Zafir

INDICATIONS AND USAGE Zafirlukast is indicated for the prophylaxis and chronic treatment of asthma in adults and children 5 years of age and older.

DOSAGE AND ADMINISTRATION Because food can reduce the bioavailability of zafirlukast, zafirlukast should be taken at least 1 hour before or 2 hours after meals. Adults and Children 12 years of age and older The recommended dose of zafirlukast in adults and children 12 years and older is 20 mg twice daily. Pediatric Patients 5 through 11 years of age The recommended dose of zafirlukast in children 5 through 11 years of age is 10 mg twice daily. Elderly Patients Based on cross-study comparisons, the clearance of zafirlukast is reduced in elderly patients (65 years of age and older), such that C max and AUC are approximately twice those of younger adults. In clinical trials, a dose of 20 mg twice daily was not associated with an increase in the overall incidence of adverse events or withdrawals because of adverse events in elderly patients. Patients with Hepatic Impairment Zafirlukast is contraindicated in patients with hepatic impairment including hepatic cirrhosis (see Contraindications). The clearance of zafirlukast is reduced in patients with stable alcoholic cirrhosis such that the C max and AUC are approximately 50 to 60% greater than those of normal adults. Zafirlukast has not been evaluated in patients with hepatitis or in long-term studies of patients with cirrhosis. Patients with Renal Impairment Dosage adjustment is not required for patients with renal impairment.

CLINICAL PHARMACOLOGY Mechanism of Action Zafirlukast is a selective and competitive receptor antagonist of leukotriene D 4 and E 4 (LTD 4 and LTE 4 ), components of slow-reacting substance of anaphylaxis (SRSA). Cysteinyl leukotriene production and receptor occupation have been correlated with the pathophysiology of asthma, including airway edema, smooth muscle constriction, and altered cellular activity associated with the inflammatory process, which contribute to the signs and symptoms of asthma. Patients with asthma were found in one study to be 25 to 100 times more sensitive to the bronchoconstricting activity of inhaled LTD 4 than nonasthmatic subjects. In vitro studies demonstrated that zafirlukast antagonized the contractile activity of three leukotrienes (LTC 4 , LTD 4 and LTE 4 ) in conducting airway smooth muscle from laboratory animals and humans. Zafirlukast prevented intradermal LTD 4 -induced increases in cutaneous vascular permeability and inhibited inhaled LTD 4 -induced influx of eosinophils into animal lungs. Inhalational challenge studies in sensitized sheep showed that zafirlukast suppressed the airway responses to antigen; this included both the early-and late-phase response and the nonspecific hyperresponsiveness. In humans, zafirlukast inhibited bronchoconstriction caused by several kinds of inhalational challenges. Pretreatment with single oral doses of zafirlukast inhibited the bronchoconstriction caused by sulfur dioxide and cold air in patients with asthma. Pretreatment with single doses of zafirlukast attenuated the early-and late-phase reaction caused by inhalation of various antigens such as grass, cat dander, ragweed, and mixed antigens in patients with asthma. Zafirlukast also attenuated the increase in bronchial hyperresponsiveness to inhaled histamine that followed inhaled allergen challenge. Clinical Pharmacokinetics and Bioavailability Absorption Zafirlukast is rapidly absorbed following oral administration. Peak plasma…

ADVERSE REACTIONS Adults and Children 12 years of age and older The safety database for zafirlukast consists of more than 4,000 healthy volunteers and patients who received zafirlukast, of which 1,723 were asthmatics enrolled in trials of 13 weeks duration or longer. A total of 671 patients received zafirlukast for 1 year or longer. The majority of the patients were 18 years of age or older; however, 222 patients between the age of 12 and 18 years received zafirlukast. A comparison of adverse events reported by ≥1% of zafirlukast-treated patients, and at rates numerically greater than in placebo-treated patients, is shown for all trials in the table below. Adverse Event Zafirlukast N=4,058 PLACEBO N=2,032 Headache 12.9% 11.7% Infection 3.5% 3.4% Nausea 3.1% 2.0% Diarrhea 2.8% 2.1% Pain (generalized) 1.9% 1.7% Asthenia 1.8% 1.6% Abdominal Pain 1.8% 1.1% Accidental Injury 1.6% 1.5% Dizziness 1.6% 1.5% Myalgia 1.6% 1.5% Fever 1.6% 1.1% Back Pain 1.5% 1.2% Vomiting 1.5% 1.1% SGPT Elevation 1.5% 1.1% Dyspepsia 1.3% 1.2% The frequency of less common adverse events was comparable between zafirlukast and placebo. Rarely, elevations of one or more liver enzymes have occurred in patients receiving Zafirlukast in controlled clinical trials. In clinical trials, most of these have been observed at doses four times higher than the recommended dose. The following hepatic events (which have occurred predominantly in females) have been reported from postmarketing adverse event surveillance of patients who have received the recommended dose of zafirlukast (40 mg/day): cases of symptomatic hepatitis (with or without hyperbilirubinemia) without other attributable cause; and rarely, hyperbilirubinemia without other elevated liver function tests. In most, but not all postmarketing reports, the patient’s symptoms abated and the liver enzymes returned to normal or near normal after stopping zafirlukast. In rare cases, patients have presented with fulminant hepatitis or progressed to…

CONTRAINDICATIONS Zafirlukast is contraindicated in patients who are hypersensitive to zafirlukast or any of its inactive ingredients. Zafirlukast is contraindicated in patients with hepatic impairment including hepatic cirrhosis.

WARNINGS Hepatotoxicity Cases of life-threatening hepatic failure have been reported in patients treated with zafirlukast. Cases of liver injury without other attributable cause have been reported from post-marketing adverse event surveillance of patients who have received the recommended dose of zafirlukast (40 mg/day). In most, but not all post-marketing reports, the patient’s symptoms abated and the liver enzymes returned to normal or near normal after stopping zafirlukast. In rare cases, patients have either presented with fulminant hepatitis or progressed to hepatic failure, liver transplantation and death. In extremely rare post-marketing cases, no clinical symptoms or signs suggestive of liver dysfunction were reported to precede the latter observations. Physicians may consider the value of liver function testing. Periodic serum transaminase testing has not proven to prevent serious injury but it is generally believed that early detection of drug-induced hepatic injury along with immediate withdrawal of the suspect drug enhances the likelihood for recovery. Patients should be advised to be alert for signs and symptoms of liver dysfunction (eg, right upper quadrant abdominal pain, nausea, fatigue, lethargy, pruritus, jaundice, flu-like symptoms, and anorexia) and to contact their physician immediately if they occur. Ongoing clinical assessment of patients should govern physician interventions, including diagnostic evaluations and treatment. If liver dysfunction is suspected based upon clinical signs or symptoms (eg, right upper quadrant abdominal pain, nausea, fatigue, lethargy, pruritus, jaundice, flu-like symptoms, anorexia, and enlarged liver), zafirlukast should be discontinued. Liver function tests, in particular serum ALT, should be measured immediately and the patient managed accordingly. If liver function tests are consistent with hepatic dysfunction, zafirlukast therapy should not be resumed. Patients in whom zafirlukast was withdrawn because of…

Drug Interactions In a drug interaction study in 16 healthy male volunteers, coadministration of multiple doses of zafirlukast (160 mg/day) to steady-state with a single 25 mg dose of warfarin resulted in a significant increase in the mean AUC (+ 63%) and half-life (+36%) of S-warfarin. The mean prothrombin time (PT) increased by approximately 35%. This interaction is probably due to an inhibition by zafirlukast of the cytochrome P450 2C9 isoenzyme system. Patients on oral warfarin anticoagulant therapy and zafirlukast should have their prothrombin times monitored closely and anticoagulant dose adjusted accordingly (see WARNINGS , Concomitant Warfarin Administration ). No formal drug-drug interaction studies with zafirlukast and other drugs known to be metabolized by the cytochrome P450 2C9 isoenzyme (eg, tolbutamide, phenytoin, carbamazepine) have been conducted; however, care should be exercised when zafirlukast is coadministered with these drugs. In a drug interaction study in 11 asthmatic patients, coadministration of a single dose of zafirlukast (40 mg) with erythromycin (500 mg three times daily for 5 days) to steady-state resulted in decreased mean plasma levels of zafirlukast by approximately 40% due to a decrease in zafirlukast bioavailability. Coadministration of zafirlukast (20 mg/day) or placebo at steady-state with a single dose of sustained release theophylline preparation (16 mg/kg) in 16 healthy boys and girls (6 through 11 years of age) resulted in no significant differences in the pharmacokinetic parameters of theophylline. Coadministration of zafirlukast (80 mg/day) at steady-state with a single dose of a liquid theophylline preparation (6 mg/kg) in 13 asthmatic patients, 18 to 44 years of age, resulted in decreased mean plasma levels of zafirlukast by approximately 30%, but no effect on plasma theophylline levels was observed. Rare cases of patients experiencing increased theophylline levels with or without clinical signs or symptoms of…