Eplerenone, film-coated tablets, 25 mg, 50 mg, Inspra®, July 2005
Public Summary Document for Eplerenone, film-coated tablets, 25 mg, 50 mg, Inspra®, July 2005.
Page last updated: 24 October 2005
Public Summary Document
Product: Eplerenone, film-coated tablets, 25 mg,
50 mg, Inspra®
Sponsor: Pfizer Australia Pty Ltd
Date of PBAC Consideration: July 2005
1. Purpose of Application
The application sought listing on the Pharmaceutical Benefits Scheme (PBS) as an authority required benefit for the prevention of cardiovascular death in combination with standard medical therapy in patients who have evidence of heart failure and left ventricular impairment.
2. Background
This was the first application to list this product on the PBS.
3. Registration Status
Eplerenone was registered for marketing by the Therapeutic Goods Administration on
22 June 2005. Registration is for the following indication: “To reduce the risk of
cardiovascular death in combination with standard therapy in patients who have evidence
of heart failure and left ventricular impairment within 3-14 days of an acute myocardial
infarction”.
4. Listing Requested and PBAC’s View
The submission requested the following authority required listing:
“To reduce the risk of cardiovascular death in combination with standard medical therapy
in patients who have evidence of heart failure and left ventricular impairment within
3 to 14 days of an acute myocardial infarction.”
The PBAC considered that it would be possible for PBS subsidy of Eplerenone to commence
after fourteen days of the acute myocardial infarction (for example after discharge
from hospital), so long as this is a continuation of Eplerenone treatment which had
commenced within the required timeframe specified in the restriction.
To ensure use of the drug is cost-effective, the PBAC also considered that the key
trial eligibility criterion for left ventricular dysfunction should be a requirement
of PBS availability, though acknowledging that in some situations there will be difficulties
in accessing the appropriate tests.
5. Clinical Place for the Proposed Therapy
Eplerenone represents an additional treatment option as add-on therapy to current standard therapies, in patients who have suffered an acute myocardial infarction. It has been shown, when given in addition to existing standard therapies, to reduce the risk of death in patients with heart failure and left ventricular impairment in the period immediately following acute myocardial infarction.
6. Comparator
The submission nominated placebo (standard medical management) as the comparator.
This was considered to be appropriate by the PBAC.
7. Clinical Trials
The submission presented a single randomised trial comparing Eplerenone (up to 50mg/day) with placebo in patients who have evidence of heart failure and left ventricular impairment within 3-14 days of an acute myocardial infarction (followed over ~14 months). This trial, known as the Eplerenone Post-Acute Myocardial Infarction Efficacy and Survival Study (EPHESUS) had been published as follows:
|
Trial/first author |
Protocol title |
Publication citation |
|---|---|---|
| Pitt et al. | Eplerenone, a Selective Aldosterone Blocker, in Patients with Left Ventricular Dysfunction after Myocardial Infarction. | N Engl J Med 2003; 348 (14): 1309-21. |
8. Results of Trials
The results of the EPHESUS trial are summarised in the table below. The rates for primary and secondary outcomes were statistically significantly lower amongst patients treated with Eplerenone compared to those who received placebo.
|
PlaceboN=3313 |
EplerenoneN=3319 |
Riskratio(95%CI)a |
Absolute risk difference |
NNT |
|
|
|---|---|---|---|---|---|---|
|
Primary outcomes |
||||||
| All-cause mortality |
554 (16.7) |
478 (14.4) |
0.85 (0.75, 0.96) |
2.3% |
44 |
0.008 |
| CV mortality or hospitalisation c |
993 (30.0) |
885 (26.7) |
0.87 (0.79, 0.95) |
3.3% |
31 |
0.002 |
|
Secondary outcomes |
||||||
| CV mortality |
483 (14.6) |
407 (12.3) |
0.83 (0.72, 0.94) |
2.3% |
44 |
0.005 |
| All-cause mortality or hospitalisation |
1829 (55.2) |
1730 (52.1) |
0.92 (0.86, 0.98) |
3.1% |
33 |
0.016 |
a: Based on a proportional hazards model including treatment as the only factor, stratified
by region. 95% confidence interval is based on the Wald test.
b: From a log rank test for equality of time-to-event distribution stratified by region.
c: CV hospitalisations included in this endpoint are those due to HF, recurrent AMI,
stroke, or ventricular arrhythmia.
Significantly more placebo than Eplerenone patients experienced treatment-emergent
serious adverse events where the majority were endpoint events (such as death or hospitalisation).
There were no significant differences in the overall incidence of treatment-emergent
adverse events.
The incidence of hyperkalaemia was significantly higher amongst patients treated with
Eplerenone than with placebo. One placebo patient and no Eplerenone patient died from
hyperkalaemia. There were more patients in the Eplerenone group hospitalised due to
hyperkalaemia: 12 (0.4%) for epleronone vs 3 (0.1%) for placebo. Eplerenone is contraindicated
in patients with clinically significant hyperkalaemia (serum potassium >5.5mmol/L
at initiation) or with creatinine clearance ≤30mL/min.
9. Clinical Claim
The submission claimed that Eplerenone had significant clinical advantages over the
main comparator, but had more toxicity.
The PBAC considered that the evidence supports the conclusion that use of Eplerenone
results in a survival benefit in the proposed treatment population in comparison with
placebo. There is also a reduction in heart failure admissions, but not in all-cause
hospital admissions.
10. Economic Analysis
The submission presented a preliminary economic evaluation. The PBAC considered the
choice of the cost-effectiveness approach to be valid.
The trial-based incremental cost per death averted was in the range $45,000 – $75,000.
A modelled economic evaluation was also presented using two models. Model 1 was based
on the trial period only and model 2 was based on a lifetime period. The base case
modelled incremental cost per extra life-year gained under both models was < $15,000.
11. Estimated PBS Usage and Financial Implications
The submission estimated that the likely number of patients per year would be in the
range of 10,000 – 50,000 per year in Year 4 after listing, with the estimate of the
cost to the PBS being in the range of $10 – $30 million per year by Year 4.
The PBAC considered that the estimates presented in the submission were uncertain
and possibly high with the main areas of uncertainty relating to likely patient numbers,
access of patients to the drug and potential for management problems associated with
potassium monitoring.
12. Recommendation and Reasons
The PBAC recommended listing on the basis of acceptable cost-effectiveness compared
with placebo (for standard medical management) where Eplerenone treatment is commenced
in eligible patients within three to fourteen days of the acute myocardial infarction.
The PBAC noted that the Australian Drug Evaluation Committee (ADEC) had recommended
that Eplerenone be contraindicated in patients older than 75 years, although the sponsor
is working to resolve this issue with the TGA. The PBAC decided to not recommend any
age restriction pending resolution of the issue.
Recommendation
List
Eplerenone, tablets 25 mg and 50 mg
| Restriction: |
CAUTION: The date of the acute myocardial infarction must be provided at the time authority
approval for initial treatment is sought. Continuation of therapy for heart failure with a left ventricular ejection fraction of 40% or less occurring following an acute myocardial infarction, where the patient has previously been issued with a PBS authority prescription for Eplerenone. NOTE: |
| Maximum Quantity: Repeats: |
30 (both strengths) 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
As noted in the Public Summary Document, registration of Inspra was finalised in June 2005. By this time the issue of age restriction had been resolved with the Australian Drug Evaluation Committee (ADEC): there is no contraindication to the use of Inspra on the basis of age in the final approved product information. The Product Information does, however, include a Precaution regarding use in the elderly.
