Montelukast is an orally available leukotriene receptor antagonist which is widely used for the prophylaxis and chronic treatment of asthma and has been linked to rare cases of clinically apparent liver injury.
Montelukast (mon" te 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. Montelukast has been shown to reduce symptoms of asthma and allergic rhinitis and prevent acute attacks. Montelukast was approved for use in the United States in 1998 and is widely used with more than 20 million prescriptions being filled yearly. Current indications for montelukast include prophylaxis and chronic treatment of asthma, prevention of exercise induced bronchoconstriction and allergic rhinitis. Montelukast is available in several generic forms and under the commercial name Singulair. The recommended dosage for adults is 10 mg once daily. Lower doses and chewable tablets are recommended for pediatric patients. Common side effects include dyspepsia, abdominal discomfort, asthenia, headache, dizziness, fatigue and fever.
In clinical trials, mild elevations in serum aminotransferase levels were found in 1% to 2% of patients taking montelukast chronically, but similar rates are reported in matched placebo recipients. The ALT abnormalities were usually mild, asymptomatic and self limited. Clinically apparent liver injury from montelukast is extremely rare; with fewer than a dozen cases reported in the literature. In these cases, the latency to onset of injury was highly variable, ranging from a few days to several years. Patients presented with anorexia, nausea, right upper quadrant pain, dark urine, and jaundice. The pattern of enzyme elevation is usually mixed, but both hepatocellular or cholestatic patterns have been reported. Allergic features and autoantibody formation were rare. Eosinophilia was often reported, but this may have been due to the underlying allergic condition rather than the liver injury. The injury usually resolved within 1 to 4 months of stopping the drug.
Mechanism of Liver Injury
The cause of hepatotoxicity from montelukast is not known, but the rare incidence, absence of immunoallergic features and long latency period suggest that it is not due to hypersensitivity but rather to altered metabolism. Montelukast is metabolized by the cytochrome P450 system (CYP3A4 and CYP2C9) and hepatotoxicity may be caused by formation of toxic intermediates.
Outcome and Management
Liver injury from montelukast is self limited and resolves in 1 to 4 months. Rechallenge with montelukast may lead to recurrence and should be avoided. Use of other leukotriene receptor antagonists has been reported to be safe, but should be done with caution.
Case 1. Cholestatic hepatitis due to montelukast.
[Modified from: Sass DA, Chopra KB, Wu T. A case of montelukast-induced hepatotoxicity. Am J Gastroenterol 2003; 98: 704-5. PubMed Citation]
A 42 year old man with asthma, sinusitis and nasal polyps developed jaundice and pruritus 10 months after starting chronic therapy with montelukast (10 mg daily). He took no other medications except for metered inhalants. He had no history of liver disease, hepatitis risk factors or alcohol abuse. On examination, he was jaundiced but had no fever, rash or enlargement of liver or spleen. Laboratory testing showed a total serum bilirubin of 7.6 mg/dL, but only modest elevations in serum enzymes (ALT ~1.5 times and Alk P 2 times ULN). There was a mild eosinophilia (9%). Despite stopping therapy promptly, he had prolonged jaundice, and a liver biopsy 3 months after drug discontinuation showed mild resolving intrahepatic cholestasis. Symptoms improved slowly and serum enzymes were normal when tested 4 months after drug withdrawal.
|| Montelukast (10 mg daily)
|Pattern:|| Cholestatic (R=0.8)|
||3+ (jaundice and hospitalization)
||10 months (to onset of jaundice)
|Recovery:|| 4 months|
|Other medications:||Beta adrenergic agonist and steroid metered dose inhalers|
Cholestatic jaundice arose after 10 months of montelukast therapy. No other cause of liver disease or jaundice was identified and he improved once montelukast was stopped, while other antiasthma medications (metered inhalants) were continued. The latency to onset was unusual and the clinical presentation was that of bland, canalicular cholestasis similar to what occurs with anabolic steroid use. However, this patient denied use of other medications.
REPRESENTATIVE TRADE NAMES
Montelukast – Generic, Singulair®
Product labeling at DailyMed, National Library of Medicine, NIH
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References updated: 17 February 2014
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Actis GC, Bugianesi E, Ottobrelli A, Rizzetto M. Fatal liver failure following food supplements during chronic treatment with montelukast. Dig Liver Dis 2007; 39: 953-5. PubMed Citation (45 year old woman developed severe acute hepatitis-like syndrome one week after completing a 7 day course of dietary supplement for obesity and while on long term montelukast for asthma [bilirubin 5.7 rising to 29 mg/dL, ALT 2512 U/L, GGT 31 U/L, eosinophilia], with progressive injury, hepatic failure and death; role of montelukast unclear).
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