Zafirlukast is an orally available leukotriene receptor antagonist which is widely used for the prophylaxis and chronic treatment of asthma. Zafirlukast has been linked to rare, but occasionally severe cases of acute liver injury.


Zafirlukast (za" fir loo' kast) is a leukotriene receptor antagonist that binds to the CysLT1 and CysLT2 receptors, thereby interfering with inflammatory pathways that are involved in the pathogenesis of asthma and allergic rhinitis. Pretreatment with single oral doses of zafirlukast inhibits bronchoconstriction and the early-phase and part of the late-phase inflammatory reactions in asthma. Zafirlukast was approved for use in the treatment of asthma in the United States in 1996, and it continues to be widely used with more than 2 million prescriptions filled yearly. Other leukotriene receptor antagonists include montelukast and pranlukast, but only montelukast is also available in the United States. Current indications include the prophylaxis and chronic treatment of asthma in adults and children (above the age of 5). Zafirlukast is available in 10 and 20 mg tablets generically and under the brand name Accolate. The recommended dosage of zafirlukast in adults and children >12 years is 20 mg twice daily. The recommended dose in children 5 to 11 years is 10 mg twice daily. Common side effects include nausea, diarrhea, dyspepsia, abdominal pain, headache, dizziness, myalgias, and fever.


Prospective studies have shown that ALT elevations occur in 1.5% of patients receiving zafirlukast, most of which are mild, asymptomatic and self limited even with continuing therapy. A similar rate of transient ALT elevations is often found in placebo recipients. Clinically apparent liver disease from zafirlukast is rare, but many convincing cases have been reported, several of which were severe and resulted in hepatic failure, need for liver transplantation or death. The onset of symptoms of liver injury is typically within 2 to 6 months of starting therapy, but cases with longer latency periods have been reported (8-13 months). Symptoms include fatigue, nausea, and right upper quadrant pain followed by dark urine, jaundice and pruritus. The pattern of liver enzyme elevation is usually hepatocellular and resembles acute viral hepatitis. Eosinophilia is common but immunoallergic features are usually not prominent and autoantibodies are uncommon (eosinophilia may be due to the underlying allergic asthmatic condition). Fatal cases have been described. Reexposure can lead to more rapid and severe reappearance of injury and should be avoided. Zafirlukast can also cause systemic vasculitis and eosinophilia (Churg-Strauss Syndrome) which may be accompanied by hepatic involvement and mild enzyme elevations.

Likelihood score: C (probable cause of clinical apparent liver injury).

Mechanism of Hepatotoxicity

The mechanism of hepatic injury due to zafirlukast is not known but it is clearly idiosyncratic. The extensive hepatic metabolism of zafirlukast by the cytochrome P450 (CYP2C9) system suggests that injury may be a result of a hepatotoxic or immunogenic intermediate.

Outcome and Management

Monitoring of routine liver tests for liver injury is recommended but has not been shown to be effective in preventing the rare instances of hepatic injury due to zafirlukast and the optimal timing and frequency of such testing is not well define. Patients should be alerted to the signs and symptoms of liver injury and stop therapy or be seen quickly if they occur. Typically, symptoms and liver enzymes abnormalities resolve rapidly after stopping zafirlukast. In rare cases, patients have either presented with fulminant hepatitis or progressed to hepatic failure, liver transplantation and death. Rechallenge leads to prompt recurrence and should be avoided. Switching to another leukotriene receptor antagonist such as montelukast or to zileuton, a 5-lipoxygenase inhibitor with a related mechanism of action, is usually possible but should be done with caution.

Drug Class: Antiasthmatic Agents

Other Drugs in the Subclass, Leukotriene Receptor Antagonists: Montelukast


Case 1. Acute hepatitis related to zafirlukast use.

[Modified from: Moles JM, Primo J, Fernandez JM, Hinojosa JE. Acute hepatocellular injury associated with zafirlukast. J Hepatol 2001; 35: 541-2. PubMed Citation]

A 63 year old woman with asthma developed fatigue and anorexia 8 weeks after adding zafirlukast (20 mg twice daily) to a chronic regimen of various inhalants including salbutamol, fomoterol and budesonide. Two weeks later she noted dark urine and jaundice, but waited another two weeks before seeking medical advice. She had no history of liver disease and serum aminotransferase levels had been normal in the past. She had no risk factors for viral hepatitis, did not use alcohol, and took no other medications. Her past medical history included gall bladder disease leading to a cholecystectomy 4 years previously. On examination, she was jaundiced but had no fever, rash, hepatomegaly or signs of chronic liver disease. Laboratory tests showed a total bilirubin of 4.5 mg/dL, ALT 999 U/L, AST 980 U/L, alkaline phosphatase 323 U/L and GGT 258 (normal <50) U/L. The prothrombin time was normal and tests for acute hepatitis A, B and C were negative as were autoantibodies. An abdominal ultrasound was normal. Zafirlukast was discontinued on admission and she improved rapidly (Table). Liver biopsy was not done. Symptoms and jaundice resolved within 2 weeks and liver tests were normal when she was seen 3 months after stopping.

Key Points

Laboratory Values


This patient developed an acute hepatitis-like syndrome 2 months after starting zafirlukast for chronic asthma, which began to resolve within a week of stopping the suspected agent. She was taking no other medications except inhalants which she had used for years, and clinical evaluation ruled out other common causes of liver injury. Zafirlukast has been linked to several instances of acute liver injury usually arising within 2 to 6 months of starting and presenting with jaundice and a hepatocellular pattern of liver injury. The course is usually self limiting, but several instances of acute liver failure leading to death or emergency liver transplantation have been published.

Case 2. Acute liver injury due to zafirlukast.

[Modified from: Reinus JF, Persky S, Burkiewicz JS, Quan D, Bass NM, Davern TJ. Severe liver injury after treatment with the leukotriene receptor antagonist zafirlukast. Ann Intern Med 2000; 133: 964-8. PubMed Citation]

A 42 year old woman with chronic sinusitis and asthma was found to have abnormal serum enzymes 9 months after she was started on zafirlukast. She had no symptoms, but therapy was stopped and she was switched to montelukast, on which her serum aminotransferase levels fell to normal. Zafirlukast was restarted, but 2 months later she developed symptoms and jaundice. When seen one month later, she was jaundiced and had marked serum aminotransferase elevations (Table). She had no history of exposure to viral hepatitis and did not drink alcohol. She recovered slowly, jaundice resolved within 2 months and serum enzyme elevations within 5 months of stopping.

Key Points

Laboratory Values

* Selected values estimated from Figure.


The initial ALT elevations had several possible explanations, but the reappearance of hepatocellular injury upon rechallenge is firm evidence of the role of zafirlukast. Interestingly, she tolerated montelukast, another leukotriene receptor antagonist with a somewhat similar chemical structure, without evidence of liver injury.



Zafirlukast – Generic, Accolate®


Antiasthma Agents


Product labeling at DailyMed, National Library of Medicine, NIH



References updated: 04 June 2019

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