Montelukast

What it is

Montelukast is a prescription tablet, chewable tablet or granule taken once daily, sold as Singulair and as generics. It is approved for asthma, exercise-induced bronchoconstriction and allergic rhinitis.

What the research says

It blocks the CysLT1 receptor, where leukotrienes act to narrow and inflame the airways. As sole asthma treatment it is less effective than low-dose inhaled corticosteroids. Added to inhaled corticosteroids, it halves exacerbations compared with the same corticosteroid dose. For seasonal allergic rhinitis it beats placebo by a small margin, below a clinically relevant threshold, and is weaker than nasal steroids. The current label (revised 6/2021) carries a boxed warning about serious neuropsychiatric events. Observational studies disagree on how large that risk is.

Evidence grade: Well established.

How it works

Drug class: Leukotriene receptor antagonist (CysLT1 antagonist)

Montelukast binds to the CysLT1 receptor in the airways and blocks leukotriene D4, a signal that tightens airway muscle and drives inflammation. It does not activate the receptor itself. (Source 1)

Boxed warning

Serious neuropsychiatric (NP) events have been reported with the use of SINGULAIR.

(Source 1)

What it is used for

• Less effective than low-dose inhaled corticosteroids. For every 28 people treated with an anti-leukotriene instead of an inhaled steroid, one more had an attack needing oral steroids. Evidence: established. (Source 2)
• Added to the same inhaled steroid dose, it halved exacerbations needing oral steroids (moderate quality). It did no better than a higher inhaled steroid dose. Evidence: established. (Source 3)
• Symptom scores were 5% better than placebo, below the 10% the authors counted as clinically relevant. It matched antihistamines and was less effective than nasal corticosteroids. The label now reserves it for people who cannot use other treatments. Evidence: limited. (Source 4)
• The label lists this approval. We did not retrieve the trials for it in this run. Evidence: unknown. (Source 1)
• The Cochrane review of 5 trials (1,296 infants) found uncertain effects on hospital stay and severity. The evidence quality was low. Evidence: not-supported. (Source 5)

Interactions

• Gemfibrozil (label): Gemfibrozil raised montelukast exposure 4.4-fold. (Source 1)
• Phenobarbital and other enzyme inducers (e.g. rifampin) (label): Phenobarbital lowered montelukast levels by about 40%. (Source 1)
• Food (label): A standard meal did not change absorption of the 10-mg tablet. (Source 1)

Stopping it

• Montelukast is not known to cause dependence. If neuropsychiatric symptoms appear, the label says to stop it. Symptoms often, but not always, resolved after stopping. (Source 1)
• Montelukast should not be swapped in suddenly for inhaled or oral steroids. (Source 1)

What goes wrong

When inhaled steroids were being tapered, serious adverse events were more common with an added anti-leukotriene. (Source 3)

• Systematic review, Moderate certainty.
• Size: 621 participants in 2 studies.
• Who: Adults and adolescents with asthma tapering ICS.
• How long: Varied.
• Result: RR 2.44 (1.52 to 3.92)
• Funding: Cochrane (independent)

Serious adverse events occurred more frequently among those taking anti-leukotrienes plus tapering ICS than in those taking tapering doses of ICS alone (RR 2.44, 95% CI 1.52 to 3.92

Children with a new neuropsychiatric event had nearly twice the odds of having been prescribed montelukast, mostly for anxiety and sleep disturbance. (Source 6)

• Case-control study, Low certainty.
• Size: 898 cases, 3,497 controls.
• Who: Children 5-18 with asthma, Ontario.
• How long: 2004-2015.
• Result: OR 1.91 (1.15-3.18)
• Funding: Not stated in the abstract read.

Children who experienced a new-onset neuropsychiatric event had nearly 2 times the odds of having been prescribed montelukast, compared with controls (OR 1.91, 95% CI 1.15-3.18; P = .01).

What the evidence supports

Added to inhaled corticosteroids, anti-leukotrienes (mostly montelukast) halved exacerbations needing oral steroids compared with the same inhaled steroid dose alone. (Source 3)

• Systematic review, Moderate certainty.
• Size: 815 participants in 4 studies (37 studies overall)
• Who: Adults and adolescents with persistent asthma on ICS.
• How long: Varied.
• Result: RR 0.50 (0.29 to 0.86)
• Funding: Cochrane (independent)

Anti-leukotriene agents given as adjunct therapy to ICS reduced by half the number of participants with exacerbations requiring oral corticosteroids (risk ratio (RR) 0.50, 95% confidence interval (CI) 0.29 to 0.86

What the evidence does not support

As sole asthma treatment, anti-leukotrienes led to more attacks needing oral steroids than low-dose inhaled corticosteroids. (Source 2)

• Systematic review, Moderate certainty.
• Size: Randomised trials in adults and children (Cochrane)
• Who: Persistent asthma.
• How long: Varied.
• Result: RR 1.51 (1.17 to 1.96); one extra exacerbation per 28 treated (NNTH 28, 95% CI 15 to 82)
• Funding: Cochrane (independent)

For every 28 (95% CI 15 to 82) patients treated with anti-leukotrienes instead of inhaled corticosteroids, there was one additional patient with an exacerbation requiring rescue systemic corticosteroids.

Adding an anti-leukotriene was no better than raising the inhaled corticosteroid dose. (Source 3)

• Systematic review, Moderate certainty.
• Size: 1,779 participants in 4 studies.
• Who: Adults and adolescents with persistent asthma.
• How long: Varied.
• Result: RR 0.90 (0.58 to 1.39)
• Funding: Cochrane (independent)

Results showed no statistically significant difference in the number of participants with exacerbations requiring oral corticosteroids (RR 0.90, 95% CI 0.58 to 1.39

In an FDA Sentinel cohort, montelukast was not linked to more hospitalisation for depression or self-harm than inhaled corticosteroids. (Source 7)

• Cohort study, Low certainty.
• Size: 457,377 matched patients.
• Who: People 6 years and older with asthma, US claims data.
• How long: 2000-2015.
• Result: Inpatient depression HR 1.06 (0.90-1.24); self-harm HR 0.92 (0.69-1.21)
• Funding: FDA (government)

When compared with use of ICS, we did not find associations between montelukast use and hospitalizations for depression or self-harm events.

In infant bronchiolitis, the effect of montelukast on hospital stay and severity was uncertain. (Source 5)

• Systematic review, Low certainty.
• Size: 1,296 participants in 5 RCTs.
• Who: Infants under 2 hospitalised with bronchiolitis.
• How long: Varied.
• Result: Length of stay MD -0.95 days (-3.08 to 1.19) as summarised.
• Funding: Cochrane (independent)

The effects of montelukast on length of hospital stay and clinical severity score were uncertain due to considerable heterogeneity

Where the evidence is mixed

In seasonal allergic rhinitis, symptom scores were 5 percentage points better than placebo and 12 points worse than nasal corticosteroids. The authors' clinical-relevance threshold was 10%. (Source 4)

• Meta-analysis, Certainty not rated.
• Size: 3,924 patients in 8 studies.
• Who: Seasonal allergic rhinitis.
• How long: Varied.
• Result: 5% (3% to 7%) better than placebo; nasal steroids 12% (5% to 18%) better than montelukast-class drugs.
• Funding: Not stated in the abstract read.

Leukotriene receptor antagonists reduced mean daily rhinitis symptom scores (in absolute terms) 5% (95% confidence interval [CI]: 3% to 7%) more than did placebo.

Side effects overall were not significantly different between anti-leukotrienes and inhaled steroids. (Source 2)

• Systematic review, Moderate certainty.
• Size: Randomised trials (Cochrane)
• Who: Persistent asthma.
• How long: Varied.
• Result: Not significantly different.
• Funding: Cochrane (independent)

Risk of side effects was not significantly different between both groups.

Where the research disagrees

Whether montelukast raises the risk of psychiatric events

• Glockler-Lauf et al. 2019, Nested case-control study: Clinicians should be aware of the association between montelukast and neuropsychiatric events in children with asthma (Source 6)
• Sansing-Foster et al. 2021 (FDA Sentinel), Propensity-matched cohort: When compared with use of ICS, we did not find associations between montelukast use and hospitalizations for depression or self-harm events. (Source 7)
• FDA via the Singulair label (2021 revision), a position, Regulatory position based on post-marketing reports: Because of the risk of NP events, the benefits of SINGULAIR may not outweigh the risks in some patients (Source 1)

How much

• Reference intake: Dosing is set by the prescriber. As a position, the 2021 Singulair label gives adults with asthma a single 10-mg tablet once daily in the evening. (Source 1)
• Upper limit: No separate maximum is stated in the label text we read beyond the fixed once-daily dose, which is a position. (Source 1)
• Studied: The trials pooled in the Cochrane add-on review mostly used montelukast (24 of 37 studies) added to inhaled corticosteroids. (Source 3)

A common belief, and what the research shows

The belief: Montelukast is a good substitute for an inhaled steroid in asthma.

What the research shows: Cochrane: 'As monotherapy, inhaled corticosteroids display superior efficacy to anti-leukotrienes in adults and children with persistent asthma'. The label adds that 'SINGULAIR is not indicated for use in the reversal of bronchospasm in acute asthma attacks'.

Questions and answers

What is it?

Montelukast is a once-daily prescription medicine for asthma, exercise-induced airway narrowing and allergic rhinitis. (Source 1)

What does it do in the body?

It blocks the CysLT1 receptor, stopping leukotriene D4 from tightening and inflaming the airways. (Source 1)

Is it good or bad for you?

It is modestly helpful. It helps asthma when added to inhaled steroids, but it is weaker than inhaled steroids alone and weaker than nasal steroids for hay fever. It carries a boxed warning for neuropsychiatric events, and studies of that risk disagree. (Source 4)

How do you get more of it?

Does not apply as a nutrient would. Montelukast is prescription-only, and the label reserves it in allergic rhinitis for people who cannot use other treatments. (Source 1)

If it is harmful, what reduces it?

If mood or behaviour changes, the label says to stop and contact a clinician. Symptoms usually, but not always, resolved after stopping. (Source 1)

Why might someone be low in it or missing it?

Does not apply. Montelukast is a synthetic drug, not a nutrient or body substance. (Source 1)

We searched: Searched the label; no natural source or deficiency state exists.

Which whole foods contain it or feed it?

No food contains montelukast, and meals did not change how well the tablet was absorbed. (Source 1)

What happens if you do not have it?

Not taking it is the normal state. For asthma control, low-dose inhaled steroids outperformed anti-leukotrienes as sole treatment. (Source 2)

How can you test for it?

No blood test is used to guide montelukast treatment in the sources we read. (Source 1)

We searched: Searched the Singulair label and Cochrane summaries for drug-level monitoring; none described.

References

1. US National Library of Medicine DailyMed (FDA-approved label). SINGULAIR (montelukast sodium) prescribing information (Organon), DailyMed. 2021. Read the source
2. Cochrane Database of Systematic Reviews. Anti-leukotriene agents compared to inhaled corticosteroids in the management of recurrent and/or chronic asthma in adults and children (Cochrane review CD002314). 2012. DOI 10.1002/14651858.CD002314.pub3. Read the source
3. Cochrane Database of Systematic Reviews. Addition of anti-leukotriene agents to inhaled corticosteroids for adults and adolescents with persistent asthma (Cochrane review CD010347). 2017. DOI 10.1002/14651858.CD010347.pub2. Read the source
4. The American Journal of Medicine. Leukotriene receptor antagonists for allergic rhinitis: a systematic review and meta-analysis. 2004. DOI 10.1016/j.amjmed.2003.10.030. Read the source
5. Cochrane Database of Systematic Reviews. Leukotriene inhibitors for bronchiolitis in infants and young children (Cochrane review CD010636, summary page). 2015. Read the source
6. The Journal of Pediatrics. Montelukast and Neuropsychiatric Events in Children with Asthma: A Nested Case-Control Study. 2019. DOI 10.1016/j.jpeds.2019.02.009. Read the source
7. The Journal of Allergy and Clinical Immunology: In Practice. Risk of Psychiatric Adverse Events Among Montelukast Users. 2021. DOI 10.1016/j.jaip.2020.07.052. Read the source