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Continuing Education Activity

Zafirlukast is a medication used in the management and treatment of chronic asthma. It is in the leukotriene receptor antagonist (LTRA) class. Zafirlukast is available as 10 mg and 20 mg tablets and chewable tablets, which are FDA-approved for managing chronic asthma in adults and children five years and older. It is used off-label in managing chronic urticaria, preventing exercise-induced bronchospasm, and allergic rhinitis. According to the GINA (Global Initiative for Asthma) guidelines, LTRA (montelukast or zafirlukast) is an essential controller therapy for patients unable to tolerate ICS inhaled corticosteroids. This activity reviews the indications, action, and contraindications for zafirlukast as an agent in the management and prophylaxis of chronic asthma. In addition, this activity will highlight the mechanism of action, adverse event profile, and other vital factors pertinent to the care of patients with chronic asthma.


  • Identify the mechanism of action of zafirlukast.
  • Describe the possible adverse effects of zafirlukast.
  • Review the appropriate monitoring for patients using zafirlukast.
  • Summarize interprofessional team strategies for improving care coordination and communication to advance the proper usage of zafirlukast and improve outcomes.


Zafirlukast is an orally available drug (10 mg and 20 mg tablets and chewable tablets), which is FDA-approved for managing chronic asthma in adults and children five years and older. It is used off-label in managing chronic urticaria, preventing exercise-induced bronchospasm, and allergic rhinitis.[1][2] According to the GINA (Global Initiative for Asthma) guidelines, LTRA (montelukast or zafirlukast) is an essential controller therapy for patients unable to tolerate ICS inhaled corticosteroids.[3]

A recent study indicates that membrane ion channel TMEM16A is a potential drug target for treating adenocarcinoma of the lung. Zafirlukast can target the TMEM16A channel to inhibit the proliferation and migration of lung adenocarcinoma cells. Furthermore, in vivo experiments showed that zafirlukast can significantly inhibit lung adenocarcinoma tumor growth in mice. The research identified zafirlukast as a novel TMEM16A channel inhibitor with remarkable anticancer activity. Zafirlukast is a promising drug candidate for future preclinical and clinical studies for patients with adenocarcinoma of the lung.[4]

Mechanism of Action

Zafirlukast (empirical formula C31H33N3O6S) is a leukotriene receptor antagonist, 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 associated with the underlying disease process of asthma. Therefore, limiting proinflammatory leukotrienes through competitive inhibition leads to decreased neutrophil and eosinophil migration, neutrophil and monocyte aggregation, leukocyte adhesion, airway edema, inflammation, and bronchial aggregation constriction.[5]

In addition, zafirlukast is a selective receptor antagonist of leukotriene D4 and E4 (LTD4 and LTE4), components of the slow-reacting substance of anaphylaxis (SRSA). Zafirlukast inhibits bronchoconstriction caused by several kinds of inhalational challenges. Pretreatment with zafirlukast inhibited the bronchoconstriction caused by cold air and sulfur dioxide in patients with asthma. Pretreatment also attenuated the early- and late-phase reaction caused by inhaling antigens such as cat dander, ragweed, grass, and other antigens in patients with asthma. Zafirlukast also reduced the increase in bronchial hyperresponsiveness to inhaled histamine that followed inhaled allergen challenge.


Absorption: Zafirlukast is rapidly absorbed after oral administration. Peak plasma concentration (Cmax) is approximately 3 hours after oral administration. When taking the medication with food, the bioavailability is reduced by 40%. Zafirlukast takes 2 to 6 weeks for optimal effect and has a half-life of 10 (8 to 16) hours. 

Distribution: Zafirlukast has a high plasma protein binding (99%). It binds predominantly to albumin. The volume of distribution of 70L suggests moderate tissue distribution. In preclinical studies, zafirlukast did not significantly cross the blood-brain barrier.

Metabolism: Zafirlukast is metabolized primarily by hepatic CYP2C9.[6]

Excretion: The oral clearance of zafirlukast is approximately 20 L/h. Preclinical studies suggest that the biliary route is the major route of excretion. Urinary excretion accounts for approximately 10% of the dose following oral administration, and the remainder is excreted in feces.[7]


Zafirlukast has a 40% reduction in bioavailability with food; 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.[7][8]

  • 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. The recommended dose for children aged five to eleven is 10 mg twice daily. There is no clinical data on the safety of zafirlukast in children under five years old, and it is not indicated for this age group.[9]

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 improved symptoms.[10] 
  • For chronic urticaria, a dose of 20 mg twice daily for 3 to 6 weeks has improved outcomes.[11]
  • 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.[12]

Use in Specific Patient Population

  • Patients with Renal Impairment: Zafirlukast does not require dose adjustment for patients with renal disease
  • Patients with Hepatic Impairment: 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.[13] Patients over 65 years of age may have reduced hepatic clearance, suggesting the need to monitor therapy and liver function tests.
  • Pregnancy Considerations: Zafirlukast is a Pregnancy Category B drug based on reassuring animal studies and no reported evidence of major fetal malformations in humans.[14][15]
  • Breastfeeding Considerations: There is a lack of data on zafirlukast during breastfeeding; however, the manufacturer's labeling indicates that zafirlukast's concentration in milk is low. Hence, If the mother requires zafirlukast, it is not a reason to discontinue breastfeeding. However, an alternate therapy may be preferred, especially while nursing a newborn or preterm infant.[16]

Adverse Effects

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 transaminases and discontinuation if clinical suspicion of hepatoxic effects occurs. Generally, The resolution of transaminases occurs in most cases after discontinuation. However, in rare cases, patients have either presented with fulminant hepatitis or progressed to hepatic failure, liver transplantation, and death. In such cases, a rechallenge trial of zafirlukast leads to rapid recurrence and must be avoided.[17]

Neuropsychiatric events, including depression and insomnia, have been reported, and clinicians should educate patients to report related symptoms. In patients over 55 years of age, there are reports of increased respiratory tract infection. In patients over 65, there is decreased clearance of zafirlukast with approximately a two to three-fold increase in maximum concentration.

Common adverse drug reactions of zafirlukast include:

  • Headache (10%), dizziness, neuropathy, hallucinations, insomnia, depression, and abnormal dreams[18]
  • Nausea (3%), diarrhea (3%), abdominal pain (3%), vomiting, and dyspepsia[19]
  • transaminase elevation(AST/ALT), symptomatic hepatitis, hyperbilirubinemia, fulminant hepatitis, and progressive hepatic failure[20]
  • Myalgia, back pain, arthralgia, theophylline toxicity symptoms, edema, and malaise[19]
  • Pain (2%), asthenia (2%), injury, and fever[18]
  • Respiratory tract infection in patients 55 or older with coadministration of inhaled corticosteroids (3%)
  • Menorrhagia, thrombocytopenia, alopecia, bruising, pruritis, urticaria, angioedema, and rashes[19]
  • Granulomatosis, agranulocytosis, eosinophilia, eosinophilic pneumonia, and Churg-Strauss-related syndrome[21][22]

Zafirlukast is a CYP2CP9 substrate and weak inhibitor which may interact with or decrease concentrations of alpelisib (kinase inhibitor), 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(INR) and requires monitoring for optimal control of coagulability.[7][8]


Zafirlukast is contraindicated for patients with a history of hypersensitivity reaction to the active drug component and the formulation's 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.[13]


Patients with chronic asthma require regular monitoring for improvements in pulmonary function tests with treatment. In patients with signs of hepatic injury, transaminases and bilirubin should be monitored for early detection as cessation can often lead to a resolution of mild liver injury. In patients taking zafirlukast with warfarin, the international normalized ratio may increase and should have close monitoring.[17]


Clinical studies have reported zafirlukast at high doses of 80 mg to cause a rise in transaminases.[23] In animal studies, zafirlukast dose of 2000 mg/kg in mice and 500 mg/kg in dogs has no reported deaths. Based on manufacturer guidelines, four overdose cases with a dose of 200 mg have reportedly survived, noting mild symptoms such as rash and upset stomach. The recommended intervention is gastric lavage, close clinical monitoring, and supportive therapy in acute overdose of zafirlukast.

Enhancing Healthcare Team Outcomes

Zafirlukast received approval for asthma treatment in the United States in 1996, and it continues to be a widely used agent, with more than 2 million prescriptions filled yearly. Managing chronic asthma requires an interprofessional team of clinicians (MDs, DOs, NPs, and PAs), pharmacists, laboratory technologists, nurses, and other healthcare providers. Asthma affects nearly 25 million people in the US, including 7.7% of all adults and 8.4% of all children.[24] The National Surveillance for Asthma suggests that LTRs such as zafirlukast can be used as an alternative or in addition to inhaled corticosteroids in the stepwise approach for those requiring a second or third therapy with no improvement.[25] 

Zafirlukast is a commonly prescribed medication in the outpatient setting for chronic asthma, which is not controlled or not treatable with short-acting beta-agonists and inhaled corticosteroids. Since zafirlukast takes weeks to reach peak effect, follow-up with healthcare providers to monitor pulmonary function and symptomatic improvement are important. The interprofessional team, comprised of clinicians, specialists, nurses, respiratory therapists, and pharmacists, is essential in coordinating the care, including:

  • Conducting follow-up appointments to assess for improvement
  • Monitoring INR in warfarin patients taking zafirlukast
  • Monitoring liver function tests in patients with decreased hepatic function or clearance
  • Monitoring for symptoms related to an allergic reaction to the medication, eosinophilic vasculitis, neuropsychiatric complaints, and hepatic dysfunction
  • Consult with a pulmonologist or allergy specialist for the treatment of chronic severe asthma 
  • Consult with a pharmacist for the safety of usage with other drugs
  • Collaboration with multiple inpatient and outpatient teams for management of acute asthma exacerbations
  • Knowledge of the latest guidelines, such as GINA guidelines, is essential for patient-centered care.[3]
  • Follow the evidence-based guidelines National Asthma Education and Prevention Program Coordinating Committee Expert Panel (NAEPP), supported by the National Heart, Lung, and Blood Institute. The goal is to optimize patient care and support informed decision-making about asthma management.[26]

Any interprofessional team member who becomes aware of the issues listed above, any other adverse events, or therapeutic failure should record their findings in the patient's health record and report this information to the rest of the team to implement corrective actions. Utilizing a collaborative interprofessional methodology with open communication and information sharing will improve therapeutic results with zafirlukast, with fewer adverse events. [Level 5]

(Click Image to Enlarge)
Zafirlukast mechanism of action, indications, and contraindications diagram.
Zafirlukast mechanism of action, indications, and contraindications diagram.
Contributed by Amareen Dhaliwal
Article Details

Article Author

Amareen Dhaliwal

Article Editor:

Tushar Bajaj


6/10/2022 3:37:08 PM

PubMed Link:




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