What are the potential adverse events associated with Singulair (montelukast)?

Singulair (Montelukast) Adverse Events

The FDA issued a black box warning in 2020 regarding serious neuropsychiatric events associated with montelukast, including suicidal thoughts and actions, depression, anxiety, sleep disturbances, and behavioral changes—these risks should be carefully weighed against benefits, particularly in patients with mild disease that can be adequately treated with alternative medications like intranasal corticosteroids. 1, 2

Serious Neuropsychiatric Adverse Events (FDA Black Box Warning)

The most concerning adverse events with montelukast are neuropsychiatric in nature:

• Suicidal thoughts and behavior (including completed suicide) have been reported, with disproportionate reporting in children compared to adults 1, 2, 3
• Depression and anxiety are frequently reported, with depression showing a reporting odds ratio of 6.93 in the global pharmacovigilance database 4
• Sleep disturbances including insomnia, nightmares, and sleep interruption affect 15.1% of pediatric patients, with sleep disorders being the most common adverse event in infants under 2 years 5, 3
• Behavioral changes including agitation (10.4% in children), aggressive behavior or hostility, irritability, and restlessness 2, 5
• Psychotic symptoms including hallucinations, dream abnormalities, and somnambulism (sleepwalking) 2
• Hyperactivity and attention problems affecting 6.8% of pediatric patients 5

Age-Specific Neuropsychiatric Risk Patterns

Different age groups show distinct adverse event profiles:

• Infants (<2 years): Sleep disorders are the predominant adverse event 3
• Children (2-11 years): Depression/anxiety, sleep disturbances, agitation, and unexpectedly high rates of suicidal behavior (reporting odds ratio 5.01) and completed suicide 3
• Adolescents (12-17 years): Suicidal behavior, depression/anxiety, and psychotic reactions are more common 3
• Adults: Older adults may be particularly susceptible to anxiety and sleeping disorders 6

Common Non-Neuropsychiatric Adverse Events

• Headache is the most common general adverse effect 1, 2
• Gastrointestinal symptoms including abdominal pain, diarrhea, indigestion, nausea, and vomiting 2
• Pain affecting 9.4% of pediatric patients 5
• Allergic reactions including swelling of face, lips, tongue, and/or throat (which may cause trouble breathing or swallowing), hives, and itching 2
• Increased bleeding tendency 2

Rare but Serious Adverse Events

• Hepatitis and elevated liver enzymes are less common but important adverse effects 1, 2
• Eosinophilia and Churg-Strauss syndrome: Patients may present with systemic eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy, though a causal association has not been definitively established 1, 2, 4
• Pancreatitis has been reported in clinical trials but causality has not been established 7

Critical Risk-Benefit Considerations

The FDA explicitly states that the benefits of montelukast may not outweigh the risks, especially when disease symptoms are mild and can be adequately treated with other medications. 1

• Montelukast is less effective than intranasal corticosteroids for allergic rhinitis and should not be considered first-line therapy when intranasal steroids are appropriate 1
• The EPOS2020 steering group does not advise adding montelukast to nasal corticosteroids based on lack of demonstrated benefit 7

Monitoring and Patient Counseling Requirements

• Monitor for unusual behavioral or mood changes when starting montelukast, particularly in the first weeks of therapy 1, 8
• Explicitly discuss neuropsychiatric risks before initiating therapy, including the potential for suicidal thoughts and behavioral changes 1
• Patients should be instructed to notify their prescriber immediately if neuropsychiatric events occur 2
• Do not prescribe montelukast for mild disease when safer alternatives like intranasal corticosteroids are available and appropriate 1
• Do not continue therapy without reassessing risk-benefit if any neuropsychiatric symptoms emerge, even if mild 1

Important Clinical Context

Recent large-scale observational studies show conflicting evidence:

• A 2025 Swedish nationwide cohort study of 74,291 children found no association between montelukast use and neuropsychiatric adverse events compared to long-acting β-agonists (HR 0.99; 95% CI 0.84-1.16) 9
• However, a 2023 systematic review found no significant association with suicide-related events in six observational studies, but four studies using antidepressant prescriptions as the outcome identified significant associations 6
• Real-world pediatric data from six tertiary centers reported a 31.9% prevalence of adverse drug reactions, predominantly neuropsychiatric 5

Despite some conflicting observational data, the FDA black box warning remains in effect and should guide prescribing decisions, particularly given the availability of safer alternatives for most indications. 1, 2