A US Food and Drug Administration (FDA) boxed warning issued in 2020 for montelukast was associated with significant reductions in prescribing for asthma across all age groups, according to a recent study.1 The findings suggest that the agency’s strongest safety warning altered clinician prescribing behavior despite ongoing uncertainty about the drug’s neuropsychiatric risks.
Montelukast, a leukotriene receptor antagonist widely used for asthma and allergic rhinitis, received an FDA boxed warning in March 2020 following reports of neuropsychiatric adverse events, including depression, aggression, and suicidal ideation. The warning advised clinicians to weigh risks and benefits on an individual basis when prescribing the drug for asthma and to reserve its use in allergic rhinitis for patients who had not responded to other therapies.
Commenting on the FDA’s decision, Sami Hossri, MD, FCCP, Assistant Professor of Medicine and Director of the Asthma Program at UTHealth Houston, said the warning was justified as a precautionary measure even though the underlying evidence remains mixed.
“Large observational datasets, including the FDA’s Sentinel System evaluation of more than 450,000 patients with asthma, did not demonstrate a statistically significant increase in neuropsychiatric events compared to inhaled corticosteroids. However, the warning was justified as a precautionary risk-communication action,” he said.
To assess how the warning affected prescribing, investigators led by Hariharan Shanmugam and colleagues analyzed data from the Merative MarketScan commercial claims database. The study included monthly cohorts of insured patients aged 6 years and older with asthma from October 2017 through December 2022. Monthly cohort sizes ranged from approximately 594,000 to more than 614,000 patients.
Using interrupted time-series analysis, the researchers examined both the prevalence of montelukast use and the incidence of new prescriptions before and after implementation of the warning. Prior to the boxed warning, montelukast prevalence was modeled at 160 users per 1,000 patients with asthma, while new initiations occurred at a rate of 5.8 per 1,000 nonusers each month. Following the warning, the incidence of new montelukast prescribing fell immediately. New prescriptions decreased by 1.7 per 1,000 patients, representing an almost 30% decline in incident use that persisted for at least two years.
The effect on ongoing use was more gradual. While there was no significant immediate drop in overall prevalence, montelukast use declined by 0.9 prescriptions per 1,000 patients per month relative to the prewarning period. By December 2022, estimated prevalence had fallen to about 152 users per 1,000 patients. Overall, prevalent use declined by roughly 5% during the two years following the warning.
Importantly, decreases were observed across all patient subgroups examined, including children, adults, older adults, patients using inhaled corticosteroids, and those with markers of more severe asthma such as prior asthma-related emergency department visits or hospitalizations. The decline was particularly pronounced among pediatric patients, which researchers suggested may reflect heightened public and media attention surrounding reports of neuropsychiatric adverse effects in children.
The study also addressed the challenge of distinguishing the impact of the boxed warning from the onset of the COVID-19 pandemic, which occurred during the same period. In sensitivity analyses, use of other noninhaled asthma medications continued to increase after March 2020, while montelukast use declined. These findings support the conclusion that the observed prescribing changes were likely related to the FDA action rather than broader pandemic-related shifts in health care utilization.
Although prescribing decreased, experts emphasize that montelukast continues to play an important role for select patients.
Dr. Hossri said it remains a vital tool for patients with aspirin-exacerbated respiratory disease, and it continues to play a role in patients with allergic rhinitis and asthma, exercise-induced bronchospasm, and those with significant barriers to inhaler use.
The study did not evaluate safety outcomes directly but rather measured the effect of regulatory action on prescribing behavior. Evidence linking montelukast to neuropsychiatric adverse effects remains mixed, with some studies finding no association and others reporting elevated risks, particularly in children.
For clinicians who continue to prescribe the drug, Dr. Hossri said, careful patient selection and counseling are essential.
“Montelukast should never be a default ‘add-on,’” he said. “The benefit in airway control must clearly outweigh the mental health risk profile for that specific individual.”
According to the investigators, the results demonstrated that boxed warnings can meaningfully influence clinical practice. However, many patients already receiving montelukast continued treatment after the warning, possibly because clinicians judged the benefits to outweigh potential risks or because therapeutic alternatives remained limited.
Dr. Hossri noted that the prescribing response seen with montelukast may reflect the particular impact of neuropsychiatric safety concerns on both clinicians and patients.
“Empirical claims data show that the warning prompted an immediate and sharp drop in new prescriptions. However, the shift in overall prevalence was more modest, as many clinicians and stable patients opted to continue long-standing therapy,” he said.
References
1. Shanmugam H, Kesselheim AS, Liu ITT, Feldman WB, Rome BN. Changes in the use of montelukast for asthma after a US Food and Drug Administration boxed warning. JAMA Netw Open. 2026;9(5):e2614274. doi:10.1001/jamanetworkopen.2026.14274
