Montelukast (Singulair)
montelukast sodium
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Asthma — prophylaxis and chronic treatment | ≥12 months | Controller (monotherapy or adjunctive to ICS) | FDA Approved |
| Exercise-induced bronchoconstriction (EIB) — prevention | ≥6 years | Acute prophylaxis (single dose ≥2 h pre-exercise) | FDA Approved |
| Seasonal allergic rhinitis (SAR) | ≥2 years | Symptom relief (second-line after alternative therapies) | FDA Approved |
| Perennial allergic rhinitis (PAR) | ≥6 months | Symptom relief (second-line after alternative therapies) | FDA Approved |
Montelukast is a selective CysLT1 receptor antagonist that blocks leukotriene-mediated airway inflammation and bronchoconstriction. For asthma, it is generally positioned as an alternative to low-dose ICS for mild persistent asthma or as add-on therapy. For allergic rhinitis, montelukast is now restricted to second-line use (patients with inadequate response or intolerance to alternatives) due to its boxed warning regarding neuropsychiatric events. It is not a rescue medication and should never be used for acute asthma attacks.
Chronic urticaria: Montelukast is sometimes used as add-on to antihistamines for chronic spontaneous urticaria. Evidence quality: Moderate (several small RCTs, EAACI/GA2LEN guidelines mention as third-line option).
Aspirin-exacerbated respiratory disease (AERD): Used as part of multi-drug therapy alongside aspirin desensitisation and ICS. Evidence quality: Moderate (observational studies, expert consensus).
Dosing
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Asthma — adults & adolescents ≥15 years | 10 mg once daily (evening) | 10 mg once daily | 10 mg/day | Take in the evening for asthma Not a rescue medication; patients must have SABA available |
| Asthma — children 6–14 years | 5 mg chewable once daily (evening) | 5 mg once daily | 5 mg/day | Chewable tablet formulation Safety and efficacy similar to adult profile |
| Asthma — children 2–5 years | 4 mg chewable or granules once daily (evening) | 4 mg once daily | 4 mg/day | Chewable tablet or oral granules Granules may be mixed with applesauce, carrots, rice, or ice cream; administer within 15 min of opening |
| Asthma — children 12–23 months | 4 mg oral granules once daily (evening) | 4 mg once daily | 4 mg/day | Oral granules only May dissolve in breast milk or formula; not established for <12 months in asthma |
| EIB prevention — ≥6 years | Age-appropriate dose at least 2 h before exercise | Single dose PRN | 1 dose per 24 h | Do not take additional dose if already on daily montelukast Not established to prevent acute EIB episodes when taken daily for chronic asthma |
| Allergic rhinitis — adults & adolescents ≥15 years | 10 mg once daily (any time) | 10 mg once daily | 10 mg/day | Second-line only (reserve for inadequate response or intolerance to alternatives) Morning or evening dosing acceptable; no food restriction |
Patients with both asthma and allergic rhinitis should take only one montelukast dose daily in the evening. A single dose treats both conditions. When using montelukast daily for asthma, do not take an additional dose for EIB prevention. Montelukast should not be abruptly substituted for inhaled or oral corticosteroids — ICS dose may be gradually reduced under medical supervision if montelukast is added.
Pharmacology
Mechanism of Action
Montelukast is a selective and orally active leukotriene receptor antagonist that binds with high affinity to the cysteinyl leukotriene type 1 (CysLT1) receptor. Cysteinyl leukotrienes (LTC4, LTD4, LTE4) are released from mast cells, eosinophils, and other inflammatory cells during the allergic inflammatory cascade. They bind to CysLT1 receptors on airway smooth muscle cells, leading to bronchoconstriction, mucus secretion, increased vascular permeability, and eosinophil recruitment. By competitively blocking LTD4 at the CysLT1 receptor, montelukast inhibits these effects, reducing both the early- and late-phase bronchoconstrictor responses to allergen challenge. In clinical studies, doses as low as 5 mg produce substantial blockade of LTD4-induced bronchoconstriction.
Importantly, animal studies have shown that montelukast distributes into the brain in rats, and FDA research in 2024 confirmed binding to multiple brain receptors. The mechanisms underlying montelukast-associated neuropsychiatric events remain under investigation but may relate to CysLT1 receptor activity in the central nervous system.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Rapid; Tmax ~3–4 h (tablet), ~2 h (chewable); bioavailability 60–70% (tablet); food does not clinically affect absorption | Can be taken with or without food; evening dosing for asthma based on diurnal leukotriene physiology |
| Distribution | Vd 8–11 L; protein binding >99%; crosses into the brain (demonstrated in rats) | Very high protein binding limits free drug; CNS distribution may underlie neuropsychiatric effects |
| Metabolism | Primarily CYP2C8 (~72–80% in vivo); CYP3A4 (minor metabolite M5 formation, ~16%); CYP2C9 (negligible contribution, ~12%); gemfibrozil (CYP2C8 inhibitor) increases AUC 4.3-fold | CYP2C8 is the dominant pathway despite older PI listing CYP3A4/2C9; strong CYP2C8 inhibitors significantly increase exposure; CYP3A4 inhibitors (e.g., itraconazole) have no clinically significant effect |
| Elimination | t½ 2.7–5.5 h (mean ~5 h adults); plasma clearance 45 mL/min; excreted almost exclusively via bile; negligible urinary excretion | No renal dose adjustment needed; mild-moderate hepatic impairment increases AUC by 41% (t½ 7.4 h) but no dose change required; severe hepatic impairment not studied |
Side Effects
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Headache | 18.4% | Similar to placebo rate; not considered drug-related; extremely common across all arms of asthma trials |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Influenza | 4.2% | Influenza-like illness; not clearly drug-related |
| Cough | 2.7% | Reported in asthma trials; difficult to distinguish from underlying disease |
| Upper respiratory infection | 1.9% vs 1.5% placebo (SAR trials) | Most commonly cited event across all age groups and indications |
| Abdominal pain | ≥2% | Gastrointestinal complaint; may partly relate to lactose excipient |
| Dyspepsia | ~2% | Mild GI symptoms; usually self-limiting |
| Dizziness | ~2% | Reported in adult asthma trials |
| Elevated ALT/AST | ~2% | Mild aminotransferase elevations; similar rate to placebo; usually transient |
| Nasal congestion | 1.6% | Difficult to distinguish from underlying allergic rhinitis |
| Rash | ~2% | Non-specific; discontinue if hypersensitivity suspected |
In paediatric trials (2–14 years), the most frequent events (≥2% and > placebo) also included: fever, pharyngitis, otitis media, rhinorrhea, sinusitis, diarrhoea, ear pain, gastroenteritis, eczema, urticaria, varicella, and conjunctivitis (FDA PI).
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Neuropsychiatric events (agitation, aggression, depression, suicidal thoughts/behaviour, hallucinations, insomnia, somnambulism) | Frequency not well established; postmarketing (82 completed suicides reported to FAERS through 2020) | Variable — during or after discontinuation; may persist | Discontinue immediately; contact prescriber; ongoing monitoring — some symptoms persist after stopping |
| Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) | Very rare (<0.01%) | Weeks to months; often during oral corticosteroid taper | Stop montelukast; rheumatology/immunology referral; systemic steroids; watch for eosinophilia, vasculitic rash, neuropathy, cardiac complications |
| Anaphylaxis / angioedema | Very rare (postmarketing) | Minutes to hours | Emergency treatment; permanent discontinuation |
| Hepatotoxicity (cholestatic, hepatocellular, or mixed) | Rare (postmarketing); ALT/AST elevations 1–2% in trials (similar to placebo) | Weeks to months | Discontinue if clinically significant hepatitis; usually resolves 1–4 months after stopping |
| Stevens-Johnson syndrome / toxic epidermal necrolysis | Very rare (postmarketing) | Days to weeks | Emergency dermatology; permanent discontinuation; supportive care |
Events include agitation, aggression, anxiety, depression, hallucinations, dream abnormalities, insomnia, somnambulism, suicidal thoughts and behaviour, tic, tremor, and stuttering. They occur in adults and children, with and without prior psychiatric history. In most cases, symptoms resolved after stopping montelukast, but some symptoms persisted after discontinuation. Before prescribing, ask about psychiatric history. Advise patients and caregivers to report any behavioural changes immediately.
Drug Interactions
Montelukast is predominantly metabolised by CYP2C8, with minor contributions from CYP3A4 and CYP2C9. Despite older PI labelling, updated pharmacokinetic research shows CYP2C8 accounts for approximately 72–80% of metabolism. Montelukast is a potent CYP2C8 inhibitor in vitro but does not inhibit CYP2C8 clinically due to very high protein binding (>99%). It has a remarkably low interaction potential for a drug metabolised by CYP enzymes.
Monitoring
- Neuropsychiatric SymptomsEach visit; ongoing
RoutineScreen for mood changes, agitation, aggression, sleep disturbances, depression, suicidal ideation at every encounter. Ask patients and parents/caregivers directly. Discontinue immediately and seek evaluation if NP symptoms emerge. Events can occur in patients with or without prior psychiatric history. - Asthma ControlEvery 1–3 months initially
RoutineAssess symptom frequency, rescue inhaler use, and peak flow or FEV1 to confirm adequate response. Montelukast is generally less effective than low-dose ICS as monotherapy; step up if control is inadequate. - Eosinophil CountIf symptoms suggestive of vasculitis
Trigger-basedWatch for systemic eosinophilia, particularly during oral corticosteroid tapering. Eosinophilia with vasculitic rash, worsening pulmonary symptoms, cardiac symptoms, or neuropathy may indicate eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome). - Liver FunctionIf symptoms of hepatotoxicity
Trigger-basedNot routinely required. ALT elevations of 1–2% occurred in trials but at rates similar to placebo. Check LFTs if patient develops jaundice, dark urine, or right upper quadrant pain.
Contraindications & Cautions
Absolute Contraindications
- Hypersensitivity to montelukast or any component of the product.
Relative Contraindications (Specialist Input Recommended)
- Pre-existing psychiatric disorder: Given the boxed warning, the risk-benefit balance should be carefully considered in patients with a history of depression, anxiety, or other psychiatric conditions. Ask about psychiatric history before initiating.
- Allergic rhinitis as the sole indication: For allergic rhinitis, montelukast should only be used after an inadequate response or intolerance to antihistamines, intranasal corticosteroids, or other first-line therapies.
Use with Caution
- Aspirin-sensitive patients: Must continue aspirin/NSAID avoidance; montelukast does not fully protect against aspirin-induced bronchoconstriction.
- Concomitant oral corticosteroid tapering: Watch for eosinophilic granulomatosis with polyangiitis during corticosteroid dose reduction.
- Phenylketonuria: 4 mg and 5 mg chewable tablets contain phenylalanine (0.674 mg and 0.842 mg, respectively).
- Severe hepatic impairment: Pharmacokinetics not studied; use with caution.
Serious neuropsychiatric events have been reported with montelukast, including agitation, aggression, depression, sleep disturbances, hallucinations, obsessive-compulsive symptoms, suicidal thoughts and behaviour (including completed suicides). Events have occurred in adults, adolescents, and children, with and without prior psychiatric history. Some events persisted after drug discontinuation. Because of this risk, the benefits may not outweigh the risks for allergic rhinitis when symptoms can be treated with alternative therapies. For asthma and EIB, prescribers should weigh benefits versus risks. All patients and caregivers must be advised to report any behavioural changes immediately and discontinue the drug if NP events occur.
Patient Counselling
Purpose of Therapy
Montelukast is a daily tablet that helps control asthma and allergy symptoms by blocking leukotrienes, chemicals that cause airway narrowing and inflammation. It is a controller medicine — not a rescue inhaler. Always carry your rescue inhaler for sudden breathing difficulty. Take montelukast every day even when you feel well, unless your prescriber tells you to stop.
How to Take
Take one tablet once daily. For asthma, take it in the evening. For allergies only, take it at any time that suits you. For children who cannot swallow tablets, chewable tablets or oral granules are available. Granules can be mixed into applesauce, carrots, rice, or ice cream, and must be taken within 15 minutes of opening the packet. Do not dissolve granules in liquid other than breast milk or formula.
Sources
- Singulair (montelukast sodium) Prescribing Information. Merck Sharp & Dohme. Revised April 2020 (boxed warning update). FDA AccessDataPrimary source for all dosing, contraindications, adverse reaction data, boxed warning language, and pharmacokinetic parameters.
- FDA Drug Safety Communication: FDA requires boxed warning about serious mental health side effects for montelukast (Singulair). March 2020. FDA.govDetails the FDA rationale for strengthening the warning, including 82 reported completed suicides and Sentinel System analysis.
- Reiss TF, Chervinsky P, Dockhorn RJ, et al. Montelukast, a once-daily leukotriene receptor antagonist, in the treatment of chronic asthma. Arch Intern Med. 1998;158(11):1213-1220. doi:10.1001/archinte.158.11.1213Pivotal multicenter RCT establishing efficacy of montelukast 10 mg daily in chronic asthma with improvements in FEV1 and symptom scores.
- Leff JA, Busse WW, Pearlman D, et al. Montelukast, a leukotriene-receptor antagonist, for the treatment of mild asthma and exercise-induced bronchoconstriction. N Engl J Med. 1998;339(3):147-152. doi:10.1056/NEJM199807163390302NEJM trial demonstrating efficacy in mild asthma and EIB prevention, supporting dual indications.
- Philip G, Hustad C, Noonan G, et al. Reports of suicidality in clinical trials of montelukast. J Allergy Clin Immunol. 2009;124(4):691-696.e6. doi:10.1016/j.jaci.2009.08.010Merck analysis of clinical trial data finding no increased suicidality risk with montelukast in controlled trials; however, postmarketing data subsequently prompted the boxed warning.
- Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention, 2024 Update. ginasthma.orgPositions LTRAs as alternative controller option for mild asthma (Step 2), generally less preferred than low-dose ICS monotherapy.
- Bousquet J, Schunemann HJ, Togias A, et al. Next-generation ARIA care pathways for rhinitis and asthma: a model for multimorbid chronic diseases. Clin Transl Allergy. 2019;9:44. doi:10.1186/s13601-019-0279-2ARIA pathway positions LTRAs as second-line for allergic rhinitis, consistent with the FDA’s 2020 restriction.
- Lynch KR, O’Neill GP, Liu Q, et al. Characterization of the human cysteinyl leukotriene CysLT1 receptor. Nature. 1999;399(6738):789-793. doi:10.1038/21658Foundational paper characterising the CysLT1 receptor molecular structure and confirming it as the pharmacological target of montelukast.
- Haarman MG, van Hunsel F, de Vries TW. Adverse drug reactions of montelukast in children and adults. Pharmacol Res Perspect. 2017;5(5):e00341. doi:10.1002/prp2.341Analysis of Dutch and WHO VigiBase pharmacovigilance data characterising the neuropsychiatric ADR profile in children vs adults; aggression most reported in children, depression in adults.
- Karonen T, Neuvonen PJ, Backman JT. CYP2C8 but not CYP3A4 is important in the pharmacokinetics of montelukast. Br J Clin Pharmacol. 2012;73(2):257-267. doi:10.1111/j.1365-2125.2011.04086.xLandmark in vivo interaction study proving CYP2C8 accounts for ~80% of montelukast metabolism; corrects the older PI attribution to CYP3A4/2C9.
- Cheng H, Leff JA, Amin R, et al. Pharmacokinetics, bioavailability, and safety of montelukast sodium (MK-0476) in healthy males and females. Pharm Res. 1996;13(3):445-448. doi:10.1023/A:1016056912698Early PK characterisation establishing oral bioavailability (60–70%), >99% protein binding, and biliary excretion pathway.