ZAFIRLUKAST

Zafirlukast is a synthetic, selective peptide leukotriene receptor antagonist (LTRA), with the chemical name 4-(5-cyclopentyloxy-carbonylamino-1-methyl-indol-3-ylmethyl)-3-methoxy-N-o-tolylsulfonylbenzamide. The molecular weight of zafirlukast is 575.7 and the structural formula is: The molecular formula is: C 31 H 33 N 3 O 6 S Zafirlukast, white to pale yellow coloured powder, freely soluble in tetrahydrofuran, and dimethylsulfoxide and practically insoluble in water. Zafirlukast is supplied as 10 and 20 mg tablets for oral administration. Inactive ingredients: Film coated tablets containing hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol 400, sodium starch glycolate (Type-A) and titanium dioxide. . structure

Zafirlukast tablets are indicated for the prophylaxis and chronic treatment of asthma in adults and children 5 years of age and older.

Because food can reduce the bioavailability of zafirlukast, zafirlukast tablets 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 tablets 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 tablets 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.

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

Adults and Children 12 years of age and older The safety database for zafirlukast consists of more than 4000 healthy volunteers and patients who received zafirlukast, of which 1723 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. Zafirlukast PLACEBO Adverse Event N=4058 N=2032 Headache 12.9% 11.7% Infection 3.5% 3.4% Nausea 3.1% 2% 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 hepatic failure, liver transplantation and death (see WARNINGS, Hepatotoxicity and PRECAUTIONS, Information for Patients ). In clinical trials, an increased proportion of zafirlukast patients over the age of 55 years reported infections as compared to placebo-treated patients. A similar finding was not observed in other age groups studied. These infections were mostly mild or moderate in intensity and predominantly affected the respiratory tract. Infections occurred equally in both sexes, were dose-proportional to total milligrams of zafirlukast exposure, and were associated with coadministration of inhaled corticosteroids. The clinical significance of this finding is unknown. In rare cases, patients with asthma on zafirlukast may present with systemic eosinophilia, eosinophilic pneumonia, or clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic steroid therapy. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. These events have usually, but not always, been associated with the reduction and/or withdrawal of steroid therapy. The possibility that zafirlukast may be associated with emergence of Churg-Strauss syndrome can neither be excluded nor established (see PRECAUTIONS, Eosinophilic Conditions ). Neuropsychiatric adverse events, including insomnia and depression, have been reported in association with zafirlukast therapy, (see PRECAUTIONS, Neuropsychiatric Events ), Hypersensitivity reactions, including urticaria, angioedema and rashes, with or without blistering, have been reported in association with zafirlukast therapy. Additionally, there have been reports of patients experiencing agranulocytosis, bleeding, bruising, or edema, arthralgia, myalgia, malaise, and pruritus in association with zafirlukast therapy. Rare cases of patients experiencing increased theophylline levels with or without clinical signs or symptoms of theophylline toxicity after the addition of zafirlukast to an existing theophylline regimen have been reported. The mechanism of the interaction between zafirlukast and theophylline in these patients is unknown and not predicted by available in vitro metabolism data and the results of two clinical drug interaction studies (see CLINICAL PHARMACOLOGY and PRECAUTIONS, Drug Interactions ). Pediatric Patients 5 through 11 years of age Zafirlukast has been evaluated for safety in 788 pediatric patients 5 through 11 years of age. Cumulatively, 313 pediatric patients were treated with zafirlukast 10 mg twice daily or higher for at least 6 months, and 113 of them were treated for one year or longer in clinical trials. The safety profile of zafirlukast 10 mg twice daily-versus placebo in the 4- and 6-week double-blind trials was generally similar to that observed in the adult clinical trials with zafirlukast 20 mg twice daily. In pediatric patients receiving zafirlukast in multi-dose clinical trials, the following events occurred with a frequency of ≥ 2% and more frequently than in pediatric patients who received placebo, regardless of causality assessment: headache (4.5 vs. 4.2%) and abdominal pain (2.8 vs. 2.3%). The post-marketing experience in this age group is similar to that seen in adults, including hepatic dysfunction, which may lead to liver failure.

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 theophylline toxicity after the addition of zafirlukast to an existing theophylline regimen have been reported. The mechanism of the interaction between zafirlukast and theophylline in these patients is unknown (see ADVERSE REACTIONS ). Coadministration of zafirlukast (40 mg/day) with aspirin (650 mg four times daily) resulted in mean increased plasma levels of zafirlukast by approximately 45%. In a single-blind, parallel-group, 3-week study in 39 healthy female subjects taking oral contraceptives, 40 mg twice daily of zafirlukast had no significant effect on ethinyl estradiol plasma concentrations or contraceptive efficacy. Coadministration of zafirlukast with fluconazole, a moderate CYP2C9 inhibitor, resulted in increased plasma levels of zafirlukast, by approximately 58% (90% CI:28, 95). The clinical significance of this interaction is unknown. Zafirlukast exposure is likely to be increased by other moderate and strong CYP2C9 inhibitors. Coadministration of zafirlukast with itraconazole, a strong CYP3A4 inhibitor, caused no change in plasma levels of zafirlukast. No other formal drug-drug interaction studies between zafirlukast and marketed drugs known to be metabolized by the P450 3A4 (CYP3A4) isoenzyme (eg, dihydropyridine calcium-channel blockers, cyclosporin, cisapride) have been conducted. As zafirlukast is known to be an inhibitor of CYP3A4 in vitro , it is reasonable to employ appropriate clinical monitoring when these drugs are coadministered with zafirlukast.