Escitalopram oxalate, tablets, 10 mg and 20 mg (base), Lexapro - SAD, March 2008
Public summary document for Escitalopram oxalate, tablets, 10 mg and 20 mg (base), Lexapro - SAD, March 2008
Page last updated: 04 July 2008
Public Summary Documents
Product: Escitalopram oxalate, tablets, 10 mg and 20 mg (base), Lexapro
Sponsor: Lundbeck Australia Pty Ltd
Date of PBAC Consideration: March 2008
1. Purpose of Application
To seek an extension to the restricted benefit listing of escitalopram to include social anxiety disorder (social phobia; SAD).
2. Background
At the September 2003 meeting, the PBAC recommended listing escitalopram on a cost-minimisation
basis with citalopram for the treatment of major depressive disorders, with escitalopram
10 mg being equivalent to citalopram 20 mg and escitalopram 20 mg being equivalent
to citalopram 40 mg. Escitalopram was listed as a PBS item on 1 February 2004.
At the March 2007 meeting, the PBAC rejected a combined submission seeking an extension
to the listing of escitalopram to include social anxiety disorder (social phobia)
and generalised anxiety disorder because of uncertain cost-effectiveness. The PBAC
acknowledged that, in the most severe forms, these conditions are debilitating and
serious but considered there is potential for overuse of these drugs.
3. Registration Status
Escitalopram was registered by the TGA on 16 September 2003 and is indicated for:
- Treatment of major depression.
- Treatment of social anxiety disorder (social phobia).
- Treatment of generalised anxiety disorder.
- Treatment of obsessive-compulsive disorder.
The TGA registered indications were extended to include treatment of social anxiety disorder on 19 September 2005.
4. Listing Requested and PBAC’s View
Restricted benefit
For the treatment of moderate to severe social anxiety disorder (social phobia; SAD),
as defined by DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth
Edition).
See Recommendation and Reasons for PBAC’s view.
5. Clinical Place for the Proposed Therapy
Individuals with Social Phobia experience concerns about many or most social situations,
especially those involving social interaction. They almost always experience symptoms
of anxiety (e.g. palpitations, tremors, sweating, diarrhoea, muscle tension, blushing,
and confusion) and in severe cases, these symptoms may meet the criteria for a Panic
Attack. They recognise that the fear is excessive or unreasonable but will typically
avoid feared situations.
Escitalopram would provide a treatment option for social anxiety disorder.
6. Comparator
The re-submission nominated placebo as the main comparator. This was accepted by the PBAC as appropriate.
7. Clinical Trials
The re-submission presented three studies comparing escitalopram and placebo. All
studies were double-blind, randomised, controlled, multicentre, parallel-group direct
comparisons. The re-submission also provided a meta-analysis for studies 99012 and
99270.
Details of the trials published at the time of submission are shown in the table below.
|
Trial ID |
Protocol title/ Publication title |
Publication citation |
|---|---|---|
|
99270 |
Efficacy and tolerability of escitalopram in 12- and 24-week treatment of social anxiety disorder: Randomised, double-blind, placebo-controlled, fixed-dose study. |
Depression and Anxiety 2004; 19(4):241-248. |
|
99012 |
Escitalopram in the treatment of social anxiety disorder: Randomised, placebo-controlled, flexible-dosage study. |
British Journal of Psychiatry 2005; 186(MAR.):222-226. |
|
99269 |
A 24-week randomized, double-blind, placebo-controlled study of escitalopram for the prevention of generalized social anxiety disorder. |
Journal of Clinical Psychiatry 2005; 66(10):1270-1278. |
8. Results of Trials
The primary outcome of trials 99270 and 99012 was the difference in the mean improvement
from baseline to study endpoint in the Leibowitz Social Anxiety Scale (LSAS) Total
Score. This was a key secondary outcome in relapse prevention Study 99269. An improvement
of at least 10 points on the LSAS has been suggested as showing a clinically relevant
improvement. The key results are summarised in the table below.
Results of primary outcome: (adjusted mean change in LSAS total score, LOCF) -Escitalopram
versus placebo
|
99270 |
99012 |
99269 |
||
|---|---|---|---|---|
|
ESC 10mg |
ESC 20mg |
Escitalopram |
Escitalopram |
|
|
Week 12 |
-5.07 |
-10.31 |
-7.29 |
-10.97 |
|
Week 24 |
-7.45 |
-15.09 |
-12.82 |
|
|
Meta analysis (Week 12) |
-8.74 (-12.60, -4.89) |
|||
The mean change in LSAS total score for escitalopram 10 mg was -5.07 (at week 12)
and
-7.45 (at week 24), and for escitalopram 20 mg was -10.31(at week 12) and -15.09 (at
week 24) for study 99270, -7.29 for study 99012 and -10.97 (at week 12) and -12.82
(at week 24) for study 99269.
The PBAC noted that although the meta-analysis of the primary outcome, adjusted mean
change in LSAS mean score, (meta-analysis of studies 99270 & 99012, mean change -8.74
(95% CI -12.60, -4.89) did not meet the clinically significant difference of 10 points
at week 12, secondary outcomes at the 24 week time point showed a significantly greater
response to therapy (based on significant improvements in the percentage of patients
with a >50% reduction in LSAS, Clinical Global Impression - Improvement (CGI-I) scores,
and Clinical Global Impression – Severity (CGI-S) scores).
The results of the relapse prevention study 99269 showed twice as many patients in
the placebo group relapsed as compared to escitalopram.
Results of primary outcome: Analysis of time to relapse (Study 99269)
|
Treatment |
n / N (%) |
No. of relapses |
% Relapsed |
Mean survival days |
|---|---|---|---|---|
|
Escitalopram |
190/190 (100) |
42 |
22.1 |
135.3 |
|
Placebo |
181/182 (99.5) |
91 |
50.3 |
103.5 |
The re-submission presented new toxicity data. The re-submission stated that the comparative
safety of escitalopram is similar/non-inferior to placebo. The key results are summarised
in the table below.
Summary results of secondary safety outcomes for meta-analysis
|
Outcome – meta-analyses * |
Escitalopram |
Placebo |
Relative Risk (95%CI) |
|---|---|---|---|
|
Total withdrawals |
75/351 |
71/343 |
1.03 (0.77, 1.37) |
|
Withdrawals - lack of efficacy |
13/351 |
31/343 |
0.41 (0.22, 0.77) |
|
Withdrawals – adverse events |
34/351 |
16/343 |
2.08 (1.17, 3.69) |
|
Treatment emergent Adverse events |
266/351 |
192/343 |
1.35 (1.21, 1.51) |
* 99270 and 99012
The meta-analysis results for Studies 99270 and 99012 showed more withdrawals due
to adverse events and treatment emergent adverse events in the escitalopram arm compared
with placebo.
The PBAC accepted escitalopram to be reasonably well tolerated with a higher adverse
event withdrawal rate than placebo.
9. Clinical Claim
10. Economic Analysis
A modelled economic evaluation was presented. The PBAC considered this approach was
appropriate. The economic model was a decision tree, with an appropriate structure.
Health outcomes were based on state- or treatment-specific utilities and the amount
of time spent in the state or treatment. Costs were based on resource use, drugs and
GP and specialist visits, but the main driver of the costs in the model are number
of visits.
The re-submission estimated the incremental cost per extra Quality-Adjusted Life-Year
(QALY) gained to be less than $15,000.
The PBAC noted a number of criticisms of the economic model. However, the PBAC considered
that irrespective of some of the identified issues with the model, the cost of the
intervention is reasonable value for money in the context, and while the incremental
cost-effectiveness ratio (ICER) predicted by the model may not be accurate, the sensitivity
analyses indicated a high probability that the ICER would be acceptable.
11. Estimated PBS Usage and Financial Implications
The re-submission estimated the expected number of escitalopram patients per year to be between 10,000 and 50,000 in Year 5. The net cost to the PBS was estimated to be less than $10 million in Year 5.
12. Recommendation and Reasons
The PBAC recommended the listing of escitalopram for the treatment of moderate to
severe social anxiety disorder (SAD) at the benchmark price based on an acceptable
cost-effectiveness ratio compared to placebo.
The PBAC noted that although the meta-analysis of the primary outcome, adjusted mean
change in LSAS mean score, (meta-analysis of studies 99270 & 99012, mean change -8.74
(95% CI -12.60, -4.89) did not meet the clinically significant difference of 10 points
at week 12, secondary outcomes at the 24 week time point showed a significantly greater
response to therapy (based on significant improvements in the percentage of patients
with a >50% reduction in LSAS, CGI-I scores, % patients with CGI-I<2 and CGI-S scores).
During the hearing, the PBAC was advised the clinical place of escitalopram was in
the treatment of the more severe patient in whom non-pharmacological methods had not
been successful. Further, that treatment benefit was usually seen at 4 months and
with the 20 mg dose.
The PBAC noted that cognitive behavioural therapy (CBT) is now funded under the Medicare
Benefits Scheme and the management of SAD could be included in General Practitioner
Mental Health Care Plans offering a more structured approach to care than previously.
The PBAC recommended that the restriction for escitalopram should be limited to the
setting of these Plans or to psychiatrist prescribers.
The PBAC therefore considered that availability of escitalopram should be limited
to the severe or moderately severe patient in whom non-pharmacological treatment had
failed. However, “non-pharmacological treatment” need not be a formal external psychological
intervention and could be provided by the prescriber.
The PBAC noted a number of criticisms of the economic model. However, the PBAC considered
that irrespective of some of the identified issues with the model, the cost of the
intervention is reasonable value for money in the context and while it may not be
cost saving as predicted by the model, the sensitivity analyses indicated a high probability
that the ICER would be acceptable.
The PBAC requested that the National Prescribing Service undertake major work on the
indications of GAD and SAD.
Recommendation
ESCITALOPRAM OXALATE, tablets, 10 mg (base) and 20 mg (base).
Extend listing to include:
Restriction:
Restricted benefit
Moderate to severe social anxiety disorder (social phobia; SAD), as defined by Diagnostic
and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, in a
patient who has not responded to non-pharmacological therapy and for whom:
(a) a GP Mental Health Care Plan, as described under item 2710 of the Medicare Benefits
Schedule, has been prepared; or
who has been assessed by a psychiatrist.
Restricted benefit
Continuing PBS subsidised treatment, for moderate to severe social anxiety disorder
(social phobia; SAD), of a patient commenced on escitalopram prior to 1 March 2008.
Maximum quantity: 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.
