Ezetimibe with Simvastatin, tablet, 10 mg-40 mg, 10 mg-80 mg, Vytorin® , July 2005
Public Summary Document for Ezetimibe with Simvastatin, tablet, 10 mg-40 mg, 10 mg-80 mg, Vytorin® , July 2005.
Page last updated: 24 October 2005
Public Summary Document
Product:Ezetimibe with Simvastatin, tablet, 10 mg-40 mg, 10 mg-80 mg, Vytorin®
Sponsors:Merck Sharp & Dohme (Australia) Pty Limited and Schering-Plough Pty Ltd
Date of PBAC Consideration:July 2005
1. Purpose of Application
This minor application sought a modification to the listing wording for the combination ezetimibe and simvastatin product recommended at the March 2005 PBAC meeting. The revised wording requested by the sponsors was the same as that proposed by the sponsors in the submission considered at the March 2005 meeting.
2. Background
The combination ezetimibe with simvastatin 10/40 mg and 10/80 mg products were recommended for listing at the March 2005 meeting of the PBAC. Consistent with its policy on fixed dose combination products, the PBAC recommended listing on a cost-minimisation basis compared to the sum of the corresponding strengths of the individual components. The PBAC considered that, because there is more than one statin listed on the PBS, but only simvastatin is included in the combination product, it would be more clinically appropriate to stabilise the patient on ezetimibe with the appropriate dose of statin before commencing the combination product. Then once the patient is transferred to the combination product, it will be apparent to the medical practitioner if lipid levels are no longer adequately controlled and that the dose of simvastatin in the combination requires adjustment. If a patient not adequately controlled on 40 mg or more of another statin is transferred directly to the combination, the medical practitioner will not know whether the dose of simvastatin is inadequate or whether the patient is a non-responder to ezetimibe. The requirement for a patient to be stabilised on the individual components of a combination before switching to the combination is also consistent with the listings of other combination products.
3. Registration Status
On 7 January 2005, the Therapeutic Goods Administration registered Vytorin for the
following indications:
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 homozygous familial hypercholesterolemia (HoFH).
Patients may also receive adjunctive treatments (e.g., LDL apheresis).
4. Listing Requested and PBAC’s View
The listing requested by the sponsors would allow eligible patients to transfer to
the fixed-dose combination product after at least 3 months of treatment at the daily
dose of 40 mg or greater of any statin.
Authority Required
Initial treatment in patients whose cholesterol levels are inadequately controlled
with a statin and who have:
(a) coronary heart disease; or
(b) diabetes mellitus.
Inadequate control with a statin is defined as 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 level results
provided must be no more than 1 month old at the time of application.
Initial treatment in patients who have previously been issued with PBS prescriptions
for ezetimibe and 40 mg or greater of statin.
Continuing treatment in patients with coronary heart disease or diabetes mellitus
whose cholesterol levels were inadequately controlled with a statin, where the patient
has previously been issued with an authority prescription for this drug.
Patients with homozygous familial hypercholesterolemia whose cholesterol levels are
inadequately controlled with a statin (as defined above) on current lipid lowering
treatment.
In support of the requested listing, the sponsors argued that:
· Under the PBAC recommended restriction patient/physician choice will be limited.
· In comparison to other combination products listed on the PBS, the simvastatin/ezetimibe
combination is more similar to the ACE/HCT and AIIRA/HCT combination products than
to the long acting beta agonist/inhaled corticosteroid products, whereas the restriction
wording recommended by the Committee is more similar to the latter.
· Allowing patients to directly access the combination simvastatin/ezetimibe product
has advantages consistent with the quality use of medicines, and would reduce patient
costs, reduce the costs of additional medical consultations, and encourage improved
compliance in the high risk population in which the listing is proposed.
· Fewer tablets will be required by patients, many of whom are already taking multiple
medications.
For PBAC’s view on the requested listing, see Recommendation and Reasons.
5. Clinical place for the proposed therapy
Vytorin is an alternative to a statin plus ezetimibe administered separately. Vytorin
may be considered for patients with coronary heart disease or diabetes mellitus who:-
· require additional lipid lowering because their cholesterol levels are inadequately
controlled with a daily dose of 40 mg or greater of a statin; or
· are already taking ezetimibe and a statin.
6. Comparator
Not applicable. There was no need for a comparator to be included in this minor submission.
7. Clinical Trials
The submission presented a series of arguments in support of its request. These referred to efficacy and safety data from the following published clinical trials:
|
Trial/First author |
Protocol/Publication title |
Publication citation |
|---|---|---|
| Davidson MH | Ezetimibe co-administered with simvastatin in patients with primary hypercholesterolemia. | Journal of the American College of Cardiology 40(12): 2125-2134, 2002. |
| Goldberg AC | Efficacy and safety of ezetimibe co-administered with simvastatin in patients with primary hypercholesterolemia: a randomised double-blind, placebo controlled trial. | Mayo Clinic Proceedings 79(5):620-629, 2004. |
| Bays HE | A multicentre, randomised, double-blind, placebo controlled, factorial design study to evaluate the lipid altering efficacy and safety profile of the ezetimibe/simvastatin tablet compared with ezetimibe and simvastatin monotherapy in patients with primary hypercholesterolemia. | Clinical Therapeutics 26(11): 1758-1773, 2004 |
| Ballantyne CM | Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: A prospective, randomised, double-blind trial. | Circulation 107(19): 2409-2415, 2003 |
| Ballantyne CM | Efficacy and safety of ezetimibe co-administered with simvastatin compared with atorvastatin in adults with hypercholesterolemia. | American Journal of Cardiology 93(12):1487-1494, 2004. |
| Ballantyne CM. | Dose-comparison study of the combination of ezetimibe and simvastatin (Vytorin) versus atorvastatin in patients with primary hypercholesterolemia: The Vytorin Versus Atorvastatin (VYVA) Study | Am. Heart J. 149(3): 464-473, 2005 |
8. Results of Trials
On the basis of the clinical trial data the sponsors also presented the following
arguments in the submission:
· At a population based level there is little value in terms of efficacy or safety
in the PBAC’s requirement for patients to be stabilised and demonstrate adequate control,
on the individual statin and ezetimibe prior to accessing the combination product.
· Most patients directly transferred to the combination will experience additional
clinical benefit, and thus the scenario envisaged by the Committee will rarely arise
in practice.
· That there are no significant differences in safety between 40 mg (or 80mg) statin
+ ezetimibe as single agents, and the relevant fixed combination.
9. Clinical Claim
Not applicable. There was no need to make a clinical claim in this minor submission.
10. Economic Analysis
Not applicable. There was no need to include an economic analysis in this minor submission.
11. Estimated PBS usage and financial implications
Not applicable. There were no revisions to previous estimates presented in this minor submission.
12. Recommendation and Reasons
The PBAC recommended that the previously recommended restriction for ezetimibe with
simvastatin be amended to allow for patients with coronary heart disease or diabetes
mellitus who were inadequately controlled after three months treatment at a daily
dose 40 mg or greater of any statin to commence treatment on Vytorin. The PBAC noted
that its previous recommendation (March 2005 meeting) had allowed for a systematic
approach for the commencement of the combination product. However, it was convinced
by the additional arguments presented to remove the requirement for adequate control
to be demonstrated based on a minimum of 3 months of concomitant treatment with PBS-subsidised
ezetimibe and PBS-subsidised statin prior to becoming eligible to commence Vytorin.
The PBAC accepted that, under its previously recommended restriction, patient/physician
choice would be limited. It also accepted that most patients directly transferred
to the combination would experience additional clinical benefit, and thus the scenario
envisaged by the Committee (that a patient inadequately controlled on another statin
at a dose of 40 mg or more might remain inadequately controlled when switching to
the corresponding simvastatin dose in Vytorin) would rarely arise in practice; and
that there are no significant differences in safety between 40 mg (or 80 mg) statin
+ ezetimibe as single agents, and the relevant fixed combination.
Recommendation:
Amend the recommended authority required restriction as detailed below:
Restriction: Authority required
Initial treatment in patients whose cholesterol levels are inadequately controlled with a HMG CoA reductase inhibitor (statin) and who have:
1. coronary heart disease; or
2. diabetes mellitus.
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
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 ezetimibe 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).
Maximum quantity: 30 (both strengths)
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
