Side Effects of Montelukast
Montelukast is generally well-tolerated with minimal side effects, but carries a significant FDA Boxed Warning for neuropsychiatric events including depression, anxiety, agitation, sleep disturbances, and suicidal thoughts/behaviors, particularly in younger patients. 1
Common Side Effects
The most frequently reported adverse effects from clinical trials include 2, 1:
- Headache
- Abdominal pain
- Nausea
- Diarrhea
- Upper respiratory tract infections
- Thirst
- Somnolence
- Vomiting
- Psychomotor hyperactivity
These effects are typically mild and self-limited. In the majority of overdosage reports, no adverse experiences occurred 1.
Neuropsychiatric Side Effects (FDA Boxed Warning)
The FDA issued a Boxed Warning in March 2020 specifically for neuropsychiatric adverse events 3, 1. These include:
- Depression
- Anxiety (11% increased risk in meta-analysis) 4
- Agitation (reported in 10.4% of pediatric patients) 5
- Sleep disturbances (most common adverse effect in children at 15.1%, including nightmares, sleep interruption, and decreased sleep) 5
- Suicidal thoughts and behaviors
- Mood changes
- Hyperactivity (6.8% in pediatric studies) 5
- Confusion and psychotic-like symptoms
Age-Related Risk Pattern
Younger patients face higher neuropsychiatric risk. Age-stratified analyses show the risk increases with decreasing age, with the highest risk in patients aged 18-29 years 6. Among adults with asthma, montelukast initiation was associated with a 14% increased risk of neuropsychiatric medication use (HR 1.14,95% CI 1.08-1.20) 6.
Important Caveat on Recent Evidence
However, a large 2025 Swedish cohort study of 74,291 children found no association between montelukast use and neuropsychiatric adverse events (weighted HR 0.99,95% CI 0.84-1.16) when compared to long-acting β-agonists 7. This conflicts with earlier observational data and spontaneous reports, suggesting the true risk may be lower than previously estimated or highly variable between individuals.
Rare but Serious Side Effects
Hepatotoxicity
Postmarketing surveillance has reported cases of reversible hepatitis and, rarely, irreversible hepatic failure resulting in death and liver transplantation 2. This is specifically noted for zafirlukast (another leukotriene modifier), but montelukast itself has "no specific adverse effects identified" in this regard 2.
Churg-Strauss Syndrome
Rare cases of systemic eosinophilia with vasculitis consistent with Churg-Strauss syndrome have occurred 2, 1. These events usually, but not always, have been associated with reduction of oral corticosteroid therapy. A causal association has not been definitively established 1.
Clinical Management Recommendations
Patients and prescribers must be alert for neuropsychiatric events 1:
- Pre-treatment counseling is mandatory - Discuss neuropsychiatric risks before initiating therapy
- Instruct patients to immediately notify prescriber if behavioral changes occur
- Carefully evaluate risks versus benefits before starting treatment, especially in patients with:
- History of psychiatric disorders
- Younger age (particularly 18-29 years)
- Depression or suicidal ideation
- Monitor regularly for behavioral changes during treatment
- Discontinue immediately if neuropsychiatric symptoms develop 8
Safety Profile Advantages
Despite these concerns, montelukast has several safety advantages 2, 9:
- No sedation (unlike first-generation antihistamines)
- No anticholinergic effects
- Does not suppress skin testing (unlike antihistamines) 9
- Minimal drug interactions - Does not significantly affect theophylline, warfarin, digoxin, oral contraceptives, or prednisone 1
- No laboratory monitoring required (unlike zileuton which requires liver enzyme monitoring) 2
Drug Interactions
Phenobarbital and rifampin decrease montelukast AUC by approximately 40%, but no dosage adjustment is recommended - employ appropriate clinical monitoring when co-administering potent CYP450 inducers 1.
Pediatric Considerations
In children, sleep disturbance is the predominant adverse effect (15.1%), followed by agitation (10.4%), pain (9.4%), and hyperactivity (6.8%) 5. The Austrian working group recommends that treatment should be started only after critical evaluation and stopped immediately upon occurrence of any neuropsychiatric side effects 8.