What are the side effects of Montelukast (Montelukast)?

Montelukast Side Effects

Montelukast carries a serious FDA black box warning for neuropsychiatric events including suicidal thoughts and actions, depression, anxiety, sleep disturbances, and behavioral changes—these risks often outweigh benefits, particularly in mild disease treatable with safer alternatives like intranasal corticosteroids. 1

Most Serious Side Effects: Neuropsychiatric Events

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

Neuropsychiatric Reactions (Most Critical)

• Depression is the most frequently reported adverse reaction globally (ROR 6.93; 95% CI: 6.5-7.4) 2
• Aggression is particularly prominent in children (ROR 29.77; 95% CI: 27.5-32.2) 2
• Suicidal thoughts and actions prompted the FDA's 2020 black box warning 1, 3
• Sleep disturbances affect 15.1% of pediatric patients, including insomnia, nightmares, sleep interruption, and decreased sleep 4, 5
• Behavioral changes including agitation (10.4% of children), hyperactivity (6.8%), and psychomotor hyperactivity 4, 6
• Anxiety is specifically mentioned in the FDA black box warning 1

Timeline and Monitoring

• Neuropsychiatric symptoms can appear from the first days to months after starting treatment 5
• Monitor for unusual behavioral or mood changes particularly in the first weeks of therapy 1
• Symptoms typically resolve after discontinuing the medication 5

Common Side Effects

Most Frequent Adverse Events

• Headache is the most commonly reported side effect (ROR 2.26; 95% CI: 1.61-3.19) 1, 2
• Abdominal pain occurs frequently, particularly in overdose situations 6, 5
• Somnolence and thirst are reported in overdose cases 6
• Vomiting and psychomotor hyperactivity 6

Pediatric-Specific Patterns

• In children aged 4-9 years, adverse drug reactions are most prevalent (52.8%), followed by adolescents (24.4%) and toddlers (22.8%) 4
• Overall, 31.9% of pediatric patients experience adverse drug reactions requiring consideration of discontinuation 4
• In one pediatric pulmonology unit, 5.7% of patients required treatment discontinuation due to adverse reactions 5

Less Common but Important Side Effects

Hepatic Effects

• Hepatitis and elevated liver enzymes are less common but clinically important 1

Hematologic Effects

• Eosinophilia is rare but serious; however, a causal association with Churg-Strauss syndrome has not been definitively established 1
• Allergic granulomatous angiitis (Churg-Strauss syndrome) has been reported in adults, often associated with corticosteroid withdrawal that may have unmasked the condition 7, 2
• Eight cases reported to the Dutch database and 563 cases in the global VigiBase® 2
• No cases of Churg-Strauss syndrome have been reported in children 7

Unusual Pediatric Reactions

• Limb paresthesia has been reported in children (2 cases), though not previously described in pediatric literature 5

Other Reported Effects

• Pancreatitis has been reported in clinical trials, though causality has not been established 1

Overdose Profile

Safety Margin

• No mortality occurred in animal studies with doses up to 5000 mg/kg in mice (335-210 times the maximum recommended human dose) and rats (230-145 times the maximum recommended dose) 6
• In clinical studies, adults tolerated doses up to 200 mg/day for 22 weeks and up to 900 mg/day for approximately one week without clinically important adverse experiences 6
• Post-marketing reports include overdoses as high as 1000 mg 6

Overdose Symptoms

• Most overdose cases are asymptomatic 6
• When symptoms occur, they are consistent with the known safety profile: abdominal pain, somnolence, thirst, headache, vomiting, and psychomotor hyperactivity 6

Critical Clinical Pitfalls to Avoid

Prescribing Decisions

• Do not prescribe montelukast for mild disease when safer alternatives like intranasal corticosteroids are available and appropriate 1
• Montelukast is less effective than intranasal corticosteroids for allergic rhinitis and should not be considered first-line therapy 1
• The European Position Paper on Rhinosinusitis (2020) does not recommend adding montelukast to nasal corticosteroids due to lack of demonstrated benefit 1

Patient Counseling

• Explicitly discuss neuropsychiatric risks before initiating therapy, including the potential for suicidal thoughts and behavioral changes 1
• Do not continue therapy without reassessing risk-benefit if any neuropsychiatric symptoms emerge, even if mild 1
• Treatment should be stopped immediately upon occurrence of any neuropsychiatric side effects 3

Treatment Discontinuation

• In the UK, prescribing databases suggest less than 25% of children discontinued montelukast, implying it is generally well tolerated in most children who do not experience adverse effects 7
• However, 5.3% of families stopped the drug due to concern about side effects, especially agitation (3%) and nightmares (0.6%) 4

Special Populations

Pregnancy

• Montelukast is Pregnancy Category B and may be used during pregnancy when there has been a uniquely favorable prepregnancy response 1

Renal and Hepatic Function

• No dose adjustment required for patients with normal hepatic and renal function 8
• Patients with moderate renal impairment may require dose adjustment, but once-daily frequency remains unchanged 8