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Leukotriene modifiers and neuropsychiatric side effects; is it a class effect


In regards to the neuropsychiatric / behavioural side effects noted as black box warnings with montelukast (Singulair), is that a class effect noted across other leukotriene modifiers as well? For example, zafirlukast (Accolate) and zileuton (Zyflo)?


On March 4th he U.S. Food and Drug Administration (FDA) is strengthening existing warnings about serious behavior and mood-related changes with montelukast (Singulair and generics), which is a prescription medicine for asthma and allergy. (1)

Benard, et al, (2) based on questionnaire survey, 12% of respondents reports neuropsychiatric symptoms associated with Montelukast. Similarly, Ernst, et al. (3) surveyed 223 patients and 106 responded. Questionnaires revealed that the incidence of neuropsychiatric ADRs serious enough to lead to cessation of therapy, was reported by 16%, or 12% if considering only ADRs that are “definitely or probably” related to montelukast. All ADRs were judged to be mild or very mild and only required cessation of therapy.

I searched PubMed for zileuton (Zyflo) and zafirlukast (Accolate) and Neuropsychiatric effects. I was unable to find a reference. Accessing the FDA website, neuropsychiatric ADR was not identified for zafirlukast (4). The FDA did state that there had been post-marketing reports of cases sleep disorders and behavior changes, though did not report incidence. (5)

Based on these findings I feel the takeaway is that neuropsychiatric side effects do not appear to be a class effect of leukotriene modifiers.

1) FDA requires Boxed Warning about serious mental health side effects for asthma and allergy drug montelukast (Singulair); advises restricting use for allergic rhinitis Accessed 4/10/20:

2) Benard B, Bastien V, Vinet B, Yang R, Krajinovic M, Ducharme FM. Neuropsychiatric adverse drug reactions in children initiated on montelukast in real-life practice. Eur Respir J. 2017;50(2):1700148. Published 2017 Aug 17. doi:10.1183/13993003.00148-2017

3) Ernst P, Ernst G. Neuropsychiatric adverse effects of montelukast in children. Eur Respir J. 2017;50(2):1701020. Published 2017 Aug 17. doi:10.1183/13993003.01020-2017

4) Accessed 4/10/20.

5) Accessed 4/10/20.

I hope you find this helpful in your clinical decision making.

Respectfully submitted,
Jeffrey G Demain, MD, FAAAAI