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
asthma indication.
2. Background
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
listing
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
(Existing Listing)
Restricted benefit
(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.
6. Comparator
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
2006.
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 | ||||
| Baseline | Montelukast | 97 (95) | 33.1 | - |
| Salmeterol | 86 (91) | 30.9 | - | |
| 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
exercise-induced asthma.
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
beta-agonist.
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.
Recommendation
MONTELUKAST SODIUM, chewable tablets, 4 mg (base), chewable tablets
and 5 mg (base).
Extend and amend the current restriction as follows:
Restriction:
(4 mg)
NOTE:
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.
(5 mg)
NOTE:
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
Repeats: 5
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
recommendation.
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.
