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Risk of psychiatric adverse events following exposure to montelukast

Published online: August 10, 2020

Singular® (montelukast), a leukotriene-modifying agent (LTMA), is approved for the treatment of asthma, acute prevention of exercise induced bronchoconstriction, and allergic rhinitis in children and adults. Prompted by pharmacovigilance data, the Food and Drug Administration (FDA) issued Drug Safety Communications (DSC) in 2008 and 2009 and updated the "Warnings and Precautions" section of the montelukast label in 2009 to include multiple psychiatric adverse events (PAEs) including depression, suicide, and suicidality. However, there have been conflicting results from post-market observational studies regarding the association of PAEs with montelukast use.

A recently published FDA study by Sansing-Foster et al. in The Journal of Allergy and Clinical Immunology: In Practice, investigated the risk of depressive disorders, self-harm and suicide associated with montelukast use compared to inhaled corticosteroid (ICS) use among individuals 6 years or older with a diagnosis of asthma. Using healthcare claims data from the FDA’s Sentinel System from January 1, 2000 to Sept. 30, 2015, new users of montelukast were matched to new users of ICS using propensity score matching. Patients were followed from the day after their initial exposure until the study outcome or any of the prespecified censoring criteria. Cox proportional hazards regression models were used to estimate the risk of depressive disorders, self-harm and suicide overall and by age, sex, psychiatric history, and time periods before and after the 2008 DSC and label change regarding psychiatric events were implemented.

The majority of PAEs identified after exposure were depressive disorders treated in an outpatient setting. The study found no association between montelukast and inpatient depression and self-harm compared to ICS overall and across age, sex, and time strata. Exposure to montelukast was associated with a 9% lower risk of depression treated in an outpatient setting compared to ICS use. Roughly one-third of subjects had a psychiatric comorbidity, and the majority of PAEs occurred among these patients. The low number of suicides identified in the Sentinel Distributed Database (SDD) precluded the ability to assess any associations with this outcome.

In summary, asthma patients treated with montelukast or inhaled corticosteroids had similar risks for self-harm and hospitalization for depression. However, psychiatric comorbidity was common and most psychiatric adverse events occurred in patients with psychiatric histories. The findings should be interpreted considering the study’s limitations, particularly its observational nature and limited statistical power to assess rare outcomes.

In 2020, FDA added a boxed warning regarding serious neuropsychiatric events, with a recommendation that montelukast not be used first-line for the indication of allergic rhinitis. This regulatory action was based on the totality of evidence available from post-marketing surveillance.

The Journal of Allergy and Clinical Immunology: In Practice is an official journal of the AAAAI, focusing on practical information for the practicing clinician.

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