Asthma Management Handbook

Guide to preventers: montelukast

Overview

Preventers are used in maintenance treatment to reduce airway inflammation. They include leukotriene receptor antagonists (montelukast).

Table. Classification of asthma medicines Opens in a new window Please view and print this figure separately: http://www.asthmahandbook.org.au/table/show/79

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Montelukast for adults: efficacy

In adults and adolescents with asthma that is not controlled by low-dose inhaled corticosteroid, the addition of a leukotriene receptor antagonist is less effective than the addition of a long-acting beta2 agonist in reducing the rate of asthma flare-ups that require treatment with oral corticosteroids.1 The addition of a leukotriene receptor antagonist is also associated with lesser improvement in lung function and quality of life than the addition of a long-acting beta2 agonist.1

Montelukast taken 1 hour before exercise can be used to manage exercise-induced bronchoconstriction, but it is less effective than short-acting beta2 agonists.2

Montelukast may improve lung function, reduce short-acting beta2 bronchodilator use, reduce symptoms, and improve quality of life in patients with aspirin-exacerbated respiratory disease.3

Montelukast is sometimes prescribed as add-on treatment for adults with severe asthma. Current evidence does not support its long-term use unless the patient shows a clear improvement in symptoms during a treatment trial.4

Note: PBS status as at March 2019: Montelukast treatment is not subsidised by the PBS for people aged 15 years or over. Special Authority is available for DVA gold card holders or white card holders with approval for asthma treatments.

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Montelukast for adults and adolescents: psychiatric effects

Post-marketing surveillance reports led to concerns about a possible association between leukotriene receptor antagonist use and suicide risk.5 A recent case-control study reported a statistically significant association between the use of leukotriene receptor antagonists and suicide attempts in people aged 19–24 years. However, this association was no longer statistically significant after adjusting for potential confounding factors, including previous exposure to other asthma medicines and previous exposure to other medicines associated with suicide.5

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Montelukast for children: efficacy
  • Montelukast use has been associated with behavioural and/or neuropsychiatric adverse effects, including suicidality.

Overview

Montelukast is a leukotriene receptor antagonist preventer. It is registered by the TGA for the treatment of asthma in children aged 2 years and older, and for the symptomatic treatment of allergic rhinitis.6

Montelukast can be used as an alternative to inhaled corticosteroids or as an add-on treatment in a child already taking regular inhaled corticosteroids.

However, it is not effective for all children. Overall, only approximately 20–30% of children will respond to montelukast treatment. The effect is thought to depend mainly on the child’s genotype.7, 8, 9 Clinically, it is not possible to predict accurately which children will benefit most from montelukast treatment.

Montelukast as first-line preventer in children aged 2–5 years

Viral-induced wheezing

Overall, regular maintenance montelukast treatment does not reduce the risk of wheezing episodes requiring oral corticosteroid treatment among preschool children who only have wheezing episodes when they have viral upper respiratory tract infections.10

However, montelukast may be effective for some children. Some randomised controlled trials have reported a reduction the risk of flare-ups in preschool children with intermittent asthma/wheeze,11, 12 while others have not.13

Persistent asthma or wheezing

A systematic review comparing montelukast with inhaled corticosteroids in preschoolers with asthma or recurrent wheezing requiring daily preventer treatment14 reported that inhaled corticosteroids appeared to achieve better symptom control and reduce flare-ups (including severe flare-ups requiring treatment with systemic corticosteroids). However, results were inconsistent and meta-analysis was not possible due to heterogeneity of outcomes measured in available clinical trials.14

Some preschool children with persistent asthma/wheeze respond to montelukast. A crossover study in preschool children with persistent asthma/wheeze reported that some children showed their best response to montelukast, while most responded better to regular inhaled corticosteroids.15 Predictors of a better response to inhaled corticosteroids than montelukast were aeroallergen hypersensitivity and blood eosinophilia (eosinophil counts ≥ 300/μL).15 However, routine blood eosinophil count is not feasible or recommended for this purpose.

Montelukast as first-line preventer children aged 6 years and over

In school-aged children with persistent asthma, inhaled corticosteroids are more effective overall than montelukast in improving lung function and controlling asthma symptoms.16, 18

However, symptoms will respond to a treatment trial of montelukast in approximately one-quarter to one-third of children,16, 19,20 and some may benefit more than from an inhaled corticosteroid.16 More severe asthma and markers of allergic inflammation may predict a better response to inhaled corticosteroids.16

Montelukast as add-on treatment

A systematic review of studies in children over 6 years and adolescents with mild-to-moderate persistent asthma found that the addition of montelukast to inhaled corticosteroids did reduce flare-ups requiring oral corticosteroids or hospital admissions for asthma, compared with the same or an increased dose.18

In a study comparing step-up treatments in children with asthma symptoms uncontrolled by low-dose inhaled corticosteroids, the addition of a long-acting beta2 agonist was effective in more children than either montelukast or increasing the dose of inhaled corticosteroid for controlling asthma symptoms and preventing flare-ups requiring systemic corticosteroids.21 However, some studies in school-aged children with persistent asthma already taking regular inhaled corticosteroids have reported that add-on montelukast reduced the risk of flare-ups21, 22 and exercise-induced asthma symptoms.22 Not all children will respond.

In a small study in children with persistent asthma already taking regular inhaled corticosteroids who were homozygous for the Arg16 genotype, montelukast was more effective as an add-on therapy than long-acting beta2 agonist in reducing symptoms, reliever use and days absent from school due to asthma, depending on the child’s beta receptor genotype.9 However, children were given inhaled corticosteroid and long-acting beta2 agonists in separate inhalers, which is which is known to be associated with increased risks.

However, genotyping it is not currently feasible in clinical practice. In practice, a treatment trial of 4–6 weeks can determine which preventer is suitable for controlling a child’s asthma symptoms,16 but longer treatment may be required to evaluate effect on flare-ups, because flare-ups may be independent of symptom control.

Exercise-induced symptoms

In school-aged children who experience exercise-induced symptoms despite taking regular inhaled corticosteroids, the addition of montelukast is effective in controlling symptoms, but not all children experience a response.2324

See: Investigation and management of exercise-induced bronchoconstriction

Short-term use in the management of flare-ups

Some, but not all studies suggest that a short course of montelukast, introduced at the first signs of an upper respiratory tract infection, may be effective in controlling flare-ups. An Australian study reported that this strategy could achieve a small reduction in symptoms, school absence and medical consultations in preschool and school-aged children with episodic wheeze.25

However, the evidence is inconsistent, with some studies showing no benefit.13,26, 27, 28, 29 The findings of one study suggested that whether or not intermittent montelukast is effective in wheezing children aged 5 years and under depends on genotype.8

Montelukast is not TGA-approved or PBS-subsidised for intermittent use.

Note: PBS status as at March 2019: Montelukast is not subsidised by the PBS for adolescents 15 years and over.

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Montelukast for children: behavioural and/or neuropsychiatric adverse effects

Montelukast is generally very well tolerated. Behavioural and psychiatric adverse effects were rare in clinical trials.30, 31 However, post-marketing surveillance reports have identified behavioural and/or neuropsychiatric adverse effects associated with montelukast use in some children.32

Behavioural treatment-associated effects are difficult to assess in young children. No factors have been identified to predict which children are at risk.

Reported adverse events include nightmares, sleep disturbance, anxiety, irritability, aggression and depression.32, 331735

Suicidal ideation has been reported in adolescents and adults taking montelukast.35 A nested case-control study concluded that children with asthma aged 5–18 years taking leukotriene receptor antagonists were not at increased risk of suicide attempts.5

Reported adverse effects are usually mild.17 The majority occur within 7–14 days of starting montelukast,3217 but some may appear after several months.35

Behavioural and/or neuropsychiatric adverse effects typically disappear within 4 days of stopping montelukast treatment.17 There is no evidence of long term effects.

The TGA recommends that clinicians treating children with montelukast should educate caregivers about these potential adverse effects and should consider providing them with the CMI. Advise them to seek medical advice if they have any concerns.

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Montelukast for exercise-induced bronchoconstriction

Montelukast is less effective against exercise-induced bronchoconstriction than short-acting beta2 agonists, but regular use is not associated with receptor tolerance.2

Montelukast taken either intermittently before exercise or daily is at least partially effective in protecting against exercise-induced bronchoconstriction in some, but not all patients.2 Some experience strong protection against exercise-induced bronchoconstriction while others experience only partial protection or no effect.2 Very few patients experience complete protection against exercise-induced bronchoconstriction.2

In children, regular montelukast, either as the child’s only preventer or in combination with an inhaled corticosteroid, is more effective than long-acting beta2 agonists in protecting against exercise-induced bronchoconstriction,24, 36 and is associated with a greater bronchodilator response to short-acting beta2 agonist after exercise.24

The onset of protection occurs within 2 hours of dosing. The duration of protective effect is 12–24 hours. Recommended doses are as follows:36

  • children aged 2–5 years 4 mg daily, or 1–2 hours before exercise
  • children aged 6–14 years 5 mg daily, or 1–2 hours before exercise
  • adults 10 mg daily, or 1–2 hours before exercise.

Notes 

PBS status as at March 2019: Montelukast treatment is not subsidised by the PBS for:

  • people aged 15 years or over (Special Authority is available for DVA gold card holders, or white card holders with approval for asthma treatments.)
  • children aged 2 to 5 years in combination with any other preventer
  • children aged 6 to 14 years with moderate to severe asthma, when used use as a single second-line preventer as an alternative to corticosteroids
  • people of any age, when used in addition to a long-acting beta-agonist.

 

  • Montelukast use has been associated with behavioural and/or neuropsychiatric adverse effects, including suicidality.

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Oral montelukast in acute asthma

Evidence from randomised controlled clinical trials does not support routine use of oral leukotriene receptor agonists in acute asthma in adults or children.26

In children with acute asthma, the addition of oral montelukast to usual care does not reduce hospital admission rates, based on the findings of a systematic review and meta-analysis.26

One small study in adults with acute asthma reported that the addition of oral montelukast to usual care resulted in a slight reduction beta2 agonist requirement,26 but this difference was clinically nonsignificant.

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References

  1. Ducharme FM. Addition of anti-leukotriene agents to inhaled corticosteroids for chronic asthma. Cochrane Database Syst Rev. 2004; Issue 1: CD003133. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD003133.pub2/full
  2. Weiler JM, Anderson SD, Randolph C, et al. Pathogenesis, prevalence, diagnosis, and management of exercise-induced bronchoconstriction: a practice parameter. Ann Allergy Asthma Immunol. 2010; 105: S1-47. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21167465
  3. Kennedy, J. L., Stoner, A. N., Borish, L.. Aspirin-exacerbated respiratory disease: Prevalence, diagnosis, treatment, and considerations for the future. Am J Rhinol Allergy. 2016; 30: 407-413. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5108840/
  4. Centre of Excellence in Severe Asthma,, Severe asthma toolkit. **, Centre of Excellence in Severe Asthma 2018. Available from: https://toolkit.severeasthma.org.au
  5. Schumock GT, Stayner LT, Valuck RJ, et al. Risk of suicide attempt in asthmatic children and young adults prescribed leukotriene-modifying agents: a nested case-control study. J Allergy Clin Immunol. 2012; 130: 368-75. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22698520
  6. Merck, Sharp and Dohme Australia Pty Ltd. Product Information: Singulair (montelukast sodium) Tablets. Therapeutic Goods Administration, Canberra, 2013. Available from: https://www.ebs.tga.gov.au/
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  8. Nwokoro C, Pandya H, Turner S, et al. Intermittent montelukast in children aged 10 months to 5 years with wheeze (WAIT trial): a multicentre, randomised, placebo-controlled trial. Lancet Respir Med. 2014; 2: 796-803. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25212745
  9. Lipworth BJ, Basu K, Donald HP, et al. Tailored second-line therapy in asthmatic children with the Arg(16) genotype. Clin Sci (Lond). 2013; 124: 521-528. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23126384
  10. Brodlie M, Gupta A, Rodriguez-Martinez CE, et al. Leukotriene receptor antagonists as maintenance and intermittent therapy for episodic viral wheeze in children. Cochrane Database Syst Rev. 2015; Issue 10: CD008202. Available from: https://www.ncbi.nlm.nih.gov/pubmed/26482324
  11. Bisgaard H, Zielen S, Garcia-Garcia ML, et al. Montelukast reduces asthma exacerbations in 2- to 5-year-old children with intermittent asthma. Am J Respir Crit Care Med. 2005; 171: 315-322. Available from: http://ajrccm.atsjournals.org/content/171/4/315.long
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  13. Valovirta, E., Boza, M. L., Robertson, C. F., et al. Intermittent or daily montelukast versus placebo for episodic asthma in children. Ann Allergy Asthma Immunol. 2011; 106: 518-26. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21624752
  14. Castro-Rodriguez JA, Rodriguez-Martinez CE, Ducharme FM. Daily inhaled corticosteroids or montelukast for preschoolers with asthma or recurrent wheezing: A systematic review. Pediatr Pulmonol. 2018; Epub ahead of print 6 November. Available from: https://www.ncbi.nlm.nih.gov/pubmed/30394700
  15. Fitzpatrick AM, Jackson DJ, Mauger DT et al. Individualized therapy for persistent asthma in young children. J Allergy Clin Immunol. 2016; 138: 1608-18.e12. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27777180
  16. Jartti T. Inhaled corticosteroids or montelukast as the preferred primary long-term treatment for pediatric asthma? Eur J Pediatr. 2008; 167: 731-6. Available from: https://www.ncbi.nlm.nih.gov/pubmed/18214538
  17. Benard, B., Bastien, V., Vinet, B., et al. Neuropsychiatric adverse drug reactions in children initiated on montelukast in real-life practice. Eur Respir J. 2017; 50: . Available from: https://www.ncbi.nlm.nih.gov/pubmed/28818882
  18. Chauhan BF, Ben Salah R, Ducharme FM. Addition of anti-leukotriene agents to inhaled corticosteroids in children with persistent asthma. Cochrane Database Syst Rev. 2013; Issue 10: CD009585. Available from: https://www.ncbi.nlm.nih.gov/pubmed/24089325
  19. Maspero, J, Guerra, F, Cuevas, F, et al. Efficacy and tolerability of salmeterol/fluticasone propionate versus montelukast in childhood asthma: a prospective, randomized, double-blind, double-dummy, parallel-group study. Clin Ther. 2008; 30: 1492-1504.
  20. Pedersen S, Maspero J, Gul N, Sharma R. Components of asthma control and treatment response of individual control criteria in children: analysis of the PEACE study. Pediatr Pulmonol. 2011; 46: 1182-8. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21751432
  21. Malka J, Mauger DT, Covar R, et al. Eczema and race as combined determinants for differential response to step-up asthma therapy. J Allergy Clin Immunol. 2014; 134: 483-5. Available from: https://www.ncbi.nlm.nih.gov/pubmed/24835502
  22. Stelmach I, Ozarek-Hanc A, Zaczeniuk M et al. Do children with stable asthma benefit from addition of montelukast to inhaled corticosteroids: randomized, placebo controlled trial. Pulm Pharmacol Ther. 2015; 31: 42-8. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25640020
  23. Grzelewski, T, Stelmach, I. Exercise-induced bronchoconstriction in asthmatic children: a comparative systematic review of the available treatment options. Drugs. 2009; 69: 1533-1553. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19678711
  24. Fogel RB, Rosario N, Aristizabal G, et al. Effect of montelukast or salmeterol added to inhaled fluticasone on exercise-induced bronchoconstriction in children. Ann Allergy Asthma Immunol. 2010; 104: 511-517. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20568384
  25. Robertson CF, Price D, Henry R, et al. Short-course montelukast for intermittent asthma in children: a randomized controlled trial. Am J Respir Crit Care Med. 2007; 175: 323-329. Available from: http://ajrccm.atsjournals.org/content/175/4/323.long
  26. Watts, K, Chavasse, R J P G. Leukotriene receptor antagonists in addition to usual care for acute asthma in adults and children. Cochrane Database Syst Rev. 2012; Issue 5: . Available from: http://cochranelibrary-wiley.com/doi/10.1002/14651858.CD006100.pub2/full
  27. Capsomidis, A., Tighe, M.. Archimedes. Question 2. Is oral montelukast beneficial in treating acute asthma exacerbations in children?. Arch Dis Child. 2010; 95: 948-50. Available from: http://adc.bmj.com/content/95/11/948.long
  28. Schuh, S, Willan, AR, Stephens, D, et al. Can montelukast shorten prednisolone therapy in children with mild to moderate acute asthma? A randomized controlled trial. J Pediatr. 2009; 155: 795-800. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19656525
  29. Bacharier LB, Phillips BR, Zeiger RS, et al. Episodic use of an inhaled corticosteroid or leukotriene receptor antagonist in preschool children with moderate-to-severe intermittent wheezing. J Allergy Clin Immunol. 2008; 122: 1127-1135. Available from: https://www.ncbi.nlm.nih.gov/pubmed/18973936
  30. Philip G, Hustad C, Noonan G, et al. Reports of suicidality in clinical trials of montelukast. J Allergy Clin Immunol. 2009; 124: 691-6.e6. Available from: http://www.jacionline.org/article/S0091-6749(09)01247-0/fulltext
  31. Philip G, Hustad CM, Malice MP, et al. Analysis of behavior-related adverse experiences in clinical trials of montelukast. J Allergy Clin Immunol. 2009; 124: 699-706.e8. Available from: http://www.jacionline.org/article/S0091-6749(09)01248-2/fulltext
  32. Wallerstedt, S. M., Brunlof, G., Sundstrom, A., Eriksson, A. L.. Montelukast and psychiatric disorders in children. Pharmacoepidemiol Drug Saf. 2009; 18: 858-64. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19551697
  33. Haarman M, van Hunsel F, de Vries T. Adverse drug reactions of montelukast in children and adults. Pharmacol Res Perspect 2017; 5: e00341. Available from: http://onlinelibrary.wiley.com/doi/10.1002/prp2.341/full
  34. Robertson, CF, Price, D, Henry, R, et al. Short-course montelukast for intermittent asthma in children: a randomized controlled trial. Am J Respir Crit Care Med. 2007; 175: 323-329. Available from: https://www.ncbi.nlm.nih.gov/pubmed/17110643
  35. Aldea Perona, A., Garcia-Saiz, M., Sanz Alvarez, E.. Psychiatric disorders and montelukast in children: a disproportionality analysis of the VigiBase®. Drug Saf. 2016; 39: 69-78. Available from: https://www.ncbi.nlm.nih.gov/pubmed/26620206
  36. Stelmach I, Grzelewski T, Majak P, et al. Effect of different antiasthmatic treatments on exercise-induced bronchoconstriction in children with asthma. J Allergy Clin Immunol. 2008; 121: 383-389. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17980416