Lercanidipine with Enalapril, tablets, 10 mg-10 mg, 10 mg-20 mg, Zan Extra, March 2008
Public summary document for Lercanidipine with Enalapril, tablets, 10 mg-10 mg, 10 mg-20 mg, Zan Extra, March 2008
Page last updated: 04 July 2008
Public Summary Documents
Product: Lercanidipine with Enalapril, tablets, 10 mg-10 mg, 10 mg-20 mg, Zan Extra
Sponsor: Solvay Pharmaceuticals
Date of PBAC Consideration: March 2008
1. Purpose of Application
The submission sought a Restricted benefit listing for hypertension in patients who are not adequately controlled with either lercanidipine or enalapril monotherapy.
2. Background
The PBAC had not previously considered this combination.
Lercanidipine has been listed on the PBS since November 2001. Enalapril has been listed
on the PBS since August 1986 and is available in numerous generic versions.
3. Registration Status
Zan-Extra tablets were registered by the TGA on 14 February 2008 for the treatment of hypertension. Treatment should not be initiated with these fixed dose combinations.
4. Listing Requested and PBAC’s View
Restricted benefit
Hypertension in patients who are not adequately controlled with either lercanidipine
or enalapril monotherapy.
NOTE:
Treatment should not be initiated with these fixed dose combinations.
The PBAC had no objections to the requested wording of the restriction.
5. Clinical Place for the Proposed Therapy
Zan-Extra is a combination of lercanidipine (a calcium channel blocker) and enalapril (an angiotensin converting enzyme inhibitor) suitable for patients whose hypertension is not adequately controlled by lercanidipine or enalapril monotherapy.
6. Comparator
The submission nominated lercanidipine and enalapril monotherapy as the comparator. The PBAC agreed that this was appropriate.
7. Clinical Trials
The submission presented three key trials and one supportive trial. Two bioequivalence studies were presented as supplementary trials. Details of the trials are in the table below.
|
Trial ID |
Protocol / Title |
|---|---|
|
Key trials |
|
|
CPL1-0018 |
A multi-centre, randomised, parallel group, double-blind phase III trial to study the efficacy and tolerability of a combination of lercanidipine and enalapril in patients with mild to moderate essential hypertension not adequately controlled by lercanidipine treatment (add-on to lercanidipine). |
|
CPL1-0019 |
A multi-centre, randomised, parallel group, double-blind phase III trial to study the efficacy and tolerability of a combination of lercanidipine and enalapril in patients with mild to moderate essential hypertension not adequately controlled by enalapril treatment (add-on to enalapril). |
|
IT-CL 0044 |
A double-blind, placebo controlled, crossover study comparing lercanidipine, enalapril and their combination in the treatment of elderly patients with essential hypertension. |
|
Supportive trial |
|
|
CPL2-0008 |
A multi-centre, randomised, double-blind, parallel group trial to determine the optimal dose combinations of lercanidipine and enalapril in comparison to each component administered alone. |
|
Supplementary trials |
|
|
PK 0152 |
Bioequivalence Study of a fixed combination versus a Combination of Marketed Tablets of Lercanidipine HCl (10 mg) and Enalapril maleate (10 mg). |
|
PK 0159 |
Bioequivalence Study of a fixed combination versus a Combination of Marketed Tablets of Lercanidipine HCl (10 mg) and Enalapril maleate (20 mg). |
8. Results of Trials
The results from the three key trials are shown in the tables below.
Summary of primary and secondary efficacy outcomes for the key trials CPL1-0018 and
CPL1-0019
|
Trial CPL1-0018 |
Trial CPL1-0019 |
|||||
|---|---|---|---|---|---|---|
|
L 10 + E 10 |
L 10 |
Difference |
L 10 + E 20 |
E 20 |
Difference |
|
|
Primary outcome |
||||||
|
Mean change in SDBP (mmHg) |
-7.1 |
-4.3 |
-2.8 |
-9.2 |
-7.5 |
-1.8 |
|
Secondary outcome |
||||||
|
Mean change in SSBP (mmHg) |
-7.7 |
-2.3 |
-5.4 |
-9.8 |
-6.7 |
-3.1 |
Abbreviations: L + E = lercanidipine + enalapril; L = lercanidipine; E = enalapril;
SDBP = sitting diastolic blood pressure; SSBP = sitting systolic blood pressure.
Summary of primary efficacy outcomes for the key trial CL-0044
|
Trial CL-0044* |
|||
|---|---|---|---|
|
L 10mg |
E 20mg |
L 10mg + E 20mg |
|
|
Mean baseline SBP (mmHg) |
151 |
151 |
151 |
|
Mean SE 24-h SBP (mmHg) |
138 11 |
133 12 |
128 10 |
|
Change in mean 24-h SBP versus placebo |
-6.6 13.4 |
-11.4 13.0 |
-16.5 12.7 |
|
Least square means SBP unadjusted (mean SE), (mmHg) |
-6.7 1.5 |
-11.7 1.5 |
-17.0 1.5 |
|
Least square means adjusted for carry-over (meanSE), (mmHg) |
-7.4 1.6 |
-12.7 1.5 |
-17.6 1.5 |
Abbreviations: L + E = lercanidipine + enalapril; L = lercanidipine; E = enalapril;
P = placebo; SBP = systolic blood pressure, DBP = Diastolic blood pressure.
*Cross-over trial
The key trials, CPL1-0018 and CL-0044 showed the superiority of the combination therapy
over monotherapy with the individual components in reducing blood pressure. Trial
CPL1-0019 shows non-inferiority of Zan-Extra 10/20 over enalapril 20 mg.
Two bioequivalence studies demonstrated the equivalence of the combination drug with
the two monotherapies administered concurrently.
The combination product has similar side effects to its constituent drugs, lercanidipine
and enalapril, i.e. dizziness, cough, headache, nasopharyngitis, flushing, vertigo
and palpitations.
9. Clinical Claim
The submission claimed lercanidipine with enalapril combination tablet to be equivalent
in terms of comparative effectiveness and equivalent in terms of comparative safety
over lercanidipine in combination with enalapril. The submission claimed the combination
tablet to be superior in terms of comparative effectiveness over lercanidipine and
enalapril monotherapies.
Based on the supporting data, the PBAC considered these claims reasonable.
10. Economic Analysis
The submission presented a cost minimisation analysis. The equi-effective doses are
estimated as Zan-Extra 10/10 or 10/20 daily over duration of therapy and lercanidipine
10 mg with enalapril 10 mg or 20 mg daily over duration of therapy.
Because of PBS Reform policy, enalapril prices will be reduced by 25% on August 1,
2008. Lercanidipine prices will be reduced by 4% on August 1, 2008 and by a further
7% on August 1, 2011. The submission noted that the mandatory price cuts for lercanidipine
and enalapril will extend to Zan-Extra.
11. Estimated PBS Usage and Financial Implications
The submission estimated that the likely number of packs dispensed per year would
be between 10,000 and 50,000 in the first year, increasing to between 100,000 and
200,000 in year 5. Market gains were predicted to be in exchange for the individually
prescribed monotherapies.
The submission estimated an increased cost to the Government in Years 1 and 2 of listing
of less than $10 million, and financial savings per year to the PBS of less than $10
million in year 5.
12. Recommendation and Reasons
The PBAC recommended a restricted benefit listing of lercanidipine with enalapril
in accordance with the combination guidelines, on a cost-minimisation basis compared
with its constituent components, lercanidipine and enalapril, the equi-effective doses
being lercanidipine with enalapril 10/10 or 10/20 daily and lercanidipine 10 mg in
combination with enalapril 10 mg or 20 mg daily over duration of therapy.
The PBAC also noted that the submission agreed that future price reductions for lercanidipine
and enalapril will also flow to the combinations lercanidipine with enalapril 10/10
and 10/20.
Recommendation:
LERCANIDIPINE HYDROCHLORIDE with ENALAPRIL MALEATE, tablets, 10 mg-10 mg, 10 mg-20
mg
Restriction: Restricted benefit
Hypertension in patients who are not adequately controlled with either lercanidipine
or enalapril monotherapy.
NOTE:
Treatment should not be initiated with these fixed dose combinations.
Maximum quantity: 30
Number of 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
The sponsor has no comments.
