Escitalopram, tablet 10 mg (base), tablet 20 mg (base), oral solution 10 mg (base) per mL, Lexapro®, March 2007
Public summary document for Escitalopram, tablet 10 mg (base), tablet 20 mg (base), oral solution 10 mg (base) per mL, Lexapro®, March 2007
Page last updated: 13 July 2007
Public Summary Document
Product: Escitalopram, tablet 10 mg (base), tablet
20 mg (base), oral solution 10 mg (base) per mL, Lexapro®
Sponsor: Lundbeck Australia Pty Ltd
Date of PBAC Consideration: March 2007
1. Purpose of Application
To seek an extension to the listing of escitalopram to include
social anxiety disorder (social phobia) (SAD) and generalised
anxiety disorder (GAD).
2. Background
Escitalopram was originally considered by the PBAC at its September
2003 meeting. The PBAC recommended listing 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.
3. Registration Status
The TGA-registered indication for escitalopram was extended on 19
September 2005 to include “the treatment of Social Anxiety
Disorder (Social Phobia), and for the treatment of Generalised
Anxiety Disorder in adults”.
4. Listing Requested and PBAC’s View
Restricted benefit
Social anxiety disorder (social phobia);
Generalised anxiety disorder.
- Tablet 10 mg (base); tablet 20 mg (base)
Special Pharmaceutical Benefits
Restricted benefit
Social anxiety disorder (social phobia);
Generalised anxiety disorder.
- Oral solution 10 mg (base) per mL
See Recommendation and Reasons for the PBAC’s
view
5. Clinical Place for the Proposed Therapy
A treatment for social and generalised anxiety disorders.
6. Comparator
The submission nominated paroxetine as the comparator. There are
currently no therapies on the PBS for SAD or GAD. Paroxetine has
TGA approval for SAD/GAD and was considered by the submission to be
the most commonly prescribed treatment for both indications in
general practice. Sertraline (SAD) and venlafaxine (SAD and GAD)
are also TGA-approved and could also be comparators.
See Recommendations and Reasons for the PBAC’s
view.
7. Clinical Trials
Social Anxiety Disorder (SAD): A single randomised trial comparing
fixed doses of escitalopram (5, 10 and 20 mg/day), paroxetine (20
mg/day) and placebo in adult patients with SAD over 24 weeks.
Generalised Anxiety Disorder (GAD): The basis of the submission was
a meta-analysis of two randomised trials, one flexible dose, direct
(head to head), comparison of escitalopram (10-20 mg) and
paroxetine (20-50 mg/day) in adult patients with GAD over 24 weeks,
and one trial comparing fixed doses of escitalopram (5, 10 and 20
mg/d), paroxetine (20 mg/d) and placebo in adult patients with GAD
over 12 weeks.
The trials have been published at the time of submission as
follows:
| First author | Protocol title | Publication citation |
| Lader et al (2004) (Trial 99570) | 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; 19:241-8. |
| Bielski et al (2005) (Trial SCT-MD-10) | A double-blind comparison of escitalopram and paroxetine in the long-term treatment of generalised anxiety disorder. | Annals of Clinical Psychiatry 2005; 17(2):65-9 |
| Baldwin DS et al (2006) (Trial 99815) | Escitalopram and paroxetine in the treatment of generalised anxiety disorder. | British Journal of Psychiatry 2006, 189:264-272. |
The PBAC noted, that although the product information stated that
long term treatment is necessary, the duration of the trials was
relatively short (12-24 weeks).
8. Results of Trials
The results of the key trials are summarised in the tables below.
SAD: Confidence intervals for differences in clinical efficacy (escitalopram 5 mg,
10 and 20 mg vs paroxetine 20 mg (week 24): trial 99270
| ESC 5 vs PAR 20 | ESC 10 vs PAR 20 | ESC 20 vs PAR 20 | ||||
| Estimate | 95%CI | Estimate | 95%CI | Estimate | 95%CI | |
| LSAS total score | 1.80 | -3.96, 7.56 | 2.19 | -3.73, 8.12 | -7.68 | -13.43, -1.93 |
| LSAS fear & anxiety | 1.07 | -1.88, 4.03 | 1.23 | -1.82, 4.28 | -3.76 | -6.72, -0.81 |
| LSAS avoidance | 0.55 | -2.47, 3.57 | 1.03 | -2.10, 4.15 | -4.10 | -7.12, -1.08 |
| CGI-S | 0.12 | -0.16, 0.41 | 0.07 | -0.22, 0.36 | -0.35 | -0.63, -0.07 |
| CGI-I | 0.00 | -0.21, 0.22 | 0.04 | -0.18, 0.26 | -0.29 | -0.51, -0.08 |
PBO = placebo; PAR = paroxetine; ESC=escitalopram; LSAS = Liebowitz Socal Anxiety
Scale; C
GI-S = Global Clinical Impresssion Severity Scale; CGI-I = Global Clinical Impression
Improvement Scale
The 95% confidence intervals fall within the post-hoc specified range of -10 to +10
on the LSAS total score (primary efficacy endpoint). Based on these results, the submission
claimed that escitalopram 5 mg and 10 mg were of equivalent efficacy to paroxetine
20 mg. Escitalopram 20 mg was claimed to be superior to paroxetine 20mg. However,
the PBAC noted the post-hoc measure of equivalence was considered invalid. Trial 99270
was designed and statistically powered to test the superiority of escitalopram versus
placebo in the total LSAS score at week 12 (LOCF). The trial was not designed to estimate
equivalence (or non-inferiority). The paroxetine trial arm was included in its lowest
recommended dose as an active control.
A meta-analysis was conducted including trial SCT-MD-20 and a subset of patients from
trial 99815 who received escitalopram 10 mg/d and paroxetine 20 mg/d. The results
of the meta-analysis are shown in the following table.
GAD: Results of meta-analysis of studies SCT-MD-20 and 99815a
| Difference escitalopram vs paroxetine (95% CI) | ||||
| Parameter | Week 12 | p-value | End of study b | p-value |
| - HAMA total score | 2.12 (0.68, 3.56) | 0.0040 | 2.08 (0.62, 3.55) | 0.0054 |
| - CGI-S | 0.28 (0.06, 0.49) | 0.0131 | 0.31 (0.08, 0.54) | 0.0074 |
| - CGI-I | 0.33(0.13,0.54) | 0.0016 | 0.33(0.12, 0.55) | 0.0024 |
| Responders % | ||||
| -Paroxetine | 59.9 | 0.0201 | 60.9 | 0.0092 |
| - Escitalopram | 70.6 | 72.7 | ||
HAMA=Hamilton Anxiety Scale, CGI-S = Global Clinical Impresssion Severity Scale; CGI-I
= Global Clinical Impression Improvement Scale
a: Includes all patients from study SCT-MD-20 and patients treated with paroxetine
and escitalopram 10 mg from study 99815
b: Week 24 for study SCT-MD-20 and week 12 for study 99815
The submission claimed the results show that escitalopram was superior to paroxetine
for the treatment of GAD. The PBAC was advised it was not valid to claim superiority
with the meta-analytic method and results presented.
The PBAC noted that there was only limited discussion in the submission about what
might constitute a clinically important change on the LSAS and HAMA scales. The submission
stated that a 10 point difference on the LSAS scale was likely to be clinically significant,
but did not provide any further evidence to support this statement.
9. Clinical Claim
The submission claimed escitalopram was no worse than paroxetine in
terms of effectiveness or toxicity. On balance the PBAC accepted
escitalopram and paroxetine are likely to be of similar efficacy
and safety on the basis of dose relationship of 1:2, although the
clinical importance of the results achieved by either drug remains
unresolved.
10.Economic Analysis
A preliminary economic evaluation was presented. The choice of the
cost-minimisation approach was valid. The resources included were
drug costs of the mean daily doses of escitalopram and paroxetine
from trial SCT-MD-20.
See Recommendations and Reasons for PBAC’s
view.
11.Estimated PBS Usage and Financial Implications
The submission estimated the financial cost per year to the PBAC
would be less than $10 million.
12.Recommendation and Reasons
The PBAC acknowledged that, in the most severe forms, these conditions are debilitating and serious but agreed that in view of the potential overuse of these drugs, the following should be added to the restriction:
- restricted to allow use only after non-pharmacological methods have failed;
- entry criteria for the trials should be included as part of the listing, including a minimum LSAS score; and
- restricted to patients over 18 years of age.
The sponsor accepted this advice and had proposed that patients
should meet the DSM-IV criteria for these conditions to qualify for
treatment under the PBS.
The PBAC noted that there are currently no therapies on the PBS for
SAD or GAD. Paroxetine has TGA approval for SAD/GAD and is
considered by the submission to be the most commonly prescribed
treatment for both indications in general practice. Sertraline
(SAD) and venlafaxine (SAD and GAD) are also TGA-approved and could
also be comparators. Given that the first line treatments of
anxiety disorder are non-pharmacological (such as cognitive
behavioural therapy), the choice of paroxetine as a subsequent line
of therapy is probably reasonable as an appropriate comparator
according to the 2006 PBAC Guidelines as the therapy likely to be
replaced in practice. However, as the cost-effectiveness of
paroxetine is unknown in SAD or GAD, the comparison did not provide
PBAC with a basis for a recommendation to list escitalopram because
the cost-minimisation approach taken by the submission was not
sufficiently informative. Although it is acknowledged that
paroxetine is probably used to treat these conditions and thus
might form a useful frame of reference, a comparison would need to
be made with standard medical management to better inform the PBAC
about the cost effectiveness of both paroxetine and
escitalopram.
It was noted that, although the product information states that
long term treatment is necessary, the duration of the trials was
relatively short (12-24 weeks). The trial in SAD was also of only
24 weeks in duration and the PBAC thus considered that there was
uncertainty about the long-term effectiveness of escitalopram in
anxiety disorders.
The submission stated that a 10-point difference on the LSAS scale
is likely to be clinically important, but did not provide any
further evidence to support this statement. In the absence of
definitive information about what a clinically important difference
might be, it is not possible to confirm non-inferiority. The PBAC
considered that this was a critical issue to enable resolution of
whether or not the differences in the subjective scores can be
extrapolated to clinical outcomes. The PBAC also noted that placebo
also produced a 10-point improvement in the LSAS scores. The PBAC
was of the opinion that the claim of equivalence for SAD is based
on weak evidence. On the basis of a dose relativity of 1:2, the
difference between escitalopram and paroxetine is small and the
upper limit of the confidence interval is within a range of +/- 10
points in the LSAS score.
The fixed dose trial regimen in presented trials does not reflect
dose titration of the drug or comparator likely to occur in
clinical practice. In addition, paroxetine is included in the fixed
dose trials at the lowest recommended dose. The dose titration
study, which best reflects clinical practice showed no difference
between the two drugs in the management of GAD with a dose
relativity of 1:2, although the clinical importance of the results
achieved by either drug remains uncertain.
The PBAC also agreed that SAD and GAD are associated with
significant psychiatric co-morbidity (major depression, panic
disorder, specific phobia and post traumatic stress disorder) that
may necessitate a change in optimal pharmacological management.
Conversely, overlapping symptoms between discrete indications may
narrow treatment options. These issues were not adequately
addressed in the submission.
However, on balance, the PBAC accepted that escitalopram and
paroxetine are likely to be of similar efficacy and safety on the
basis of a dose relativity of 1:2. However, the issue of the
cost-effectiveness of either of these products remained
unresolved.
The PBAC thus rejected the submission because of uncertain
cost-effectiveness.
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 is disappointed with the outcome and we are working with the PBAC to resolve the issues and gain PBS listing of escitalopram for social and generalized anxiety disorders.
