In the event of acute overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage. The patient should be carefully observed and given supportive treatment. As with other quinolones, adequate hydration and electrolyte balance must be maintained. Due to the possibility of prolongation of the QTc interval and complications including arrhythmias, ECG monitoring is recommended after overdosage with RAXAR. It is not known if grepafloxacin can be efficiently removed by hemodialysis or peritoneal dialysis.
At oral doses of 4500 mg/kg (14,400 mg/m2) in mice and 3000 mg/kg (21,000 mg/m2) in rats significant increases in mortality were noted. These doses were approximately equivalent to 39 (mice) and 57 rats times the human dose on a mg/m2 basis.
RAXAR (grepafloxacin) Tablets are contraindicated in persons with a history of hypersensitivity to grepafloxacin or other members of the quinolone class of antimicrobial agents. RAXAR (grepafloxacin) Tablets are contraindicated in patients with hepatic failure. Because prolongation of the QTc interval has been observed in healthy volunteers receiving RAXAR (grepafloxacin) , RAXAR (grepafloxacin) Tablets are contraindicated in patients with known QTc prolongation. RAXAR (grepafloxacin) Tablets are also contraindicated in patients being treated concomitantly with medications known to produce an increase in the QTc interval and/or torsade de pointes (e.g., terfenadine) unless appropriate cardiac monitoring can be assured (e.g., in hospitalized patients) (see WARNINGS ).
Adverse reactions were assessed in clinical trials involving approximately 2500 patients receiving single-dose or multiple-dose regimens of grepafloxacin.
Multiple dose Regimens
Most of the adverse reactions reported in clinical trials were transient in nature, mild to moderate in severity, and required no treatment. Twenty of 1069 patients (1.9%) receiving grepafloxacin 400 mg daily and 50 of 925 patients (5.4%) receiving grepafloxacin 600 mg daily discontinued RAXAR (grepafloxacin) Tablets due to an adverse reaction thought by the investigator to be drug-related.
Table 3 lists adverse events that occurred with frequencies of 1% or greater. These events were thought by the investigators to be drug-related in patients treated with grepafloxacin in multiple dose clinical trials.
Table 3 Drug-related Adverse Reactions in Grepafloxacin Treated Patients on Multiple dose Dosing Regimens in Clinical Trials| Adverse Reaction | 400 mg daily (n=1069) | 600 mg daily (n=925) |
| Nausea | 11.1 % | 15.8 % |
| Taste perversion | 9.0 % | 17.8 % |
| Headache | 4.6 % | 4.9 % |
| Dizziness | 4.3 % | 5.4 % |
| Diarrhea | 3.5 % | 4.2 % |
| Vaginitis | 3.3 % | 1.4 % |
| Abdominal pain | 2.2 % | 2.1 % |
| Vomiting | 1.7 % | 5.7 % |
| Pruritus | 1.6 % | 1.2 % |
| Dyspepsia | 1.5 % | 3.1 % |
| Leukorrhea | 1.4 % | 0.0 % |
| Asthenia | 1.4 % | 2.3 % |
| Infection | 1.3 % | 0.4 % |
| Insomnia | 1.3 % | 2.1 % |
| Rash | 1.1 % | 1.9 % |
| Anorexia | 0.8 % | 1.8 % |
| Somnolence | 1.0 % | 1.5 % |
| Dry mouth | 0.8 % | 1.1 % |
| Photosensitivity reaction | 0.7 % | 1.8 % |
| Constipation | 0.7 % | 2.2 % |
| Pain | 0.6 % | 1.0 % |
| Nervousness | 0.6 % | 1.7 % |
Additional drug-related events, occurring in multiple-dose clinical trials at a rate of less than 1% were:
Body as a Whole: Back pain, body odor, chest pain, chills, facial edema, fever, malaise, neck rigidity, pelvic pain.
Cardiovascular System: Arrhythmia, hypotension, palpitations, peripheral vascular disorder, postural hypotension, syncope, tachycardia, vasodilatation.
Digestive System: Abnormal liver function tests, abnormal stools, cheilitis, dysphagia, eructation, flatulence, gastritis, gastrointestinal disorder, gingivitis, glossitis, increased appetite, melena, mouth ulceration, oral moniliasis, rectal disorder, rectal hemorrhage, stomatitis, tenesmus, thirst, tongue discoloration, tongue disorder, tongue edema.
Hemic and Lymphatic System: Anemia, eosinophilia, hypochromic, anemia, leukocytosis, leukopenia, lymphadenopathy, lymphocytosis, lymphoma like reaction, prothrombin decreased, prothrombin increased, reticuloendothelial hyperplasia, thrombocytopenia, thromboplastin increased.
Metabolic and Nutritional System: Dehydration, edema, electrolyte abnormality, gout, hyperglycemia, hyperlipidemia, hypernatremia, hyperuricemia, increased alkaline phosphatase, increased BUN, increased creatinine, increased gamma glutamyl transpeptidase, increased SGOT, increased SGPT, peripheral edema, weight loss.
Musculoskeletal System: Arthralgia, myalgia.
Nervous System: Abnormal dreams, abnormal gait, agitation, anxiety, confusion, depression, emotional lability, hallucinations, hyperkinesia, hypesthesia, hypokinesia, paresthesia, speech disorder, stupor, thinking abnormal, tremor, vertigo.
Respiratory System: Asthma, atelectasis, bronchitis, dyspnea, epistaxis, hemoptysis, increased cough, laryngismus, pharyngitis, pleural effusion, rhinitis, sputum increased.
Skin and Appendages: Acne, alopecia, dry skin, epidermal necrolysis, exfoliative dermatitis, fungal dermatitis, herpes simplex, maculopapular rash, skin disorder, sweating, urticaria, vesiculobullous rash.
Special Senses: Amblyopia, conjunctivitis, deafness, dry eyes, ear disorder, eye pain, lacrimation disorder, parosmia, photophobia, taste loss, tinnitus.
Urogenital System: Albuminuria, balanitis, dysuria, hematuria, impotence, polyuria, urethral pain, uricaciduria, urinary frequency, urinary tract disorder, urination impaired, urine abnormality, vulvovaginal disorder.
Single dose Regimens
In clinical trials, patients were treated for uncomplicated gonorrhea using a single dose of RAXAR (grepafloxacin) 400 mg. There were no deaths or permanent disabilities in these studies.
Table 4 lists the adverse events which occurred with frequencies of 1% or greater. These events were thought by the investigators to be drug related in patients treated with RAXAR (grepafloxacin) Tablets in single-dose clinical trials.
Table 4 Drug-related Adverse Reactions in Grepafloxacin Treated Patients on a Single dose Dosing Regimen in Clinical Trials| Adverse Reaction | 400 mg daily (n=487) |
| Vaginitis | 5.0% |
| Nausea | 3.3% |
| Dizziness | 2.1% |
| Vomiting | 2.1% |
| Headache | 1.8% |
| Leukorrhea | 1.2% |
| Abdominal pain | 1.2% |
| Diarrhea | 1.2% |
| Pruritus | 1.2% |
| Taste perversion | 1.2% |
Additional drug-related events occurring in single dose clinical trials at a rate of less than 1 were:
Observed During Clinical Practice
In addition to adverse reactions reported from clinical trials the following events have been identified during post-approval use of grepafloxacin formulations. Because they are reported voluntarily from a population of unknown size estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to grepafloxacin.
RAXAR (grepafloxacin) Tablets are indicated for treatment of adults with mild to moderate infections caused by susceptible strains of the designated microorganisms in the infections listed below:
Acute Bacterial Exacerbations of Chronic Bronchitis caused by Haemophilus influenzae, Streptococcus pneumoniae, or Moraxella catarrhalis (see CLINICAL PHARMACOLOGY: CLINICAL STUDIES subsection).
Community-acquired Pneumonia caused by Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis, or Mycoplasma pneumoniae (see CLINICAL PHARMACOLOGY: CLINICAL STUDIES subsection).
Uncomplicated Gonorrhea urethral in males and endocervical and rectal in females caused by Neisseria gonorrhoeae (see WARNINGS ).
Nongonococcal Urethritis and Cervicitis caused by Chlamydia trachomatis (see WARNINGS ).
Appropriate culture and susceptibility testing should be performed to determine susceptibility of the causative microorganism(s) to grepafloxacin. Therapy may be started while awaiting the results of this testing. Antimicrobial therapy should be appropriately adjusted according to the results of such testing.
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 ).
PRECAUTIONSGeneral
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:
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
WARNINGS).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.
Carcinogenesis, Mutagenesis, Impairment of Fertility
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.
Pregnancy
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
WARNINGS ).Nursing Mothers
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
WARNINGS).Geriatric Use
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.
Pediatric Use
The safety and effectiveness of grepafloxacin in children and adolescents less than 18 years of age have not been established.
RAXAR (grepafloxacin) Tablets may be taken with or without meals. Sucralfate; antacids containing magnesium, calcium, or aluminum; multivitamins containing iron or zinc; 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. The usual dose for RAXAR (grepafloxacin) is 400 mg or 600 mg orally every 24 hours as described in Table 5.
Table 5 Recommended Daily Dosages| Infection* | Dose | Frequency | Duration (days) |
| Acute bacterial exacerbations of chronic bronchitis† | 400 or 600 mg | once daily | 10 |
| Community-acquired pneumonia | 600 mg | once daily | 10 |
| Nongonococcal urethritis or cervicitis | 400 mg | once daily | 7 |
| Uncomplicated gonorrhea | 400 mg | single dose | 1 |
As with other broad-spectrum antimicrobial agents prolonged use of grepafloxacin may result in overgrowth of nonsusceptible organisms. Repeated evaluation of the patient's condition and microbial susceptibility testing is essential. If superinfection occurs during therapy, appropriate measures should be taken.
Patients with Renal Failure
Dosage adjustment is not required in patients with impaired renal function.
Patients with Hepatic Disease
Metabolism and excretion of grepafloxacin are reduced in patients with hepatic failure. RAXAR (grepafloxacin) Tablets are contraindicated in patients with hepatic failure (see CLINICAL PHARMACOLOGY).
