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Gemifloxacin Mesylate: Cautions

Contraindications

Known hypersensitivity to gemifloxacin, other quinolones, or any ingredient in the formulation.

Warnings/Precautions

Warnings Prolongation of QT Interval

Certain quinolone anti-infective agents (e.g., moxifloxacin, grepafloxacin [no longer commercially available in the US], levofloxacin, sparfloxacin) have been shown to prolong the QT interval on ECG in some patients and healthy individuals.

Gemifloxacin Mesylate Cautions

Gemifloxacin also has the potential to prolong the QT interval and, if this happens, the maximal change in the QT interval occurs approximately 5-10 hours following administration of gemifloxacin. The manufacturer states that gemifloxacin should be avoided in patients with known prolongation of the QT interval, those with uncorrected electrolyte disorders (e.g., hypokalemia, hypomagnesemia), and in patients receiving class IA (e.g., quinidine, procainamide) or class III (e.g., amiodarone, sotalol) antiarrhythmic agents.

Pharmacokinetic studies with gemifloxacin and drugs that prolong the QT interval (e.g., cisapride [currently commercially available under a limited-access protocol only], erythromycin, antipsychotic agents, tricyclic antidepressants) have not been performed.

Caution is advised when any of these drugs is used concurrently with gemifloxacin and in patients with ongoing proarrhythmic conditions, such as clinically important bradycardia or acute myocardial ischemia. The manufacturer states that no cardiovascular morbidity or mortality attributable to QT prolongation occurred with gemifloxacin treatment in premarketing clinical trials in over 6700 patients, including in 653 patients concurrently receiving drugs known to prolong the QT interval and 5 patients with uncorrected hypokalemia.

Musculoskeletal Effects

Gemifloxacin, like most other quinolones, causes arthropathy and osteochondrosis in immature animals of various species. Tendinitis and rupture of the shoulder, hand, and Achilles tendons that required surgical repair or resulted in prolonged disability have been reported in patients receiving fluoroquinolones. Tendon rupture can occur either during or after treatment and may occur more frequently in geriatric patients, athletes, and patients receiving corticosteroids. Gemifloxacin should be discontinued if pain, inflammation, or rupture of a tendon occurs; patients should be advised to rest and refrain from exercise until the diagnosis of tendinitis or tendon rupture has been confidently excluded.

Nervous System Effects

Seizures, increased intracranial pressure, psychoses, and CNS stimulation, which may lead to tremor, restlessness, anxiety, lightheadedness, confusion, hallucinations, paranoia, depression, insomnia, and rarely, suicidal thoughts or acts, have been reported in patients receiving quinolones. These reactions have not been reported to date in clinical trials with gemifloxacin. However, if such adverse effects occur in patients receiving gemifloxacin, the drug should be discontinued and appropriate measures instituted. Caution is advised in patients with known or suspected CNS disorders (e.g., seizure disorders) or other risk factors predisposing to seizures. Clostridium difficile-associated Colitis Pseudomembranous colitis has been reported with numerous anti-infectives, including gemifloxacin, and may range in severity from mild to life-threatening. Evaluate and monitor patients who develop diarrhea during therapy.

Sensitivity Reactions

Serious and occasionally fatal hypersensitivity and/or anaphylactic reactions have been reported in patients receiving fluoroquinolones. Although generally reported after multiple doses, these reactions also may occur following the first dose.

Some reactions have been accompanied by cardiovascular collapse, hypotension or shock, seizure, loss of consciousness, tingling, angioedema (e.g., edema or swelling of the tongue, larynx, throat, or face), airway obstruction (e.g., bronchospasm, shortness of breath, acute respiratory distress), dyspnea, urticaria, pruritus, and other severe skin reactions.

Serious adverse effects that have been reported with gemifloxacin and that may or may not be related to hypersensitivity reactions include new-onset fever and one or more of the following: rash or severe dermatologic reaction (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome); vasculitis, arthralgia, myalgia, serum sickness; allergic pneumonitis; interstitial nephritis, acute renal insufficiency or failure; hepatitis, jaundice, acute hepatic necrosis or failure; anemia (including hemolytic and aplastic anemia), thrombocytopenia (including thrombotic thrombocytopenic purpura), leukopenia, agranulocytosis, pancytopenia, and/or other hematologic abnormalities. Gemifloxacin should be discontinued at the first appearance of a rash or any other sign of hypersensitivity. Severe acute hypersensitivity reactions should be treated with appropriate therapy (e.g., epinephrine, oxygen, antihistamines, corticosteroids, airway management) as indicated.

Major Toxicities Dermatologic Reactions

Rash has been reported in approximately 2.8% of patients receiving gemifloxacin in clinical studies. The most common form of rash associated with gemifloxacin appears to be the maculopapular type (with 0.3% of cases described as urticarial in appearance) that are of mild to moderate severity; approximately 10% of cases of rash are described as severe. Histologic examination confirmed presence of an uncomplicated exanthematous skin reaction and revealed no evidence of phototoxicity, vasculitis, or necrosis. In clinical studies, rash usually occurred within 8-10 days following initiation of therapy, and 60 or 80% of cases resolved within 7 or 14 days, respectively; approximately 19% of patients who developed rash received antihistamines and 5% received corticosteroids, although the benefit of these therapies is uncertain.

Rash occurred most frequently in patients younger than 40 years of age, in postmenopausal women receiving hormone replacement therapy, and in patients who received gemifloxacin for longer than 7 days (although this was not evident in men 40 years of age and older); the reason for this observation has not been clearly elucidated. Although no morbidity or mortality attributable to severe skin reactions have been reported with gemifloxacin in clinical trials, the manufacturer states that gemifloxacin should be discontinued at the first appearance of a rash or any other sign of hypersensitivity. Phototoxicity has been reported rarely (0.039%) in clinical trials with gemifloxacin. However, as with other quinolones, the manufacturer states that patients should be advised to avoid unnecessary exposure to strong sunlight or artificial (UV) light (e.g., sunlamps, solariums) and to use a broad-spectrum sunscreen when in bright sunlight. Gemifloxacin should be discontinued if a photosensitivity reaction is suspected.

Hepatic Effects

Increases in serum AST (SGOT) and/or ALT (SGPT) concentrations have been reported in approximately 1-2% of patients receiving the usually recommended gemifloxacin dosage in clinical studies. Such increases were not associated with clinical manifestations and resolved following discontinuance of the drug. In a limited study evaluating a higher dosage of gemifloxacin (640 mg daily), transient increases in ALT concentrations were reported in 4% of patients and were 8-10 times the upper limit of normal in at least 2 patients.

Specific Populations Pregnancy Category C. Lactation

Gemifloxacin is distributed into milk in rats. Since it is not known whether gemifloxacin is distributed into milk in humans, the drug should not be used in nursing women unless the possible benefits outweigh the potential risks.

Pediatric Use

Safety and efficacy not established in children or adolescents younger than 18 years of age.

Geriatric Use

Approximately 30% of patients included in clinical studies of gemifloxacin were 65 years of age or older and 12% were 75 years of age or older. No overall differences in safety or efficacy were observed between geriatric individuals and younger adults. However, the incidence of rash appears to be lower in geriatric patients than in those younger than 40 years of age; the reason for this observation has not been clearly elucidated. No dosage adjustment is necessary in geriatric patients.

Renal Impairment

Following administration of repeated doses of gemifloxacin (320 mg once daily) in patients with renal impairment, renal clearance of the drug was reduced and plasma elimination half-life prolonged, resulting in an average increase in area under the plasma concentration-time curve (AUC) of 70%. Dosage adjustment is recommended for patients with creatinine clearance of 40 mL/minute or less.

Hepatic Impairment

Following oral administration of a single 320-mg dose of gemifloxacin, peak plasma concentrations increased by 25 or 41% in patients with mild or moderate (Child Pugh class A or B) or severe (Child Pugh class C) hepatic impairment, respectively, and AUC increased by 34 or 45%, respectively. No dosage adjustment is necessary in these patients.

Common Adverse Effects

Adverse effects occurring in 1% or more of patients receiving gemifloxacin in clinical studies include diarrhea (2.3-5.1%), rash (2.8-5.2%), nausea (2.6-4.3%), and headache (1.2-3.4%). Adverse effects occurring in 0.1-1% of patients receiving gemifloxacin include abdominal pain, anorexia, arthralgia, constipation, dermatitis, dizziness, dry mouth, dyspepsia, fatigue, flatulence, fungal infection, gastritis, genital moniliasis, hyperglycemia, insomnia, leukopenia, moniliasis, pruritus, somnolence, taste perversion, thrombocythemia, urticaria, vaginitis, and vomiting.

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