On March 3, 2020, the FDA announced that montelukast (Singulair) would require a boxed warning and Medication Guide related to increased risk for neuropsychiatric events. Warnings for montelukast related to neuropsychiatric events were previously issued by the FDA in 2008 and 2009, however montelukast has not carried a boxed warning. This boxed warning stems from several reports of neuropsychiatric events associated with montelukast, including 82 cases of completed suicide. In contrast, an observational study conducted by the FDA examined the risk for suicide, mortality, depressive disorder and self-harm in patients 6 years and older with asthma and without chronic obstructive pulmonary disease (COPD) taking either montelukast or inhaled corticosteroids (ICS), finding no association between montelukast and any mental health outcomes. However, the will require this boxed warning due to limitations associated with observational studies, the wide variety of safe and effective medications available for allergic rhinitis, evidence from animal studies indicating that montelukast crosses the blood-brain barrier, and lack of awareness amongst healthcare professionals about the potential mental health side effects of montelukast.
Montelukast is currently labeled for allergic rhinitis, asthma, and exercise induced bronchoconstriction. Because of this new boxed warning, health care providers should perform a risk versus benefit assessment when deciding to prescribe or continue montelukast. Providers should only prescribe montelukast in patients with allergic rhinitis who cannot tolerate or have not responded to other therapies. Counsel patients on mental health adverse events and advise them to stop taking montelukast and contact a health care professional if they experience these symptoms (eg, serious behavior and mood-related changes, including suicidal thoughts or action). Monitor for neuropsychiatric symptoms even in patients without pre-existing psychiatric disease. Most of the case reports describing these events occurred during montelukast treatment and symptoms resolved after discontinuation, however in some cases the events occurred after discontinuation. Patients and professionals are also encouraged to report any additional side effects to the FDA MedWatch program online at www.accessdata.fda.gov/scripts/medwatch/.
FDA requires the distribution of Medication Guides for drugs determined to be a serious and significant public health concern. Distribution requirements and exceptions (eg, certain inpatient care situations) for Medication Guides are addressed in an FDA Guidance Document. Medication Guide distribution requirements are stricter for medications with a Risk Evaluation and Mitigation Strategy (REMS) that includes Elements To Assure Safe Use (ETASU) with specific requirements for providing and reviewing the Medication Guide. A complete list of drugs that require a Medication Guide as part of the FDA-regulated product labeling is available online at: www.fda.gov/Drugs/DrugSafety/ucm085729.htm.
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