Telmisartan with amlodipine, tablet, 40 mg – 5 mg, 40 mg – 10 mg, 80 mg – 5 mg and 80 mg – 10 mg (as besylate), Twynsta® - March 2011
Page last updated: 01 July 2011
Public Summary Document
Product: Telmisartan with amlodipine, tablet, 40
mg – 5 mg, 40 mg – 10 mg, 80 mg – 5 mg and 80 mg
– 10 mg (as besylate), Twynsta®
Sponsor: Boehringer Ingelheim Pty Ltd
Date of PBAC Consideration: March 2011
1. Purpose of Application
The submission sought a Restricted Benefit listing for the
treatment of hypertension in a patient who is not adequately
controlled on either of the drugs in the combination.
2. Background
The fixed dose combination item containing telmisartan with
amlodipine had not previously been considered by the PBAC.
3. Registration Status
Telmisartan with amlodipine tablets (Twynsta) were registered by
the TGA on 18 February 2011 for the treatment of hypertension.
Treatment should not be initiated with this fixed-dose
combination.
4. Listing Requested and PBAC’s View
Restricted Benefit
Hypertension in a patient who is not adequately controlled with
either of the drugs in the combination.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Telmisartan with amlodipine will provide an alternative choice of
an angiotensin II receptor antagonist/CCB combination product for
the treatment of hypertension in patients who have trialled and
failed monotherapy with either telmisartan or amlodipine.
6. Comparator
The submission nominated the individual equivalent strengths of the
two component products, telmisartan and amlodipine as monotherapies
which the PBAC considered appropriate.
For PBAC’s view, see Recommendation and
Reasons.
7. Clinical Trials
The basis of the submission was four direct randomised comparative
efficacy trials (BI 1235.5, BI 1235.6, BI 1235.13 and BI 1235.14)
and two bioequivalence trials comparing Twynsta with telmisartan
and amlodipine in individual equivalent strengths. All the efficacy
trials had run-in phases with amlodipine or telmisartan. Only
patients not responding to monotherapy entered the double-blind
phases of the trials.
The key trial which was published at the time of submission is
shown in the table below:
| Trial ID/ First author | Protocol title/ Publication title | Publication citation |
| Direct randomised trials | ||
| BI 1235.5 Neldam S et al | Fixed dose combination therapy with telmisartan and amlodipine 5mg in non-responders to amlodipine 5mg provides superior blood pressure reductions to, and is better tolerated than, amlodipine, 10mg. | J of Clinical Hypertension, 2009; (11) Suppl A A129 Abstract P-279. |
8. Results of Trials
Trial BI 1235.5 (amlodipine 5 mg run – in phase)
The PBAC noted the addition of telmisartan (T) 40 mg and 80 mg to
amlodipine (A) 5 mg produced statistically significantly larger
reductions in trough seated diastolic blood pressure (DBP) than
amlodipine 5 mg alone (-3.6 and -4.9 mmHg for the combinations
T40/A5 and T80/A5, respectively). The lower bound of the 95%
confidence intervals around these differences (-2.4 for T40/A5,
-3.7 for T80/A5) indicated additional reduction in blood pressure
of greater than 2 mm Hg with the addition of telmisartan 40 mg or
80 mg.
The PBAC also noted the addition of telmisartan 40 mg and 80 mg
produced statistically significantly greater changes from baseline
in trough seated DBP compared to amlodipine 10 mg alone (-1.4 and
-2.7 mmHg for T40/A5 and T40/A10 respectively). However, the lower
bound of the 95% confidence interval for the differences in both
cases was less than 2 mm Hg and therefore the combinations (T40/A5
and T80/A5) did not demonstrate a clinically important larger BP
reduction than amlodipine 10 mg. Amlodipine 10 mg was associated
with more reports of oedema than T40/A5 and T80/A5 combined (27.2%
vs 4.3%).
Trial BI 1235.6 (amlodipine 5 mg, 10 mg run-in phase)
The primary outcome was mean change in trough seated diastolic
blood pressure from baseline. Only amlodipine 10 mg is compared in
the main trial.
The PBAC noted both fixed dose combinations (FDCs) (T40/A10 and
T80/A10) were associated with trough DBP reductions that were
statistically significantly greater than those achieved with A10
monotherapy, with additional blood pressure reductions of -2.8 mm
Hg (95% CI -3.8, -1.8) in each case. The lower bound of the 95% CI
suggests blood pressure reduction of -1.8 mm Hg, just below the
clinically important difference of 2 mm Hg.
Trial BI 1235.13 (amlodipine 5 mg run- in phase)
The primary endpoint is mean change from baseline in trough seated
diastolic blood pressure.
The PBAC noted combination therapy with T40/A5 achieved
significantly greater reduction in DBP than those receiving
amlodipine 5 mg alone. This difference was both statistically
significant (5.11 mm Hg, 95% CI: 3.98, 6.23) and clinically
important.
Trial BI 1235.14 (telmisartan 40 mg run-in phase)
The primary endpoint is change from baseline in trough seated
DBP.
The PBAC noted patients treated with T40/A5 had a mean reduction in
DBP from baseline of 13.49 mm Hg compared to those receiving T40
who had a reduction of 5.47 mm Hg. This difference, 8.02 mm Hg, was
both statistically significant and clinically important (95% CI:
6.41, 9.63).
Meta-Analysis of change from baseline in trough seated DBP – T40/A5 vs. A5:
A meta-analysis for the primary endpoint of the mean change from
baseline in DBP was conducted for trials BI 1235.5 and BI
1235.13.
The PBAC noted the pooled estimate of treatment effect was an
additional reduction in trough seated BP of 4.32 mm Hg with the use
of the T40/A5 combination compared to
A5 alone (-4.32 mm Hg, 95% CI -5.69, -2.96).
The secondary endpoints included the change in trough seated
systolic blood pressure (SBP) from baseline, trough seated DBP and
SBP control and trough seated DBP and SBP response. For all
secondary endpoints, the telmisartan/amlodipine combinations were
more effective than telmisartan or amlodipine alone.
For PBAC’s view, see Recommendation and
Reasons.
The most frequently reported adverse event (AE) in the clinical
trials was peripheral oedema. Patients with AEs that led to
discontinuation were higher in the A10 group (7.6%) compared to any
other treatment group.
9. Clinical Claim
The submission described the administration of telmisartan with
amlodipine fixed-dose combination as “at least no worse
than” telmisartan and amlodipine administered individually in
terms of comparative effectiveness and comparative safety.
The PBAC considered this reasonable based on the supporting
data.
10. Economic Analysis
The submission presented a cost minimisation analysis, with the
proposed FDCs equi-effective to their monotherapy components on a
milligram for milligram basis.
11. Estimated PBS Usage and Financial Implications
The financial savings/year to the PBS was estimated by the
submission to be less than $10 million in Year 5.
12. Recommendation and Reasons
The PBAC recommended listing telmisartan with amlodipine (as
besylate), tablets
40 mg – 5 mg, 40 mg – 10 mg, 80 mg – 5 mg and 80
mg – 10 mg on the PBS as a Restricted Benefit for
hypertension in a patient who is not adequately controlled with
either of the drugs in the combination, in accordance with the
Combination Product Guidelines, on a cost-minimisation basis
compared with the corresponding strengths of the constituent
components, telmisartan and amlodipine, given concomitantly.
The PBAC considered that the data presented in the submission
adequately demonstrate that telmisartan/amlodipine combinations
produce additional blood pressure reductions over amlodipine and
telmisartan alone, and for most comparisons the differences are
statistically significant and clinically important.
The PBAC noted that PBS listing was unlikely to increase
utilisation in the market, rather, it would provide an additional
treatment choice to the currently listed angiotensin-II receptor
antagonist with calcium channel blocker combination products.
The PBAC recommended that telmisartan with amlodipine is suitable
for inclusion in the PBS medicines for prescribing by nurse
practitioners within collaborative arrangements.
Recommendation:
TELMISARTAN with AMLODIPINE, tablet, 40 mg – 5 mg, 40 mg
– 10 mg, 80 mg - 5 mg and 80 mg – 10 mg (as
besylate)
Restriction:
Restricted Benefit
Hypertension in a patient who is not adequately controlled with either of the drugs in the combination.
Max qty: 28
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 further comment.
