Prescription Drugs

CLINICAL PHARMACOLOGY Absorption Grepafloxacin is rapidly and extensively absorbed following oral administration of RAXAR (grepafloxacin) Tablets Bioavailability of the tablet is equivalent to the bioavailability of an oral solution of grepafloxacin. The absolute bioavailability of RAXAR (grepafloxacin) Tablets was estimated by comparing the areas under the plasma grepafloxacin concentration versus time curve (AUC) after intravenous and oral administration of grepafloxacin in separate studies. The absolute bioavailability is approximately 70%. Single-dose and steady-state pharmacokinetic parameters following administration of 400 mg and 600 mg doses to healthy adult males are displayed in Table 1. Table 1 Single-dose and Steady-state Pharmacokinetic Parameters in Healthy Adult Males Parameter Single-dose Pharmacokinetic Parameters Steady-state Pharmacokinetic Parameters 400 mg (n=40) 600 mg (n=31) 400 mg (n=10) 600 mg (n=46) *AUC (µgh/mL) 12.27 ± 3.81 22.66 ± 5.65 14.08 ± 2.80 27.51 ± 6.95 Cmax (µg/mL) 1.11 ± 0.34 1.58 ± 0.37 1.35 ± 0.25 2.25 ± 0.48 Trough (µg/mL) not applicable not applicable 0.21 ± 0.08 0.55 ± 0.22 *AUC=AUC¥ for single-dose; AUC0-24 for steady-state. On average, the peak plasma drug concentration (Cmax) is achieved 2 to 3 hours after dosing. Steady-state concentrations of grepafloxacin are achieved within 7 days of once a day dosing. Grepafloxacin pharmacokinetic parameters were determined following administration of 600 mg grepafloxacin immediately following a high fat meal (1000 kcal, 67 grams fat, 38 grams protein, 63 grams carbohydrates) and administration in the fasted state (n=29). There was no difference in grepafloxacin pharmacokinetic parameters between the fasted and fed treatments. Milk had no effect on the Cmax, Tmax, or AUC of grepafloxacin after oral administration. Neutralization of gastric acidity by intravenous administration of the histamine type-2 receptor antagonist famotidine did not affect the absorption or other pharmacokinetic properties of RAXAR (grepafloxacin) Tablets Distribution The apparent volume of distribution after oral administration of grepafloxacin 400 mg was 5.07 ± 0.95 L/kg, suggesting that grepafloxacin distributes widely into extravascular spaces. Binding of grepafloxacin to human plasma proteins is low (approximately 50%). Table 2 summarizes the concentrations of grepafloxacin in fluids and tissues compared with serum drug concentration. Table 2 Distribution of Grepafloxacin into Tissues and Fluids After Oral Administration n=number of subjects Concentration Mean ± SD Tissue or Fluid Oral Dose (mg) Hours Post-Dose n Serum (µg/mL) Tissue or Fluid (µg/mL or µg/g) Ratio Alveolar lining fluid 400 4-5 5 1.76 27.1 15.4 Alveolar macrophages 400 4-5 5 1.76 278 158 Cervix uteri 100 4-5 5 1.23 ± 0.26 3.42 ± 0.65 2.8 Portio vaginalis 100 4-5 5 1.23 ± 0.26 2.58 ± 0.69 2.1 Sputum 200 4 7 0.47 ± 0.11 1.04 ± 0.48 2.2 Metabolism and Excretion The plasma elimination half-life of grepafloxacin at steady-state was 15.7 ± 4.2 hours Grepafloxacin is eliminated predominantly through hepatic metabolism and biliary excretion. Less than 10% of an oral dose is excreted as unchanged grepafloxacin in urine. Approximately 88% of an oral dose of radiolabeled grepafloxacin 400 mg was recovered in urine (38%) and feces (50%) over 7 days post dose. Approximately one half of the AUC in plasma for the 12 hours after dosing was due to unchanged grepafloxacin; 68% of AUC in plasma for 12 hours after dosing was due to unchanged grepafloxacin plus known metabolites. Unchanged grepafloxacin (6% of dose) and several metabolites (in amounts ranging from 0.08% to 5.57% of dose) were recovered in urine. Unchanged grepafloxacin (27% of dose) and several metabolites (in amounts ranging from 1.83% to 3.91% of dose) were recovered in feces. Grepafloxacin metabolites include glucuronide (major metabolite) and sulfate conjugates and oxidative metabolites. The oxidative metabolites are formed mainly by cytochrome P450 1A2 (CYP1A2), while the cytochrome P450 3A4 (CYP3A4) has minor involvement. The nonconjugated metabolites have little antimicrobial activity compared with the parent drug. The conjugated metabolites have no antimicrobial activity. Special Populations Gender: Following administration of RAXAR (grepafloxacin) 600 mg daily for 7 days, Cmax was approximately 30% to 50% higher and AUC was approximately 20% to 50% higher in females compared to males. The observed differences appear to be due mainly to differences in body weight. Total clearance (per unit body weight), renal clearance (per unit body weight), and half-life did not differ between males and females. The observed differences in pharmacokinetic properties by gender do not necessitate any difference between males and females in dosage and administration. Geriatric: There are no significant differences in grepafloxacin pharmacokinetics between young and elderly subjects. Pediatric: Grepafloxacin has not been evaluated in pediatric patients. Hepatic Insufficiency: Two studies were performed to assess the effect of hepatic failure on grepafloxacin pharmacokinetics. Both studies evaluated subjects with normal hepatic function, with mild (Child-Pugh class A) hepatic failure, or moderate hepatic failure (Child-Pugh class B). In one study, oral clearance was reduced by approximately 50% in patients with mild hepatic failure (n=5)relative to subjects with normal hepatic function (n=6). In the second study oral clearance was reduced by approximately 15% in subjects with mild hepatic failure (n=5)relative to subjects with normal hepatic function (n=8). Due to the different results for the two studies, it is not possible to determine an appropriate dose adjustment for subjects with mild hepatic failure. In both studies oral clearance was decreased by >50% in subjects with moderate hepatic failure (n=9, n=3) compared to subjects with normal hepatic function (n=6, n=8). RAXAR (grepafloxacin) Tablets are contraindicated for use in patients with hepatic failure (see DOSAGE AND ADMINISTRATION .) Renal Insufficiency: Renal clearance of grepafloxacin was 0.458 ± 0.04 mL/min per kg in adults with normal renal function. The effect of varying degrees of renal function on the pharmacokinetics of grepafloxacin was assessed in 15 patients with impaired renal function (creatinine clearances ranging from 7.5 to 64 mL/min) compared with five adults with normal renal function. Varying degrees of renal function did not substantially affect the pharmacokinetic properties of grepafloxacin Smokers: In a population pharmacokinetics study of grepafloxacin in patients with acute bacterial exacerbations of chronic bronchitis grepafloxacin clearance was 35% to 43% faster in patients who smoked relative to patients who did not smoke. This observation is consistent with the involvement of C.P.A. in the metabolism of grepafloxacin and the known induction of this enzyme in smokers. However, in the pivotal clinical trials, smoking did not have an effect on clinical efficacy. Drug Interactions (See also PRECAUTIONS, DRUG INTERACTIONS). Antacids: Following administration of 200 mg grepafloxacin with 1 gram aluminum hydroxide, grepafloxacin AUC and Cmax were both decreased by approximately 60% relative to administration of grepafloxacin alone (n=6) (see PRECAUTIONS, DRUG INTERACTIONS). Probenecid: Administration of 200 mg grepafloxacin with 500 mg probenecid followed by 500 mg probenecid every 12 hours for three doses did not alter grepafloxacin pharmacokinetics (n=6). Theophylline: Grepafloxacin is a competitive inhibitor of theophylline metabolism. Twelve healthy subjects received an individualized regimen of sustained-release theophylline alone for 7 days, followed by coadministration of the theophylline regimen with 600 mg grepafloxacin once daily for 10 days. Following the addition of grepafloxacin, theophylline clearance decreased by approximately 50%, from 0.78 ± 0.25 to 0.40 ± 0.08 mL/min per kg. Steady-state peak theophylline concentration increased from 8.30 ± 1.54 µg/mL to 15.12 ± 3.69 µg/mL (see PRECAUTIONS, DRUG INTERACTIONS). Warfarin: Fourteen healthy subjects received an individualized regimen of warfarin alone for 14 days, followed by coadministration of the warfarin regimen with 600 mg grepafloxacin once daily for 10 days. Grepafloxacin did not alter the anticoagulant effect of warfarin. Other quinolones have been reported to enhance the anticoagulant effects of warfarin (see PRECAUTIONS, DRUG INTERACTIONS). Microbiology Grepafloxacin has in vitro activity against a wide range of gram-positive and gram-negative aerobic microorganisms, as well as some atypical microorganisms. Grepafloxacin exerts its antibacterial activity by inhibiting bacterial topoisomerase II (DNA gyrase) and topoisomerase IV, essential enzymes for duplication, transcription, and repair of bacterial DNA. Beta-lactamase production has no effect on grepafloxacin activity and penicillin-resistant Streptococcus pneumoniae strains have undiminished in vitro susceptibility to grepafloxacin. Grepafloxacin is bactericidal at concentrations equal to or slightly greater than minimum inhibitory concentrations (MICs). Resistance to grepafloxacin through spontaneous mutation in vitro occurs at a low frequency (10-8 to 10-10). As with other fluoroquinolones, the mutation frequency was higher for Pseudomonas species and Stenotrophomonas maltophilia than for other microorganisms. When resistance develops, it does so through slow stepwise increases in MICs. In clinical trials, grepafloxacin-resistant mutants were rarely encountered during the treatment of infections caused by susceptible isolates When they did occur, they were usually Pseudomonas species isolates. Although cross-resistance has been observed between grepafloxacin and some other fluoroquinolones, some organisms resistant to other quinolones are susceptible to grepafloxacin. Quinolones differ in chemical structure and mode of action from other classes of antimicrobial agents, including beta-lactam antibiotics and aminoglycosides; therefore, microorganisms resistant to these other classes of drugs may be susceptible to grepafloxacin and other quinolones. In vitro tests show that grepafloxacin has reduced activity against some gram-positive microorganisms when combined with rifampin. Grepafloxacin 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: Streptococcus pneumoniae (penicillin-susceptible strains) Aerobic Gram negative Microorganisms: Haemophilus influenzae Moraxella catarrhalis Neisseria gonorrhoeae Other Microorganisms: Chlamydia trachomatis Mycoplasma pneumoniae The following in vitro data are available, but their clinical significance is unknown. Grepafloxacin exhibits in vitro MICs of 1 µg/mL or less against most (³90%) strains of the following microorganisms; however, the safety and effectiveness of grepafloxacin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials. Aerobic Gram positive Microorganisms: Staphylococcus aureus (methicillin-susceptible strains) Staphylococcus epidermidis (methicillin-susceptible strains) Streptococcus agalactiae Streptococcus pneumoniae (penicillin-resistant strains) Streptococcus pyogenes. Aerobic Gram negative Microorganisms: Citrobacter freundii Citrobacter (diversus) koseri Enterobacter aerogenes Enterobacter cloacae Escherichia coli Haemophilus parainfluenzae Klebsiella oxytoca Klebsiella pneumoniae Morganella morganii Proteus mirabilis Proteus vulgaris Other Microorganisms Legionella pneumophila Susceptibility Tests Dilution Techniques: Quantitative methods are used to determine MICs. These M.C. provide estimates of the susceptibility of bacteria to antimicrobial compounds. The M.C. 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 grepafloxacin powder. The MIC values should be interpreted according to the following criteria: For testing aerobic organisms other than Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria gonorrhoeae: MIC (µg/mL) Interpretation £ 1 Susceptible (S) 2 Intermediate (I) ³ 4 Resistant (R) For testing Streptococcus pneumoniae:a MIC (µg/mL) Interpretation £ 1 Susceptible (S) a These interpretive standards are applicable only to broth microdilution susceptibility tests using cation-adjusted Mueller-Hinton broth with 2% to 5% lysed horse blood. The current absence of data on resistant strains precludes defining any categories other than "Susceptible". Strains yielding MIC results suggestive of a "Nonsusceptible" category should be submitted to a reference laboratory for further testing. For testing Haemophilus influenzae:b MIC (µg/mL) Interpretation £ 0.25 Susceptible (S) b These interpretive standards are applicable only to broth microdilution susceptibility testing with Haemophilus influenzae using Haemophilus Test Medium HTM1. The current absence of data on resistant strains precludes defining any categories other than "Susceptible". Strains yielding MIC results suggestive of a "Nonsusceptible" category should be submitted to a reference laboratory for further testing. For testing Neisseria gonorrhoeae:c MIC (µg/mL) Interpretation £ 0.06 Susceptible (S) c These interpretive standards are applicable only to agar dilution tests with GC agar base and 1% defined growth supplement. The current absence of data on resistant strains precludes defining any categories other than "Susceptible". Strains yielding MIC results suggestive of a "Nonsusceptible" category should be submitted to a reference laboratory for further testing. A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentration 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 a 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 concentration 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 grepafloxacin powder should provide the following MIC values: Microorganism MIC Range (µg/mL) Escherichia coli ATCC 25922 0.004-0.03 Haemophilus influenzae ATCC 49247a 0.002-0.016 Neisseria gonorrhoeae ATCC 49226b 0.004-0.03 Staphylococcus aureus ATCC 29213 0.03-0.12 Streptococcus pneumoniae ATCC 49619c 0.06-0.5 a This quality control range is applicable only to H influenzae ATCC 49247 tested by a broth microdilution procedure using HTM.1 b This quality control range is applicable only to N gonorrhoeae ATCC 49226 tested by agar dilution using GC agar base with 1% defined growth supplement. c This quality control range is applicable only to S pneumoniae ATCC 49619 tested by a broth microdilution procedure using cation-adjusted Mueller-Hinton broth with 2 to 5 lysed horse blood. 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 grepafloxacin to test the susceptibility of microorganisms to grepafloxacin. Reports from the laboratory providing results of the standard single disk susceptibility test with a 5-µg disk should be interpreted according to the following criteria: For aerobic organisms other than Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria gonorrhoeae: Zone Diameter (mm) Interpretation ³ 18 Susceptible (S) 15-17 Intermediate (I) £ 14 Resistant (R) For testing Streptococcus pneumoniae:a Zone Diameter (mm) Interpretation ³ 19 Susceptible (S) a These zone diameter standards for Streptococcus pneumoniae are applicable only to tests performed using Mueller-Hinton agar supplemented with 5% sheep blood and incubated in 5% CO2. The current absence of data on resistant strains precludes defining any categories other than "Susceptible". Strains yielding zone diameter results suggestive of a "Nonsusceptible" category should be submitted to a reference laboratory for further testing. For testing Haemophilus influenzae:b Zone Diameter (mm) Interpretation ³ 24 Susceptible (S) b These zone diameter standards are applicable only to disk diffusion testing with Haemophilus influenzae using HTM2. The current absence of data on resistant strains precludes defining any categories other than "Susceptible". Strains yielding zone diameter results suggestive of a "Nonsusceptible" category should be submitted to a reference laboratory for further testing. For testing Neisseria gonorrhoeae:c Zone Diameter (mm) Interpretation ³ 37 Susceptible (S) c These zone diameter standards for Neisseria gonorrhoeae are applicable only to disk diffusion tests with GC agar base and 1% growth supplement. The current absence of data on resistant strains precludes defining any categories other than "Susceptible." Strains yielding zone diameter results suggestive of a "Nonsusceptible" category should be submitted to a reference laboratory for further testing. 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 grepafloxacin. 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 grepafloxacin disk should provide the following zone diameters in these laboratory test quality control strains: Microorganism Zone Diameter (mm) Escherichia coli ATCC 25922 28-36 Haemophilus influenzae ATCC 49247a 32-39 Neisseria gonorrhoeae ATCC 49226b 44-52 Staphylococcus aureus ATCC 25923 26-31 Streptococcus pneumoniae ATCC 49619c 21-28 a This quality control range is applicable only to H. influenzae ATCC 49247 tested by a disk diffusion procedure using HTM.2 b This quality control range is applicable only to N. gonorrhoeae ATCC 49226 tested by a disk diffusion procedure using GC agar base with 1% defined growth supplement. c This quality control range is applicable only to S. pneumoniae ATCC 49619 tested by a disk diffusion procedure using Mueller-Hinton agar supplemented with 5% sheep blood and incubated in 5% CO2. CLINICAL STUDIES Acute Bacterial Exacerbations of Chronic Bronchitis Two separate controlled randomized trials of grepafloxacin in the treatment of acute bacterial exacerbations of chronic bronchitis yielded overall efficacy rates of grepafloxacin 400 mg and grepafloxacin 600 mg which demonstrated equivalence to comparators. However, these studies suggest that grepafloxacin 400 mg once daily for 10 days may be less effective against S. pneumoniae than grepafloxacin 600 mg once daily for 10 days or comparator for 10 days. These studies excluded patients whose respiratory status required the initiation of steroid therapy or an increase in maintenance steroid doses greater than prednisone 10 mg per day (or its equivalent). Clinical success at end of treatment did not always predict clinical success at follow-up. Table 6 presents efficacy data from these two trials at end of treatment (1 to 5 days posttreatment) and at follow-up (14 to 28 days posttreatment). Table 6 Clinical Efficacy in Studies of Acute Bacterial Exacerbations of Chronic Bronchitis Study 106-92-301 End of Treatment (1-3 Days Posttreatment) Follow-up (14 Days Posttreatment) Grepafloxacin 400 mg q.d. Grepafloxacin 600 mg q.d. Comparator Grepafloxacin 400 mg q.d. Grepafloxacin 600 mg q.d. Comparator Overall Efficacy 142/57 (90.4%) 140/150 (93.3%) 152/161 (94.4%) 123/153 (80.4%) 124/149 (83.2%) 137/161 (85.1%) Efficacy by Individual Organism: S. pneumoniae 36/42 (85.7%) 40/41 (97.6%) 43/44 (97.7%) 29/40 (72.5%) 35/41 (85.4%) 38/44 (86.4%) H. influenzae 63/68 (92.6%) 61/68 (89.7%) 84/90 (93.3%) 55/67 (82.1%) 51/67 (76.1%) 76/90 (84.4%) M. catarrhalis 41/43 (95.3%) 32/32 (100%) 29/30 (96.7%) 38/42 (90.5%) 31/32 (96.9%) 26/30 (86.7%) Study 106-92-206 End of Treatment (3-5 Days Posttreatment) Follow-up (14-28 Days Posttreatment) Grepafloxacin 400 mg q.d. Grepafloxacin 600 mg q.d. Comparator Grepafloxacin 400 mg q.d. Grepafloxacin 600 mg q.d. Comparator Overall Efficacy 66/72 (91.7%) 66/71 (93.0%) 65/70 (92.9%) 58/71 (81.7%) 61/71 (85.9%) 54/66 (81.8 %) Efficacy by Individual Organism: S. pneumoniae 8/8 (100%) 8/9 (88.9%) 3/5 (60%) 7/8 (87.5%) 6/9 (66.7%) 3/5 (60%) H. influenzae 18/19 (94.7%) 15/16 (93.8%) 17/18 (94.4%) 17/19 (89.5%) 14/16 (87.5%) 15/18 (83.3%) M. catarrhalis 20/21 (95.2%) 20/21 (95.2%) 18/19 (94.7%) 19/21 (90.5%) 18/21 (85.7%) 15/16 (93.8%) Community-acquired Pneumonia The two pivotal clinical trials that assessed the efficacy of grepafloxacin in the treatment of community-acquired pneumonia excluded patients whose respiratory status required the initiation of steroid therapy or an increase in maintenance steroid doses greater than prednisone 10 mg per day (or its equivalent). Study 106-92-302 was a randomized controlled study that assessed the efficacy of grepafloxacin 600 mg once daily for 10 days compared with comparator for 10 days. Study 106-92-205 was an open study that assessed clinical efficacy of grepafloxacin 600 mg once daily for 10 days. Table 7 presents efficacy results from the two pivotal studies: Table 7 Clinical Efficacy in Community-acquired Pneumonia in Two Pivotal Studies Grepafloxacin 600 mg q.d. Comparator Study 106-92-302 Success 89/110 (80.9%) 94/117 (80.3%) Failure 21/110 (19.1%) 23/117 (19.7%) Study 106-92-205 Success 116/125 (92.8%) Failure 9/125 (7.2%) ANIMAL PHARMACOLOGY Quinolones have been shown to cause arthropathies in juvenile rats and dogs. In addition, these drugs are associated with an increased incidence of osteochondrosis in rats as compared with the incidence in vehicle-treated rats. Grepafloxacin-associated joint toxicity (cavitation with loss of cartilaginous matrix and chondrocytes with cartilage fibrillation) was observed in juvenile dogs receiving 100 mg/kg by intravenous or subcutaneous injection for 1 week. Grepafloxacin associated joint toxicity (blisters of the articular cartilage) was observed in juvenile dogs given oral doses of 80 mg/kg per day (approximately 4.3 times the recommended maximum daily human dose on a mg/m2 basis for 4 weeks. No joint toxicity was observed at lower oral doses of 60 mg/kg per day approximately 3.2 times the recommended maximum daily human dose on a mg/m2 basis) for 4 weeks. The clinical relevance of these observations is unknown. In the dog, oral doses of 30 mg/kg and above ( ³ 1.5 times the maximum human dose on a mg/m2 basis) caused prolongation of the QT interval, although the results were variable. Intravenous administration of grepafloxacin at 10 mg/kg elicited a moderate hypotension in anesthetized dogs and rabbits. In phototoxicity tests, mice exposed to ultraviolet A radiation (similar to that used in tanning booths, sunlight contains a wider spectrum of UV radiation) after administration of grepafloxacin as a single 200 mg/kg oral dose (1.6 times the highest recommended human dose based upon body surface area) showed a mild redness on the ears. Phototoxic reactions such as this have been reported with other quinolones. Lenticular opacities, sometimes observed after long-term, high-dose use with other quinolones, were not observed with grepafloxacin in a 52-week study in monkeys. Drug interactions resulting in seizures have been reported between some quinolones and NSAIDs. Grepafloxacin did not induce seizures when administered with a variety of NSAIDs. in rats. The NSAIDs. studied were fenbufen, flurbiprofen, indomethacin, phenylbutazone, ibuprofen, and diflunisal.

DESCRIPTION RAXAR Tablets contain grepafloxacin hydrochloride RAXAR (grepafloxacin) is a broad-spectrum fluoroquinolone antimicrobial agent for oral administration. The chemical name for grepafloxacin is (±)-1-cyclopropyl-6-fluoro-1,4-dihydro-5-methyl- 7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid monohydrochloride sesquihydrate. Its molecular formula is C19H22FN3O3HCl 3/2 H2O and it has a molecular weight of 422.88. It is soluble in water and very slightly soluble in ethanol. RAXAR (grepafloxacin) Tablets are white to pale yellow, film-coated, biconvex, bevel-edged tablets containing either 200 mg, 400 mg, or 600 mg of grepafloxacin base, formulated as a hydrochloride salt. Each tablet contains the following inactive ingredients: low substituted hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose 2910, magnesium stearate, microcrystalline cellulose, talc, and titanium dioxide.

OVERDOSE 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. CONTRAINDICATIONS 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 ).

SIDE EFFECTS 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: Body as a Whole: Asthenia, chest pain, chills, flu-like syndrome, infection, malaise. Cardiovascular System: Syncope, vasodilatation. Digestive System: Anorexia, constipation, increased appetite, tenesmus. Hemic and Lymphatic System: Lymphadenopathy. Nervous System: Hyperkinesia, insomnia, nervousness, somnolence. Respiratory System: Rhinitis. Skin and Appendages: Acne, rash, sweating. Urogenital System: Balanitis. 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. Eye: Disturbances in vision. Non Site specific: Allergic reactions, including anaphylactoid reaction/anaphylactic shock, angioedema, laryngeal edema. 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 CYP3A4-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.