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warnings
WARNINGS Hepatotoxicity: Cases of life-threatening hepatic failure have been reported in patients treated with Zafirlukast Tablets. 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 Tablets (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 Tablets. 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 Tablets 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 Tablets therapy should not be resumed. Patients in whom Zafirlukast Tablets was withdrawn because of hepatic dysfunction where no other attributable cause is identified should not be re-exposed to Zafirlukast Tablets (see PRECAUTIONS , Information for Patients and ADVERSE REACTIONS ). Bronchospasm: Zafirlukast Tablets are not indicated for use in the reversal of bronchospasm in acute asthma attacks, including status asthmaticus. Therapy with Zafirlukast Tablets can be continued during acute exacerbations of asthma. Concomitant Warfarin Administration: Coadministration of zafirlukast with warfarin results in a clinically significant increase in prothrombin time (PT). Patients on oral warfarin anticoagulant therapy and Zafirlukast Tablets should have their prothrombin times monitored closely and anticoagulant dose adjusted accordingly (see PRECAUTIONS , Drug Interactions ).
ADVERSE REACTIONS Adults and Children 12 years of age and older The safety database for Zafirlukast Tablets consists of more than 4000 healthy volunteers and patients who received Zafirlukast Tablets, of which 1723 were asthmatics enrolled in trials of 13 weeks duration or longer. A total of 671 patients received Zafirlukast Tablets 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 Tablets. 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 TABLETS N=4058 PLACEBO N=2032 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 Tablets and placebo. Rarely, elevations of one or more liver enzymes have occurred in patients receiving Zafirlukast Tablets 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 Tablets (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 Tablets. 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 Tablets 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 reductions and/or withdrawal of steroid therapy. The possibility that Zafirlukast Tablets 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 Tablets therapy (see PRECAUTIONS, Neuropsychiatric Events ). Hypersensitivity reactions, including urticaria, angioedema and rashes, with or without blistering, have also been reported in association with Zafirlukast Tablets therapy. Additionally, there have been reports of patients experiencing agranulocytosis, bleeding, bruising, or edema, arthralgia, myalgia, malaise, and pruritus in association with Zafirlukast Tablets therapy. Rare cases of patients experiencing increased theophylline levels with or without clinical signs or symptoms of theophylline toxicity after the addition of Zafirlukast Tablets to an existing theophylline regimen have been reported. The mechanism of the interaction between Zafirlukast Tablets 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 Tablets have been evaluated for safety in 788 pediatric patients 5 through 11 years of age. Cumulatively, 313 pediatric patients were treated with Zafirlukast Tablets 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 Tablets 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 Tablets 20 mg twice daily. In pediatric patients receiving Zafirlukast Tablets 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. To report SUSPECTED ADVERSE REACTIONS, contact Rising Pharma Holdings, Inc. at 1-844-474-7464 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .