Adverse Effects of Montelukast
Montelukast has minimal common adverse effects similar to placebo, but carries a serious FDA black box warning for neuropsychiatric events including suicidal thoughts and actions, depression, anxiety, sleep disturbances, and behavioral changes that must be carefully weighed against benefits, particularly in patients with mild disease. 1, 2, 3
Neuropsychiatric Adverse Events (Most Critical)
The FDA issued a black box warning in 2020 specifically for serious neuropsychiatric events. 1, 2 These include:
- Suicidal thoughts and actions (including completed suicide) 2, 3
- Depression and anxiety 2, 3
- Sleep disturbances including insomnia, nightmares, and sleepwalking 2, 3, 4
- Behavioral changes: agitation, aggressive behavior, hostility, irritability, restlessness 3
- Hallucinations and dream abnormalities 3
- Tremor 3
Monitor patients for unusual behavioral or mood changes, particularly in the first weeks of therapy. 1, 2 The FDA explicitly states that benefits may not outweigh risks, especially when disease symptoms are mild and can be adequately treated with alternative medications like intranasal corticosteroids. 2
Evidence Context on Neuropsychiatric Risk
Recent large-scale observational studies show conflicting evidence. A Swedish cohort study of 74,291 children found no increased risk of neuropsychiatric events compared to LABA users (HR 0.99,95% CI 0.84-1.16). 5 However, a Korean case-crossover study of 161,386 pediatric patients found increased risk across all time windows (7-day aOR 1.29,95% CI 1.26-1.33; 14-day aOR 1.34,95% CI 1.31-1.37). 6 Despite this conflicting research evidence, the FDA black box warning takes precedence and must guide clinical decision-making. 1, 2
Common Adverse Effects (Generally Mild)
The overall incidence of clinical adverse events is similar to placebo in controlled trials. 7 Common side effects include:
- Headache 3
- Abdominal pain, nausea, vomiting, diarrhea, indigestion 3, 4
- Upper respiratory infections (similar frequency to placebo) 7
- Drowsiness and somnolence 3
Less Common but Important Adverse Effects
- Allergic reactions: Facial, lip, tongue, and/or throat swelling (which may cause breathing or swallowing difficulty), hives, itching 3
- Increased bleeding tendency 3
- Hepatitis and elevated liver enzymes 8, 3
- Paresthesias (pins and needles/numbness) 3, 4
- Seizures 3
- Palpitations 3
- Nosebleeds 3
- Inflammation of the pancreas 3
- Joint pain, muscle aches and cramps 3
Rare but Serious: Churg-Strauss Syndrome
In rare cases, patients on montelukast may present with systemic eosinophilia, sometimes with clinical features of vasculitis consistent with Churg-Strauss syndrome. 8, 3 These events usually, but not always, occur with reduction of oral corticosteroid therapy. 3 Physicians should be alert to:
A causal association between montelukast and Churg-Strauss syndrome has not been definitively established. 8, 3
Pediatric-Specific Considerations
In a clinical series, 5.7% of pediatric patients required treatment discontinuation due to adverse effects. 4 The most frequent were:
Symptoms appeared from the first days to months after starting treatment and resolved after discontinuation. 4
Overdose Profile
No mortality occurred in animal studies with doses up to 5000 mg/kg. 3 In humans, doses up to 1000 mg have been reported with adverse experiences consistent with the known safety profile, most frequently abdominal pain, somnolence, thirst, headache, vomiting, and psychomotor hyperactivity. 3 No dose-related adverse effects were observed in adults treated with up to 200 mg daily (20 times the recommended dose) for 5 months. 7
Special Populations
Montelukast is Pregnancy Category B and may be used during pregnancy when there has been a uniquely favorable prepregnancy response, though it should be reserved for asthma management rather than rhinitis alone until additional safety data becomes available. 8
Critical Clinical Pitfalls to Avoid
- Do not prescribe montelukast for mild disease when safer alternatives like intranasal corticosteroids are available and appropriate. 2 Montelukast is less effective than intranasal corticosteroids for allergic rhinitis. 8, 2
- Do not continue therapy without reassessing risk-benefit if any neuropsychiatric symptoms emerge, even if mild. 2
- Explicitly discuss neuropsychiatric risks before initiating therapy, including the potential for suicidal thoughts and behavioral changes. 2
- Instruct patients to notify their prescriber immediately if behavioral or mood-related changes occur. 3
- Do not abruptly substitute montelukast for inhaled or oral corticosteroids. 3
Monitoring Recommendations
Patients should be instructed to notify their physician if neuropsychiatric events occur while using montelukast. 3 For zafirlukast (another leukotriene modifier), monitor hepatic enzymes due to reports of reversible and irreversible hepatic failure. 8