What are the risks associated with taking Singulair (montelukast)?

Risks of Singulair (Montelukast)

The FDA issued a black box warning in 2020 for montelukast due to serious neuropsychiatric events including suicidal thoughts and actions, depression, anxiety, sleep disturbances, and behavioral changes—risks that may outweigh benefits, particularly in patients with mild disease that can be adequately treated with alternative medications. 1

Neuropsychiatric Risks (Black Box Warning)

The most concerning risks of montelukast are neuropsychiatric adverse events, which prompted the FDA's strongest warning label. 1, 2

Specific Neuropsychiatric Manifestations:

• Suicidal behavior and ideation: Over-represented across all age groups, with particularly concerning data showing completed suicides reported more frequently in children (ages 2-11) than in adolescents or adults 3
• Depression and anxiety: Especially prominent in children aged 2-11 years and adolescents 3
• Sleep disturbances: Most common in infants and young children, including sleep difficulties, sleep interruption, decreased sleep, and nightmares, affecting 15.1% of pediatric patients in one study 4, 3
• Behavioral changes: Agitation (10.4%), hyperactivity (6.8%), aggressive behavior, hostility, anxiousness, irritability, and restlessness 2, 4
• Psychotic symptoms: Hallucinations (both visual and auditory), dream abnormalities, and somnambulism 2, 5

Age-Specific Patterns:

• Infants (<2 years): Predominantly sleep disorders 3
• Children (2-11 years): Depression/anxiety, sleep disturbances, agitation, and notably higher rates of completed suicide reports 4, 3
• Adolescents (12-17 years): Suicidal behavior, depression/anxiety, and psychotic reactions 3

Common Non-Psychiatric Adverse Effects

Adults and Adolescents (≥15 years):

• Upper respiratory infection (1.9% vs 1.5% placebo) 2
• Headache (18.4% vs 18.1% placebo) 2
• Influenza (4.2% vs 3.9% placebo) 2
• Gastrointestinal: Dyspepsia (2.1% vs 1.1% placebo), abdominal pain (2.9% vs 2.5% placebo), nausea, diarrhea 2

Pediatric Patients (6-14 years):

• Respiratory: Pharyngitis, influenza, sinusitis, laryngitis 2
• Infections: Otitis, viral infection 2
• Gastrointestinal: Nausea, diarrhea, dyspepsia 2
• Fever 2

Young Children (2-5 years):

• Fever, cough, abdominal pain, diarrhea (≥2% frequency) 2
• Respiratory: Rhinorrhea, sinusitis, otitis, influenza 2
• Dermatologic: Rash, eczema, urticaria, dermatitis 2

Infants (6-23 months):

• Upper respiratory infection, wheezing, otitis media 2
• Pharyngitis, tonsillitis, cough, rhinitis 2

Serious but Rare Adverse Events

Hepatic Toxicity:

• Rare cases of cholestatic hepatitis, hepatocellular liver injury, and mixed-pattern liver injury have been reported, often with confounding factors such as concomitant medications or underlying liver disease 2
• Elevated ALT (2.1% vs 2.0% placebo) and AST (1.6% vs 1.2% placebo) 2

Hypersensitivity Reactions:

• Anaphylaxis (very rare) 2
• Angioedema 2
• Hepatic eosinophilic infiltration (very rare) 2

Churg-Strauss Syndrome:

• Systemic eosinophilia with vasculitic features may occur in asthma patients, usually associated with reduction of oral corticosteroid therapy 2
• Presents with eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy 2
• Causal relationship not established but requires physician vigilance 2

Other Serious Events:

• Pancreatitis (very rare) 2
• Seizures 2
• Palpitations 2
• Epistaxis 2

Drug Interactions

Montelukast has minimal clinically significant drug interactions, but one notable concern exists: 6

• Potential additive neuropsychiatric effects when combined with other medications causing CNS effects (e.g., efavirenz in HIV patients showed worsening neuropsychiatric symptoms including disturbed sleep, vivid dreams, irritability, confusion, and concentration difficulties) 7
• No contraindications with common cold medications like DayQuil (acetaminophen, dextromethorphan, phenylephrine) 6

Clinical Context and Risk-Benefit Assessment

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

Key Considerations:

• For allergic rhinitis: Montelukast is less effective than intranasal corticosteroids and should not be considered first-line therapy when intranasal steroids are appropriate 1
• For asthma: Leukotriene receptor antagonists are appropriate alternative therapies for mild persistent asthma in patients unable or unwilling to use inhaled corticosteroids, but inhaled corticosteroids remain preferred 8
• Prevalence of adverse reactions: One study reported 31.9% of pediatric patients experienced adverse drug reactions, predominantly in ages 4-9 years (52.8%) 4

Monitoring and Patient Counseling Requirements

Before initiating therapy:

• Explicitly discuss neuropsychiatric risks including potential for suicidal thoughts and behavioral changes 1
• Assess for pre-existing psychiatric conditions or family history of mental health disorders 1

During therapy:

• Monitor for unusual behavioral or mood changes, particularly in the first weeks of therapy 1, 6
• Question patients about sleep disturbances, mood changes, agitation, and suicidal ideation at each visit 1
• Reassess risk-benefit if any neuropsychiatric symptoms emerge, even if mild 1

Critical Pitfalls to Avoid

• Do not prescribe montelukast for mild disease when safer alternatives like intranasal corticosteroids (for allergic rhinitis) or inhaled corticosteroids (for asthma) are available and appropriate 1
• Do not continue therapy without reassessing risk-benefit if neuropsychiatric symptoms develop 1
• Do not dismiss sleep disturbances or behavioral changes as unrelated to montelukast—these are well-documented adverse effects that may require discontinuation 4, 3
• Do not assume montelukast is universally safe because it lacks the need for laboratory monitoring—the neuropsychiatric risks are substantial and potentially life-threatening 1, 3

Overdose

• No mortality reported with single oral doses up to 5000 mg/kg in animal studies 2
• Doses up to 1000 mg in humans have been reported with adverse experiences consistent with the known safety profile (abdominal pain, somnolence, thirst, headache, vomiting, psychomotor hyperactivity) 2
• Treatment is supportive: Remove unabsorbed material, clinical monitoring, and supportive therapy as needed 2
• Not removed by dialysis 2