No Risk of Neuropsychiatric AEs With Montelukast Over LABA Agents for Asthma, Allergic Rhinitis

A new study has found no association between use of montelukast (Singulair; Organon) and the risk of neuropsychiatric adverse events in children and adolescents with asthma and allergic rhinitis compared to that of long-acting β-agonists (LABA).1

“Spontaneous reports have indicated that montelukast increases the risk of neuropsychiatric adverse events, and the US FDA added a boxed warning about these risks in 2020. However, the potential mechanism is not well understood, and the observational evidence is scarce, particularly in children,” lead investigator Viktor Wintzell, PhD, Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden, and colleagues wrote.1

Wintzell and colleagues conducted a nationwide register-based cohort study using data children aged 6 to 17 years from Sweden from 2007 to 2021. Participants included used montelukast and long-acting β-agonists (LABA). Investigators performed data analysis from December 2023 to April 2024. Altogether, the study included 74,291 children with a mean age of 12.3 years (standard deviation [SD], 3.3), 35,446 of which were female, 26,462 of which used montelukast and 47,829 of which used LABA.1

The investigators found that over a mean follow-up of 5.8 months (SD, 3.2), there were 310 neuropsychiatric adverse events (AEs) in the montelukast population and 566 events in the LABA population. In the weighted cohort, montelukast users had a 2.39 incidence rate per 100 patient-years of neuropsychiatric AEs and LABA users had a 2.41 incidence rate per 100 patient-years. These incidence rates translated to a weighted hazard rate (HR) of 0.99 (95% CI, 0.84-1.16) for montelukast users, showing no difference between groups, which was further corroborated over subgroup and sensitivity analyses.1

Wintzell and colleagues also found no substantial differences when looking at specific neuropsychiatric AEs, with HRs of 0.79 (95% CI, 0.54-1.14) for anxiety; 1.16 (95% CI, 0.70-1.95) for depression; 0.93 (95% CI, 0.76-1.13) for sleep-related disorders; 1.31 (95% CI, 0.64-2.69) for suicide and suicidal actions; 1.27 (95% CI, 0.84-1.90) for disrupted control of activity, attention, and behavior; and 0.51 (95% CI, 0.05-5.53) for confusion and psychotic-like symptoms.1

“In this nationwide cohort study of children and adolescents, we found no support for an association between montelukast and the risk of neuropsychiatric adverse events, defined as a composite of specific events. In addition to other relevant pediatric studies, this large-scale observational study can inform regulatory agencies and clinical practice. Robust safety data on montelukast are crucial given its role in the management of asthma and allergic rhinitis,” Wintzell and colleagues wrote.1

The FDA originally added a boxed warning to montelukast for neuropsychiatric AEs in 2008 and added an advisement to avoid prescription for mild asthma or allergic rhinitis in March 2020.2 The warnings were informed by data were received through the FDA AEs Reporting System (FAERS), published observational studies, and the Sentinel Distributed Database External Link Disclaimer, as well as a presentation of findings in an FDA advisory committee meeting in 2022.

“Importantly, there are many other safe and effective medications to treat allergies with extensive history of use and safety, such that many products are available over the counter without a prescription,” Sally Seymour, MD, director of the Division of Pulmonary, Allergy, and Rheumatology Products in the FDA’S Center for Drug Evaluation and Research, said at the time.2

The new findings cast doubt on the necessity of such warnings for montelukast’s label while the same warnings are not present on labels for LABA agents.3

REFERENCES

1. Wintzell V, Brenner P, Halldner L, Rhedin S, Gong T, Almqvist C. Montelukast Use and the Risk of Neuropsychiatric Adverse Events in Children. JAMA Pediatr. Published online January 21, 2025. doi:10.1001/jamapediatrics.2024.5429

2. Kunzmann K. FDA Adds Boxed Warning to Montelukast Label. HCPLive. March 4, 2020. https://www.hcplive.com/view/fda-boxed-warning-montelukast-label

3. Long-Acting Beta-Agonists (LABAs). American Academy of Allergy, Asthma & Immunology. Updated May 2024. https://www.aaaai.org/tools-for-the-public/drug-guide/long-acting-beta-agonists-(labas)