Escitalopram oxalate, tablets, 10 mg and 20 mg (base), Lexapro - GAD, March 08
Public summary document for Escitalopram oxalate, tablets, 10 mg and 20 mg (base), Lexapro - GAD, March 08
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 generalised anxiety disorder (GAD).
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.
4. Listing Requested and PBAC’s View
Restricted benefit
For the treatment of moderate to severe generalised anxiety disorder (GAD), 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
Generalised anxiety disorder (GAD) is characterised by chronic and uncontrollable
worrying and somatic anxiety such as tension, hypervigilance and insomnia. The sufferer
knows the worry is excessive or unrealistic but feels unable to control it. GAD is
associated with other psychiatric disorders.
Escitalopram would provide an alternative treatment option for generalised anxiety
disorders.
6. Comparator
The re-submission nominated benzodiazepines, particularly diazepam and oxazepam, and placebo as the main comparators. This was as previously advised by the PBAC.
7. Clinical Trials
An indirect comparison between escitalopram and benzodiazepines, using placebo as
a common comparator, was undertaken.
The re-submission presented six studies comparing escitalopram and placebo, and one
study comparing diazepam and placebo. All studies were double-blind, randomised, controlled,
multicentre, parallel-group direct comparisons. The re-submission also presented one
supportive, non-randomised, open-label extension study of the safety and efficacy
of escitalopram in GAD.
Details of the trials published at the time of submission are shown in the table below.
|
Trial/First Author |
Publication title |
Citation |
|---|---|---|
|
Escitalopram |
||
|
SCT-MD-07 |
Escitalopram in the treatment of generalised anxiety disorder: Double-blind, placebo controlled, flexible-dose study. |
Depression and Anxiety 2004; 19(4):234-240. |
|
99815 |
Escitalopram and Paroxetine in the treatment of generalized anxiety disorder (GAD). |
British Journal of Psychiatry 2006; 189:264-272. |
|
99769 |
Prevention of relapse in generalized anxiety disorder by escitalopram treatment. |
International Journal of Neuropsychopharmacology 2006;9(5):495-505. |
|
SCT-MD-17(MD-17) |
Safety and efficacy of escitalopram in the long-term treatment of generalized anxiety disorder |
Journal of Clinical Psychiatry 2005;66(11):1441-14465. |
|
Benzodiazepine |
||
|
Hackett |
A method for controlling for a high placebo response rate in a comparison of venlafaxine XR and diazepam in the short-term treatment of patients with generalised anxiety disorder. |
European Psychiatry, 2003. 18(4): 182-187. |
8. Results of Trials
The primary outcome of the trials was the difference in the mean improvement from
baseline to study endpoint in the Hamilton Anxiety Scale (HAM-A) Total Score. The
HAM-A is considered the gold standard scale for measuring the severity of illness
in patients with GAD.
The PBAC agreed that the clinical trial data presented demonstrate small, but statistically
significant, differences between escitalopram and placebo (1-3 points, meta-analysis
2 points) in the HAM-A score.
A summary of the meta-analyses of secondary outcomes (psychic symptoms – anxious mood,
psychic tension) at eight weeks was presented. The PBAC noted that there were significantly
improved outcomes in all key secondary efficacy outcomes at 8 weeks, favouring escitalopram.
The following table shows the results of relapse prevention study.
Summary of results relapse prevention study
|
Trial |
Rx |
n/N |
Baseline |
Time 1 (SD) |
Time 2 |
Mean |
Mean change T2 |
Diff Esc-Pbo (95%CI) P value |
|---|---|---|---|---|---|---|---|---|
|
Escitalopram 99769 relapse prevention study |
||||||||
|
Open label phasec |
Esc |
187 |
27.26 (4.15) |
8.37 (5.63) |
5.74 (3.06) |
-18.88 (7.16) |
-21.51 |
NR |
|
Randomised phased |
Esc |
186/187 (99) |
5.67 (2.88) |
7.78 (6.47) |
7.80 (7.31) |
2.12 |
2.13 |
T1 -5.96 (-7.54, |
Notes: c: In the open label phase the three treatment groups are: Esc = open label
phase responders later randomised to esc; Pbo=open label responders later randomised
to placebo; NonR=Non-responders in open label phase.
d: 99769 - baseline for double blind phase, difference esc vs placebo was calculated
by the re-submission as statistical analyses were not conducted for secondary outcomes.
NR=not reported; SD standard deviation.
In the relapse study (99769), time to relapse was the primary outcome and HAM-A total
score was a secondary outcome. Patients received 12 weeks of open-label therapy prior
to randomisation to escitalopram or placebo. A significant placebo response was observed
in the first 12 week open label period. At the end of 12 weeks, responders (HAM-A<10)
were randomly assigned to active drug or placebo for a minimum of 24 weeks additional
treatment. In this phase the HAM-A score in the placebo arm changed significantly
(from a mean of 5 to 13.8) indicating a worsening of the condition but the HAM-A score
in the active arm only changed from 5.7 to 7.8. Similarly, the relapse rate was 19%
in the escitalopram arm and 56% rate in the placebo arm, a difference which was statistically
significant (Chi-squared test, p<0.001) in favour of escitalopram.
The re-submission presented new toxicity data. In the escitalopram studies, there
was no difference in total withdrawals and withdrawals due to efficacy but there were
more withdrawals due to adverse events in the escitalopram arm compared with placebo
arm. There were no differences in the diazepam study.
9. Clinical Claim
The re-submission claimed that escitalopram is superior in terms of comparative effectiveness
and equivalent in terms of comparative safety over placebo, and that escitalopram
is equivalent in terms of comparative effectiveness and comparative safety over diazepam.
See Recommendation and Reasons for PBAC's view.
10. Economic Analysis
The re-submission presented a modelled economic evaluation. The PBAC considered that
this was appropriate.
The incremental cost per Quality-Adjusted Life-Year (QALY) gained was estimated in
the re-submission to be less than $15,000. The PBAC was advised of a number of uncertainties
with the economic model.
11. Estimated PBS Usage and Financial Implications
12. Recommendation and Reasons
The PBAC recommended the listing of escitalopram for the treatment of moderate to
severe generalised anxiety disorder (GAD) at the benchmark price based on an acceptable
cost-effectiveness ratio compared to placebo.
The PBAC agreed that the clinical trial data presented demonstrate small, but statistically
significant, differences between escitalopram and placebo (1-3 points, meta-analysis
2 points) in the HAM-A score. The PBAC noted the argument that other secondary outcomes
were also clinically meaningful. The PBAC further agreed that the significant difference
in HAM-A would extrapolate to patient relevant outcomes.
The Committee also noted that in the summary of the meta-analyses of secondary outcomes
at eight weeks (trial 99815 was at 12 weeks) there were significantly improved outcomes
in all key secondary efficacy outcomes, favouring escitalopram.
In the relapse study (99769), time to relapse was the primary outcome and HAM-A total
score was a secondary outcome. Patients received 12 weeks of open-label therapy prior
to randomisation to escitalopram or placebo. A significant placebo response was observed
in the first 12 week open label period. At the end of 12 weeks, responders (HAM-A<10)
were randomly assigned to active drug or placebo for a minimum of 24 weeks additional
treatment. In this phase the HAM-A score in the placebo arm changed significantly
(from a mean of 5 to 13.8) indicating a worsening of the condition but the HAM-A score
in the active arm only changed from 5.7 to 7.8. Similarly, the relapse rate was 19%
in the escitalopram arm and 56% rate in the placebo arm, a difference which was statistically
significant (Chi-squared test, p<0.001) in favour of escitalopram.
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. Patient improvement was expected by 4 months, and duration of treatment
could be up to 12 months during which time other co-morbidities (depression, alcohol
and drug abuse) could be addressed.
The PBAC noted that cognitive behavioural therapy (CBT) is now funded under the Medicare
Benefits Scheme and the management of GAD 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 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 recommended that the restriction
for escitalopram should include an acceptable severity scale and score threshold capable
of accurately determining moderate to severe GAD.
The PBAC noted a number of uncertainties in the model, however, notwithstanding the
issues the PBAC accepted that the use of this drug in severe GAD would yield a relatively
low ICER and could be cost saving if the outcomes on costs i.e. medical visits are
realised.
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 generalised anxiety disorder (GAD), 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
(b) who has been assessed by a psychiatrist.
Restricted benefit
Continuing PBS subsidised treatment, for moderate to severe generalised anxiety disorder
(GAD), 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.
14. Sponsor’s Comment
Lundbeck Australia welcomes the PBAC’s decision to recommend Lexapro for listing on
the PBS for the treatment of Generalised Anxiety Disorder.
