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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Zafirlukast

Last Update: June 4, 2019.

OVERVIEW

Introduction

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.

Background

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.

Hepatotoxicity

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 REPORTS

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

Medication:Zafirlukast (20 mg twice daily)
Pattern:Hepatocellular (R=19.2)
Severity:3+ (hospitalization for jaundice)
Latency:8 weeks to symptoms, 10 weeks to jaundice
Recovery:3 months
Other medications:Salmeterol and fomoterol aerosol and budesonide inhaler

Laboratory Values

Time After StartingTime After StoppingALT
(U/L)		Alk P
(U/L)		Bilirubin (mg/dL)Other
8 weeksAnorexia and fatigue
10 weeksDark urine and jaundice
12 weeks09993234.5Zafirlukast stopped
13 weeks7 days9186832.6Normal ultrasound
14 weeks18 days5607291.6
5 months2 months1303031.0Asymptomatic
6 months3 months212490.6
9 months6 months272600.7
Normal Values <40 <280 <1.2

Comment

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

Medication:Zafirlukast (20 mg twice daily)
Pattern:Hepatocellular
Severity:3+ (hospitalization for jaundice)
Latency:Initially, 9 months, 2 months on rechallenge
Recovery:5 months on rechallenge
Other medications:Salmeterol aerosol and fluticasone propionate inhaler and nasal spray

Laboratory Values

Time After StartingTime After StoppingALT* (U/L)Alk P (U/L)Bilirubin* (mg/dL)Other
Started zafirlukast 20 mg twice daily
9 months02950.7Started montelukast
13 months4 monthsNormal0.7
Resumed zafirlukast 20 mg twice daily
2 months0Symptoms and jaundice: zafirlukast stopped
3 months1 month15666.2
4 months2 months2703.1
5 months3 months1.4
6 months4 months1.2
7 months5 monthsNormal0.5Asymptomatic
Normal Values <35 <130 <1.2

* Selected values estimated from Figure.

Comment

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.

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Zafirlukast – Generic, Accolate®

DRUG CLASS

Antiasthma Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NUMBERMOLECULAR FORMULASTRUCTURE
Zafirlukast 107753-78-6 C31-H33-N3-O6-S
Zafirlukast Chemical Structure

ANNOTATED BIBLIOGRAPHY

References updated: 04 June 2019

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    (Expert review of hepatotoxicity published in 1999; mentions that theophylline has been incriminated in hepatic injury rarely; no mention of montelukast, zafirlukast or zileuton).
  • Lewis JH. Nonsteroidal anti-inflammatory drugs and leukotriene receptor antagonists. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013. pp. 389-90.
    (Expert review of liver injury caused by leukotriene receptor antagonists mentions that there were no reports of clinically apparent liver injury during premarketing studies of zafirlukast, but that more than 100 reports of clinically apparent injury appeared thereafter, at least 14 resulting in liver failure).
  • Barnes PJ. Pulmonary pharmacology. In, Brunton LL, Hilal-Dandan R, Knollman BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill, 2018, pp. 727-30.
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    (Review article on leukotriene pathway in asthma and rhinitis and efficacy and safety of montelukast, zafirlukast and zileuton; mentions that abnormal ALT elevations can occur).
  • Gozalo Reques F, Estrada Rodriguez JL. Tolerability of leukotriene modifiers in asthma: a review of clinical experience. Biodrugs 1999; 11: 385-94. [PubMed: 18031150]
    (Review of safety of leukotriene antagonists without new information).
  • Grossman J, Smith LJ, Wilson AM, Thyrum PT. Long-term safety and efficacy of zafirlukast in the treatment of asthma: interim results of an open-label extension trial. Ann Allergy Asthma Immunol 1999; 82: 361-9. [PubMed: 10227334]
    (Open labeled continuation of controlled trial of zafirlukast for 39 weeks; among 443 patients, 4.4% had ALT elevations, but peak value 340 U/L and all were self limited; one patient was withdrawn because of ALT elevations).
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    (68 year old woman developed jaundice 4 months after starting zafirlukast [bilirubin 21.1 mg/dL, ALT 1217 U/L, Alk P 225 U/L], resolving upon stopping).
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    (Three patients developed jaundice 5, 6 and 9 months after starting zafirlukast [peak bilirubin 6.2, 39.1 and 20.3 mg/dL, ALT 1750, 1157, and 1212 U/L, Alk P not given], one patient developed acute liver failure and 2 recovered within 4 months of stopping: Case 2).
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    (54 year old man developed jaundice 8 months after starting zafirlukast [bilirubin 3.9 mg/dL, ALT 661, and Alk P 135 U/L] with prolonged course despite corticosteroids, histology revealed severe injury with collapse).
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    (55 year old woman developed severe hepatitis 5 months after starting zafirlukast [bilirubin not given, ALT 2113 U/L, GGT 15 times ULN], there was a delay in stopping therapy and liver biopsy showed submassive necrosis and recovery was slow).
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    (63 year old woman developed jaundice 2 months after starting zafirlukast [bilirubin 4.5 mg/dL, ALT 999 U/L, Alk P 683 U/L, GGT 258 U/L], resolving within 3 months of stopping: Case 1).
  • Spector SL; Antileukotriene Working Group. Safety of antileukotriene agents in asthma management. Ann Allergy Asthma Immunol 2001; 86 (6 Suppl 1): 18-23. [PubMed: 11426912]
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    (36 year old woman developed jaundice 13 months after starting zafirlukast [peak bilirubin 28 mg/dL, ALT 3135 U/L, Alk P not given], followed by liver failure and emergency liver transplantation).
  • Soy M, Ozer H, Canataroglu A, Gumurdulu D, Erken E. Vasculitis induced by zafirlukast therapy. Clin Rheumatol 2002; 21: 328-9. [PubMed: 12189465]
    (54 year old man developed purpura, malaise, pleural effusions and atectasis 2 weeks after starting zafirlukast [bilirubin normal, ALT 98 U/L, Alk P 780 U/L, 35% eosinophils], improving upon stopping drug and use of corticosteroids, felt to be Churg-Straus syndrome).
  • Su CW, Wu JC, Huang YH, Huang YS, Chang FY, Lee SD. Zafirlukast-induced acute hepatitis. Zhonghua Yi Xue Za Zhi(Taipei) 2002; 65: 553-6. [PubMed: 12583521]
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  • Davern TJ, Bass NM. Leukotriene antagonists. Clin Liver Dis 2003; 7: 501-12, viii. [PubMed: 12879996]
    (Review of literature on hepatotoxicity of leukotriene inhibitors; in premarketing studies, 1.5% of 4058 of zafirlukast vs 1.1% of placebo recipients had ALT elevations, none serious and all transient; review of literature identified 9 cases of zafirlukast hepatotoxicity, 7 with jaundice, 3 with rash and eosinophilia, arising after 1.5 to 13 months, with liver transplantation required in two).
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    (Database of UK medical practice with questionnaire requesting information on zafirlukast treated patients, 7976 forms returned from 21,557 requests; 61% of physicians considered it effective, 53% of patients were treated for >6 months; 152 adverse events were reported in 120 patients [1.5%] including 34 hepatic events [4 with jaundice, 2 with hepatitis], but none were fatal and the authors concluded that “none of the events were serious”).
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  • Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-Induced liver injury in the general population of Iceland. Gastroenterology 2013; 144: 1419-25. [PubMed: 23419359]
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  • Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52. [PMC free article: PMC4446235] [PubMed: 25754159]
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  • Leung JS, Johnson DW, Sperou AJ, Crotts J, Saude E, Hartling L, Stang A. A systematic review of adverse drug events associated with administration of common asthma medications in children. PLoS One 2017; 12: e0182738. [PMC free article: PMC5549998] [PubMed: 28793336]
    (Systematic review of adverse events in reported in 46 clinical studies of commonly used asthma medications including 25 events associated with leukotriene antagonists affecting 9 organ systems; hepatotoxicity not mentioned).
  • Drugs for asthma. Med Lett Drugs Ther 2017; 59 (1528): 139-146. [PubMed: 28880849]
    (Concise review of medications used for asthma including the leukotriene modifiers; mentions that zafirlukast and zileuton have been reported to cause life-threatening hepatic injury and that monitoring of liver tests during therapy is recommended).

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