Zafirlukast is an orally available drug (available in 10 mg and 20 mg tablets and chewable tablets), which is FDA-approved for the management of chronic asthma in adults and children ≥ 5 years old. It is used off-label for the management of chronic urticaria, prevention of exercise-induced bronchospasm, and those with asthma and allergic rhinitis.[1][2]

Zafirlukast (empirical formula C31H33N3O6S) is a leukotriene receptor antagonist, which is a highly selective and competitive blocker of the cysteinyl leukotriene-1 receptor (CYSLTR1). Zafirlukast competes with proinflammatory cysteinyl-leukotrienes C4, D4, and E4 (LTC, LTD, and LTE) at CYSLTR1 to prevent leukotriene-induced inflammation. Leukotriene binding to CYSLTR1 causes inflammatory reactions associations with the underlying disease process of asthma. Limiting proinflammatory leukotrienes through competitive inhibition; therefore, leads to decreased neutrophil and eosinophil migration, neutrophil and monocyte aggregation, leukocyte adhesion, airway edema, inflammation, and bronchial constriction.[3] Zafirlukast takes 2 to 6 weeks for optimal effect and has a half-life of 10 (8 to 16) hours with a volume of distribution of 70L. When taking the medication with food, the bioavailability is reduced by 40%. Zafirlukast metabolism is by hepatic CYP2C9 and is excreted primarily in the feces.[4][5]

Zafirlukast has a 40% reduction in bioavailability with food, and therefore tablets should be taken on an empty stomach, at least 1-hour pre-prandial, or 2 hours post-prandial. Chewable zafirlukast tablets contain up to 0.842 mg of phenylalanine.[5][6]

• For chronic asthma, the dose should be administered on an empty stomach, twice daily, and 10 to 12 hours apart as the half-life of zafirlukast is 8 to 16 hours. The recommended dosage is 20 mg twice daily for adults and children over 12 years. For children five to eleven, the recommended dose is 10 mg twice a day. There is no clinical data on the safety of zafirlukast in children under 5 years old and is not indicated for this age group.[7]

Zafirlukast takes 2 to 6 weeks for optimal effect and does not reverse acute bronchospasm. Therefore, zafirlukast should not be used for acute asthma exacerbations or status asthmaticus. 

• For asthma with allergic rhinitis, a dose of 20 mg twice daily for two weeks has shown to improve symptoms.[8] 
• For chronic urticaria, a dose of 20 mg twice daily for 3 to 6 weeks has been shown to reduce.[9]
• For exercise-induced asthma, a dose of 20 mg twice daily for two weeks has been shown to help prevent exercise-induced bronchospasm within 8 hours of dosing.[10]

Zafirlukast does not require dose-adjustment for patients with renal disease. Patients with hepatic impairment should not use zafirlukast as hepatic clearance will be impaired, and there will be a 50 to 60% increase in the maximum plasma concentration.[11] Patients over 65 may have reduced hepatic clearance, suggesting the need for monitoring of therapy and liver function tests.

Zafirlukast is a Pregnancy Category B drug based on reassuring animal studies and no reported evidence of major fetal malformations in humans.[12][13][14] For breastfeeding mothers, zafirlukast is not a reason to discontinue breastfeeding; however, limited data on breastfeeding and infant use is available, so an alternative drug with more supporting data may be a consideration. The manufacturer reports that for a 40 mg twice daily dose, the zafirlukast concentration in breastmilk is 50 mcg/L.[15]

Researchers have studied the adverse effects of zafirlukast in adults and children 12 years or older. There are rare reports of eosinophilia with vasculitis in patients taking zafirlukast; therefore, eosinophilia, rash, worsening asthma, cardiac issues, and neuropathy should warrant further workup. There are over 100 reported cases of severe hepatic failure with zafirlukast. Signs of hepatitis, including right upper quadrant pain, jaundice, and pruritus, should warrant monitoring of transaminases and discontinuation if clinical suspicion of hepatoxic effects occurs.[16] The resolution of transaminases occurs in most cases after discontinuation. Neuropsychiatric events, including depression and insomnia, have been reported, and clinicians should educate patients to be aware to report related symptoms. In patients over 55, there are reports of increased respiratory tract infection. In patients over 65, there is decreased clearance of zafirlukast with approximately a two-three fold increase in maximum concentration.

Side effects of zafirlukast include:

• Headache (10%), dizziness, neuropathy, hallucinations, insomnia, depression, and abnormal dreams
• Nausea (3%), diarrhea (3%), abdominal pain (3%), vomiting, and dyspepsia
• SGPT elevation, transaminase elevation, symptomatic hepatitis, hyperbilirubinemia, fulminant hepatitis, and progressive hepatic failure[17]
• Myalgia, back pain, arthralgia, theophylline toxicity symptoms, edema, and malaise
• Pain (2%), asthenia (2%), injury, and fever
• Respiratory tract infection in patients 55 or older with coadministration of inhaled corticosteroids (3%)
• Menorrhagia, thrombocytopenia, alopecia, bruising, pruritis, urticaria, angioedema, and rashes
• Granulomatosis, agranulocytosis, eosinophilia, eosinophilic pneumonia, and Churg-Strauss related syndrome.[18][19][20][21]

Zafirlukast is a CYP2CP substrate and weak inhibitor which may interact or decrease concentrations of alpelisib, dabrafenib, enzalutamide, lumacaftor, ivacaftor, and rifapentine. Erythromycin and theophylline can decrease the concentration of zafirlukast. Aspirin can increase the concentration of zafirlukast. Inhaled loxapine with zafirlukast should be avoided due to the increased risk of bronchospasm. Zafirlukast use with warfarin can cause a rise in the international normalized ratio and requires monitoring for optimal control of coagulability.[5][6]

Zafirlukast is contraindicated for patients with a history of hypersensitivity reaction to the active drug component and its inactive compounds such as povidone, lactose, titanium dioxide, or cellulose. Zafirlukast is also contraindicated in patients with hepatic impairment and cirrhosis based on case reports of hepatic failure.[11]