Montelukast sodium, chewable tablets, 4 mg (base), chewable tablets 5 mg (base), and film coated tablet, 10 mg (base), Singulair®
Public summary document for Montelukast sodium, chewable tablets, 4 mg (base), chewable tablets 5 mg (base), and film coated tablet, 10 mg (base), Singulair®
Page last updated: 30 October 2009
Public Summary Document
Product: Montelukast sodium, chewable tablets, 4 mg (base), chewable tablets 5 mg (base), and film coated tablet, 10 mg (base), Singulair®
Sponsor: Merck Sharp and Dohme (Australia) Pty Ltd
Date of PBAC Consideration: July 2009
1. Purpose of Application
The submission requested (1) an extension of the current PBS
listing for the use of 4 and 5 mg montelukast as adjunctive therapy
to inhaled corticosteroids in children aged two to five years with
exercise-induced asthma; (2) a new listing for 10 mg montelukast as
adjunctive therapy to inhaled corticosteroids in patients aged 15
years and older with exercise-induced asthma; and (3) a restricted
benefit PBS listing for both the current Authority Required
(STREAMLINED) indication (children with frequent intermittent or
mild persistent asthma) as well as for the new exercise-induced
At the December 2001 meeting, montelukast 4 mg and 5 mg were
recommended for listing on a cost-minimisation basis compared with
sodium cromoglycate metered dose inhaler, with one tablet (4 mg or
5 mg) montelukast sodium being equivalent to 27.8 mg sodium
cromoglycate for children aged 2 years up to 14 years.
At the December 2003 meeting the PBAC considered an application to transfer the current Authority required listings to Restricted benefits listings
The PBAC was of the view that a transfer
to the Restricted benefit listing would be highly likely to lead to
widespread usage outside the restriction and that such use would be
inappropriate. At the same meeting the PBAC also considered an
application to list the 10 mg montelukast tablets for children aged
15 years or more who were previously eligible for subsidised
montelukast 5 mg. The PBAC rejected the submission because no
clinical or cost effectiveness data were provided to support the
3. Registration Status
Montelukast sodium 5 mg and 10 mg tablets were TGA registered on 11
May 1998. Montelukast sodium 4 mg tablets were TGA registered on 23
May 2001. All strengths are indicated for:
Prophylaxis and treatment of chronic asthma in adults and children over 2 years,
Symptomatic treatment of seasonal allergic rhinitis.
4. Listing Requested and PBAC’s View
(For the 4 mg and 5 mg tablets) First line preventer medication, as the single preventer agent for children aged 2 to 5 years (6 to 14 years for the 5 mg tablet) with frequent intermittent or mild persistent asthma, as an alternative to sodium cromoglycate or nedocromil sodium.
(Requested Additional Listing)
For use in patients whose asthma is otherwise well controlled while receiving optimal dose inhaled corticosteroid, but have residual exercise-related symptoms requiring short acting beta agonists 3 or more times per week for prevention or relief of symptoms.
Exercise-induced asthma may be detected when the patient reports MORE asthma symptoms (such as shortness of breath, wheeze) immediately AFTER exercise.
Montelukast sodium is an alternative to long acting beta-2-agonists (such as salmeterol xinafoate or eformoterol fumarate) when added to an inhaled corticosteroid (either as single agents or in fixed dose combinations) in the above mentioned patients.
(For 10 mg tablet) For use in patients whose asthma is otherwise well controlled while receiving an optimal dose inhaled corticosteroid, but have residual exercise-related symptoms requiring beta-2-agonist use 3 or more times per week for prevention or relief of symptoms.
Due to concerns about usage beyond the restriction, which are greater than for long-acting beta-agonists, the PBAC recommended that, rather than the requested Restricted Benefit, a Streamlined Authority should apply consistent with the current restriction; and that particular attention be given to the notes accompanying the restriction. In particular, the importance of adhering to on-going use rather than intermittent use immediately before exercise and the distinction between exercise-induced asthma and dyspnoea during exercise both needed to be emphasised.
5. Clinical Place for the Proposed Therapy
Montelukast sodium would provide a treatment option for children
and adults with exercise induced asthma to prevent symptoms and
reduce recovery time.
The submission nominated long acting beta-agonists (eformoterol
fumarate dihydrate and salmeterol xinafoate) as the comparators as
these were the recommended add on treatment for patients on optimal
doses of inhaled corticosteroids who were still experiencing asthma
symptoms with exercise in the Asthma Management Handbook
For PBAC's views see the Recommendations and Reasons.
7. Clinical Trials
The submission presented four direct randomised trials in adults
and two direct randomised trials in children comparing montelukast
with long-acting beta-agonists in patients with documented
exercise-induced asthma. The submission provided no trial evidence
to support the new listing of montelukast versus long-acting beta-2
agonists for the management of exercise-induced asthma in children
aged 2-5 years, although the Pre-Sub-Committee Response mentioned a
placebo-controlled study (Knorr 2001) and a biological rationale
that asthma, including exercise-induced asthma, was a similar
disease across age groups.
The studies published at the time of submission are as follows:
|Trial/First author||Protocol title/Publication title||Publication citation|
|Adult direct randomised controlled trials|
|Edelman JM, 2000||Oral montelukast compared with inhaled salmeterol to prevent exercise-induced bronchoconstriction.||Ann Intern Med 2000; 132: 97-104|
|Steinshamn S, 2004||Effects of montelukast and salmeterol on physical performance and exercise economy in adult asthmatics with exercise-induced bronchoconstriction.||Chest 2004; 126: 1154-1160.|
|Storms W, 2004||A comparison of the effects of oral montelukast and inhaled salmeterol on response to rescue bronchodilation after challenge.||Respiratory Medicine 2004; 98: 1051-1062.|
|Villaran C, 1999||Montelukast versus salmeterol in patients with asthma and exercise-induced bronchoconstriction.||J Allergy Clin Immunol 1999; 104: 547-53.|
|Children direct randomised controlled trials|
|Stelmach I, 2008||Effect of different antiasthmatic treatments on exercise-induced bronchoconstriction in children with asthma.||J Allergy Clin Immunol 2008; 121: 383-9.|
All of the included trials withheld short-acting beta-agonist treatment (i.e. salbutamol, terbutaline) for at least 6 hours prior to an exercise challenge.
8. Results of Trials
The summary results for maximum percent fall in FEV1 after exercise (adults) are presented in the following table.
|Exercise challenge||Treatment arm||N (%)||Mean (SD)||Mean change from baseline (SD)|
|Edelman (2000), primary outcome|
|Baseline||Montelukast||97 (100)||36.99 (11.49)||-|
|Salmeterol||94 (100)||36.58 (12.31)||-|
|Week 8||Montelukast||93 (96)||16 a||-21 a|
|Salmeterol||90 (96)||25 a||-12 a|
|Difference||-9 a||-9 a|
|Steinshamn (2004), secondary outcome, cross-over trial|
|Baseline||Montelukast||18 (100)||20.1 (8.2)||-|
|Salmeterol||18 (100)||20.1 (8.2)||-|
|Day 5||Montelukast||18 (100)||10 (12.2)||-10.1|
|Salmeterol||18 (100)||16.2 (11.0)||-3.9|
|Difference||-6.2; p < 0.001||-6.2|
|Storms (2004), secondary outcome, all patients treated with ICS|
|Baseline||Montelukast||36 (92)||12.9 (11.3)||-|
|Salmeterol||36 (92)||12.9 (12.2)||-|
|Week 4||Montelukast||36 (92)||7.7 (8.1)||-5.5|
|Salmeterol||34 (87)||10.5 (10.0)||-3.1|
|Difference||-2.8||-2.4; p > 0.05|
|Villaran (1999), primary outcome|
|Week 8||Montelukast||97 (95)||15.9||-17.2 (14.3)|
|Salmeterol||86 (91)||20.2||-10.7 (14.3)|
|Difference||-4.3||-7.2; p = 0.001|
Abbreviations: FEV1, forced expiratory volume in one second; SD, standard deviation
a Submission converted reported median % inhibition values (an alternative measure of FEV1 decrease) to an approximate maximum post-exercise percent fall in FEV1. The differences between montelukast and salmeterol were statistically significant in favour of montelukast at Week 8 (p = 0.002) using the % inhibition measure.
The summary results for maximum percent fall in FEV1 after exercise (children) are summarised in the following table.
|Exercise challenge||Treatment arm||n (%)||Mean (SD)||Mean change from baseline (SD)|
|Stelmach (2008), primary outcome|
|Baseline||Montelukast + budesonide||17 (85)||25.5 (SE 0.74)||-|
|Eformoterol + budesonide||18 (90)||25.2 (SE 0.77)||-|
|Week 4||Montelukast + budesonide||17 (85)||12.1 (SE 1.13)||-13.4 b|
|Eformoterol + budesonide||18 (90)||18.9 (SE 0.65||-6.3 b|
|Difference||-6.8||-7.1; p < 0.001|
Abbreviations: FEV1, forced expiratory volume in one second; ICS, inhaled corticosteroids; SD, standard
deviation; SE, standard error.
a Montelukast with budesonide compared to Eformoterol with budesonide
b Calculated as Week 4 mean minus Baseline mean.
Montelukast was generally associated with statistically significant reductions in the maximum FEV1 decrease after exercise compared to salmeterol/eformoterol. The submission also presented results for maximum FEV1 after salbutamol administration, time-to-recovery of pre-exercise FEV1 levels, use of rescue salbutamol, symptoms of exercise-induced asthma, FEV1 AUC, rescue broncho-dilation (FEV1 measure) and pre-exercise FEV1. Generally, these results favoured montelukast, however the differences appeared to be small.
From the studies in the submission, montelukast and salmeterol appeared to have similar short-term safety profiles.
A review undertaken by the US Food and Drug Administration was evaluating a possible association between leukotriene receptor antagonists (montelukast, zafirlukast and zileuton) and behaviour/mood changes, suicidality and suicide, based on post-marketing reports of neuropsychiatric events. An update of this review in January 2009 reported that no link had been identified between treatment and suicide or suicidal behaviour in the clinical trials. The FDA has since decided to include a warning about neuropsychiatric side effects on the labelling (product information) of these drugs.
The submission had also outlined safety concerns regarding the risk of serious adverse events associated with regular salmeterol treatment in patients with chronic asthma.
9. Clinical Claim
The submission described montelukast as superior in terms of
comparative effectiveness and similar in terms of comparative
safety over long-acting beta-agonists for the treatment if
For PBAC’s views see Recommendation and Reasons
10. Economic Analysis
The submission presented a cost minimisation analysis. The
equi-effective doses of montelukast and salmeterol were based on
the daily doses used in the included trials: with montelukast 5 mg
equivalent to salmeterol 100 micrograms in children aged 6-14
years; and montelukast 10 mg equivalent to salmeterol 100
micrograms in adults and children over 15 years of age.
No trial assessed the comparative effectiveness of montelukast 4 mg in children aged 2-5 years. The submission assumed that montelukast 4 mg would be considered equivalent to salmeterol 100 micrograms in children aged 2-5 years.
For PBAC’s views see Recommendation and Reasons
11. Estimated PBS Usage and Financial Implications
The submission estimated financial savings to the PBS of < $1
million per year in Year 5 for the full requested restriction
(adults and children), and < $100,000 per year in Year 5 for the
approved restriction. This saving arose because patients would have
to make two co-payments for concomitant montelukast and inhaled
corticosteroids rather than one co-payment for a fixed dose
combination of inhaled corticosteroid/long-acting
12. Recommendation and Reasons
The PBAC recommended montelukast sodium chewable tablets, 5 mg
(base) for the new indication of prevention of exercise-induced
asthma in certain children aged 6 to 14 years on a
cost-minimisation basis against salmeterol. In this new eligible
population, the equi-effective doses are based on the daily doses
used in the included trials: with montelukast 5 mg equivalent to
salmeterol 100 micrograms. The PBAC noted that implementation of
this recommendation would require a reduced price for this strength
of montelukast, calculated as the weighted average of the current
price based on the extent of use in the current restricted
population and the requested price based on the extent of expected
use in the new eligible population.
The PBAC agreed that the differentiation between exercise-induced asthma and dyspnoea during exercise was important to minimise usage beyond the restriction, but that it would not be pragmatic to impose an objective differential diagnosis as part of the restriction. Due to concerns about usage beyond the restriction, which were greater than for long-acting beta-agonists, the PBAC recommended that, rather than the requested Restricted Benefit, a Streamlined Authority should apply consistent with the current restriction; and that particular attention be given to the notes accompanying the restriction. In particular, the importance of adhering to on-going use rather than intermittent use immediately before exercise and the distinction between exercise-induced asthma and dyspnoea during exercise both needed to be emphasised.
The potential for usage beyond the intention of the requested restriction was a particular concern as it would undermine the cost-minimisation premise of the submission because there would be no reduction in using a long-acting beta-agonist to off-set the increased cost of using montelukast. The PBAC therefore decided not to recommend the film coated 10 mg tablets because of particular concerns with usage beyond the restriction in adults, partly due to the reduced prevalence of exercise-induced asthma in adults.
The PBAC agreed that long-acting beta-agonists were the appropriate main comparator, noting that the intended eligible population would also be taking inhaled corticosteroids at optimal doses with either montelukast or long-acting beta agonist. However, the PBAC noted that long-acting beta-agonists were not TGA-approved in children less than 4 years of age. The PBAC therefore decided not to recommend the chewable 4 mg (base) tablets because this strength tablet is recommended for use in children aged 2 to 5 years, and so it would not be appropriate to accept a reduction in using long-acting beta-agonist to off-set the increased cost of using montelukast in a proportion of this population. In addition, the PBAC noted that there was no direct comparative randomised trial evidence in this age group or for this strength tablet, and so there is greater uncertainty in having to rely on a placebo-controlled randomised trial of montelukast in this age group and a biological rationale that asthma, including exercise-induced asthma, is a similar disease across age groups.
The PBAC noted the results of the six randomised trials comparing montelukast with long-acting beta-agonists. The PBAC concluded that this represented reasonable, but not good, evidence to support the claim of non-inferiority for montelukast compared to long-acting beta-agonists. Only one of the trials (protocol 911) recruited patients which met the specific requirements of the requested restriction, in terms of being well controlled on optimal doses of inhaled corticosteroids. The other trials were less directly applicable.
The PBAC noted that, although tachyphylaxis and delays in response have not been demonstrated with montelukast, the clinical importance of these having been reported with beta-agonists in exercise-induced asthma remains unclear. The PBAC also noted that there were emerging concerns about neuropsychiatric adverse reactions to montelukast, which were balanced to some extent by concerns about increased risk of death with long-acting beta-agonists, especially when they are used as monotherapy outside the PBS restriction. The PBAC concluded that these additional findings did not change its overall conclusion of non-inferiority when montelukast is used children aged 6 to 14 years who are eligible according to the intention of the requested restriction.
MONTELUKAST SODIUM, chewable tablets, 4 mg (base), chewable tablets and 5 mg (base).
Extend and amend the current restriction as follows:
Montelukast sodium is not PBS-subsidised for use in a child aged 2 to 5 years with moderate to severe asthma. It is not intended as an alternative for a child aged 2 to 5 years who requires a corticosteroid as a preventer medication.
Montelukast sodium is not subsidised in a child aged 2 to 5 years for use in combination with other preventer medications. PBS subsidy for montelukast sodium will therefore cease for a child aged 2 to 5 years who requires a preventer medication in addition to montelukast sodium.No applications for increased maximum quantities and/or repeats will be authorised.
Authority required (STREAMLINED)
First-line preventer medication, as the single preventer agent for children aged 2 to 5 years with frequent intermittent or mild persistent asthma, as an alternative to sodium cromoglycate or nedocromil sodium.
Montelukast sodium is not PBS-subsidised for use in a patient aged 15 years or older, or for use in addition to a long-acting beta-agonist in any age group, or for use as a single second line preventer, as an alternative to corticosteroids, in a child aged 6 to 14 years with moderate to severe asthma.
No applications for increased maximum quantities and/or repeats will be authorised.
Authority required (STREAMLINED)
First-line preventer medication, as the single preventer agent for children aged 6 to 14 years with frequent intermittent or mild persistent asthma, as an alternative to sodium cromoglycate or nedocromil sodium.
Authority Required (STREAMLINED)
Prevention of exercise-induced asthma, as an alternative to adding salmeterol xinafoate or eformeterol fumarate, in a child aged 6 to 14 years whose asthma is otherwise well controlled while receiving optimal dose inhaled corticosteroid, but who requires short-acting beta-2 agonist 3 or more times per week for prevention or relief of residual exercise-related symptoms.
Max qty: 28
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be
subsidised in Australia. It considers submissions in this context.
A PBAC decision not to recommend listing or not to recommend
changing a listing does not represent a final PBAC view about the
merits of the medicine. A company can resubmit to the PBAC or seek
independent review of the PBAC decision.
14. Sponsor’s Comment
The sponsor understands the PBAC's rationale and
The sponsor hopes that in the future, montelukast will be available to all children with exercise-induced asthma, and will work with the PBAC to address the uncertainties identified in the submission.