Action And Clinical Pharmacology: Grepafloxacin is a broad-spectrum fluoroquinolone antibiotic. It 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. Grepafloxacin is bactericidal at concentrations equal to or slightly greater than minimum inhibitory concentrations (MICs). Fluoroquinolones differ in chemical structure and mode of action from other classes of antimicrobial agents such as beta-lactam antibiotics, aminoglycosides, and macrolides. Beta-lactamase production and alterations in penicillin binding proteins have no effect on grepafloxacin activity. Therefore, microorganisms resistant to the latter classes of antimicrobial agents may be susceptible to fluoroquinolones including grepafloxacin. Conversely, microorganisms resistant to quinolones, including grepafloxacin may be susceptible to these other classes of antimicrobial agents.
Although cross-resistance has been observed between grepafloxacin and some other fluoroquinolones, some microorganisms resistant to other fluoroquinolones may be susceptible to grepafloxacin. Conversely some microorganisms resistant to grepafloxacin may be susceptible to some other fluoroquinolones.
Grepafloxacin has been shown to be active against most strains of H. influenzae (including beta-lactamase-producing strains), M. catarrhalis (including beta-lactamase-producing strains), and N. gonorrhoeae (including strains resistant to penicillin or tetracycline), both in vitro and in specific clinical infections as described in the Indications section.
Pharmacokinetics: Absorption: Grepafloxacin is rapidly and extensively absorbed following oral administration of grepafloxacin tablets. The absolute bioavailability is approximately 70%.
Multiple oral doses of 400 and 600 mg once a day, provided steady-state concentrations of grepafloxacin within 7 days.
There was no difference between the fasting and postprandial state and milk had no effect on the pharmacokinetic properties of grepafloxacin tablets. Neutralization of gastric acidity by histamine type-2 receptor antagonists did not affect the absorption or other pharmacokinetic properties of grepafloxacin tablets.
Distribution: Grepafloxacin distributes widely into extravascular spaces. Binding of grepafloxacin to human plasma proteins is low (approximately 50%). Following oral administration, grepafloxacin is rapidly and extensively distributed into tissues and body fluids, including the respiratory tract and sputum as well as male and female genital tract tissues. High intracellular concentrations are achieved significantly above the plasma concentrations.
Metabolism and Excretion: The plasma elimination half-life of grepafloxacin at steady-state was approximately 12 hours. Grepafloxacin is eliminated predominantly through hepatic metabolism and biliary excretion. Renal excretion of unchanged drug is a lesser route of elimination (less than 10% of an oral dose is excreted as unchanged grepafloxacin in urine).
The nonconjugated metabolites have little antimicrobial activity compared with the parent drug. The conjugated metabolites have no antimicrobial activity.
The metabolism and excretion of grepafloxacin is significantly reduced in patients with hepatic disease (see Contraindications, Precautions and Dosage).
Renal clearance of grepafloxacin was 0.458Â±0.04 mL/min/kg in adults with normal renal function. Varying degrees of renal function did not substantially affect the pharmacokinetic properties of grepafloxacin.
Indications And Clinical Uses: For treatment of adults 18 years of age and older with infections caused by susceptible strains of the designated microorganisms in the infections listed as follows: acute bacterial exacerbations of chronic bronchitis caused by H. influenzae, S. pneumoniae, or M. catarrhalis (see Dosage); community-acquired pneumonia caused by H. influenzae, S. pneumoniae, M. catarrhalis, M. pneumoniae, or L. pneumophila; uncomplicated gonorrhea (urethral in males and endocervical and rectal in females) caused by N. gonorrhoeae (see Warnings); nongonococcal cervicitis and urethritis caused by C. trachomatis.
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.
Contra-Indications: Patients with known or suspected hypersensitivity to grepafloxacin, other quinolone antibiotics or any other components of grepafloxacin tablets. Also contraindicated in patients with hepatic disease (see Pharmacology, Precautions and Dosage). Because prolongation of the QT interval has been observed in healthy volunteers receiving grepafloxacin, it is contraindicated in patients with existing QT prolongation. Grepafloxacin is also contraindicated in patients being treated concomitantly with medications known to produce an increase in the QT interval and/or torsades de pointes (e.g., class I antiarrhythmic agents, [e.g., disopyramide, flecainide, quinidine, procainamide], class III antiarrhythmic agents [e.g., amiodarone, sotalol], as well as erythromycin, terfenadine, astemizole, cisapride, pentamidine, tricyclic antidepressants, some antipsychotics including phenothiazines) unless appropriate cardiac monitoring can be assured (e.g., in hospitalized patients). tag_WarningWarnings
Manufacturers’ Warnings In Clinical States: The safety and efficacy of grepafloxacin in patients under 18 years of age, pregnant women, or lactating women have not been established (see Precautions, Children, Pregnancy and Lactation). Histopathological examination of the weight-bearing joints of juvenile dogs revealed permanent lesions of the cartilage. Related quinolone-class drugs also produce lesions of cartilage of weight-bearing joints and other signs of arthropathy in immature animals of various species.
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.
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.
In healthy male and female volunteers who received grepafloxacin, prolongation of the QTc interval was observed. Because of a potential risk of cardiac arrhythmias, including torsades de pointes, patients should not receive grepafloxacin concomitantly with medications known to prolong the QT interval, e.g., class I antiarrhythmic agents, (e.g., disopyramide, flecainide, quinidine, procainamide), class III antiarrhythmic agents (e.g., amiodarone, sotalol), as well as erythromycin, terfenadine, astemizole, cisapride, pentamidine, tricyclic antidepressants, some antipsychotics including phenothiazines when appropriate cardiac monitoring cannot be assured, e.g., during outpatient therapy (see Contraindications). Grepafloxacin is not recommended for use in patients with ongoing proarrhythmic conditions (e.g., electrolyte imbalances, such as hypokalemia and hypomagnesemia, significant bradycardia, congestive heart failure, myocardial ischemia, and atrial enlargement).
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. 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 Adverse Effects).
Convulsions, increased intracranial pressure, and toxic psychosis have been reported in patients receiving quinolones. Quinolones may also cause CNS 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, 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 Effects).
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 broad-spectrum antibiotics alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by C. difficile is a primary cause of “antibiotic-associated colitis”. After the diagnosis of pseudomembranous colitis has been established, appropriate therapeutic measures should be initiated.
Precautions: General: Phototoxicity reactions have been observed in patients who were exposed to direct sunlight while receiving some quinolones, including grepafloxacin. Excessive sunlight should be avoided. Therapy should be discontinued if phototoxicity occurs.
Geriatrics: Grepafloxacin tablets were administered to 343 elderly adults (age >65 years old) in clinical trials. There was no apparent difference in the frequency, type, or severity of adverse reactions in elderly adults compared with other adults.
The pharmacokinetic properties of grepafloxacin in younger adults and elderly adults did not differ significantly.
Children: The safety and effectiveness of grepafloxacin in children and adolescents below the age of 18 years has not been established.
Pregnancy : Grepafloxacin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus (see Warnings). Adequate and well-controlled studies have not been conducted in pregnant women. Reproductive studies performed in rats and rabbits indicate that placental transfer of grepafloxacin occurs. Studies in these species did not show any evidence of teratogenicity, impairment of fertility or impairment of peri- or postnatal development of their offspring following administration of grepafloxacin.
Lactation: Limited evidence indicates that grepafloxacin is excreted in human milk. Grepafloxacin was detected 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.
It is known that other quinolones are secreted 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 the drug to the mother (see Warnings).
Patients with Hepatic Disease: Grepafloxacin is contraindicated in patients with hepatic disease (see Dosage).
Two studies were performed to assess the effect of hepatic failure on grepafloxacin pharmacokinetics. In both studies, subjects were given a single 400 mg dose of grepafloxacin. Subjects with normal hepatic function, with mild (Child-Pugh class A) hepatic failure, or moderate hepatic failure (Child-Pugh class B) were evaluated. 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 as 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 2 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).
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 zinc 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 after grepafloxacin administration.
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. In a pharmacokinetic study in 12 adults receiving concomitant theophylline during a 10-day course of grepafloxacin, oral clearance of theophylline decreased from 0.78±0.25 (without grepafloxacin: mean±S.D.) to 0.40±0.08 mL/min/kg (with grepafloxacin), steady-state peak theophylline concentration increased from 8.30±1.54 µg/mL to 15.12±3.69 µg/mL, and AUC over a 12-hour interval increased from 85.9±16.6 to 165.9±36.9 µg.h/mL. In these normal volunteers, concomitant administration of grepafloxacin and theophylline increased the frequency of theophylline-related adverse events.
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.
Caffeine: Grepafloxacin, like other quinolones, may inhibit the metabolism of caffeine. In some patients, this may lead to reduced clearance of caffeine, prolongation of its plasma half-life, and enhanced effects of caffeine.
Drugs Metabolized by Cytochrome P450 Enzymes: Grepafloxacin is metabolized primarily by the cytochrome P450 enzymes, particularly the isoenzyme CYP1A2 and to a lesser extent the isoenzyme CYP3A4. Like most quinolone drugs, grepafloxacin may competitively inhibit cytochrome P450 enzyme activity. This may result in impaired metabolism of certain other drugs that are also metabolized by this system such as cimetidine, cyclosporine, terfenadine, astemizole, cisapride, midazolam and triazolam.
Probenecid: In clinical studies, probenecid did not significantly alter the pharmacokinetic properties of a single 200 mg oral dose of grepafloxacin.
Warfarin: Grepafloxacin did not alter the anticoagulant effect of warfarin in a study of 16 adults receiving grepafloxacin 600 mg daily. In this same study, warfarin did not alter the pharmacokinetic properties of grepafloxacin. 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.
Nonsteroidal Anti-inflammatory Drugs (NSAIDs): Drug interactions resulting in seizures have been reported between some quinolones and NSAIDs. In animal studies grepafloxacin did not induce seizures when administered with a variety of NSAIDs.
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.
Adverse Reactions: Adverse reactions were assessed in clinical trials involving approximately 2 500 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 1 069 patients (1.9%) receiving grepafloxacin 400 mg daily and 94 of 1 406 patients (6.7%) receiving grepafloxacin 600 mg daily discontinued grepafloxacin due to an adverse reaction.
Additional drug-related events, occurring in multiple-dose clinical trials at a rate of less than 1%, were: Body as a Whole: allergic reaction, back pain, body odor, chest pain, chills, facial edema, pain, fever, malaise, neck rigidity, pelvic pain.
Cardiovascular: arrhythmia, hypotension, palpitations, peripheral vascular disorder, postural hypotension, syncope, tachycardia, vasodilation.
Digestive: abnormal liver function tests, abnormal stools, cheilitis, dysphagia, eructation, flatulence, gastritis, gastrointestinal disorder, dry mouth, 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: anemia, eosinophilia, hypochromic anemia, leukocytosis, leukopenia, lymphadenopathy, lymphocytosis, lymphoma-like reaction, prothrombin decreased, prothrombin increased, reticuloendothelial hyperplasia, thrombocytopenia, thromboplastin increased.
Metabolic and Nutritional: dehydration, edema, electrolyte abnormality, gout, hyperglycemia, hyperkalemia, hyperlipidemia, hypernatremia, hyperuricemia, hypoglycemia, increased alkaline phosphatase, increased BUN, increased creatinine, increased gamma glutamyl transpeptidase, increased serum phosphorus, increased AST, increased ALT, peripheral edema, weight loss.
Musculoskeletal: arthralgia, myalgia.
CNS: abnormal dreams, abnormal gait, agitation, anxiety, confusion, depression, emotional lability, hallucinations, hyperkinesia, hypesthesia, hypokinesia, paresthesia, speech disorder, stupor, thinking abnormal, tremor, vertigo.
Respiratory: 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: 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 grepafloxacin 400 mg. Table III lists the drug-related adverse reactions which occurred with frequencies of 1% or greater in patients treated with grepafloxacin in single-dose clinical trials.
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: syncope, vasodilation.
Digestive: anorexia, constipation, increased appetite, tenesmus.
Hemic and Lymphatic: lymphadenopathy.
CNS: hyperkinesia, insomnia, nervousness, somnolence.
Skin and Appendages: acne, rash, sweating.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: Information on overdosage with grepafloxacin is limited. 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 QT interval and complications including arrhythmias, ECG monitoring for at least 24 hours after overdosage with grepafloxacin is recommended. It is not known if grepafloxacin can be efficiently removed by hemodialysis or peritoneal dialysis.
Dosage And Administration: Grepafloxacin may be taken with or without meals. Table IV summarizes the recommended daily dosages.
Clinical trials of grepafloxacin in the treatment of acute exacerbations of chronic bronchitis suggest that grepafloxacin 600 mg once daily may be more effective against S. pneumoniae than grepafloxacin 400 mg once daily.
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: Grepafloxacin was well tolerated in a study of a limited number of patients with impaired renal function. Since renal excretion is a lesser route of elimination of grepafloxacin, 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 disease.
Grepafloxacin is contraindicated in patients with hepatic disease (see Contraindications and Pharmacology).
Availability And Storage: Each white to pale yellow, film-coated, round, biconvex, beveled edged tablet, imprinted with “GX CK3” on one side, contains: grepafloxacin HCl 200 mg. Nonmedicinal ingredients: grey printing ink, hydroxypropyl cellulose, hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, talc and titanium dioxide. Plastic bottles of 60. Store at controlled room temperature between 15 to 30°C protected from light. Replace cap securely after each opening.
RAXAR Glaxo Wellcome Grepafloxacin HCl Antibacterial