Budesonide with Eformoterol Fumarate Dihydrate, powder for oral inhalation in breath actuated device, 100 micrograms-6 micrograms per dose, 200 micrograms-6 micrograms per dose Symbicort Turbuhaler®, March 2007
Public summary document for Budesonide with Eformoterol Fumarate Dihydrate, powder for oral inhalation in breath actuated device, 100 micrograms-6 micrograms per dose, 200 micrograms-6 micrograms per dose Symbicort Turbuhaler®, March 2007
Page last updated: 29 June 2007
Public Summary Document
Product: Budesonide with Eformoterol Fumarate
Dihydrate, powder for oral inhalation in breath actuated device,
100 micrograms-6 micrograms per dose, 200 micrograms-6 micrograms
per dose Symbicort Turbuhaler®
Sponsor: AstraZeneca Pty Ltd
Date of PBAC Consideration: March 2007
1. Purpose of Application
To extend the current Restricted Benefit listing to include
initiation of single maintenance and reliever therapy in patients
who experience asthma symptoms while receiving treatment with
inhaled or oral corticosteroids and in patients who experience
asthma symptoms while receiving treatment with a combination of an
inhaled corticosteroid and a long acting beta-2 agonist.
2. Background
The PBAC has not previously considered an application to extend the
listing to include single maintenance and reliever therapy.
3. Registration Status
Symbicort Turbuhalers 100/6 and 200/6 are registered by the TGA for
the treatment of asthma where use of a combination (inhaled
corticosteroid and long acting beta-agonist) is appropriate. This
includes: patients who are symptomatic on inhaled corticosteroid
therapy; patients who are established on regular long acting
beta-agonist and inhaled corticosteroid therapy.
There are two alternative treatment regimens:
- Symbicort maintenance and reliever therapy, which was approved by the TGA in July 2006;
- Symbicort maintenance therapy.
Symbicort Turbuhaler 400/12 strength is not registered for the
Symbicort maintenance and reliever therapy treatment regimen and
should only be used in patients aged 18 years and older.
4. Listing Requested and PBAC’s View
The requested listing comprised the addition of the following
wording to the existing PBS listing :
Restricted benefit
For initiation of single maintenance and reliever therapy in
patients who experience asthma symptoms while receiving treatment
with inhaled corticosteroids;
For initiation of single maintenance and reliever therapy in
patients who experience asthma symptoms while receiving treatment
with a combination of an inhaled corticosteroid and a long acting
beta-2 agonist.
The sponsor requested the listing of additional two-inhaler
presentations for both strengths for initiation of therapy.
The sponsor subsequently requested that patients who experience
symptoms while receiving treatment oral corticosteroids also be
included.
5. Clinical Place for the Proposed Therapy
The new restriction would allow use of a single maintenance and
reliever therapy regimen for adults and adolescents (aged 12 years
and older) who experience asthma symptoms while receiving treatment
with oral or inhaled corticosteroids and in patients who experience
asthma symptoms while receiving treatment with a combination of an
inhaled corticosteroid and a long acting beta-2 agonist.
6. Comparator
The submission nominated the fixed combination of fluticasone and
salmeterol (Seretide®) plus as needed short acting beta agonist
as the appropriate comparator.
7. Clinical Trials
The basis of the submission was 3 head-to-head randomised comparative trials comparing
Symbicort as both maintenance and reliever asthma therapy with the main comparator,
Seretide plus a short acting beta agonist for as-needed relief. The submission also
included two additional head-to-head randomised comparative trials comparing Symbicort
as both maintenance and reliever asthma therapy with Symbicort as maintenance therapy
plus a short acting beta agonist for as-needed relief.
The trials published at the time of the submission were as follows:
| Trial/First author | Protocol title/Publication title | Publication citation |
|---|---|---|
| COSMOS Vogelmeier, C (2005) | Budesonide/formoterol maintenance and reliever therapy: an effective asthma treatment option? | European Respiratory Journal 2005; 26(5):819-28 |
| STAY/O’Byrne (2005) | Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma. | Am J Resp Crit Care Med 2005; 171:129-37. |
| SMILE/Rabe, K.F (2006) | Effect of budesonide in combination with formoterol for reliever therapy in asthma exacerbations: a randomised controlled, double-blind study. | Lancet 2006; 368: 744-53 |
8. Results of Trials
Symbicort maintenance and reliever therapy demonstrated superiority over Seretide
plus a short acting beta agonist in the time to first severe asthma exacerbation in
all the key trials except for one as yet unpublished randomised trial where there
was no significant difference between the highest doses of Seretide and Symbicort
maintenance and reliever therapy. Symbicort maintenance and reliever regimen also
demonstrated superiority in reducing the total number of asthma exacerbations, time
to hospitalisation and oral steroid use compared to Seretide plus a short acting beta
agonist.
The results of the analysis of the primary outcome measure in the key trials are summarised
in the table below.
Analysis of the primary outcome-time to the first severe asthma exacerbationa in the key head-to-head trials.
| Study (Treatment groups compared) (ITT) | Treatment doses compared | Hazard Ratio | 95% Confidence interval | p-value |
|---|---|---|---|---|
| COMPASS 735 (N=3335) SymMR vs. Ser+T |
Symbicort® 200/6 mcg/inhalation twice daily plus as-needed (SymMR) vs. two inhalations of Seretide® 25/125 mcg/ inhalation twice daily plus short acting ß2 agonist (terbutaline 0.4 mg/ inhalation) as-needed, (Ser+T) | 0.67 | (0.52,0.87) | 0.003 |
| SymMR vs. Sym+T | Symbicort® 200/6 mcg/inhalation twice daily plus as-needed (SymMR) vs. Symbicort® 400/12 mcg/inhalation twice daily plus short acting ß2 agonist (terbutaline 0.4 mg/ inhalation) as needed(Sym+T) | 0.74 | (0.56,0.96) | 0.023 |
| COSMOS 691 (N=2143) SymMR vs. Ser+S |
Symbicort® 200/6 mcg/inhalation, twice daily plus as-needed vs. Seretide® Diskus® 50/100, 50/250 or 50/500 mcg) as maintenance plus short acting ß2 agonist (salbutamol 0.4 mg/ inhalation) as-needed | 0.75 b | (0.61,0.93) | 0.0076 |
a time to first severe exacerbation defined as at least one of the following: an oral
glucocorticosteroid treatment due to asthma for ≥3 days and/or judged by the investigator
and hospitalisation/emergency room treatment due to asthma. The COSMOS comparative
trial is the only key trial that included an ‘unscheduled visit’ initiated by the
patient in the definition of severe exacerbation; analysis conducted using Cox Proportional
Hazards Model;
b hazard ratio excluding unscheduled visit criteria is 0.77 with a 95% CI (0.60, 0.93);
SymMR = Symbicort® maintenance and reliever therapy; Ser+T = Seretide® + terbutaline
(short acting ß2 agonist) as needed; Ser+S = Seretide ®+ salbutamol (short acting
ß2 agonist) as needed (Seretide® Diskus 50/100, 50/250 or 50/500mcg).
9. Clinical Claim
Symbicort, as maintenance and reliever, is more effective than and has a similar toxicity to
- Seretide plus a short acting beta agonist and
- Symbicort as a maintenance regimen plus a short acting beta agonist for as-needed relief.
10. Economic Analysis
Multiple preliminary economic evaluations, which were essentially
cost-analysis in nature, were presented. The only resources
included were drug costs.
Dominance (i.e. clinical advantages at a lower cost) was claimed in
the trial-based cost analysis, but no information was presented
about any confidence region on the incremental cost-effectiveness
plane.
A modelled economic evaluation was not presented.
11. Estimated PBS Usage and Financial Implications
The sponsor estimated that the likely number of patients per year
was between 50,000 to 100,000 in Year 5. The submission estimated
that the net cost to the PBS to extend the listing to include
single maintenance and reliever therapy would be $10 to 30 million
per year.
However, the submission claimed that due to cost offsets associated
with substitution of other fixed dose combinations and reduction in
use of short-acting beta2 agonists there would be
savings to the PBS. The PBAC noted advice that the
overall market is expected to grow or to grow more rapidly as a
result of listing Symbicort for maintenance and reliever therapy
due to the promotional benefits of listing and the broader (more
convenient) prescribing restrictions.
12. Recommendation and Reasons
The PBAC noted that the ‘maintenance and reliever’
approach using a combination of budesonide and eformoterol offers
clinical advantages over the comparators, in regard to most of the
outcome measures of the trials presented in the submission, at a
potentially lower cost and at a reduced oral corticosteroid usage
and lower inhaled corticosteroid burden.
The PBAC also noted that the National Asthma Campaign Handbook
(2006) lists budesonide and eformoterol maintenance and reliever as
an alternative in moderate to severe patients suitable for
combination treatment. The sponsor requested that patients who
experience symptoms while receiving treatment with oral
corticosteroids also be included. The PBAC considered this to be
reasonable.
The PBAC recommended amending the current listing as a restricted
benefit to include single maintenance and reliever therapy in
patients who had frequent asthma symptoms while taking oral or
inhaled corticosteroids. The PBAC considered that it would be
essential for the National Prescribing Service (NPS) to develop a
RADAR document on this recommendation to ensure that the
maintenance and reliever approach is not assumed to be suitable
with any corticosteroid/long acting beta agonist combination or for
the 400/12 budesonide-eformoterol strength.
The PBAC recommended that the Drug Utilisation Sub-Committee (DUSC)
monitor usage based on concerns around the cost offsets associated
with an anticipated decrease in the use of other reliever
medications. The PBAC recommended a maximum quantity of one
inhaler, as two inhalers as requested by the sponsor was not
considered to be warranted for this more expensive reliever
medication.
Recommendation
Budesonide with Eformoterol Fumsrate Dihydrate, powder for oral
inhalation in breath actuated device, 100 micrograms-6 micrograms
per dose, 200 micrograms-6 micrograms per dose.
Add to the current restriction for Symbicort 100/6 and
200/6 to read:
Restriction:Restricted
benefit
For single maintenance and reliever therapy in a patient who
experiences frequent asthma symptoms while receiving treatment with
oral corticosteroids;
For single maintenance and reliever therapy in a patient who
experiences frequent asthma symptoms while receiving treatment with
inhaled corticosteroids;
For maintenance and reliever therapy in a patient who experiences
frequent asthma symptoms while receiving treatment with a
combination of an inhaled corticosteroid and a long acting beta-2
–agonist.
Maximum Quantity: ‡1 (under all scenarios)
Repeats: 5 (under all scenarios)
Budesonide with Eformoterol Fumarate Dihydrate, powder for oral
inhalation in breath actuated device, 400 micrograms-12 micrograms
per dose
Consequential to the recommendation to extend the current listings
for Symbicort 100/6 and 200/6, the PBAC recommended that a NOTE
precluding use of the 400/12 strength as ‘maintenance and
reliever’ therapy be added to the current restriction.
Recommendation
Add to the current restriction for Symbicort 400/12 to read :
NOTE: Symbicort 400/12 is not recommended nor
PBS-subsidised for use as ‘maintenance and reliever’
therapy.
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
AstraZeneca Australia welcomes the PBAC recommendation that Symbicort single maintenance and reliever therapy be listed on the PBS.
