Budesonide with eformoterol fumarate dihydrate, powder for oral inhalation, fixed dose combination, 400 micrograms-12 micrograms per dose, Symbicort Turbuhaler 400/12®
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oral inhalation, fixed dose combination, 400 micrograms-12 micrograms per dose, Symbicort
Turbuhaler 400/12 ® (PDF 47 KB)
Product: Budesonide with eformoterol fumarate
dihydrate, powder for oral inhalation, fixed dose combination, 400
micrograms-12 micrograms per dose, Symbicort Turbuhaler
400/12®
Sponsor: AstraZeneca Pty Ltd
Date of PBAC Consideration: November 2010
1. Purpose of Application
The submission sought a Restricted Benefit listing for the
symptomatic treatment of patients with chronic obstructive
pulmonary disease (COPD) who meet certain criteria.
2. Background
The PBAC recommended the restricted benefit listings of budesonide with eformoterol
Turbuhaler® 200 micrograms/6 micrograms (March 2002 meeting) and 400 micrograms/12 micrograms
(March 2004 meeting), on a cost-minimisation basis compared with the individual components,
for the treatment of asthma in patients who meet certain criteria. Listing was effective
1 February 2003 and 1 August 2004, respectively.
At the November 2004 meeting, the PBAC recommended the listing of budesonide with
eformoterol Turbuhaler® 100 micrograms/6 micrograms strength, and to broaden the restriction to include those
patients “… with frequent episodes of asthma who are receiving treatment with optimal
doses of budesonide”. Listing was effective 1 April 2005.
At the March 2007 meeting, the PBAC recommended amending the current restricted benefit
listing for the 200/6 and 100/6 strengths to include single maintenance and reliever
therapy (SMART) in patients who had frequent asthma symptoms while taking oral or
inhaled corticosteroids.
Full details in the March 2007 Public Summary Document (PSD) available.
3. Registration Status
As at 15 October 2010, budesonide with eformoterol 400/12
Turbuhaler® was TGA registered for the symptomatic
treatment of moderate to severe COPD (FEV1 less than or
equal to 50% predicted normal) in adults with frequent symptoms
despite long-acting bronchodilator use and/or a history of
recurrent exacerbations. Symbicort Turbuhaler is not indicated for
the initiation of bronchodilator therapy in COPD.
It is also TGA registered 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 and patients who are established on
regular long acting beta-agonist and inhaled corticosteroid
therapy. Symbicort 400/12 should only be used in patients aged 18
years and over. The 400/12 strength should not be used for the
Symbicort maintenance and reliever therapy regimen.
4. Listing Requested and PBAC’s View
Restricted Benefit
The symptomatic treatment of moderate to severe chronic obstructive
pulmonary disease (COPD) where the FEV1 is less than or
equal to 50% predicted normal in adults with frequent symptoms
despite long acting bronchodilator use and/or a history of
recurrent exacerbations.
NOTE:
Budesonide with eformoterol is not indicated for the initiation of
bronchodilator therapy in COPD
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
COPD is a progressive disease and lung function is expected to
worsen over time. As such, treatment tends to be cumulative with
more medications being required as the disease state worsens.
Combined therapy with inhaled corticosteroids and long-acting beta
2-adrenoceptor agonists is used in patients with COPD who
experience repeated exacerbations. The submission claimed that
budesonide with eformoterol would provide an alternative therapy to
fluticasone with salmeterol.
6. Comparator
The submission nominated fluticasone with salmeterol
(Seretide®) as the comparator.
This was considered appropriate by the PBAC and is consistent with
current guidelines where a long-acting beta 2-adrenoceptor agonists
(LABA) is usually given with an inhaled corticosteroid (ICS).
7. Clinical Trials
The submission presented an indirect comparison including a meta-analysis of four
randomised trials comparing Symbicort® with placebo in patients with COPD (Calverley et al 2003, SHINE, SUN, and Szafranski
et al 2003), and a meta-analysis of seven randomised trials (Barnes et al 2006, Mahler
et al 2002, SCO104925, SFCT01, TORCH, TRISTAN, and Zheng et al 2006) comparing Seretide
with placebo in patients with COPD.
The submission also presented a second indirect comparison including one randomised
trial comparing Symbicort® plus tiotropium with tiotropium monotherapy (CLIMB) and a meta-analysis of two randomised
trials comparing Seretide plus tiotropium with tiotropium monotherapy in patients
with COPD (Aaron et al 2007, Cazzola et al 2007).
Publication details of the studies presented in the submission are in the table below.
| Trial ID / First author | Protocol title / Publication title | Publication citation | |
| Common reference: placebo | |||
| Symbicort ® vs placebo | |||
| Calverly et al | Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease | Eur Respir J, 2003, Dec; 22(6): 912-919 | |
| SHINE Tashkin et al | Efficacy and safety of budesonide and formoterol in one pressurized metered-dose inhaler in patients with moderate to very severe chronic obstructive pulmonary disease: results of a 6-month randomized clinical trial | Drugs, 2008; 68(14): 1975-2000 | |
| SUN Rennard et al | Efficacy and tolerability of budesonide/formoterol in one hydrofluoroalkane pressurized metered-dose inhaler in patients with chronic obstructive pulmonary disease: results from a 1-year randomized controlled clinical trial | Drugs, 2009; 69(5): 549-565 | |
| Szafranski et al Calverley et al | Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease. Relationship between respiratory symptoms and medical treatment in exacerbations of COPD | Eur Respir J, 2003, 21: 74-81 Eur Respir J, 2005, 26: 406-413 | |
| Seretide ® vs placebo | |||
| Barnes et al | Antiinflammatory effects of salmeterol/fluticasone propionate in chronic obstructive lung disease | Am J Crit Care Med, 2006, 173: 736-743 | |
| Mahler et al | Effectiveness of Fluticasone Propionate and salmeterol Combination Delivered via the Diskus Device in the Treatment of Chronic Obstructive Pulmonary Disease | Am J Crit Care Med, 2002, 166: 1084-1091 | |
|
TORCH Calverley et al Celli et al Crim et al Ferguson et al Jenkins et al McGarvey et al 2007 Vestbo et al Vestbo et al |
Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease ffect of pharmacotherapy on rate of decline of lung function in chronic obstructive pulmonary disease: results from the TORCH study Pneumonia risk in COPD patients receiving inhaled corticosteroids alone or in combination: TORCH study results Prevalence and progression of osteoporosis in patients with COPD: results from the TOwards a Revolution in COPD Health study Efficacy of salmeterol/fluticasone propionate by GOLD stage of chronic obstructive pulmonary disease: analysis from the randomised, placebo-controlled TORCH study TORCH Clinical Endpoint C. Ascertainment of cause-specific mortality in COPD: operations of the TORCH Clinical Endpoint Committee The TORCH (towards a revolution in COPD health) survival study protocol Adherence to inhaled therapy, mortality and hospital admission in COPD |
N Engl J Med, 2007, Feb 22;356(8):775-789 Am J Respir Crit Care Med, 2008, Aug 15;178(4):332-338 Eur Respir J, 2009, Sep; 34(3):641-647 Chest, 2009, Dec; 136(6):1456-1465 Respir Res, 2009;10:59 Thorax, 2007, May; 62(5):411-415 Eur Respir J, 2004, Aug; 24(2):206-210 Thorax, 2009, Nov; 64(11):939-943 |
|
|
TRISTAN Calverley et al Calverley et al Keene et al Keene et al Vestbo et al Vestbo et al |
Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial The severity of airways obstruction as a determinant of treatment response in COPD Statistical analysis of exacerbation rates in COPD: TRISTAN and ISOLDE revisited. Analysis of exacerbation rates in asthma and chronic obstructive pulmonary disease: example from the TRISTAN study TRISTAN study g. Early onset of effect of salmeterol and fluticasone propionate in chronic obstructive pulmonary disease Gender does not influence the response to the combination of salmeterol and fluticasone propionate in COPD |
Lancet, 2003, Feb 8;361(9356):449-456 Int J Chron Obstruct Pulmon Dis, 2006; 1(3):209-218 European Respiratory Journal, 2008, July; 32(1):17-24 Pharm Stat, 2007, Apr-Jun; 6(2):89-97 Thorax, 2005, Apr; 60(4):301-304 Respir Med, 2004, Nov; 98(11):1045-1050 |
|
| Zheng et al | The efficacy and safety of combination salmeterol (50 microg)/fluticasone propionate (500 microg) inhalation twice daily via accuhaler in Chinese patients with COPD | Chest, 2007, Dec; 132(6):1756-1763 | |
| Common reference: tiotropium; co-treatment with tiotropium | |||
| Symbicort ® plus tiotropium vs tiotropium monotherapy | |||
| CLIMB Welte et al 2009 | Efficacy and tolerability of budesonide/formoterol added to tiotropium in patients with chronic obstructive pulmonary disease | Am J Respir Crit Care Med, 2009, Oct 15; 180(8): 741-750 | |
| Seretide ® plus tiotropium vs tiotropium monotherapy | |||
|
Aaron et al Aaron et al |
Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial The Canadian Optimal Therapy of COPD Trial: design, organization and patient recruitment |
Ann Intern Med, 2007, Apr 17;146(8): 545-555 Can Respir J, 2004, Nov-Dec; 11(8):581-585 |
|
| Cazzola et al | A pilot study to assess the effects of combining fluticasone propionate/salmeterol and tiotropium on the airflow obstruction of patients with severe-to-very severe COPD | Pulm, Pharmacol, Ther, 2007; 20(5):556-561 | |
8. Results of Trials
The key outcomes presented in the submission were the rate of COPD
exacerbations, mean change from baseline as measured by St George
Respiratory Questionnaire (SGRQ) and mean change from baseline for
pre- and post-dose Forced Expiratory Volume in one second
(FEV1).
The results of the indirect comparisons are presented below. The
results of the indirect comparison should be interpreted with
caution due to the heterogeneity between the trials included in the
analyses.
Rate of exacerbations
The meta-analysis of rate ratios for Symbicort versus placebo
showed a statistically significant reduction in the rate of COPD
exacerbations in favour of Symbicort (0.72, 95% CI: 0.64 to 0.81).
Similarly, meta-analysis of rate ratios for Seretide versus placebo
showed a statistically significant reduction in the rate of COPD
exacerbations compared to placebo (0.75, 95% CI: 0.70 to 0.80). The
indirect comparison using placebo as common reference showed no
statistically significant difference between Symbicort and Seretide
(0.96, 95% CI: 0.84 to 1.10), and the upper 95% CI of the indirect
comparison did not cross the Minimal Clinically Important
Difference (MCID) of 1.22.
Symbicort plus tiotropium resulted in a statistically significantly
lower rate of exacerbations compared to tiotropium alone (0.38, 95%
CI: 0.25 to 0.57), while Seretide plus tiotropium did not result in
a statistically significant lower rate of exacerbation compared to
tiotropium alone (0.85, 95% CI: 0.65 to 1.11). The indirect
comparison using tiotropium as the common reference suggested that
Symbicort might be superior to Seretide, when used in combination
with tiotropium (0.46, 95% CI: 0.27 to 0.73), however, the
submission considered that the analysis needed to be interpreted
with caution, as the trials were of different duration and patients
enrolled in the Aaron trial were able to initiate pulmonary
rehabilitation programs during the trial as well as oxygen therapy.
St George Respiratory Questionnaire (SGRQ)
The St George’s Respiratory Questionnaire is a
standardised self-completed questionnaire for measuring impaired
health and perceived well-being (‘quality of life’) in
patients with disease of the airways.
The submission presented indirect comparisons based on the change
in SGRQ from baseline using placebo and tiotropium as common
references.
There was no statistically significant difference in change in SGRQ
from baseline between Symbicort (with or without tiotropium) and
Seretide (with or without tiotropium) in either indirect comparison
(indirect mean difference [95% CI] -0.04 [-1.5, 1.5] using placebo
as common reference and 1.8 [-0.9, 4.6] using tiotropium as common
reference).
The treatments appeared to confer an average improvement which was
less than the 4-unit difference considered in clinical guidelines
to be the MCID, i.e. the trials do not provide evidence that either
Symbicort or Seretide results in a clinically important improvement
in SGRQ score, as monotherapy compared to placebo, or in
combination with tiotropium compared to tiotropium alone.
Pre and post dose FEV1
The magnitude of change observed in FEV1 from
baseline depends on a number of factors including baseline lung
function and severity of disease. The absolute change observed is
less marked in patients with lower baseline lung function. The PBS
listing for Seretide restricts use to patients with baseline
FEV1 less than 50% predicted normal; however unlike the
Symbicort trials, the Seretide trial population included patients
with baseline FEV1 greater than 50% predicted normal. As
such, to facilitate comparability, analysis of both pre and
post-dose FEV1 only included those patients with
baseline FEV1 less than 50% predicted normal.
Symbicort resulted in a statistically significant increase in
pre-dose FEV1 from baseline compared to placebo
treatment; however, this increase of 0.09 L was below 0.12 L, which
the submission considered the MCID. Similarly, Seretide resulted in
a statistically significant increase in pre-dose FEV1
(0.11 L), which was also below the MCID. There was no statistically
significant difference between Symbicort and Seretide using placebo
as common reference.
When used in combination with tiotropium, neither Symbicort nor
Seretide showed a statistically significant difference in pre-dose
FEV1 compared to tiotropium alone. There was no
statistically significant difference between Symbicort plus
tiotropium and Seretide plus tiotropium, using tiotropium as the
common reference.
Results from the indirect comparison based on change in post-dose
FEV1 from baseline showed that Symbicort resulted in
statistically and clinically significant increases in post-dose
FEV1, compared to placebo treatment. Seretide treatment
resulted in statistically significant, but not clinically
significant, differences in post-dose FEV1. The
submission claimed that there was a statistically significant
difference with regard to the change in post-dose FEV1
in favour of Symbicort compared to Seretide, using placebo as
common reference (indirect mean difference 0.10: 95% CI 0.07 to
0.13). The submission claimed that as the upper confidence interval
crosses the upper threshold of the MCID of 0.12 L, Symbicort may
result in a clinically relevant improvement compared to Seretide
treatment.
For PBAC’s view of these results, see Recommendations and
Reasons.
The submission claimed that while there was an increase in adverse
events when Symbicort was compared to placebo treatment, there were
no statistically significant difference between Symbicort and
Seretide, when the TORCH trial was excluded. The submission
justified the exclusion of the TORCH trial, as this trial was of
longer duration than the other studies included in the safety
analyses. The submission claimed that there were no other
differences in safety outcomes between Symbicort and placebo or
Symbicort plus tiotropium and tiotropium as well as between
Symbicort (with or without tiotropium) and Seretide (with or
without tiotropium) as demonstrated by the indirect comparisons
using either placebo or tiotropium as the common reference.
The assessment of extended comparative harm did not reveal
additional safety concerns.
9. Clinical Claim
The submission claimed Symbicort as non-inferior in terms of
comparative effectiveness and at least as effective in terms of
comparative safety over Seretide.
The PBAC considered that this was reasonable, despite the
uncertainties raised with the indirect comparisons.
10. Economic Analysis
The submission presented a cost minimisation analysis. The
equi-effective doses were estimated as Symbicort 400/12 micrograms
twice daily and Seretide 500/50 micrograms twice daily, based on
the recommended dose in the Australian Product Information (PI).
The doses used for the claim of equi-effectiveness were similar to
the doses used in the clinical trials.
Each prescription of eformoterol with budesonide provides two
months supply of this combination compared to the salmeterol with
fluticasone combination currently PBS listed for COPD, which
provides one month’s supply. The submission claimed an
incremental dispensed price for maximum quantity (DPMQ) saving per
2 months to the Government of $6.42 per prescription (equivalent to
one pharmacy dispensing fee), as a result of the listing.
11. Estimated PBS Usage and Financial Implications
The likely number of patients per year was estimated in the
submission to be in the range of 10,000 to 50,000 in Year 4. This
was considered to be uncertain.
The submission estimated financial savings per year to the PBS of
less than $10 million in Year 5 based on a weighted price. Upon
request from the ESC, revised financial estimates based on the COPD
price were provided in the sponsor’s Pre-PBAC Response. This
analysis estimated an overall net cost to the PBS of less than $10
million in Year 5 which resulted from a reduction in patient
co-payments associated with Symbicort.
For PBAC’s view, see Recommendation and
Reasons.
12. Recommendation and Reasons
The PBAC recommended listing on a cost minimisation basis with equi-effective doses
being salmeterol 50 micrograms with fluticasone 500 micrograms and eformoterol 12
micrograms with budesonide 400 micrograms, both agents administered twice daily. The
PBAC stated that there should be no additional cost associated with this recommendation
for the listing of budesonide with eformoterol on the PBS.
The PBAC noted the results of the indirect comparison presented in the submission,
agreeing with the concerns raised by ESC around the comparability of the clinical
trials used in the indirect comparison. The PBAC noted that the pooled results for
the change from baseline for the St George Respiratory Questionnaire and the pre-dose
FEV1 were not statistically significantly different from the reference therapy and that
the point estimates were not greater than the Minimum Clinical Important Difference.
The indirect comparison for post-dose FEV1 showed a statistically significant difference in favour of budesonide with eformoterol,
but these results may be uncertain because of the differences in the trials. Overall,
on the totality of the evidence, the PBAC considered that the claim of non-inferiority
of budesonide with eformoterol compared to fluticasone with salmeterol was reasonable.
The PBAC noted that budesonide with eformoterol for COPD should be included in the
PBS medicines for prescribing by nurse practitioners within collaborative arrangements.
Recommendation:
BUDESONIDE WITH EFORMOTEROL FUMARATE DIHYDRATE, powder for oral inhalation in breath
actuated devices 400 micrograms-12 micrograms per dose (60 doses), 2
Extend the current restriction to include:
Restriction: Restricted Benefit
Symptomatic treatment of chronic obstructive pulmonary disease (COPD), where the FEV1 is less than 50% predicted normal and there is a history of repeated exacerbations with significant symptoms despite regular beta-2 agonist bronchodilator therapy.
NOTE: Budesonide with eformoterol fumarate dihydrate is not indicated for the initiation of bronchodilator therapy in COPD.
Maximum quantity: 1
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
AstraZeneca welcomes the recommendation by the PBAC to extend the
listing for Symbicort, to provide access to an additional treatment
option for patients with chronic obstructive pulmonary disease.
