Perindopril Arginine with Amlodipine Besylate, tablet, 5 mg-5 mg, 5 mg-10 mg, 10 mg-5 mg and 10 mg-10 mg, Coveram® - March 2010
Public Summary Document for Perindopril Arginine with Amlodipine Besylate, tablet, 5 mg-5 mg, 5 mg-10 mg, 10 mg-5 mg and 10 mg-10 mg, Coveram® - March 2010
Page last updated: 02 July 2010
Public Summary Document
Product: PERINDOPRIL ARGININE with AMLODIPINE
BESYLATE, tablet, 5 mg-5 mg, 5 mg-10 mg, 10 mg-5 mg and 10 mg-10
mg, Coveram®
Sponsor: Servier Laboratories (Australia) Pty
Ltd
Date of PBAC Consideration: March 2010
1. Purpose of Application
The submission sought a Restricted benefit listing for substitution
therapy in patients stabilised on perindopril and amlodipine given
concomitantly.
2. Background
This drug combination had not previously been considered by the
PBAC.
3. Registration Status
Perindopril arginine with amlodipine besylate tablets were
registered by the Therapeutic Goods Administration (TGA) on 11
January 2010 and are indicated as substitution therapy for the
treatment of hypertension and/or stable coronary heart disease in
patients already controlled with separate doses of perindopril and
amlodipine, given concurrently at the same dose level. Treatment
should not be initiated with this combination.
4. Listing Requested and PBAC’s View
Restricted benefit
Substitution therapy in patients who are stabilised on treatment
with perindopril and amlodipine, given concurrently at the same
dose level. Treatment should not be initiated with this
combination.
The PBAC noted that perindopril with amlodipine is only registered
for use as substitution therapy. However, the PBAC considered that
titration would occur in clinical practice and the restriction for
the hypertension indication should be consistent with the changes
recommended for the angiotensin converting enzyme
inhibitor/angiotensin II receptor antagonist (ACEI/ATRA) with
diuretic combination products and the ACEI/ATRA with calcium
channel blocker. The PBAC was of the view that all ACEI or ATRA
calcium channel blocker (CCB) combinations should have the same
restriction for hypertension.
5. Clinical Place for the Proposed Therapy
Perindopril with amlodipine would provide a fourth angiotensin
converting enzyme inhibitor with calcium channel blocker
combination product treatment option on the Pharmaceutical Benefits
Scheme (PBS).
6. Comparator
The submission nominated perindopril arginine and amlodipine besylate given concomitantly as the comparator
.
The PBAC considered that this was the
appropriate comparator.
7. Clinical Trials
The basis of the submission was three bioequivalence studies
comparing fixed-dose combinations of perindopril arginine and
amlodipine (10 mg/10 mg, 10 mg/5 mg and 5mg/10 mg) with perindopril
erbumine and amlodipine combinations (8 mg/10 mg, 8 mg/5 mg and 4
mg/10 mg) given concomitantly in healthy volunteers.
One small (n = 26) randomised controlled crossover trial (Stokes et
al. 1998) was also presented. The trial examined the effect of the
addition of amlodipine to perindopril monotherapy and the addition
of perindopril to amlodipine monotherapy using lower doses than
those present in the fixed dose combination formulations proposed
for listing on the PBS. The PBAC noted that the trial was conducted
in a relatively young population (average age approximately 55
years), used a lower dose of perindopril and amlodipine than
requested for this listing (2 mg perindopril erbumine (equiv 2.5 mg
perindopril arginine)/2.5 mg amlodipine besylate) and that the
primary outcome was in terms of blood pressure not coronary heart
disease. Further, the results were presented in graphical format
only, so their significance could not be verified.
Details of the Stokes et al. (1998) trial are shown below:
| Trial ID / First author | Protocol title / Publication title | Publication citation |
|---|---|---|
| Stokes GS et al. (1998) | Double-blind crossover study of the interaction between perindopril and amlodipine on blood pressure and hormones related to fluid and electrolyte balance in patients with essential hypertension. | Journal of Human Hypertension 1998; 12: 129-134. |
8. Results of Trials
Three bio-equivalence studies established bioequivalence of the
combination product (Coveram®) with its perindopril
and amlodipine components administered concomitantly.
The Stokes trial examined the effect of the addition of amlodipine
to perindopril monotherapy. There was no statistically significant
difference in the reduction of mean blood pressure (BP) or systolic
blood pressure (SBP) with the addition of amlodipine (2.5 mg) or
placebo to established perindopril (2 mg) therapy. Adding
perindopril (2 mg) to established amlodipine (2.5 mg) therapy
produced a statistically significant reduction in mean BP compared
to amlodipine alone.
There were some differences in BP measures at clinic visits. The
low doses of perindopril and amlodipine (doses used for titration
in clinical practice), and the small study size, limited the
clinical inferences that may could be drawn from this study.
A meta-analysis conducted by Wald et al. (2009) was presented as
evidence that adding a second drug from another therapeutic class
is approximately 5 times more effective than doubling the dose of a
monotherapy agent and the effect from the combination therapy is
additive (including ACEI + CCB combinations). This meta-analysis
did not include studies examining the combination of perindopril
and amlodipine.
The PBAC agreed that the data presented in the studies were
difficult to interpret with confidence and that even though the
PBAC had previously relied on bioequivalence studies for the
listing of a combination product, the currently listed ACEI with
CCB combinations had also provided data on efficacy and safety, in
addition to bioequivalence, for the combination compared to the
individual monotherapies for each of the combinations. Nonetheless,
the PBAC accepted that perindopril with amlodipine was non-inferior
in terms of comparative effectiveness and equivalent in terms of
comparative safety over perindopril and amlodipine
monotherapies.
The most commonly reported adverse events associated with the
perindopril/amlodipine treatment regimen were cough, peripheral
oedema, joint swelling and dizziness.
9. Clinical Claim
The submission described Coveram® as non-inferior in
terms of comparative effectiveness and equivalent in terms of
comparative safety over perindopril and amlodipine
monotherapies.
The PBAC accepted that perindopril with amlodipine was non-inferior
in terms of comparative effectiveness and equivalent in terms of
comparative safety over perindopril and amlodipine
monotherapies.
10. Economic Analysis
The submission presented a cost minimisation analysis. The equi-effective doses were estimated as:
- Coveram® 5 mg/5 mg equivalent to perindopril 4 mg/5 mg (erbumine/arginine) plus amlodipine 5 mg
- Coveram® 5 mg/10 mg equivalent to perindopril 4 mg/5 mg (erbumine/arginine) plus amlodipine 10 mg
- Coveram® 10 mg/5 mg equivalent to perindopril 8 mg/10 mg (erbumine/arginine) plus amlodipine 5 mg
- Coveram® 10 mg/10 mg equivalent to perindopril 8 mg/10 mg (erbumine/arginine) plus amlodipine 10 mg
11. Estimated PBS Usage and Financial Implications
The likely number of scripts/year estimated in the submission was
in the range of 10,000 – 50,000 scripts in Year 5 for the 5
mg/5 mg and 5 mg/10 mg perindopril/amlodipine strengths and in the
range of 100,000 – 200,000 scripts in Year 5 for the 10 mg/5
mg and 10 mg/ 10 mg perindopril/amlodipine strengths.
The estimated financial savings/year to the PBS were initially
estimated by the submission to be less than $15,000 in Year 5.
Revised estimates correcting for perindopril and amlodipine used in
other combination products such as Coversyl Plus®
(perindopril plus indapamide) and Caduet®
(amlodipine plus atorvastatin) indicated savings in the range of
$45,000 - $75,000 in Year 5.
12. Recommendation and Reasons
The PBAC recommended the restricted benefit listing of perindopril with amlodipine
in accordance with the combination guidelines, on a cost-minimisation basis compared
with the corresponding strengths of its constituent components, perindopril (erbumine/arginine)
and amlodipine given concomitantly.
The PBAC agreed that the data presented in the studies were difficult to interpret
with confidence and that even though the PBAC had previously relied on bioequivalence
studies for the listing of a combination product, the currently listed ACEI with CCB
combinations had also provided data on efficacy and safety, in addition to bioequivalence,
for the combination compared to the individual monotherapies for each of the combinations.
Nonetheless, the PBAC accepted that perindopril with amlodipine was non-inferior in
terms of comparative effectiveness and equivalent in terms of comparative safety over
perindopril and amlodipine monotherapies.
The PBAC noted the sponsor’s comments that perindopril with amlodipine was only registered
for use as substitution therapy. However, the PBAC considered that titration would
occur in clinical practice and the restriction for the hypertension indication should
be consistent with the changes recommended for the ACEI/ATRA with diuretic combination
products and the ACEI/ATRA with calcium channel blocker. The PBAC was of the view
that all ACEI or ATRA CCB combinations should have the same restriction for hypertension.
Recommendation:
PERINDOPRIL ARGININE with AMLODIPINE BESYLATE, tablets, 5 mg – 5 mg, 5 mg – 10 mg,
10 mg – 5 mg and 10 mg – 10 mg
Restriction: Restricted benefit
Hypertension in a patient who is not adequately controlled with either of the drugs in the combination.Stable coronary heart disease in a patient who is stabilised on treatment with perindopril and amlodipine at the same doses.
CAUTION:
Use of ACE inhibitors during pregnancy is contraindicated since these drugs have been associated with foetal death in utero.
NOTE:
Treatment should not be initiated with this combination.
Maximum quantity: 30
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
Servier supports the decision to list with the same restriction as other ACEI/ATRA/CCB products.
