Clinical manifestations of serious adverse events may include one or more of the following: fever, rash, or severe dermatologic reactions (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome, etc.); vasculitis, arthralgia, myalgia, serum sickness; allergic pneumonitis; interstitial nephritis, acute renal insufficiency/failure; hepatitis, jaundice, acute hepatic necrosis/failure; tendon pain, inflammation, or rupture; anemia (including hemolytic and aplastic anemia) thrombocytopenia, including thrombotic thrombocytopenic purpura, leukopenia, agranulocytosis, pancytopenia, and/or other hematologic abnormalities. Grepafloxacin should be discontinued immediately at the first appearance of any such reaction and appropriate intervention should be instituted (see PATIENT INFORMATION and ADVERSE REACTIONS).
The efficacy of grepafloxacin for treatment of syphilis is not known. Antimicrobial agents used in high doses for short periods of time to treat gonorrhea may mask or delay the symptoms of incubating syphilis. All patients with gonorrhea should have a serologic test for syphilis at the time of diagnosis. Patients treated with grepafloxacin should have a follow-up serologic test for syphilis 3 months after treatment for gonorrhea.
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including quinolones, 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". After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated.
Achilles and other tendon ruptures that required surgical repair or resulted in prolonged disability have been reported in patients receiving quinolone antibiotics. Grepafloxacin should be discontinued if the patient experiences pain inflammation or rupture of a tendon (see PATIENT INFORMATION ).
Phototoxicity reactions have been observed in patients who were exposed to direct sunlight or tanning booths while receiving some quinolones including grepafloxacin. Excessive sunlight should be avoided. Therapy should be discontinued if phototoxicity occurs.
Information for Patients
Patients should be advised:
- that grepafloxacin may be taken with or without meals.
- that grepafloxacin increases the effects of theophylline, and to advise their physician immediately if they are taking theophylline.
- that multivitamins (containing iron or zinc), antacids (containing magnesium, calcium, or aluminum), sucralfate, or VIDEX (didanosine) chewable/buffered tablets or the pediatric powder for oral solution should not be taken within 4 hours before or 4 hours after taking grepafloxacin (see DRUG INTERACTIONS).
- that grepafloxacin may increase the effects of other drugs metabolized by the liver, and to advise their physician of any of the drugs they are taking.
- to drink fluids liberally.
- that grepafloxacin may increase the effects of caffeine.
- that grepafloxacin may be associated with hypersensitivity reactions, even following a single dose, and to discontinue the drug at the first sign of skin rash, hives, or other skin reactions, a rapid heartbeat, difficulty in swallowing or breathing, or any other symptom of an allergic reaction (see
- that grepafloxacin 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 and coordination.
- to discontinue treatment; rest and refrain from exercise; and to contact their physician immediately if they experience pain, inflammation or rupture of a tendon .
- to avoid excessive sunlight or artificial ultraviolet light while taking grepafloxacin and to discontinue therapy if phototoxicity (e.g., sunburn-like reaction or skin eruptions) occurs.
Drug Interactions (See also DRUG INTERACTIONS.)
Antacids, Sucralfate, Metal Cations, Multivitamins: Quinolones form chelates with alkaline earth and transition metal cations. Administration of quinolones with antacids containing aluminum, magnesium, or calcium, with sucralfate, with metal cations such as iron, or with multivitamins containing iron or zinc, or with formulations containing divalent and trivalent cations such as VIDEX (didanosine) chewable/buffered tablets or the pediatric powder for oral solution, may substantially interfere with the absorption of quinolones, resulting in systemic concentrations considerably lower than desired. These agents should not be taken within 4 hours before or 4 hours after grepafloxacin administration.
Caffeine Theobromine: Grepafloxacin, like other quinolones, may inhibit the metabolism of caffeine and theobromine. These stimulants are commonly found in coffee and tea, respectively. In some patients, this may lead to reduced clearance, prolongation of plasma half-life, and enhanced effects of caffeine and theobromine.
Theophylline: Grepafloxacin is a competitive inhibitor of the metabolism of theophylline. Serum theophylline concentrations increase when grepafloxacin is initiated in a patient maintained on theophylline. When initiating a multi-day course of grepafloxacin in a patient maintained on theophylline, the theophylline maintenance dose should be halved for the period of concurrent use of grepafloxacin and monitoring of serum theophylline concentrations should be initiated as a guide to further dosage adjustments.
Warfarin: In subjects receiving warfarin, no significant change in clotting time was observed when grepafloxacin was coadministered. However, because some quinolones have been reported to enhance the effects of warfarin or its derivatives, prothrombin time or other suitable anticoagulation test should be monitored closely if a quinolone antimicrobial is administered with warfarin or its derivatives.
Drugs Metabolized by Cytochrome P450 Enzymes: The drug interaction study evaluating the effect of grepafloxacin on theophylline indicates that grepafloxacin inhibits theophylline metabolism, which is mediated by CYP1A2. While no clinical studies have been conducted to evaluate the effect of grepafloxacin on the metabolism of C.P.A. substrates, in vitro data suggest similar effects of grepafloxacin in CYP3A4, mediated metabolism and theophylline metabolism. In addition, other quinolones have been reported to decrease the C.P.A. mediated metabolism of cyclosporine. Other drugs metabolized by C.P.A. include terfenadine, astemizole, cisapride, midazolam, and triazolam. The clinical relevance of the potential effect of grepafloxacin on the metabolism of C.P.A. substrates is not known. Patients receiving concurrent administration of substrates of C.P.A. were not excluded from clinical trials of grepafloxacin.
Nonsteroidal Anti inflammatory Drugs (NSAIDs): The concomitant administration of a nonsteroidal anti inflammatory drug with a quinolone may increase the risks of CNS stimulation and convulsions (see
Antidiabetic Agents: Disturbances of blood glucose, including hyperglycemia and hypoglycemia, have been reported in patients treated concomitantly with quinolones and an antidiabetic agent. Therefore, careful monitoring of blood glucose is recommended when these agents are coadministered.
Long-term studies to determine the carcinogenic potential of grepafloxacin hydrochloride have not been performed. Grepafloxacin was not mutagenic in the Ames test, a forward gene mutation assay, mouse micronucleus assay, and an assay of unscheduled DNA repair (UDS) using rat hepatocytes. Grepafloxacin was mutagenic in a bacterial DNA repair test and in an in vitro chromosome aberration test.
In a rat intravenous fertility study, grepafloxacin produced no drug related changes in the estrous cycle of females; copulation or fertility of males or females.
Teratogenic Effects: Pregnancy Category C. Grepafloxacin had neither embryolethal nor teratogenic effects in rats when administered orally or intravenously. There was no compound-related effect on maintenance of pregnancy, parturition, implantation of females, ovulation, nursing, or on viability, body weight, or morphology of fetuses. However, a decrease in placental weight and in the number of ossified saccrococcygeal vertebrae were observed in rats at 2.4 times the recommended maximum daily human dose based on mg/m2 (15 times the recommended maximum daily human dose on a mg/kg basis); this was associated with maternal toxicity (decreased body weight and food consumption). No effect was noted at 420 mg/m2 per day (equivalent to the human dose).
Grepafloxacin had no embryolethal or teratogenic effects in rabbits. However, fetal body weight was suppressed and there was a tendency for a decrease in placental weight at 60 mg/kg doses. Maternal toxicity was demonstrated by abortion in rabbits at doses of 40 mg/kg or higher, a finding which is common in reproductive studies with antibacterial agents in rabbits.
In a perinatal/postnatal study in rats, death and prolongation of delivery time were observed at 2.4 times the recommended maximum daily human dose based on a mg/m2 basis (15 times the recommended maximum daily human dose on a mg/kg basis). There was no drug-related effect on delivery index, lactation, or offspring.
Adequate and well-controlled studies have not been conducted in pregnant women. Grepafloxacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus (see
Grepafloxacin is excreted in human milk. Grepafloxacin was detectable in breast milk of one patient who was studied on the ninth day of treatment at 4 to 5 hours after oral administration of 400 mg of grepafloxacin.
Blood and milk concentrations of radioactivity were determined after oral administration of radiolabeled grepafloxacin at a dose of 40 mg/kg in lactating rats at 12 to 13 days post partum. The concentration of radioactivity in milk reached a maximum of 9.03 mg Eq/mL at 1 hour after administration and decreased to 3.20 mg Eq/mL at 24 hours after administration. The AUC(0-48 h) of radioactivity concentration in milk was 16 times that observed in the blood.
It is known that other quinolones are excreted in human milk. Because of the potential for serious adverse experiences from grepafloxacin in nursing infants a decision should be made to discontinue nursing or discontinue administration of the drug, taking into account the importance of this drug to the mother (see
Of the total number of subjects in clinical studies of RAXAR (grepafloxacin) , 409 were 65 and over, while 104 were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
The safety and effectiveness of grepafloxacin in children and adolescents less than 18 years of age have not been established.
This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 12/8/2004
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