Duloxetine Hydrochloride, capsules, 30 mg and 60 mg (base), Cymbalta, March 2008
Public summary document for Duloxetine Hydrochloride, capsules, 30 mg and 60 mg (base), Cymbalta, March 2008
Page last updated: 04 July 2008
Public Summary Documents
Product: Duloxetine Hydrochloride, capsules, 30 mg and 60 mg (base), Cymbalta
Sponsor: Eli Lilly Australia Pty Ltd
Date of PBAC Consideration: March 2008
1. Purpose of Application
The submission sought a restricted benefit listing for treatment of major depressive disorder (MDD).
2. Background
Duloxetine was first considered by the PBAC at its meeting in July 2007. The Committee rejected the submission because it had failed to demonstrate that duloxetine was non-inferior to the comparator, venlafaxine, in terms of effectiveness and because of uncertainty about its comparative safety.
3. Registration Status
Duloxetine was TGA registered on 14 March 2007 for the treatment of major depressive disorder (MDD).
4. Listing Requested and PBAC’s View
Restricted benefit
Major depressive disorders
The PBAC had no objections to the requested wording of the restriction.
5. Clinical Place for the Proposed Therapy
Duloxetine would provide an alternative serotonin-noradrenaline reuptake inhibitor (SNRI) for the treatment of major depressive disorder.
6. Comparator
7. Clinical Trials
As in the previous submission, two multicentre, randomised, double blind, parallel
controlled trials comparing 60-120 mg duloxetine and 75-225 mg venlafaxine over a
12 week period (HMBU and HMBQ) were presented. The trials were designed a priori to
be pooled. Non-inferiority assessment and additional analyses of the trial data using
a mixed-model repeated measures (MMRM) approach are presented in the re-submission.
Details of the trials presented in the re-submission are shown in the table below.
|
Trial/First author |
Protocol title |
Publication citation |
|---|---|---|
|
HMBU |
||
|
Perahia D et al, 2006 |
Comparing Duloxetine and Venlafaxine in the Treatment of Major Depressive Disorder using a Global Benefit-Risk Approach. |
New Clinical Drug Evaluation Unit (NCDEU) Conference June 6-9, 2005; Boca Raton, FL. |
|
HMCQ |
||
|
Perahia D et al, 2005 |
Comparing Duloxetine and Venlafaxine in the Treatment of Major Depressive Disorder using a Global Benefit-Risk Approach |
New Clinical Drug Evaluation Unit (NCDEU) Conference June 6-9, 2005; Boca Raton, FL. |
|
Perahia D et al, 2008 |
A randomized, double-blind comparison of duloxetine and venlafaxine in the treatment of major depressive disorder. |
Journal of Psychiatric Research. 42(1):22-34, Jan 2008 |
8. Results of Trials
The focus of the re-submission was determining non-inferiority of duloxetine over
venlafaxine using overall mean change from baseline to endpoint on HAMD17 (17-item
Hamilton Rating Scale for Depression) total scores at 6 and 12 weeks.
The key results are summarised in the tables below.
Mean change in HAMD17 total scores from baseline to endpoint (pooled data):
|
Population |
Duloxetine |
Venlafaxine |
||||||
|---|---|---|---|---|---|---|---|---|
|
N |
Baseline |
Endpoint |
Change |
N |
Baseline |
Endpoint |
Change |
|
|
Study Period II (weeks 1-6) |
||||||||
|
ITT |
318 |
22.70 (3.66) |
11.94 (7.23) |
-10.76 (6.99) |
330 |
22.69 (3.37) |
11.20 (6.78) |
-11.49 (6.53) |
|
PP |
244 |
22.71 (3.68) |
10.94 (6.96) |
-11.77 (6.49) |
272 |
22.71 (3.42) |
10.47 (6.54) |
-12.24 (6.25) |
|
Study Period II/III (weeks 1-12) |
||||||||
|
ITT |
318 |
22.70 (3.66) |
10.08 (7.64) |
-12.62 (7.62) |
330 |
22.69 (3.37) |
9.10 (7.01) |
-13.58 (6.75) |
|
PP |
231 |
22.74 (3.72) |
8.54 (7.06) |
-14.21 (6.81) |
250 |
22.65 (3.41) |
7.90 (6.44) |
-14.76 (6.18) |
Abbreviations: HAMD17: 17-item Hamilton Rating Scale for Depression; ITT: intent-to-treat;
PP: per-protocol.
Difference of Least Squares Mean change (Duloxetine-Venlafaxine) in HAMD17 Total Score
for Study Period II and II/III (pooled data):
|
Method |
Population |
LS Mean Difference (95%CI) |
P-value from 1-sided 97.5% CI for non-inferiority |
|---|---|---|---|
|
LOCF II |
ITT |
0.74 (-0.24, 1.72) |
0.2061 |
|
PP |
0.51 (-0.54, 1.55) |
0.1139 |
|
|
LOCF II/III |
ITT |
0.79 (-0.33, 1.91) |
0.2643 |
|
PP |
0.66 (-0.45, 1.77) |
0.1935 |
|
|
MMRM II |
ITT |
0.04 (-0.70, 0.77) |
0.0014 |
|
PP |
0.15 (-0.66, 0.96) |
0.0078 |
|
|
MMRM II/III |
ITT |
0.12 (-0.62, 0.86) |
0.0031 |
|
PP |
0.24 (-0.57, 1.05) |
0.0141 |
Abbreviations: HAMD17: 17-item Hamilton Rating Scale for Depression; LOCF: Last Observation
Carried Forward (ANCOVA analysis); MMRM:- mixed-model repeated measures; ITT: intent-to-treat;
PP:– per-protocol.
In the July 2007 submission, an ANCOVA last observation carried forward (LOCF) analysis
was used to compare mean change in HAMD17 total scores from baseline to endpoint in
the two treatment groups. The re-submission stated that the results of the ANCOVA
LOCF analyses are inconclusive in determining non-inferiority of duloxetine over venlafaxine.
This is because the LOCF approach underestimates differences which would produce a
result that is less conservative in a non-inferiority test. However, the re-submission
claimed that using the MMRM overall mean estimate clearly demonstrates that duloxetine
is non-inferior compared to venlafaxine on the HAMD17 total score, as the upper bound
of the 97.5% one-sided CI meets the pre-specified non-inferiority margin of 1.15 in
all study periods and populations analysed.
The MMRM approach was accepted by the PBAC as providing a more valid estimate of the
true difference between duloxetine and venlafaxine compared with the last observation
carried forward (LOCF) values, because the outcome values from all time points are
used.
Serious adverse events were reported in five (1.5%) venlafaxine-treated patients compared
with one (0.3%) duloxetine-treated patient.
The most frequently reported treatment-emergent adverse events in both treatment groups
were nausea, headache, dry mouth, constipation, excessive sweating, and dizziness.
Statistically significantly more duloxetine patients reported incidences of nausea
(43.6% vs. 35.0%) and dizziness (16.1% vs. 10.4%) in study period II (first 6 weeks
of treatment). The maximum reported severity of nausea was statistically significantly
higher with duloxetine (mild, 18%; moderate, 20%; severe, 6.1%) compared with venlafaxine
(mild, 20%; moderate, 13%; severe, 2.7%; p=0.022).
The re-submission also presented new toxicity data. There was no evidence presented
to suggest that duloxetine treatment has clinically relevant effects on heart rate,
blood pressure or ECG profiles in the patients who participated in the clinical trials.
There were no data presented to suggest an increased risk of hepatic toxicity when
taking duloxetine. The re-submission stated that duloxetine is well tolerated in long-term
use, and has a similar toxicity profile in elderly patients with major depressive
disorders (MDD) as in the general population of patients with MDD.
9. Clinical Claim
The re-submission described duloxetine as non-inferior in terms of comparative effectiveness over venlafaxine. It stated that there was a higher incidence of treatment emergent adverse events associated with duloxetine in the initial period of treatment, however this reduced with ongoing treatment. The PBAC considered this claim reasonable.
10. Economic Analysis
11.Estimated PBS Usage and Financial Implications
The submission estimated the likely number of patients per year to be over 200,000 in Year 5, and financial savings per year to the PBS to be between $10-30 million in Year 5.
12.Recommendation and Reasons
The PBAC recommended the listing of duloxetine on the PBS for major depressive disorders
on a cost-minimisation basis compared with venlafaxine and that the equi-effective
doses are duloxetine 60 mg and venlafaxine 150 mg, noting that the submission’s lower
proposed price for the 60 mg capsule is acceptable.
The PBAC considered the claim that duloxetine was non-inferior to venlafaxine with
a higher incidence of treatment emergent adverse effects as reasonable.
The PBAC considered that the 30 mg capsules should have no repeats as the 30 mg dosage
is mainly used for titration purposes and therefore repeats cannot be justified. No
evidence was presented that indicated the 30 mg dose had efficacy in addition to the
use for titration.
Recommendation
DULOXETINE HYDROCHLORIDE, capsules, 30 mg and 60 mg (base)
Restriction: Restricted benefit
Major depressive disorders.
Maximum quantity:28 (30 mg and 60 mg)
Repeats: Nil (30 mg)
5 (60 mg)
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.
