Ezetimibe, tablet, 10 mg, Ezetrol®; ezetimibe with Simvastatin, tablets, 10 mg-40 mg, 10 mg-80 mg, Vytorin® , November 2005
Public Summary Document for ezetimibe, tablet, 10 mg, Ezetrol®; ezetimibe with Simvastatin, tablets, 10 mg-40 mg, 10 mg-80 mg, Vytorin® , November 2005
Page last updated: 27 February 2006
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Public Summary Document
Product: Ezetimibe, tablet, 10 mg, Ezetrol®; ezetimibe with Simvastatin, tablets,
10 mg-40 mg, 10 mg-80 mg, Vytorin®
Sponsor: Merck Sharp & Dohme (Australia) Pty Ltd Schering Plough Pty Ltd
Date of PBAC Consideration: November 2005
1. Purpose of Application
To add three conditions (symptomatic peripheral vascular disease; symptomatic cerebrovascular
disease; and heterozygous familial hypercholesterolaemia) to the ezetimibe listing
for co-administration with a statin in patients eligible for subsidised lipid lowering
medication with coronary heart disease or diabetes mellitus, whose cholesterol levels
are inadequately controlled with a statin.
2. Background
At the June 2003 meeting, the PBAC recommended an authority required listing for ezetimibe
for:
(1) patients who were eligible to receive lipid lowering medication when statins were
unsuitable or contraindicated;
(2) homozygous sitosterolemia; and
(3) patients with homozygous familial hypercholesterolemia in combination with a statin.
At its December 2003 meeting, the PBAC recommended listing in patients eligible for
subsidised lipid lowering medication, with coronary heart disease and/or diabetes
mellitus, on the basis of acceptable cost-effectiveness. Also at this meeting, listing
for heterozygous familial hypercholesterolemia (HeFH) was rejected because of uncertain
clinical benefit and the resulting uncertain cost-effectiveness.
Ezetrol was listed 1 August 2004.
The March 2005 PBAC meeting recommended listing of ezetimibe with simvastatin on a
cost-minimisation basis compared to the sum of the corresponding strengths of the
individual components.
The July 2005 PBAC meeting amended the previously recommended restriction for ezetimibe
with simvastatin to allow for patients with coronary heart disease or diabetes mellitus
who were inadequately controlled after three months treatment at a daily dose of 40
mg or greater of any statin to commence treatment.
Vytorin was listed on 1 February 2006.
3. Registration Status
Ezetimibe (Ezetrol)
Primary Hypercholesterolaemia: Ezetrol administered alone, or with an HMG-CoA reductase
inhibitor (statin), is indicated as adjunctive therapy to diet in patients with primary
(heterozygous familial and non-familial) hypercholesterolaemia.
Homozygous Familial Hypercholesterolaemia (HoFH): Ezetrol, administered with a statin,
is indicated for patients with HoFH. Patients may also receive adjuctive treatments
(e.g. LDL apheresis).
Homozygous Sitosterolaemia (Phytosterolaemia): Ezetrol is indicated for the reduction
of elevated sitosterol and campestrol levels in patients with homozygous familial
sitosterolaemia.
Ezetimibe with Simvastatin (Vytorin)
Vytorin is indicated as adjunctive therapy to diet in patients with primary (heterozygous
familial and non-familial) hypercholesterolemia or mixed hyperlipidemia where use
of combination product is appropriate: Patients not appropriately controlled with
a statin or ezetimibe alone. Patients already treated with a statin and ezetimibe.
Vytorin is indicated in patients with HoFH. Patients may also receive adjunctive treatments
(e.g., LDL apheresis).
4. Listing Requested and PBAC’s View
EZETIMIBE
Authority required
Initial treatment for co-administration with an HMG CoA reductase inhibitor (statin)
in
patients whose cholesterol levels are inadequately controlled with a statin and who
have:
(a) coronary heart disease; or
(b) diabetes mellitus; or
(c) symptomatic peripheral vascular disease; or
(d) symptomatic cerebrovascular disease; or
(e) heterozygous familial hypercholesterolaemia.
Inadequate control with a statin is defined as a cholesterol level in excess of the
initial threshold for PBS-subsidy according to the General Statement for Lipid-Lowering
Drugs after at least 3 months of treatment at a daily dose of 40 mg or greater of
a statin. The cholesterol level after 3 months of treatment with a statin and the
dose of the statin must be provided at the time of application. The cholesterol level
results provided must be no more than 1 month old at the time of application;
Continuing treatment for co-administration with HMG CoA reductase inhibitors (statins)
in patients with coronary heart disease or diabetes mellitus or symptomatic peripheral
vascular disease or symptomatic cerebrovascular disease or heterozygous familial hypercholesterolaemia
whose cholesterol levels were inadequately controlled with a statin, where the patient
has previously been issued with an authority prescription for this drug.
EZETIMIBE with SIMVASTATIN
Authority required
Initial treatment in patients whose cholesterol levels are inadequately controlled
with a HMG CoA reductase inhibitor (statin) and who have:
(a) coronary heart disease; or
(b) diabetes mellitus; or
(c) symptomatic peripheral vascular disease; or
(d) symptomatic cerebrovascular disease; or
(e) heterozygous familial hypercholesterolaemia.
Inadequate control with a statin is defined as a cholesterol level in excess of the initial threshold for PBS-subsidy according to the General Statement for Lipid Lowering Drugs after at least 3 months of treatment at the daily dose of 40 mg or greater of a statin.
The cholesterol level after 3 months of treatment with a statin and the dose of the
statin must be provided at the time of application. The cholesterol levels provided
must be no more than 1 month old at the time of application.
Continuing treatment in patients with coronary heart disease or diabetes mellitus
or symptomatic peripheral vascular disease or symptomatic cerebrovascular disease
or heterozygous familial hypercholesterolaemia whose cholesterol levels were inadequately
controlled with a statin, where the patient has previously been issued with an authority
prescription for this item or the combination of ezetemibe and 40 mg or greater of
a statin.
Patients with homozygous familial hypercholesterolaemia who are eligible for PBS-subsidised
lipid lowering medication (according to the criteria set out in the General Statement
for Lipid-Lowering Drugs).
The PBAC noted that lipid levels for treatment of cerebrovascular disease are not
included in the current General Statement for Lipid-Lowering Drugs. For more on the
PBAC’s view, see Recommendation and Reasons.
5. Clinical Place for the Proposed Therapy
A portion of high risk patients are not achieving sufficient lowering of cholesterol
on statin therapy alone, even at maximal recommended or tolerated doses. In such patients
the addition of ezetimibe, which has a complementary mechanism of action, provides
incremental lipid lowering and facilitates the attainment of treatment goals.
6. Comparator
The PBAC accepted the submission’s nomination of placebo co-administered with a statin
(dose not qualified) as the appropriate main comparator.
7. Clinical Trials
The submission included the two key trials that were previously considered at the
June and December 2003 PBAC meetings (i.e. the P00693 Atorvastatin Filter Study and
P02173/P02246 Ezetimibe Add-on Study). Seven supportive trials comparing ezetimibe
co-administered with statins with statins alone in adults with cardiovascular heart
disease (CHD) and/or diabetes and/or CHD-risk equivalents over 6 to 24 weeks were
also presented. Below are details relating to the key trials.
|
Trial/First author |
Protocol title |
Publication citation |
|---|---|---|
| P00693 Stein E |
Atorvastatin Filter Study | Am Heart J 2004; 148(3):447-55. |
| P02173; P02246/ 1) Gagne C 2) Simons L |
Ezetimibe Add-on Study | 1) Am J Cardiol 2002; 90:1084-91. 2) Curr Med Res Opin 2004; 20(9):1437-45 |
8. Results of Trials
The results of the key trials are summarised in the tables below.
Proportion of patients achieving LDL-C target at trial endpoint
|
P02173/P02246 Ezetimibe Add-On Study |
|
|
|
|---|---|---|---|
| NCEP ATP II target levels* |
218/309 (71.5%) |
61/323 (18.9%) |
52% (45, 58)# |
| P00693 Atorvastatin Filter Study |
Ezetimibe with atorvastatin up-titration |
Atorvastatin up-titration alone |
Difference (95% CI) |
| LDL-C ≥2.59mmol/L |
67/305 (22%) |
23/316 (7%) |
15% (9, 20)## |
NCEP ATP II = National Cholesterol Education Program Adult Treatment Panel.
LDL-C = Low-density lipoprotein cholesterol.
*Patients above target levels at baseline
#p<0.001 ##p<0.01
Mean percent change of lipid parameters from baseline to trial endpoint (unless otherwise indicated)
| P02173/P02246 Ezetimibe Add-on Study |
Ezetimibe with statin (N=379) |
Statin alone (N=390) |
Difference (95% CI) |
| LDL-C Total-C HDL-C TG |
-25.14% |
-3.67% |
-21.5% (-23.5, -19.5) |
* At Week 4, maximum titration of atorvastatin had not occurred in the 14-week treatment
period
Total-C = Total cholesterol, HDL = High-density lipoprotein cholesterol, TG = Triglycerides,
LDL-C = Low-density lipoprotein cholesterol.
#p<0.05
Generally, the outcomes reported in the trials were the mean percent change from baseline
of lipid parameters and the proportion of patients achieving target LDL-C levels.
These outcomes were variously defined as either primary or secondary outcomes in the
trials.
There were significantly more patients who achieved target LDL-C levels (variously
defined depending on trial, favouring ezetimibe co-administered with statins compared
to statins alone. Overall, differences in mean LDL-C percent change from baseline
to endpoint across the trials also significantly favoured the ezetimibe co-administered
with statin treatment groups.
Results for the sub-groups also significantly favoured the ezetimibe co-administered
with statins group. No results were reported for the sub-group of patients with symptomatic
CVD and symptomatic PVD, although some of these patients may be present in the sub-group
of patients with CHD risk equivalents.
Results from Protocol P00693 Atorvastatin Filter Study: HeFH sub-group
|
|
|
|
|---|---|---|
| Proportion achieving LDL-C 2.59mmol/L at Week 14 Difference (95% CI) |
31/181 (17%) |
8/181 (4%) |
|
13%(6%,19%) |
||
| LDL-C (direct) Mean percent change at Week 4 * from baseline (%) Difference (95% CI) |
-23.59 |
-7.44 |
|
|
||
| Total-C Mean percent change at Week 4 * from baseline (%) Difference (95% CI) |
-18.10 |
-5.50 |
|
|
||
| Triglycerides Mean percent change at Week 4 * from baseline (%) Difference (95% CI) |
-5.82 |
3.00 |
|
|
||
| HDL-CMean percent change at Week 4 * from baseline (%) Difference (95% CI) |
1.90 |
0.75 |
|
1.16 (-0.92, 3.24) |
||
# Bolded numbers indicate statistically significant difference, p<0.01
* At Week 4, maximum titration of atorvastatin had not occurred in the 14-week treatment
period
The above table shows that in the heterozygous HeFH sub-group, a statistically significant
difference for ezetimibe co-administered with atorvastatin compared to atorvastatin
alone was reported for LDL-C, Total-C and TG at four weeks.
The PBAC noted that, generally, there were no differences in the percentage of subjects
reporting adverse effects between any randomised groups.
9. Clinical Claim
The PBAC accepted that ezetimibe co-administered with statins is associated with significant
advantages in effectiveness over statins alone.
10. Economic Analysis
A preliminary economic evaluation was presented. The PBAC considered that the adoption
of a cost-effectiveness approach was appropriate. The resources included were the
costs of ezetimibe and statins only.
The modelled economic evaluation presented also adopted a cost-effectiveness approach,
using a Markov state transition model to obtain cost per life-years gained. The PBAC
also considered this approach appropriate. The average duration of the model was about
30 years. The resources included were drug costs, costs of cardiovascular heart disease
death, cost of myocardial infarction and cost of angina.
The incremental cost/extra life year gained in cerebrovascular disease patients, peripheral
vascular disease patients and HeFH patients was between $15,000-$45,000.
11. Estimated PBS Usage and Financial Implications
The submission estimated use by up to 10,000-50,000 patients with symptomatic cerebrovascular
disease and/or symptomatic peripheral vascular disease and up to 2,000-10,000 patients
with HeFH in Year 4 of listing.
The financial cost was estimated to be up to $5-10 million in Year 5 of listing.
12. Recommendation and Reasons
The PBAC recommended the addition of two indications to the current listing for ezetimibe,
namely peripheral vascular disease and heterozygous familial hypercholesterolaemia,
on the basis of acceptable cost-effectiveness in these patient groups. The PBAC was
unable to agree to the addition of cerebrovascular disease because the current General
Statement for Lipid-Lowering Drugs does not include this patient group.
Recommendation
EZETIMIBE, tablet, 10 mg
Amend restriction for use in patients who have coronary heart disease or diabetes
mellitus to read:
| Restriction: |
Authority required Continuing treatment for co-administration with HMG CoA reductase inhibitors (statins) in patients with coronary heart disease or diabetes mellitus or peripheral vascular disease or heterozygous familial hypercholesterolaemia whose cholesterol levels were inadequately controlled with a statin, where the patient has previously been issued with an authority prescription for this drug. |
| Maximum quantity Repeats: |
30 5 |
Recommendation and Reasons
The PBAC recommended the addition of two indications to the current recommended listing
for ezetimibe with simvastatin, namely peripheral vascular disease and heterozygous
familial hypercholesterolaemia, on the basis of acceptable cost-effectiveness in these
patient groups. The PBAC was unable to agree to the addition of cerebrovascular disease
because the current General Statement for Lipid-Lowering Drugs does not include this
patient group.
Recommendation
EZETIMIBE with SIMVASTATIN, tablets, 10 mg-40 mg, 10 mg-80 mg
Amend recommended restriction to read:
| Restriction: |
Authority required Inadequate control with a statin is defined as a cholesterol level in excess of the initial threshold for PBS-subsidy according to the General Statement for Lipid Lowering Drugs after at least 3 months of treatment at the daily dose of 40 mg or greater of a statin, in conjunction with dietary therapy and exercise. The cholesterol level after 3 months of treatment with a statin and the dose of the statin must be provided at the time of application. The cholesterol level results provided must be no more than 1 month old at the time of application; Continuing treatment in patients with coronary heart disease or diabetes mellitus
or peripheral vascular disease or heterozygous familial hypercholesterolaemia where
the patient has previously been issued with an authority prescription for this item
or the combination of ezetimibe and 40 mg or greater of a statin. |
| Maximum quantity Repeats: |
30 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
No Comment
