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SECTION B 
 
B.2  Listing of all direct randomised trials 
 
B.2.1  Direct randomised trials: search results 
Table B.2.1 summarises the search results for direct randomised trials.  
 
UNDER 
1982 
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SECTION B 
 
Kasper et al, 2002a5 
 
Kasper S., Loft H., Smith JR., Escitalopram is well tolerated in the treatment of 
social anxiety disorder. Anxiety disorders association of America (ADAA). 
March 2002.  
Kasper et al 2002b6 
 
Kasper S., Loft H., Nil R., Escitalopram is well tolerated in the treatment of 
social anxiety disorder. Scandinavian College of Neuropsychopharmacology 
(SCNP), April 2002 
Kasper et al 2002c7 
 
Kasper S., Escitalopram is well tolerated in the treatment of social anxiety 
disorder. American Psychiatric association (APA), May 2002 
Kasper et al 2002d8 
 
Kasper S., Loft H., Nil R., Treatment of social anxiety disorder: Escitalopram is 
well tolerated and efficacious. Collegium Internationale Neuro-
Psychopharmacologicum (CINP), June2002 
UNDER 
Kasper et al 2002e9 
 
1982 
Kasper S., Loft H., Smith JR., Escitalopram is efficacious and well tolerated in 
ACT 
the treatment of SAD. Association of European Psychiatrists  (AEP), May 
RELEASED 
2002. 
99269  
Integrated Clinical Study Report: 
No 
BEEN  HEALTH 
A double-blind, randomised, placebo-controlled, flexible-to fixed-dose relapse 
New Study 
HAS 
OF 
prevention study with Lu 26-054 in Social Anxiety Disorde
INFORMATION r (Report No. 
226/311, 2000; dated 18 July 2002) 
OF 
Montgomery et al 200510: 
 
Montgomery SA, Nil R, Durr-Pal N, Loft H, Boulenger JP. A 24-week 
DOCUMENT 
randomized, double-blind, placebo-controlled 
DEPARTMENT study of escitalopram for the 
FREEDOM 
prevention of g
THIS  eneralized social anxiety disorder. Journal of Clinical Psychiatry 
THE  THE 
2005;66(10):1270-1278. 
BY 
Montgomery et al 200511: 
 
Relapse Prevention in Patients Suffering From Social Anxiety Disorder. 158th 
Annual Meeting of the American Psychiatric Association; 2005 May 21-26. 
 
 
All study details and results are taken from the Clinical Study Reports (rather than the 
published papers) as these contain the most comprehensive details and results for the 
studies.  The details reported in the cited published papers have been compared with 
the study reports and any discrepancies are detailed in the relevant part of Section B 
of the submission. 
 
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HAS INFORMATION 
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OF 
DOCUMENT 
FREEDOM 
DEPARTMENT 
THIS 
THE  THE 
BY 

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HAS INFORMATION 
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DOCUMENT 
FREEDOM 
DEPARTMENT 
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BY 

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SECTION B 
 
B.3   Assessment of the measures taken by investigators to 
minimise bias in the direct randomised trials 
 
Summary 
The three key studies were all studies providing the highest level of evidence.  They 
were randomised, double-blind, parallel-group, multicentre direct comparisons of 
escitalopram and placebo.  Randomisation was provided off-site by a third party, 
identical study product was provided for each group and patients, investigators and 
assessors were fully blinded treatment assignment.  Full details of the adequacy of 
randomisation and blinding are provided.  Intention-to-treat (last observation carried 
forward) analysis was used, with full details of patient follow-up provided. 
UNDER 
 
1982 
 
 
ACT 
RELEASED 
All the information provided in Section B.3 was sourced from the Clinical Study 
Reports for Study 99270, Study 99012 and Study 99269.   These reports are provided 
BEEN  HEALTH 
in electronic form on the CD-ROM labelled Clinical Study Reports and References.  
HAS INFORMATION 
OF 
Hard copies of the Study Reports are also provided. 
OF 
 
DOCUMENT 
B.3.1  Randomisation 
FREEDOM 
DEPARTMENT 
The patients in the studies were all randomised, following a run-in period.  As Study 
THIS 
THE  THE 
99269 was a relapse prevention study, all patients received open-label escitalopram 
BY 
for 12-weeks prior to randomisation.  With this type of study all patients have to 
receive treatment to allow them to respond to treatment so that the efficacy of the 
antidepressant agent with regard to relapse prevention can be compared to placebo in 
the double-blind phase of the study. 
 
Patients admitted to the double-blind period in all three studies were randomly 
allocated to either placebo or escitalopram according to a randomisation code 
generated by Lundbeck.  Randomisation numbers and study product were prepared, 
equally assigned to each treatment group (2 groups in 99269, 99012 and 5 groups in 
99270).  Block randomisation was used in all the studies, to ensure that equal numbers 
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SECTION B 
 
of patients entered each treatment group.  At each centre the 4-digit randomisation 
number was to be assigned consecutively, starting with the lowest number available. 
 
 
B.3.2  Blinding 
The studies were all double-blind.  The study products were encapsulated tablets for 
oral administration in Studies 99270 and 99269.  In Study 99012 identical active and 
placebo tablets were used.  Patients took either one or two tablets daily, equivalent to 
escitalopram 10mg or 20mg daily in the active group.  All tablets were oval, white, 
scored and film-coated (not specified in 99269).  All capsules were identical.  The 
randomisation code was not broken in Studies 99270 or 99012.  In Study 99269 the 
randomisation code was broken for one patient, after the patient had stoppe
UNDER 
d treatment 
with placebo. 
1982 
 
ACT 
RELEASED 
 
BEEN 
B.3.3  Adequacy of follow-up 
HEALTH 
 
HAS INFORMATION 
OF 
OF 
Studies 99270 and 99012 
The following analysis sets were defined a priori: 
DOCUMENT 
•  All-patients-randomised set (APRS) –
DEPARTMENT   all patients randomised into the study 
FREEDOM 
•
THIS 
  All-patients treated set (APTS) – all randomised patients who took at least one 
THE  THE 
dose of double-bli
BY  nd study product 
•  Full-analysis set (FAS) – all randomised patients who took at least one dose of 
double-blind study product and who had at least one post-baseline assessment 
of the LSAS total score  
•  Per-protocol set (PPS) – all randomised patients who had no major protocol 
violations (as pre-defined in the Statistical Analysis Plan), who received 
double-blind study product at least up to Week 4, and who had at least one 
post-baseline assessment of the LSAS total score at or after Week 4. 
 
All efficacy analyses were conducted on the FAS.  Note that the primary study 
outcome is a continuous variable and it is therefore necessary to have at least one 
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SECTION B 
 
post-baseline assessment to allow a valid result to be recorded for that patient.  All 
safety analyses were conducted on the APTS. 
 
In both studies all efficacy analyses, including the primary analysis of the change in 
LSAS total score over the study period was based on the FAS using last observation 
carried forward (LOCF).   
 
Study 99269 
The following analysis sets were defined a priori: 
•  All-patients treated set (APTS) – all patients enrolled in the open-label period 
who took at least one dose of study product 
•  All-patients-randomised set (APRS) – all patients randomise
UNDER  d into the study 
•  Full-analysis set (FAS) – all randomised patients who took a
1982  t least one dose of 
double-blind study product. 
ACT 
• 
RELEASED 
Per-protocol set (PPS) – all randomised patients in the FAS who did not 
relapse or withdraw at or before Day 7 and omitting all subsequent 
BEEN  HEALTH 
assessments for patients committing major protocol violations.  
HAS 
OF 
 
INFORMATION 
OF 
All efficacy analyses were conducted for the FAS and, when considered relevant, also 
for the PPS.  All safety analyses were based on the APTS and the FAS for the open-
DOCUMENT 
label and double-blind periods, respectively. 
FREEDOM 
DEPARTMENT 
 
THIS 
THE  THE 
The primary analysis of efficacy consisted of a log-rank test on the FAS comparing 
BY 
the time to relapse for the escitalopram and the placebo groups.  Actual treatment days 
were used in the analysis, which was supplemented with Kaplan-Meier plots. 
 
 
A summary of the measures taken to minimise bias in the key studies is presented in 
TableB.3.1.   
 
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SECTION B 
 
B.4  Characteristics of the direct randomised trials 
 
Summary 
This resubmission included two new studies: Study 99012 and 99269.  This meant 
that the effective duration of therapy for assessment was 48 weeks (24 weeks for 
Study 99270 and an additional 24 weeks from the relapse prevention study 99269); a 
total of 70 weeks of data for SAD patients on escitalopram.  s38
 
 
 
 
The key randomised, controlled studies (Study 99270, 99012 and 99269 all included 
UNDER 
patients diagnosed with moderate to severe SAD whose lives were severely disrupted 
1982 
because of fear and avoidance of normal social situations.  Patients did not have other 
psychiatric co-morbidities. 
ACT 
RELEASED 
 
The studies were all parallel group, randomised controlled trials of 12 week (Study 
BEEN  HEALTH 
99012) or 24 week (Study 99270) duration.  Study 99269 was a relapse prevention 
HAS INFORMATION 
OF 
study with patients receiving 12 weeks of open-label escitalopram, with responders 
OF 
then randomised to receive a further 24 weeks therapy with either escitalopram or 
placebo.  Patients were randomised to either a fixed dose of escitalopram or placebo 
DOCUMENT 
(Study 99270), or a flexible dose of escitalopra
DEPARTMENT  m dose (Study 99012 and 99269).  Full 
FREEDOM 
THIS 
details of the interventions received are presented in Section B.4.2, including details 
THE  THE 
of the actual escitalopram dos
BY 
es taken.   
 
The baseline characteristics of patients (age, sex, race, duration and onset of SAD) 
across the studies and in the treatment arms within studies were all similar.   
 
 
The characteristics of patients included in the key randomised, controlled trials are 
presented in Section B.4.  The eligibility criteria are detailed followed by the baseline 
demographic and clinical characteristics of the patients.  The study designs are 
explained, including the daily dose of the interventions received in each treatment 
group (escitalopram and placebo) and the duration of the trials.  All trials have been 
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SECTION B 
 
B.4.1  Selection of the study population 
The key studies included adult patients with SAD diagnosed based on DSM-IV 
criteria.  These patients had a Liebowitz Social Anxiety Score (LSAS) of 70 or more.  
The LSAS is designed to assess SAD through evaluation of fear and avoidance in 
social situations.  A minimum entry score of at least 70 in SAD investigational drug 
studies is recommended to ensure that patients have moderate to severe SAD 
(European College of Neuropsychopharmacology (ECNP) Guidelines, 200313).  For 
study inclusion patients also had to experience fear and avoidance in at least four 
distinct social situations (based on LSAS baseline scores) to ensure that patients had 
the more severe generalised form of SAD13. 
 
Patients were excluded from study entry if they suffered from other psychiatric 
UNDER 
disorders or co-morbidities.  While patients with SAD often do suffer from co-
1982 
morbidities such as alcohol/substance abuse and depression, it is usual to exclude or 
ACT 
control for the confounding variable (i.e. the co-morbidity) which may affect the 
RELEASED 
results.  The ECNP Guidelines recommend that “In all cases the primary diagnosis 
should be SAD and patients with other recent or 
BEEN  current psychiatric diagnoses should 
HEALTH 
be excluded”13.   
HAS INFORMATION 
OF 
 
OF 
The ECNP Guidelines further state that “In studies that include a putative or potential 
antidepressant, patients suffering from concomitant major depression as well as those 
DOCUMENT 
with a history of major depression over the pr
DEPARTMENT  evious 3-6 months, should be excluded.  
FREEDOM 
THIS 
Some “depressive symptoms”
THE   are part of SAD.  However current depressive 
THE 
symptoms should neverth
BY  eless be restricted to a mild level, with a maximum permitted 
score on a depression rating scale below that normally used to include patients into 
depression studies.  The results of these studies may then be generalisable to the 
population with SAD without concerns of an indirect effect via depression”13.  The 
Montgomery and Åsberg Depression Rating Scale (MADRS) was administered to 
patients in order to exclude patients with depression from the key studies. 
 
The inclusion and exclusion criteria for the direct randomised trials are presented in 
TableB.4.2. 
 
 
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DEPARTMENT 
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HAS INFORMATION 
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DOCUMENT 
FREEDOM 
DEPARTMENT 
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THE  THE 
BY 

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SECTION B 
 
B.4.3  Doses used in the clinical trials   
 
Study 99270 
Study 99270 used fixed doses of escitalopram or placebo as described in Table B.4.3. 
 
Study 99012 
There was a 1-week, single-blind run-in period with placebo, followed by a 12-week, 
double-blind treatment period with escitalopram or placebo.  The initial dose of 
escitalopram was 10mg daily.  At Week 4, 6 or 8 investigators had the option of 
doubling a patient’s dosage of study product from 10mg to 20mg, if his/her response 
had been unsatisfactory or if there was an aggravation of the disorder based on the 
Clinical Global Impression Severity (CGI-S) score.  Investigators could decrease the 
UNDER 
dosage to the original dosage at any time if there were adverse events. 
1982 
 
ACT 
The percentages of patients in each treatment group who had their dosage of study 
RELEASED 
drug doubled from 10 to 20mg at Week 4, 6 or 8 were 68% for the escitalopram group 
and 69% for the placebo group (APTS population, i
BEEN 
.e. all randomised patients who 
HEALTH 
took at least one dose of double-blind study product).  Of these, 4% of escitalopram-
HAS INFORMATION 
OF 
treated patients and 2% of placebo-treated patients had their dosage of study drug 
OF 
reduced to 10mg after dose increase.  The majority of patients had their dosage 
doubled at Week 4 (escitalopram 61%, placebo 65%).  (Source – Study Report 99012 
DOCUMENT 
p. 50 and Table 16).  TableB.4.4 below reports the
DEPARTMENT 
 mean daily doses used in each 
FREEDOM 
THIS 
treatment arm during the study
THE  .  At the end of the treatment period patients on 
THE 
escitalopram were taking
BY   a mean dose of 17.1mg daily. 
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SECTION B 
 
 
a) Study 99270 
This was a multicentre, fixed-dose, randomised, double-blind, placebo-controlled, 
active-reference study with five parallel treatment groups.  The study consisted of a 1-
week single-blind placebo run-in period after which patients were randomised in a 
(1:1:1:1:1 ratio) to 24 weeks of double-blind treatment with fixed doses of 
escitalopram (5, 10 or 20mg/day), paroxetine (20mg/day) or placebo.  The paroxetine 
arm results are not presented in this submission as it is not a comparator.  The 
escitalopram 5mg daily treatment results are also not presented, as this is not an 
approved dosage for SAD in Australia.  Patients who completed double-blind 
treatment entered a 2-week single-blind run-out period during which they received 
placebo.  The overall study design is presented in Figure B.4.1. 
UNDER 
 
1982 
Figure B.4.1: Overall study design (Study 99270) 
ACT 
 
RELEASED 
Placebo 
 
 
BEEN 
Paroxetine 20mg/day 
HEALTH 
 
HAS INFORMATION 
OF 
 
OF 
Placebo 
Escitalopram 5mg/day 
 
Placebo 
 
Run-in 
Run-out 
DOCUMENT 
DEPARTMENT 
 
E
FREEDOM scitalopram 10mg/day 
THIS 
 
THE  THE 
BY 
 
Escitalopram 20mg/day 
 
 
Week -1 
Weeks 1-24 
 
Weeks 25-26 
 
 
 
Rationale for study design: 
A double-blind, placebo controlled design is an expected design for investigating the 
efficacy and safety profile of a medication for this type of indication.  The duration of 
12 weeks for the acute treatment period was chosen since clinically and statistically 
significant improvements in SAD have been seen with other SSRIs within a 12-week 
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SECTION B 
 
treatment period14 15 16.  The treatment extension to 24 weeks was included to 
demonstrate whether the acute treatment effects were sustained, and to evaluate the 
response to therapy after an additional 12 weeks of treatment. 
 
A one-week, single-blind, placebo run-in period allowed for the exclusion of patients 
who responded (Clinical Global Impression – Improvement (CGI-I) score of 1 or 2) to 
placebo therapy as well as washout psychoactive medication, which had been taken 
prior to screening and which may have influenced social behaviour.  It also provided 
time for the assessment of clinical safety laboratory test results and 
electrocardiograms (ECGs). A two-week, single-blind, placebo run-out period was 
included to examine potential treatment withdrawal reactions.   
 
UNDER 
b) Study 99012 
1982 
This study was a multinational, randomised, double-blind, parallel-group, placebo 
ACT 
controlled flexible-dose study.  There was a one-week single-blind run-in period with 
RELEASED 
placebo, followed by a 12-week, double-blind treatment period with escitalopram or 
placebo.  The initial dose of escitalopram was 10
BEEN  mg daily.  At Week 4, 6 or 8 
HEALTH 
investigators had the option of doubling a patient’s dosage of study product from 10 
HAS INFORMATION 
OF 
to 20mg daily if his/her response had been unsatisfactory or if there was an 
OF 
aggravation of the disorder based on the Clinical Global Impression - Severity (CGI-
S) score.  Investigators could decrease the dosage to the original dosage at any time 
DOCUMENT 
DEPARTMENT 
after the increase in dosage if there
FREEDOM   was an adverse event.  
THIS 
 
THE  THE 
BY 
The overall study design is presented in Figure B.4.2. 
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SECTION B 
 
 
Figure B.4.2:Overall study design (Study 99012) 
 
Run-in 
Double-blind Period 
 
Period 
      12 Weeks 
 
1 Week 
 
Escitalopram 10 or 20mg dailya  
 
 
 
Placebo  
 
a.  All patients were dosed with 10mg/day at the start of the double-blind period.  The dose 
could be increased to 20mg/day at Week 4, 6 or 8. 
 
UNDER 
Rationale for study design: 
1982 
A double-blind, placebo-controlled design is the ‘gold standa
ACT  rd’ design for 
RELEASED 
investigating the efficacy and safety profile of a compound for this type of indication.  
The treatment duration of 12 weeks was chosen since clinically and statistically 
BEEN  HEALTH 
significant improvements in SAD have been seen with other SSRIs within a 12-week 
HAS INFORMATION 
OF 
treatment period14 15 16.  
OF 
 
The dose of 10-20mg/day of escitalopram was chosen since it was expected that it 
DOCUMENT 
would be equivalent to the dose range of 20-40mg/day of citalopram already shown to 
FREEDOM 
DEPARTMENT 
be effective in open-labe
THIS  l studies of this disorder (consistent with the PBPA 
THE  THE 
Therapeutic Relativities and the escitalopram Approved Product Information).  A 
BY 
placebo run-in period allowed both the opportunity to exclude patients who respond to 
placebo therapy to be excluded and washout psychoactive medication which had been 
taken prior to screening and which may influence social behaviour.  The one-week 
duration also provided time for assessment of laboratory test results and ECGs. 
 
 
b) Study 99269 
This multinational, multicentre study consisted of a 12-week open-label period with 
flexible doses of escitalopram doses and a 24-week randomised, double-blind, 
parallel-group, fixed dose comparison of escitalopram and placebo in the prevention 
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SECTION B 
 
of relapse of SAD.  Throughout the double-blind period the investigators evaluated 
relapse symptoms.  Relapse was defined either as a Liebowitz Social Anxiety Scale 
(LSAS) total score >10 points greater than that at randomisation; or as withdrawal of 
the patient from the study due to unsatisfactory treatment response (lack of efficacy), 
as judged by the investigator.  The overall study design is presented in Figure B.4.3. 
 
 
Figure B.4.3:Overall study design (Study 99269) 
 
Open-label Period 
Double-blind Period 
 
      12 Weeks 
      24 Weeks 
 
 
Escitalopram 10 or 20mg dailyb  
UNDER 
 
Escitalopram 10-20mg dailya   c
1982 
 
  
Placebo  
ACT 
 
RELEASED 
 
Visits 1 to 7  
 
Visits 8 to 16  
 
BEEN  HEALTH 
a.  All patients were dosed with 10mg/day at study start.  The dose could be increased to 
HAS INFORMATION 
OF 
20mg/day at Week 2, 4 or 8. 
OF 
b.  The patients remained on the dose to which they responded during the open-label period. 
c.  Response was defined as a score of 1 or 2 (very much or much improved) on the CGI-I 
scale.  Non-responders left th
DOCUMENT  e study. 
FREEDOM 
DEPARTMENT 
 
THIS  THE 
 
THE 
BY 
Rationale for study design: 
The open-label period was included to detect responders to escitalopram treatment.  
The duration of 12 weeks was chosen since clinically and statistically significant 
improvements in SAD have been seen within a 12-week period14 15 16.  The double-
blind, placebo-controlled design is widely accepted for examining relapse prevention.  
In addition, treatment of patients for a total of 9 months provides long-term 
tolerability and safety data.  
 
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SECTION B 
 
 
Summary of the key aspects of the identified trials 
While all three studies provide useful information on the overall efficacy of 
escitalopram, Study 99269 is a relapse prevention study and thus the design is 
markedly different to that of the other two studies.  Therefore, while the study is 
considered a key study and provides important information on whether patients 
continue to respond to escitalopram therapy, the results of this study cannot be 
combined to give an overall assessment of effect (i.e. meta-analysed) with the other 
two studies.  Full details of the meta-analysis undertaken are provided in Section 
B.5.3. 
 
 
UNDER 
B.4.5  Subject characteristics 
1982 
Subject characteristics in the treatments arms were generally similar, both within and 
ACT 
across studies.  The key subject characteristics are discusse
RELEASED  d below.  TableB.4.5 
presents the baseline characteristics of participants in the treatment arms in the three 
BEEN  HEALTH 
key direct randomised trials. 
HAS 
OF 
 
INFORMATION 
OF 
Age, Sex, Race 
Patients’ mean age in the different treatment groups in the 3 studies ranged from 36-
DOCUMENT 
39 years.  SAD has an early age of onset, of around 15 years of age and is usually 
FREEDOM 
DEPARTMENT 
associated with a long a 
THIS  particularly prolonged duration prior to diagnosis and 
THE  THE 
treatment with the prevalence of SAD tending to decline in the elderly13.  Generally, 
BY 
there was a higher prevalence of SAD in females.  From the literature review there 
was approximately a 1:5 to a 1:2 ratio or males to females (these figures vary from 
country to country: see Attachment 2).  In Australia the prevalence of SAD was 3% 
for females and 2.4% for males.17 
 
SAD onset 
The age of SAD onset was consistent in all of the studies and treatment arms within 
studies, ranging from 15-18 years.  This is also consistent with the age of onset 
generally reported13.  SAD usually develops in adolescence, though it may be many 
years later that patients are formally diagnosed.  As the mean patient age was 36-39 
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SECTION B 
 
years in the studies, the mean duration of SAD was 19-20 years.  The onset of SAD 
rarely occurs after the age of 25.18 
 
Level of impairment at baseline 
The mean LSAS total score ranged from 92 to 96.  In study 99270 the baseline LSAS 
values in the escitalopram 10mg group was numerically similar, but statistically 
significantly lower (p=0.028) than in the placebo group.  In the relapse prevention 
study (Study 99269), the patients’ mean baseline LSAS score prior to them receiving 
12 weeks of open-label escitalopram was similar to baseline values in the other 
studies.  After 12 weeks of open-label escitalopram therapy (i.e. prior to being 
randomised to receive 24 weeks of either escitalopram or placebo) the patients’ mean 
LSAS Total Score had significantly improved to around 42. 
UNDER 
 
1982 
The LSAS was used to assess the level of impairment of patients at baseline and the 
ACT 
efficacy of therapy with active treatment.  The maximum possible score is 144 of the 
RELEASED 
LSAS19.  Patients with SAD generally score above 50 points, whilst normal 
volunteers score below 30 points.  Scores betwe
BEEN  en 50-70 may be considered moderate 
HEALTH 
and are associated with distress while scores over 70, and particularly over 90, are 
HAS INFORMATION 
OF 
considered severe and are associated with functional impairment.  In the studies a 
OF 
score of greater than or equal to 82 on the LSAS is classified as severe SAD 
(LSAS>70 is considered severe), thus with a mean score of 92-96 points in the current 
DOCUMENT 
DEPARTMENT 
studies the patients are classified a
FREEDOM s having severe SAD associated  with functional 
THIS 
impairment. 
THE  THE 
BY 
 
The baseline MADRS total score was used to ensure that patients met the exclusion 
criteria of MADRS>18.  MADRS total scores were used to assess the level of 
depressive symptoms still present in the study population even though patients with 
major depressive disorder were excluded.  Patients in all groups and studies 
demonstrated a low level of depressive symptoms at baseline, based on the MADRS.  
In studies 99270 and 99012 all patient groups had a mean score of <8.  In Study 
99269 the mean scores were <4, as patients had received 12 weeks of open-label 
escitalopram at baseline. 
 
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SECTION B 
 
 
Source documents 
Data provided in this section is taken from the Study Reports provided.  Page and/or 
table references are provided under the tables or in text. 
UNDER 
1982 
ACT 
RELEASED 
BEEN  HEALTH 
HAS INFORMATION 
OF 
OF 
DOCUMENT 
FREEDOM 
DEPARTMENT 
THIS 
THE  THE 
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SECTION B 
 
B.5  Outcome measures and analysis of the direct randomised 
trials 
 
Summary 
The methods of analysis of the primary and secondary study outcomes are fully 
presented.  In studies 99270 and 99012 the primary outcome was mean change from 
baseline to study endpoint in the Liebowitz Social Anxiety Scale (LSAS).  This 
outcome was analysed using analysis of covariance (ANCOVA).  Study 99269 
investigated the relapse of patients following successful escitalopram therapy, with 
time to relapse as the primary study outcome. 
UNDER 
 
1982 
The LSAS is considered a gold standard, patient-relevant outcome in assessing the 
ACT 
impact of therapy in SAD.  s38
 
RELEASED 
 
BEEN 
  A change
HEALTH   of (minus) 10 points on 
the LSAS has been suggested in the liter
HAS  ature as sh
OF  owing a clinically relevant 
INFORMATION 
improvement.   
OF 
 
Other patient-relevant outcomes such a
DOCUMENT 
s changes in the Clinical Global Impression – 
FREEDOM 
DEPARTMENT 
Improvement (CGI-I) and Clinical Global Impression – Severity (CGI-S) scales, 
THIS  THE 
Sheehan Disability Sca
THE  le (SDS) and adverse event information are also reported in the 
BY 
studies and in this submission. 
 
Details of the meta-analyses undertaken for this submission are provided in this 
section and in Attachment 5.  Two of the three key studies (Study 99270 and 99012) 
have been meta-analysed to give an overall treatment effect at Week 12.  Due to 
significant differences in study design, the results of one study (Study 99269) cannot 
validly be meta-analysed with the other two and thus the results for this study are 
presented separately in Section B.6. 
 
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SECTION B 
 
The primary and secondary outcomes for the three key studies are presented in 
Section B.5.1 and B.5.2.  Full details of the analyses undertaken are provided, 
including the meta-analysis of two of the key trials.  The clinical importance of the 
outcomes measured in the trials is reviewed. 
 
 
B.5.1  Primary outcomes 
The primary outcomes, methods of statistical analysis and information on the sample 
size calculations in the three randomised, controlled trials are presented in TableB.5.1 
below.   
UNDER 
1982 
ACT 
RELEASED 
BEEN  HEALTH 
HAS INFORMATION 
OF 
OF 
DOCUMENT 
FREEDOM 
DEPARTMENT 
THIS 
THE  THE 
BY 
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SECTION B 
 
B.5.2  Secondary outcomes 
All secondary outcomes and the statistical analysis methods used in the three direct 
randomised, controlled trials are presented in Table B.5.2 below. 
 
The results of secondary outcomes not considered patient-relevant are not presented in 
this submission.  See Section B.5.3.3 for a full listing of patient-relevant secondary 
outcomes that are reported in Section B.6 in this submission (and meta-analysed if 
sufficient data is available).   
 
A full list of secondary outcomes that are not considered patient-relevant is also 
provided in Section B.5.3.3.  The results of all secondary outcomes are available in 
the individual Study Reports provided 
UNDER 
 
1982 
 
ACT 
RELEASED 
BEEN  HEALTH 
HAS INFORMATION 
OF 
OF 
DOCUMENT 
FREEDOM 
DEPARTMENT 
THIS 
THE  THE 
BY 
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SECTION B 
 
B.5.3  Analysis of the trial data 
A large number of primary and secondary outcomes have been analysed in the three 
key studies.  In addition, the results of patient-relevant outcomes have been meta-
analysed as described in Section B.5.3.2.  The primary and patient-relevant secondary 
outcomes have been meta-analysed (if sufficient data is available) and reported in this 
submission.   
 
 
B.5.3.1 
Analysis of the individual studies 
The method of analysis of the primary and secondary outcomes of the three key 
studies has been provided in Section B.5.2.  A large number of clinical outcomes were 
assessed.  The clinical importance of these outcomes is discussed in Section B.5.4. 
UNDER 
 
1982 
Study 99270 and 99269 both had 24-week (double-blind) active treatment periods, 
ACT 
while Study 99012 had a 12-week active treatment period.  D
RELEASED  ata is reported at study 
endpoint (Week 24) and at Week 12 (where available) for Study 99270 and 99269. 
BEEN 
 
HEALTH 
HAS 
OF 
The Clinical Study Reports contain results for mean cha
INFORMATION  nge from baseline for the 
continuous outcomes (e.g. LSAS, SDS S
OF  cores) as well as adjusted mean change from 
baseline (using ANCOVA) for the same outcome.  As adjusted mean change was 
DOCUMENT 
specified in the analysis for the primary and secondary outcomes, these results are 
FREEDOM 
DEPARTMENT 
reported in the individual study results in Section B.6.  However the (unadjusted) 
THIS 
THE  THE 
change values are used for the meta-analysis.  This leads to slight differences in the 
BY 
values reported for the individual studies and in the individual study meta-analysis 
data.   
 
 
B.5.3.2 
Meta-analyses undertaken 
A meta-analysis combining the results of two of the key studies (Study 99270 and 
Study 99012) has been undertaken.  See Attachment 5 for full details of study 
methodology and results.  Some key issues in the design and conduct of the meta-
analysis are highlighted below. 
 
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SECTION B 
 
Excluded study (Study 99269) 
Study 99269 has not been meta-analysed with the other two key studies.  It is not 
possible to validly combine the results of the three direct comparative studies, due to 
significant differences in the objectives and design of Study 99269 compared with the 
other two key studies, leading to different patient populations being randomised to 
active treatment.   
 
Study 99269 was a relapse prevention study.  The trial was undertaken in order to 
determine the rate of patient relapse following successful treatment of SAD.  All 
patients who met the eligibility criteria received open-label escitalopram for 12 weeks 
prior to study randomisation.  Only patients who responded to therapy were 
randomised to continue in the relapse prevention study (since in order to be able to 
UNDER 
relapse, a patient must have responded to treatment).  Thus the patients entering the 
1982 
randomised active treatment phase of this study were a “responder sub-population” of 
ACT 
the patients with SAD who were initially eligible to enter the study.  This is a different 
RELEASED 
total patient population to that of Study 99270 and 99012.  Due to the significant 
differences in the patient population randomise
BEEN  d in Study 99269 (the relapse 
HEALTH 
prevention study), compared with the other treatment studies, the results could not 
HAS INFORMATION 
OF 
validly be combined in a meta-analysis. 
OF 
 
Escitalopram treatment arms combined in the meta-analysis 
DOCUMENT 
DEPARTMENT 
Study 99270 was a fixed-dose study
FREEDOM   comparing three doses of escitalopram - 5mg, 
THIS 
10mg and 20mg daily – with pl
THE  acebo.  Study 99012 was a flexible dose study with 
THE 
BY 
patients taking escitalopram 10mg to 20mg daily or placebo.  Patients in this study 
took a mean daily dose of 17.1mg at Week 12.  The meta-analysis combined the 
results of the fixed dose escitalopram 20mg daily treatment arm in Study 99270 with 
the flexible dose escitalopram arm in Study 99012, as these were the most similar 
study treatment arms that could be combined. 
 
Treatment time-point analysed 
Study 99012 had a 12 week active treatment phase.  Study 99270 had a 24 week 
active treatment phase, with most outcomes also being reported after the first 12 
weeks.  The 12 week outcome data for each of the two studies was combined in the 
meta-analysis.  This is important, as patients generally continued to improve from 
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SECTION B 
 
weeks 12-24 in the two 24 week studies.  Thus the results of the meta-analysis are 
likely to underestimate the true value of escitalopram therapy.  Section B.6 for details 
of 12 and 24 week responses in Study 99270 and 99269. 
 
 
B.5.3.3 
Outcomes analysed in the meta-analysis and/or individual 
studies and reported in Section B.6 
 
There are a large number of secondary outcomes reported in Study 99270 and Study 
99012.TableB.5.3lists the outcomes that have been meta-analysed and/or reported in 
the individual studies with the results presented in Section B.6 of the submission. 
UNDER 
1982 
ACT 
RELEASED 
BEEN  HEALTH 
HAS INFORMATION 
OF 
OF 
DOCUMENT 
FREEDOM 
DEPARTMENT 
THIS 
THE  THE 
BY 
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SECTION B 
 
TableB.5.4:Secondary outcome results that are not presented in Section B.6 (with 
reasons) 
Secondary outcomes 
Trial ID 
Reason 
 
Study 99270  Study 99012 
Study 99269 
Change from baseline to each visit 
 
 
 
 
in LSAS Score 
 
Proportion of patients with a >50% 
 
 
 
 
reduction in LSAS score at each visit 
 
CGI-I Score per visit  
 
 
 
Change from 
baseline to Week 12 
Number and % patients with CGI-I<2   
 
 
and Week 24 (i.e. 
at each visit 
study mid and/or 
CGI-S Score per visit  
 
 
 
endpoint) results 
reported, rather than 
Number and % patients with CGI-
 
 
 
per visit 
S<2 at each visit 
Change from baseline to each visit 
 
 
 
in MADRS Score 
Change in CGI-S score per visit 
 
 
 UNDER 
Change from baseline to last 
 
 
 
 
1982 
assessment in LSAS single items 
Total Score results 
reported. 
Change in mean LSAS Avoidance 
 
 
 
ACT 
Sub-scale Score 
 
RELEASED 
Subscale results are 
Change in mean LSAS Fear/Anxiety   
 
 
difficult to interpret 
Sub-scale Score 
BEEN 
meaningfully. 
Change in LSAS single items 
 
 
 
HEALTH 
 
OF 
CGI-I score in open-label period 
 
HAS   
 
Randomised, double-
INFORMATION 
blind phase results 
OF 
reported 
Total adverse events 
 
 
 
Treatment-emergent 
AEs and AEs leading 
DOCUMENT 
to withdrawal 
DEPARTMENT 
reported 
FREEDOM 
DESS score 
THIS 
 
 
 
Looks at 
THE  THE 
discontinuation 
BY 
effects after 
completion of active 
treatment 
Key: 
 = results for this outcome available in the Study Report, however the results are not presented in Section B.6 for 
the reasons provided 
 
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SECTION B 
 
 
B.5.4  Clinical importance of the outcomes used in the studies 
 
Liebowitz Social Anxiety Scale (LSAS) 
Change in mean LSAS Total Score is the primary outcome in Study 99270 and 99012.  
While a variety of measurement scales have been developed to quantify the severity 
of SAD, the most widely used scale is the LSAS.  It has been able to establish efficacy 
in a large number of placebo-controlled studies in SAD and is currently viewed as the 
gold standard13.  s38
 
 
 
An improvement of 10 points on the LSAS has been suggested as showing 
UNDER 
a clinically 
relevant improvement13.  This is also in line with the clinically relevant difference 
1982 
between drug and placebo for licensing approval.20 
ACT 
 
RELEASED 
 
BEEN  HEALTH 
Clinical Global Impression– Improvement (CGI-I) 
HAS 
OF 
CGI-I score results are secondary study outcomes in the
INFORMATION   studies.  The CGI-I scale has 
OF 
been used to identify responders to therapy, specifically patients reporting a score of 1 
or 2 (very much or much improved) on the CGI-I scale have been defined as 
DOCUMENT 
responding to therapy.  While this global scale is not recommended as a primary 
FREEDOM 
DEPARTMENT 
scale, it may be useful a
THIS  s a secondary scale to help judge the clinical relevance of the 
THE  THE 
finding13.  This was consistent with the pre-specified magnitude identified in the 
BY 
trials. 
 
 
B.5.5  Measurement scales used as primary and secondary outcomes in the 
studies  
 
Liebowitz Social Anxiety Scale (LSAS) 
The LSAS21 is designed to assess SAD through evaluation of fear and avoidance. 
The LSAS is a clinician-administered (interview) scale to evaluate the wide range of 
social situations within the last 7 days that are typically difficult for individuals with 
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SECTION B 
 
SAD.  The LSAS includes 24 items:  13 describe performance situations and 11 
describe social interaction situations.  Each item is rated with respect to fear (0 to 3 = 
none, mild, moderate, severe, respectively) and avoidance (0 to 3 = never, 
occasionally, often, usually, respectively).  Thus, the LSAS provides an overall social 
anxiety severity rating, and additionally scores four subscales:  performance fear, 
performance avoidance, social fear, and social avoidance.  Total scores for fear and 
avoidance as well as total LSAS scores are obtained by adding the scores. 
 
The ratings are based upon an interview with the patient and were conducted by the 
same person at each visit, whenever possible.  Only persons accepted by the study 
sponsor and trained as raters during a co-rating session were allowed to rate patients 
on the LSAS.  The rater sessions were undertaken to increase inter-rater reliability, 
UNDER 
and were chaired by an experienced rater(s).  At these sessions, video tapes were 
1982 
shown of patients with SAD; these patients were rated and the ratings discussed. 
ACT 
 
RELEASED 
The maximum possible score is 144 of the LSAS19.  Patients with SAD generally 
score above 50 points, whilst normal voluntee
BEEN rs score below 30 points.  Scores 
HEALTH 
between 50-70 may be considered moderate and are associated with distress while 
HAS INFORMATION 
OF 
scores over 70, and particularly over 90, are considered severe and are associated with 
OF 
functional impairment.13 19 
 
DOCUMENT 
DEPARTMENT 
As mentioned earlier, an improvement of
FREEDOM 
 10 points on the LSAS has been suggested 
THIS 
as showing a clinically releva
THE  nt improvement13.  However this should not be viewed 
THE 
BY 
in isolation and proportion of patients responding and importantly remitting should be 
considered to be at the very least of equivalent importance. 
 
Responders13: LSAS: ≥35-50% reduction in score from baseline.  Defining 
responders, as having a reduction in the initial score on the severity scale of 50%, 
used in other psychiatric conditions and which seems reasonable, has been reported to 
be useful in some studies in SAD.  However, SAD tends to respond more slowly than 
the conditions where the 50% criterion has proved most useful.  The studies indicate 
that at 12 weeks a 35% reduction in initial severity appears to be a useful measure 
with approximately half the patients achieving this criterion.  This closely corresponds 
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HAS INFORMATION 
OF 
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SECTION B 
 
rates the patient from 1 (normal, not at all ill) to 7 (among the most extremely 
ill patients). 
 
Responders and Remitters on the CGI scale are classified as:  
 
Responders: CGI-I≤ 2 (much or very much improved)13 or CGI-I ≥50% reduction22. 
These patients have improved but have not yet reached remission. 
 
Remission:13 CGI-S≤ 2 (normal, not at all ill, or borderline illness).. 
 
 
Sheehan Disability Scale (SDS) 
UNDER 
The SDS26 is a 3-item scale to measure impairment.  The items address the impact of 
1982 
symptoms of SAD on work, social life, and family life, within the last 7 days.  The 
ACT 
rating is based up an interview with the patient.  This scale has proved robust in most 
RELEASED 
studies and provides evidence of an improvement is disability in almost all studies 
where it is used.13  The SDS has been able to di
BEEN  stinguish an effective treatment from 
HEALTH 
placebo, both in the short and long-term studies.  Conclusions arrived at consensus 
HAS INFORMATION 
OF 
conferences identify remission at SDS≤1 on each item (mildly disabled).23 24 
OF 
 
 
DOCUMENT 
DEPARTMENT 
Montgomery and Åsberg Depressi
FREEDOM  on Rating Scale (MADRS) 
THIS 
The MADRS27 consists of 10 items, e
THE 
ach rated on a scale from 0 (no symptoms) to 6 
THE 
BY 
(severe symptoms).  All the items are core symptoms of a depressive episode and thus 
measure the severity of a depressive episode for the previous 7 days. 
 
The symptoms rated are:  apparent sadness, reported sadness, inner tension, reduced 
sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, 
pessimistic thoughts, and suicidal thoughts. 
 
The MADRS is based on a clinical interview with the patient beginning with general 
questions about symptoms and gradually becoming more detailed to allow for a 
precise rating of depression severity. 
 
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SECTION B 
 
 
 
Source documents 
All study data provided in Section B.5 comes from the Study Reports provided (Study 
99270, 99012 and 99269).  Page and/or table references are provided under the tables 
or in text.  .  
UNDER 
1982 
ACT 
RELEASED 
BEEN  HEALTH 
HAS INFORMATION 
OF 
OF 
DOCUMENT 
FREEDOM 
DEPARTMENT 
THIS 
THE  THE 
BY 
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SECTION B 
 
B.6  Systematic overview of the results of the direct randomised 
trials 
 
Summary 
The results of the randomised, controlled, double-blind studies demonstrate that 
escitalopram treatment significantly reduces the severity of Social Anxiety Disorder, 
compared with placebo and improved patient functioning.  s38
 
 
  Mean 
improvement in LSAS Total Score was the primary study outcome in the two 
treatment studies and a key secondary outcome in the relapse-prevention study.  In all 
UNDER 
studies escitalopram significantly improved the mean LSAS total score compared 
1982 
with placebo.  In addition, the percentage of patients defined as responders (based on 
both the LSAS and CGI-I scales) and remitters (based on the CG
ACT 
I-S scale) were 
RELEASED 
significantly greater with escitalopram.  The improvements seen were both 
statistically significant and clinically meaningful, demonstrating the clear benefit of 
BEEN  HEALTH 
escitalopram to this severely incapacitated patient group.   
HAS INFORMATION 
OF 
 
OF 
Figure B.6.1 depicts the timelines for the various trials.  It outlines the level of 
information provided over a 36 week trial program for patients being treated with 
DOCUMENT 
SAD.  It clearly depicts, together with Table 
DEPARTMENT B.6.1 that there is a clinically superior 
FREEDOM 
THIS 
effect with escitalopram. 
THE  THE 
 
BY 
.  As can be seen a statistically different outcomes is observed in the primary and 
secondary outcomes.  These differences are determined to be clinically relevant, as 
will be shown in the following sections. 
 
 
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86 
SECTION B 
 
 
Table B.6.1: Summary results of primary outcome and meta-analysis 
 
99270
99012
99269
Relpase Prevention
Escitalopram 10mg
Escitalopram 20mg
Placebo
Escitalopram
Placebo
Escitalopram
Placebo
17.1mg
UNDER 
n reporting data / N (%)
164/168 (98)
163/170 (96)
165/166 (99)
177/181 (98)
176/177 (99)
189/190 (99.5)
179/181 (99)
Mean LSAS total score (SD) at:
1982 
Open Label
94.24 (15.72)
93.88 (14.09)
Baseline
92.38 (14.93)
93.98 (13.99)
96.00 (14.46
ACT ) 96.32 (17.35) 95.44 (16.35)
44.28 (20.84)
43.16 (19.94)
Week 12
59.36 (26.81)
55.35 (28.76)
67.44 (26.81)
62.25 (30.67)
68.82 (29.70)
37.95 (22.41)
48.80 (26.53)
d
RELEASED 
Week 24 (endpoint)
52.57 (29.12)
46.17 (31.55)
62.72 (30.16)
35.71 (24.27)
48.50 (26.87)
te
s
Mean change LSAS from baseline (SD) at:
ju
Week 12
-33.02 (24.19
-38.63 (27.56)
-28.56 (22.84)
-34.07 (25.81)
-26.62 (26.09) 
-6.20 (16.43)
5.54 (19.81)
BEEN 
d
HEALTH 
Week 24
-39.80 (28.31)
-47.80 (30.78)
-33.28 (26.55)
-8.43 (19.08)
5.24 (21.27)
a
Difference of mean changes (95% CI), 
n
HAS 
OF 
U
escitalopram versus placebo: Results from Meta-
INFORMATION -8.74 (-12.60, -4.89)
analysis at 12 weeks
OF 
Difference of mean changes (95% CI), 
-6.92 (n.r.)
-14.52 (n.r)
escitalopram versus placebo at 24 weeks
Adjusted* mean change LSAS from baseline (SE) at:
DOCUMENT 
Week 12
-34.55 (1.96)
-39.79 (1.97)
-29.48 (1.95)
-34.45
-27.16
-6.13 (1.56)
4.85 (1.65)
d
FREEDOM 
DEPARTMENT 
Week 24
-41.50 (2.17)
-49.13 (2.13)
-34.04 (2.17)
-8.28 (1.73)
4.55 (1.82
te
THIS 
s
Difference of adjusted* mean change LSAS (95% CI) -, escitalopram versus placebo:
THE 
ju
THE 
Week 12
-5.07
-10.31
7.29
-10.97
d
BY 
(-10.32, 0.18)
(-15.56, -5.06)
(-12.37, -2.21)
(-14.70, -7.25)
A
Week 24
-7.45
-15.09
-12.82
(-13.29, -1.62)
(-20.92,  -9.25))
(-16.95, -8.70)
 
 
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SECTION B 
 
 
 
Full details of the results of the included studies are provided in this section and in 
Attachment 6.  The results are presented in the following sub-sections: 
 
B.6.1 
Primary outcome result – Change in mean LSAS Total Score 
▪ 
For Study 99270 and 99012, presented individually 
▪ 
Meta-analysis of Study 99270 and 99012 (at Week 12) 
 
B.6.2 
Results of the primary outcome for Study 99269 – relapse-prevention 
study  
 
UNDER 
B.6.3 
Results of key secondary efficacy results for the individual studies 
1982 
(provided in full in Attachment 6) 
ACT 
 
RELEASED 
B.6.4 
Results of the meta-analysis of key secondary outcomes (Study 99270 
and 99012) at Week 12 BEEN  HEALTH 
 
HAS INFORMATION 
OF 
B.6.5 
Results of key secondary safety results for the individual studies 
OF 
(provided in full in Attachment 6) 
 
DOCUMENT 
DEPARTMENT 
B.6.6 
Summary of efficac
FREEDOM  y and safety data 
THIS 
 
THE  THE 
BY 
Change in mean LSAS total score is the primary outcome for Study 99270 and 99269.  
s47E(d)
 
  This is 
followed by the primary outcome results of the relapse-prevention study (time to 
relapse). The results of the meta-analysis of the key secondary outcomes are presented 
next.  Individual study key secondary efficacy and safety results are then presented, 
with full details available in Attachment 6. 
 
The results of Study 99270 and 99012 demonstrate the efficacy and safety of 
escitalopram in the treatment of SAD.  The results of the relapse prevention study 
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SECTION B 
 
(Study 99269) demonstrate the continued efficacy and safety of escitalopram 
treatment in patients who have been initially successfully treated with escitalopram. 
 
All results are sourced from the Clinical Study Reports, with Table and page 
references provided.  Copies of the Clinical Study Reports have been provided with 
the submission. 
 
B.6.1  Primary outcome – Mean change in LSAS Total Score 
The primary outcome in Study 99270 and 99012 was mean change in LSAS Total 
Score.  The results are presented individually for each study.  s38
 
 
UNDER 
 
  This is followed by the 
1982 
results of the meta-analysis of this outcome for Study 99270 and 99012 at Week 12. 
ACT 
 
RELEASED 
B.6.1.1 
Study 99270, Study 99012 and Study 99269 (Mean change in LSAS Total 
BEEN  HEALTH 
Score) 
HAS INFORMATION 
OF 
Study 99270 had a 24-week active treatment period.  Data is reported at Week 12 and 
OF 
24 to allow comparison with Study 99012 which was of 12 weeks duration (see Table 
B.6.2). Both mean change and adjusted mean change data is reported, as adjustment 
DOCUMENT 
using ANOVA was the pre-specified method of
DEPARTMENT   analysis in the individual studies, 
FREEDOM 
THIS 
with adjustment leading to only very small differences in the adjusted versus 
THE  THE 
unadjusted results.  BY 
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THE  THE 
BY 

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UNDER 
1982 
ACT 
RELEASED 
BEEN  HEALTH 
HAS INFORMATION 
OF 
OF 
DOCUMENT 
FREEDOM 
DEPARTMENT 
THIS 
THE  THE 
BY 

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UNDER 
1982 
ACT 
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BEEN  HEALTH 
HAS INFORMATION 
OF 
OF 
DOCUMENT 
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DEPARTMENT 
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SECTION B 
 
Of note, patients continued to improve from the time they received open-label 
escitalopram until the final assessment at Week 24, after a total of 36 weeks of 
escitalopram therapy.  
 
 
B.6.1.2  Meta-analysis 
The meta-analysis combines the primary outcome results for Study 99270 and 99012 
(using the unadjusted change data) at Week 4, 8 and 12.  The data utilised for 
99270 was 20mg arm of escitalopram patients, given that the mean dose for 99012 
was 17.1mg.  The data is presented below with full details of the study methodology 
available in Attachment 5.  As Study 99012 was only of 12 weeks duration, the 
longest time-point that could be meta-analysed was 12 weeks.  The results of Study 
UNDER 
99270 (and Study 99269) demonstrate that patients receiving escitalopram continue to 
1982 
improve during Week 12 to Week 24 of therapy.  Therefore the results of the meta-
ACT 
analysis underestimate the true value of escitalopram thera
RELEASED  py, i.e. that occurring 
beyond 12 weeks of therapy.  The results of Study 99269 could not be meta-analysed 
BEEN 
with the other two studies due to significant differences in s
HEALTH  tudy design, leading to 
HAS 
OF 
differing patient populations. 
INFORMATION 
 
OF 
The results of the meta-analysis were conducted for the duration of 4, 8 and 12 weeks.  
DOCUMENT 
Only the 12 week data is presented here, all results are presented in Attachment 5.  
FREEDOM 
DEPARTMENT 
The 12 week data is presented in Figure B.6.2. 
THIS 
THE  THE 
 
BY 
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SECTION B 
 
Figure B.6.2:Results of primary outcome (mean change in LSAS total score, LOCF) at Week 12 – meta-analysis of Study 99270 and 99012 
Review:
Escitalopram (Lexapro) - SAD
Comparison:
01 Change in Mean LSAS Total Score (FAS LOCF) - primary endpoint                                              
Outcome:
03 Change in Mean LSAS Total Score (FAS LOCF) - "Head-to-Head" comparison - 12 weeks                          
Study
 Escitalopram
 Placebo
 WMD (fixed)
 Weight
 WMD (fixed)
or sub-category
N
Mean (SD)
N
Mean (SD)
 95% CI
 %
 95% CI
01 Escitalopram trials
99012               
   177    -34.07(25.81)        176    -26.62(26.09)    
 50.62
    -7.45 [-12.86, -2.04]     
99270               
   163    -38.63(27.56)        165    -28.56(22.84)    
 49.38
   -10.07 [-15.55, -4.59]     
Subtotal (95% CI)
   340                         341
100.00
    -8.74 [-12.60, -4.89]
UNDER 
Test for heterogeneity: Chi² = 0.44, df = 1 (P = 0.51), I² = 0%
Test for overall effect: Z = 4.45 (P < 0 00001)
1982 
Total (95% CI)
   340                         341
100.00
    -8.74 [-12.60, -4.89]
Test for heterogeneity: Chi² = 0.44, df = 1 (P = 0.51), I² = 0%
ACT 
Test for overall effect: Z = 4.45 (P < 0 00001)
RELEASED 
 -100
 -50
 0
 50
 100
 Favours escitalopram
 Favours placebo
 
BEEN 
Source: Meta-analysis Report - Attachment 5 
HEALTH 
 
HAS INFORMATION 
OF 
OF 
DOCUMENT 
FREEDOM 
DEPARTMENT 
THIS 
THE  THE 
BY 
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SECTION B 
 
 
The weighted mean change in the LSAS total score continued to increase from Week 
4 to Week 12.  At Week 12 the difference in the weighted mean change was -8.74 
(95% CI -12.60, -4.89).  This is a statistically significant improvement in LSAS total 
score in the escitalopram group, compared with placebo.  Importantly, the 95% 
confidence intervals include the value 10, the clinically important improvement in 
LSAS Total Score described in Section B.5.4.  Based on the results of the 24 week 
treatment and relapse-prevention studies, it would be expected that escitalopram 
treated patients would continue to improve beyond the 12 week meta-analysis period 
reported. 
 
 
UNDER 
B.6.2  Relapse-prevention Study 99269 - primary outcome resu
1982 
lt (time to 
relapse) 
ACT 
Study 99269 was a relapse prevention study.  All patients re
RELEASED  ceived 12 weeks of open-
label escitalopram, with responders then randomised to receive 24 weeks of 
BEEN 
escitalopram or placebo.  The primary study outcome was ti
HEALTH  me to relapse.  The results 
HAS 
OF 
are presented in TableB.6.5 and graphically in Figure 
INFORMATION B.6.3. 
 
OF 
DOCUMENT 
FREEDOM 
DEPARTMENT 
THIS 
THE  THE 
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SECTION B 
 
 
Due to the relatively few relapses in the escitalopram group, median survival times 
could not be estimated satisfactorily.  Instead descriptive mean survival times have 
been presented. 
 
TableB.6.5: 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 
Log-rank P value 
Hazard Ratio 
Standard Error 
Cox-Model  
 
(Cox) 
P-value 
5.0E-09 
2.83 
1.21 
2.7E-08 
 
(NR) 
UNDER 
Source – Table 42 
NR.: not reported 
1982 
 
ACT 
 
RELEASED 
BEEN  HEALTH 
HAS INFORMATION 
OF 
OF 
DOCUMENT 
FREEDOM 
DEPARTMENT 
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THE  THE 
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SECTION B 
 
 
Figure B.6.3: Analysis of time to relapse (Study 99269) 
UNDER 
1982 
 
ACT 
 
RELEASED 
 
BEEN  HEALTH 
The results of the primary analysis show a clear beneficial effect of escitalopram 
HAS 
OF 
relative to placebo, with more than twice as many pati
INFORMATION ents in the placebo group 
relapsing. (Hazard Ratio 2.83, log rank test, p<
OF 
0.001).  This study demonstrates the 
benefit of escitalopram in reducing the risk of relapse once patients have responded to 
DOCUMENT 
therapy. 
FREEDOM 
DEPARTMENT 
 
THIS 
THE  THE 
 
BY 
B.6.3:Secondary outcome results for the individual studies - efficacy 
The key secondary efficacy results are summarised in this section and presented for 
the individual studies in full in Attachment 6.  A summary list of these efficacy 
outcomes and the studies in which they are available is presented in TableB.6.6 
below. 
 
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SECTION B 
 
The results of the key secondary outcomes measures that are markers of disease 
severity and improvement with therapy (i.e. % patients with >50% improvement in 
LSAS Score, CGI-I Score and % patients with a CGI-I or CGI-S Score <2) are 
presented for Study 99270 and Study 99012 in TableB.6.7 below.  In all cases 
escitalopram significantly improved patient outcomes. 
 
The Sheehan Disability Scales (SDS) scores (Work, Social and Family) were also 
statistically significantly improved in Study 99270 at Weeks 12 and 24.  At Week 12 
in Study 99012 there were statistically significant improvements in SDS Work and 
Social Scores, with a trend towards improvement in the Family Score.  The SDS is a 
measure of functional disability in SAD in the three key affected areas. 
 
UNDER 
1982 
ACT 
RELEASED 
BEEN  HEALTH 
HAS INFORMATION 
OF 
OF 
DOCUMENT 
FREEDOM 
DEPARTMENT 
THIS 
THE  THE 
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OF 
OF 
DOCUMENT 
FREEDOM 
DEPARTMENT 
THIS 
THE  THE 
BY 

---

UNDER 
1982 
ACT 
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HAS INFORMATION 
OF 
OF 
DOCUMENT 
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SECTION B 
 
with CGI<2 also called ‘remitters’, CGI-S).  The percentage of patients with CGI-I<2 
(or CGI-I ‘responders’, patients who are rated as ‘very much or ‘much’ improved on 
the CGI-I scale) was 50% greater with escitalopram at 12 weeks (RR 1.46; 95% CI 
1.24, 1.71).  Two functional disability measures on the Sheehan Disability Scale 
(SDS) – work and social scores - also showed a statistically significant benefit for 
escitalopram, with the exception being the SDS Family score (where there was a trend 
towards significance).   
 
The MADRS score was not an efficacy endpoint, but rather an assessment of 
depressive status.  While escitalopram was superior to placebo at week 12, the 
MADRS score seen throughout the studies in all treatment groups was below the 
recognised cut-off for a depressive episode (i.e. <8), indicating that benefits seen with 
UNDER 
escitalopram were due to treatment of SAD, rather than co-morbid depression. 
1982 
 
ACT 
Patients receiving escitalopram had a higher rate of treatment-emergent adverse 
RELEASED 
events than placebo and more adverse events leading to withdrawal, as would be 
expected of an active treatment compared with pl
BEEN  acebo.  However with escitalopram 
HEALTH 
there was a significant 62% reduction in patients withdrawing from the studies due to 
HAS INFORMATION 
OF 
lack of efficacy (RR 0.38, 95% CI 0.21, 0.67). 
OF 
 
Clinical Global Impression – Impro
DOCUMENT vement (CGI-I) 
FREEDOM 
DEPARTMENT 
Results from the meta
THIS  -analysis are presented in Figure B.6.4 to Figure B.6.6. 
THE  THE 
 
BY 
 
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SECTION B 
 
 
Figure B.6.4: CGI Improvement (LOCF) – 12 weeks 
Review:
Escitalopram (Lexapro) - SAD
Comparison:
05 CGI Improvement (FAS LOCF) - a change characteristic - secondary endpoint                                  
Outcome:
01 CGI Improvement (FAS LOCF) - "Head-to-Head" comparison - 12 weeks                                          
Study
 Escitalopram
 Placebo
 WMD (fixed)
 Weight
 WMD (fixed)
or sub-category
N
Mean (SD)
N
Mean (SD)
 95% CI
 %
 95% CI
01 Escitalopram trials
UNDER 
99012               
   177      2.55(1.05)         175      2.93(1.07)     
 53.99
    -0.38 [-0.60, -0.16]      
99270               
   162      2.38(1.16)         165      2.71(1.05)     
 46.01
    -0.33 [-0.57, -0.09]      
1982 
Subtotal (95% CI)
   339                         340
100.00
    -0.36 [-0.52, -0.19]
Test for heterogeneity: Chi² = 0 09, df = 1 (P = 0.76), I² = 0%
Test for overall effect: Z = 4.30 (P < 0.0001)
ACT 
RELEASED 
Total (95% CI)
   339                         340
100.00
    -0.36 [-0.52, -0.19]
Test for heterogeneity: Chi² = 0 09, df = 1 (P = 0.76), I² = 0%
Test for overall effect: Z = 4.30 (P < 0.0001)
BEEN  HEALTH 
 -1
 -0.5
 0
 0.5
 1
 Favours escitalopram
 Favours placebo
HAS 
OF 
 
INFORMATION 
Source: Meta-analysis Report - Attachment 1 
OF 
 
 
DOCUMENT 
FREEDOM 
DEPARTMENT 
THIS 
THE  THE 
BY 
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COMMERCIAL-IN-CONFIDENCE 
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ESCITALOPRAM (LEXAPRO®): SAD PBAC RE-SUBMISSION  
103 
SECTION B 
 
Figure B.6.5: Number and Percentage of Patients with CGI-I ≤2 (LOCF), also called ‘responders’ - 12 weeks 
Review:
Escitalopram (Lexapro) - SAD
Comparison:
06 Number of Patients with CGI-I <=2 (FAS LOCF) - secondary endpoint                                          
Outcome:
03 Number of Patients with CGI-I <=2 (FAS LOCF) - 12 weeks                                                    
Study
 Escitalopram
 Placebo
 RR (random)
 Weight
 RR (random)
or sub-category
 n/N
 n/N
 95% CI
 %
 95% CI
 99012               
      96/177             68/176       
 47.37
     1.40 [1.12, 1.77]        
 99270               
     101/163             68/165       
 52.63
     1.50 [1.21, 1.87]        
UNDER 
Total (95% CI)
340                341
100.00
     1.46 [1.24, 1.71]
Total events: 197 (Escitalopram), 136 (Placebo)
1982 
Test for heterogeneity: Chi² = 0.18, df = 1 (P = 0.67), I² = 0%
Test for overall effect: Z = 4.64 (P < 0.00001)
ACT 
 0.2
 0.5
 1
RELEASED 
 2
 5
 Favours placebo
 Favours escitalopram
 
Source: Meta-analysis Report - Attachment 5 
BEEN  HEALTH 
 
HAS 
OF 
 
INFORMATION 
OF 
DOCUMENT 
FREEDOM 
DEPARTMENT 
THIS 
THE  THE 
BY 
LUNDBECK AUSTRALIA PTY LIMITED 
COMMERCIAL-IN-CONFIDENCE 
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ESCITALOPRAM (LEXAPRO®): SAD PBAC RE-SUBMISSION  
104 
SECTION B 
 
Figure B.6.6: Change in CGI Severity (LOCF) - 12 weeks 
Review:
Escitalopram (Lexapro) - SAD
Comparison:
04 Change in CGI Severity (FAS LOCF) - secondary endpoint                                                     
Outcome:
01 Change in CGI Severity (FAS LOCF) - "Head-to-Head" comparison - 12 weeks                                   
Study
 Escitalopram
 Placebo
 WMD (fixed)
 Weight
 WMD (fixed)
or sub-category
N
Mean (SD)
N
Mean (SD)
 95% CI
 %
 95% CI
01 Escitalopram trials
99012               
   177     -1.25(1.14)         175     -0.97(1.11)     
 56.98
    -0.28 [-0.52, -0.04]      
99270               
   162     -1.62(1.37)         165     -1.05(1.11)     
 43.02
    -0.57 [-0.84, -0.30]      
Subtotal (95% CI)
   339                         340
100.00
    -0.40 [-0.58, -0.23]
UNDER 
Test for heterogeneity: Chi² = 2.52, df = 1 (P = 0.11), I² = 60.2%
Test for overall effect: Z = 4.47 (P < 0 00001)
1982 
Total (95% CI)
   339                         340
100.00
    -0.40 [-0.58, -0.23]
Test for heterogeneity: Chi² = 2.52, df = 1 (P = 0.11), I² = 60.2%
ACT 
Test for overall effect: Z = 4.47 (P < 0 00001)
RELEASED 
 -1
 -0.5
 0
 0.5
 1
 Favours escitalopram
 Favours placebo
 
BEEN 
Source: Meta-analysis Report - Attachment 5 
HEALTH 
 
HAS INFORMATION 
OF 
 
OF 
DOCUMENT 
FREEDOM 
DEPARTMENT 
THIS 
THE  THE 
BY 
LUNDBECK AUSTRALIA PTY LIMITED 
COMMERCIAL-IN-CONFIDENCE 
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ESCITALOPRAM (LEXAPRO®): SAD PBAC RE-SUBMISSION  
105 
 
SECTION B 
 
Sheehan Disability Scale (SDS) 
Results from the meta-analysis are presented in Figure B.6.7 to Figure B.6.9. 
 
 
UNDER 
1982 
ACT 
RELEASED 
BEEN  HEALTH 
HAS INFORMATION 
OF 
OF 
DOCUMENT 
FREEDOM 
DEPARTMENT 
THIS 
THE  THE 
BY 
LUNDBECK AUSTRALIA PTY LIMITED 
COMMERCIAL-IN-CONFIDENCE 
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106 
SECTION B 
 
Figure B.6.7: Change in SDS Work Scores (LOCF) - 12 weeks 
Review:
Escitalopram (Lexapro) - SAD
Comparison:
07 Change in SDS Work Scores (FAS LOCF) - secondary endpoint                                                  
Outcome:
01 Change in SDS Work Scores (FAS LOCF) - "Head-to-Head" comparison - 12 weeks                                
Study
 Escitalopram
 Placebo
 WMD (fixed)
 Weight
 WMD (fixed)
or sub-category
N
Mean (SD)
N
Mean (SD)
 95% CI
 %
 95% CI
01 Escitalopram trials
99012               
   177     -2.50(2.56)         175     -1.74(2.52)     
 52.31
    -0.76 [-1.29, -0.23]      
99270               
   163     -2.98(2.57)         163     -1.73(2.55)     
 47.69
    -1.25 [-1.81, -0.69]      
Subtotal (95% CI)
   340                         338
100.00
    -0.99 [-1.38, -0.61]
UNDER 
Test for heterogeneity: Chi² = 1.56, df = 1 (P = 0.21), I² = 36 0%
Test for overall effect: Z = 5.07 (P < 0 00001)
1982 
Total (95% CI)
   340                         338
100.00
    -0.99 [-1.38, -0.61]
Test for heterogeneity: Chi² = 1.56, df = 1 (P = 0.21), I² = 36 0%
ACT 
Test for overall effect: Z = 5.07 (P < 0 00001)
RELEASED 
 -4
 -2
 0
 2
 4
 Favours escitalopram
 Favours placebo
 
Source: Meta-analysis Report - Attachment 5 
BEEN  HEALTH 
HAS INFORMATION 
OF 
OF 
DOCUMENT 
FREEDOM 
DEPARTMENT 
THIS 
THE  THE 
BY 
LUNDBECK AUSTRALIA PTY LIMITED 
COMMERCIAL-IN-CONFIDENCE 
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ESCITALOPRAM (LEXAPRO®): SAD PBAC RE-SUBMISSION  
107 
SECTION B 
 
Figure B.6.8: Change in SDS Social Scores (LOCF) - 12 weeks 
Review:
Escitalopram (Lexapro) - SAD
Comparison:
08 Change in SDS Social Scores (FAS LOCF) - secondary endpoint                                                
Outcome:
01 Change in SDS Social Scores (FAS LOCF) - "Head-to-Head" comparison - 12 weeks                              
Study
 Escitalopram
 Placebo
 WMD (fixed)
 Weight
 WMD (fixed)
or sub-category
N
Mean (SD)
N
Mean (SD)
 95% CI
 %
 95% CI
01 Escitalopram trials
99012               
   177     -2.57(2.55)         176     -2.03(2.37)     
 50.53
    -0.54 [-1.05, -0.03]      
99270               
   163     -3.27(2.44)         163     -2.45(2.34)     
 49.47
    -0.82 [-1.34, -0.30]      
Subtotal (95% CI)
   340                         339
100.00
    -0.68 [-1.04, -0.31]
UNDER 
Test for heterogeneity: Chi² = 0.56, df = 1 (P = 0.45), I² = 0%
Test for overall effect: Z = 3.64 (P = 0.0003)
1982 
Total (95% CI)
   340                         339
100.00
    -0.68 [-1.04, -0.31]
Test for heterogeneity: Chi² = 0.56, df = 1 (P = 0.45), I² = 0%
ACT 
Test for overall effect: Z = 3.64 (P = 0.0003)
RELEASED 
 -4
 -2
 0
 2
 4
 Favours escitalopram
 Favours placebo
 
BEEN 
Source: Meta-analysis Report - Attachment 5 
HEALTH 
 
HAS INFORMATION 
OF 
 
OF 
DOCUMENT 
FREEDOM 
DEPARTMENT 
THIS 
THE  THE 
BY 
LUNDBECK AUSTRALIA PTY LIMITED 
COMMERCIAL-IN-CONFIDENCE 
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ESCITALOPRAM (LEXAPRO®): SAD PBAC RE-SUBMISSION  
108 
SECTION B 
 
Figure B.6.9: Change in SDS Family Scores (LOCF) - 12 weeks 
Review:
Escitalopram (Lexapro) - SAD
Comparison:
09 Change in SDS Family Scores (FAS LOCF) - secondary endpoint                                                
Outcome:
01 Change in SDS Family Scores (FAS LOCF) - "Head-to-Head" comparison - 12 weeks                              
Study
 Escitalopram
 Placebo
 WMD (fixed)
 Weight
 WMD (fixed)
or sub-category
N
Mean (SD)
N
Mean (SD)
 95% CI
 %
 95% CI
01 Escitalopram trials
99012               
   177     -1.44(2.05)         176     -1.62(2.27)     
 54.89
     0.18 [-0.27, 0.63]       
99270               
   163     -2.00(2.41)         163     -1.34(2.17)     
 45.11
    -0.66 [-1.16, -0.16]      
Subtotal (95% CI)
   340                         339
100.00
    -0.20 [-0.53, 0.14]
UNDER 
Test for heterogeneity: Chi² = 6.00, df = 1 (P = 0.01), I² = 83.3%
Test for overall effect: Z = 1.17 (P = 0.24)
1982 
Total (95% CI)
   340                         339
100.00
    -0.20 [-0.53, 0.14]
Test for heterogeneity: Chi² = 6.00, df = 1 (P = 0.01), I² = 83.3%
ACT 
Test for overall effect: Z = 1.17 (P = 0.24)
RELEASED 
 -4
 -2
 0
 2
 4
 Favours escitalopram
 Favours placebo
 
BEEN 
Source: Meta-analysis Report - Attachment 5 
HEALTH 
 
HAS INFORMATION 
OF 
 
OF 
DOCUMENT 
FREEDOM 
DEPARTMENT 
THIS 
THE  THE 
BY 
LUNDBECK AUSTRALIA PTY LIMITED 
COMMERCIAL-IN-CONFIDENCE 
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ESCITALOPRAM (LEXAPRO®): SAD PBAC RE-SUBMISSION  
109 
 
SECTION B 
 
Montgomery and Åsberg Depression Rating Scale (MADRS) 
Results from the meta-analysis are presented in Figure B.6.10. 
 
 
UNDER 
1982 
ACT 
RELEASED 
BEEN  HEALTH 
HAS INFORMATION 
OF 
OF 
DOCUMENT 
FREEDOM 
DEPARTMENT 
THIS 
THE  THE 
BY 
LUNDBECK AUSTRALIA PTY LIMITED 
COMMERCIAL-IN-CONFIDENCE 
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ESCITALOPRAM (LEXAPRO®): SAD PBAC RE-SUBMISSION  
 
110 
SECTION B 
 
Figure B.6.10: Change in MADRS Total Score (LOCF) - secondary endpoint - 12 weeks 
Review:
Escitalopram (Lexapro) - SAD
Comparison:
10 Change in MADRS Total Score (FAS LOCF) - secondary endpoint                                                
Outcome:
01 Change in MADRS Total Score (FAS LOCF) - "Head-to-Head" comparison - 12 weeks                              
Study
 Escitalopram
 Placebo
 WMD (fixed)
 Weight
 WMD (fixed)
or sub-category
N
Mean (SD)
N
Mean (SD)
 95% CI
 %
 95% CI
01 Escitalopram trials
99012               
   175     -2.44(5.05)         170     -0.60(4.89)     
 53.06
    -1.84 [-2.89, -0.79]      
99270               
   159     -2.76(5.09)         158     -2.06(5.04)     
 46.94
    -0.70 [-1.82, 0.42]       
Subtotal (95% CI)
   334                         328
100.00
    -1.30 [-2.07, -0.54]
UNDER 
Test for heterogeneity: Chi² = 2.13, df = 1 (P = 0.14), I² = 53.1%
Test for overall effect: Z = 3 35 (P = 0 0008)
1982 
Total (95% CI)
   334                         328
100.00
    -1.30 [-2.07, -0.54]
Test for heterogeneity: Chi² = 2.13, df = 1 (P = 0.14), I² = 53.1%
ACT 
Test for overall effect: Z = 3 35 (P = 0 0008)
RELEASED 
 -4
 -2
 0
 2
 4
 Favours escitalopram
 Favours placebo
 
BEEN 
Source: Meta-analysis Report - Attachment 5 
HEALTH 
 
HAS INFORMATION 
OF 
OF 
DOCUMENT 
FREEDOM 
DEPARTMENT 
THIS 
THE  THE 
BY 
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FOI 4150 - Document 7
s22
UNDER 
 
1982 
ACT 
B.6.6  Summary of efficacy and safety 
RELEASED 
Change in mean LSAS total score was the primary outcome for Study 99270 and 
99012, and a secondary outcome in Study 99269.  
BEEN 
s47E(d)
 
HEALTH 
 
HAS INFORMATION 
OF 
  The LSAS is widely used in treatment studies, is 
OF 
sensitive, validated and considered the gold standard measure of treatment success in 
SAD.  An improvement of 10 points on the LSAS (i.e. a mean Total Score difference 
DOCUMENT 
DEPARTMENT 
of –10) is considered a clinically re
FREEDOM  levant treatment improvement13.  Responders 
THIS 
(based on LSAS criteria) have
THE   been defined as having a greater than or equal to 35-
THE 
BY 
50% reduction in LSAS Total Score13.  Similarly, a CGI-I score of < 2 has also been 
used to define a responder to therapy, while a CGI-S score <2 suggests remission13.  
On all of these important response measures, escitalopram was shown to 
significantly improve patient outcomes, compared with the comparator. 
 
The improvement in LSAS scores seen in all three studies was statistically significant.  
The benefit of escitalopram was evident after 12 weeks of therapy and continued to 
increase from 12 to 24 weeks of therapy.  In Study 99270, treatment with 
escitalopram 20mg daily resulted in a difference in mean LSAS total score change of -
15.09 (95% CI -20.92, -9.25) at Week 24, while at 24 weeks in Study 99269 there was 
a difference of –12.82 (95% CI –16.95, -8.70), both compared with placebo.  In all 
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117 
SECTION B 
 
three studies at both 12 and 24 weeks, a difference in mean improvement of –10 in 
LSAS Total Score fell within the 95% CIs for this outcome, providing a high level of 
confidence that a clinically meaningful result was obtained.   
 
Responders to therapy, defined as either a 50% or greater reduction in LSAS total 
score or CGI-I <2, were also significantly greater with escitalopram.  In Study 99270 
at endpoint, 17.2% (95% CI 7.0%, 27.5%) of patients receiving escitalopram 10mg 
daily and 27.3% (95% CI 17.1%, 37.6%) more patients responded to escitalopram 
(based on LSAS criteria), compared with the comparator.  Improvements in CGI-I 
responders also occurred.  The percentage of CGI-S remitters (i.e. patients with a 
score of <2 on the CGI-S) were significantly greater with escitalopram.  Eighteen 
percent (risk difference 17.8%, 95% CI 8.3%, 27.3%; escitalopram 10mg daily) and 
UNDER 
27% (risk difference 26.6%, 95% CI 16.9%, 36.4%; escitalopram 20mg daily) more 
1982 
patients achieved remission at study endpoint, versus the comparator, based on CGI-S 
ACT 
improvements. 
RELEASED 
 
Thus, escitalopram consistently improved pati
BEEN  ent outcomes on all key, patient-
HEALTH 
relevant efficacy outcome measures.  This included mean improvement in the LSAS 
HAS INFORMATION 
OF 
scale Total Score (>10 point improvement) and percentage of responders (based on 
OF 
LSAS criteria), as well as responders based on CGI-I criteria.  In addition, 
significantly more patients achieved remission (based on CGI-S criteria) with 
DOCUMENT 
DEPARTMENT 
escitalopram.  The results of the ra
FREEDOM ndomised, controlled, double-blind 24 week 
THIS 
treatment studies presented de
THE  monstrate that therapy with escitalopram provides 
THE 
BY 
statistically significantly superior treatment (compared with placebo), across a range 
of outcomes, that is also clinically meaningful and relevant. 
s22
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120 
SECTION B 
 
B.8  Interpretation of the clinical evidence 
 
Summary 
Social Anxiety Disorder is a severe, disabling condition with significant negative 
patient impact on social functioning leading to educational, social and financial 
disadvantage.  Information on the importance of pharmacotherapy in improving the 
lives of patients with SAD is presented. 
 
The patients in the trials had been sufferers of SAD for 20-24 years and the mean age 
of onset was 15-18 years.  This sample of patients closely mirrors the epidemiological 
evidence (see Attachment 2).  At 12 weeks a greater proportion of these patients 
UNDER 
responded to treatment (when compared to placebo) and at 24 weeks an even larger 
1982 
response was seen.  This was reinforced by the relapse prevention study. As would be 
expected, and shown in other studies, duration of treatment wa
ACT  s important, with 
RELEASED 
greater improvements seen over time. 
 
BEEN  HEALTH 
Escitalopram provides superior efficacy and similar safety to the main 
HAS INFORMATION 
OF 
comparator (placebo).  A modelled economic evaluation is presented in Section 
OF 
C.  This assessment is based on three well designed and conducted direct comparative 
randomised, controlled studies.  The key study outcome (improvement in the LSAS 
DOCUMENT 
Total Score) was significantly improved in the
DEPARTMENT   escitalopram treatment groups, 
FREEDOM 
THIS 
compared with placebo in all studies.   
THE  THE 
 
BY 
The percentage of patients responding to therapy (based on LSAS and CGI-I criteria) 
and achieving remission (based on CGI-S criteria) were also significantly greater with 
escitalopram, demonstrating the overall superiority of escitalopram therapy across a 
range of patient-relevant outcomes. s22
 
 
   
 
s22
 
 
 
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126 
SECTION B 
s22
UNDER 
1982 
ACT 
RELEASED 
 
BEEN  HEALTH 
B.8.2  Assessment of the trial evidence for escitalopram in SAD 
HAS INFORMATION 
OF 
 
OF 
B.8.2.1 
The level of the evidence 
A comprehensive literature review was undertaken, with full details provided in 
DOCUMENT 
DEPARTMENT 
Section B.1 and B.2.  The three studi
FREEDOM  es identified in the literature search and presented 
THIS 
in the submission are all double
THE  -blind, randomised, controlled, multicentre, parallel-
THE 
BY 
group direct comparisons between escitalopram and comparator (placebo).  This is 
generally considered the highest level of clinical evidence available. 
 
 
 
B.8.2.2 
The quality of the evidence 
The studies were well designed, conducted and reported, with full details provided in 
the Clinical Study Reports provided.  Full details of the methods of randomisation, 
and blinding are provided in this submission.  Randomisation was by a third party 
service (the pharmaceutical company).  Blinding was maintained throughout the 
studies, with identical study products provided for each treatment group. 
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SECTION B 
 
 
The basis of the analysis was ‘intent to treat’, based on all randomised patients with 
one valid post-baseline assessment of the primary outcome (a continuous variable).  In 
all cases the results are presented using Last Observation Carried Forward 
methodology.  The flow of participants through each of the studies is clearly 
identified in Section B.3.   
 
Thus, the level of evidence provided in the submission is high, with the three studies 
presented all well conducted, randomised, controlled, double-blind, parallel group 
studies that provide a direct comparison with the comparator. 
 
 
UNDER 
 
B.8.2.3 
The statistical precision of the evidence 
1982 
Efficacy and safety result data presented in Subsection B.6 for the individual direct 
ACT 
randomised trial results and the pooled analyses was able to pr
RELEASED 
ovide a high level of 
statistical precision.  The primary efficacy results were presented as the difference 
BEEN 
between escitalopram and placebo in mean change from base
HEALTH  line to study endpoint in 
HAS 
OF 
LSAS Total Score (with 95%CI).  Secondary efficacy e
INFORMATION  ndpoints were presented as 
difference in mean change from baseli
OF ne to endpoint with 95% CIs (continuous data), 
with dichotomous data also being reported as a relative risk (with 95% CI) and NNT 
DOCUMENT 
(with 95% CI).  Safety results were presented with relative risk (with 95%CI) and risk 
FREEDOM 
DEPARTMENT 
difference (with 95%CI).  
THIS 
THE  THE 
 
BY 
 
 
B.8.2.4 
The size of the effect 
 
s47E(d)
 
 
 
 
 
 all studies, treatment with escitalopram resulted in statistically and 
clinically significant improvements in LSAS Total Score, compared with placebo at 
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SECTION B 
 
study endpoint.  The clinical patient relevance of the improvements is discussed in 
Section B.8.5 below.   
 
In the fixed-dose treatment Study 99270 at Week 24 the difference of the adjusted 
mean change was –7.45 (95% CI –13.29, -1.62) in the escitalopram 10mg group and –
15.09 (95% CI –20.92, -9.25) in the escitalopram group, both compared with placebo.   
 
In the flexible-dose treatment Study 99012 at Week 12 (study endpoint) the difference 
was –7.29 (95% CI –12.37, -2.21).  In this study the mean dose of escitalopram was 
17.1mg daily. 
 
When meta-analysed the non-adjusted mean change between escitalopram versus 
UNDER 
placebo was -8.74 (95% CI -12.60, -4.89) at 12 weeks.  This also needs to be 
1982 
considered in light of the final data point at 24 week mean change being -14.52.  
ACT 
These results are depicted in summary table Table B.6.1. 
RELEASED 
 
The 24 weeks results, as expected, show a higher
BEEN   difference in the adjusted mean 
HEALTH 
change in LSAS Total Score in the flexible-dose relapse prevention study –12.82 
HAS INFORMATION 
OF 
(95% CI –16.95, -8.70) for escitalopram (mean daily dose 17.3mg).  The primary 
OF 
outcome in the relapse prevention study was time to relapse.  The mean time to 
relapse was significantly greater, with a mean survival time of 135 days with 
DOCUMENT 
DEPARTMENT 
escitalopram, compared with 103.5 days f
FREEDOM 
or placebo (Cox Hazard Ratio 2.83, P = 
THIS 
2.7E-08).  More than twice as m
THE 
any patients receiving placebo relapsed (91 with 
THE 
BY 
placebo versus 42 with escitalopram. 
 
 
Secondary Study Outcomes 
The results of the key secondary outcomes (proportion of patients with >50% 
improvement in LSAS (LSAS responders), Clinical Global Impression – 
Improvement and Severity (CGI-I, CGI-S), % patients with CGI-I<2 (CGI 
responders) and % patients with CGI-S<2 (CGI-S remitters)) all improved with 
escitalopram therapy, with most improvements also being of statistical significance.  
The proportion of LSAS responders (patients with >50% change in LSAS Total 
Score) in Study 99270 was 17% greater with escitalopram 10mg daily (17.2%; 95% 
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ACT 
RELEASED 
BEEN  HEALTH 
HAS INFORMATION 
OF 
OF 
DOCUMENT 
FREEDOM 
DEPARTMENT 
THIS 
THE  THE 
BY 

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SECTION B 
 
More patients receiving escitalopram had treatment-emergent adverse events, with the 
risk statistically significantly greater in two out of three of the studies.  Total patients 
withdrawals in the two treatment groups were similar, as were withdrawals due to 
adverse events, with no statistically significant differences between the treatment 
groups in all studies.  Patient withdrawals due to lack of efficacy were significantly 
reduced with escitalopram compared with placebo in the studies at week 24 (Study 
99270: escitalopram 10mg RR 0.53, 95% CI 0.30 to 0.96, escitalopram 20mg RR 
0.38, 95% CI 0.20 to 0.75; Study 99269: RR 0.43, 95% CI 0.30 to 0.62).  In Study 
99012 at Week 12 there was a non-significance trend in favour of escitalopram (RR 
0.36, 95% CI 0.12, 1.10). 
 
 
UNDER 
 
B.8.2.5 
The clinical importance and patient-relevance of the effectiveness and 
1982 
safety outcomes 
ACT 
 
RELEASED 
Liebowitz Social Anxiety Scale (LSAS) 
BEEN 
Change in mean LSAS Total Score is the primary outcome
HEALTH   in Study 99270 and 99012.  
While a variety of measurement scales ha
HAS  ve been 
OF  developed to quantify the severity 
INFORMATION 
of SAD, the most widely used scale is t
OF  he LSAS.  It has been able to establish efficacy 
in a large number of placebo-controlled studies in SAD and is currently viewed as the 
gold standard13.  s38 DOCUMENT 
 
FREEDOM 
DEPARTMENT 
  An 
THIS  THE 
improvement of at least 1
THE  0 points on the LSAS has been suggested as showing a 
BY 
clinically relevant improvement, while patients demonstrating a >35-50% reduction in 
LSAS have been defined as treatment responders13.  Study 99270 reported patients 
achieving a >50% reduction, rather than the potentially more relevant and easier to 
obtain >35%, i.e. the ‘hurdle’ to achieve response was perhaps higher in this study 
than necessary. 
 
Interpreting the data for these disorders and determining the clinical significance of 
the results achieved can be complex. 
 
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SECTION B 
 
The patients in the trials had been sufferers of SAD for 20-24 years and the mean age 
of onset was 15-18 years.  This sample of patients closely mirrors the epidemiological 
evidence (see Attachment 2).  Patients entering into the trials had a mean LSAS at 
baseline ranging between 95.44 to 96.32, thereby, classifying patients as having 
severe SAD, (i.e. significant impairment).  At the end of 12 weeks patients on 
escitalopram achieved a mean LSAS score ranging from 55.35-62.25 and at 24 weeks 
32.28-39.80 (all results were statistically significantly better than placebo).  
Clinically, this translates into a patient improving from severe to moderate (and 
associated with less distress) or mild forms of SAD.  Given that normal volunteers 
scored LSAS<30 the results achieved by patients on escitalopram suggests a clinically 
significant improvement. 
 
UNDER 
The mean improvement, in LSAS scores in all three studies is statistically significant.  
1982 
The benefit of escitalopram was evident after 12 weeks of therapy and continued to 
ACT 
increase from 12 to 24 weeks of therapy.  In Study 99270, treatment with 
RELEASED 
escitalopram 20mg daily resulted in a difference in an adjusted mean LSAS total score 
change of -15.09 (95% CI -20.92, -9.25) at 24 we
BEEN  eks, while at 24 weeks in Study 
HEALTH 
99269 there was a benefit of –12.82 (95% CI –16.95, -8.70), both compared with 
HAS INFORMATION 
OF 
placebo.   
OF 
 
These results were also seen in the unadjusted mean change from baseline, on which 
DOCUMENT 
DEPARTMENT 
the meta-analysis was conducted.  W
FREEDOM  hen meta-analysed the mean change between 
THIS 
escitalopram versus placebo wa
THE  s -8.74 (95% CI -12.60, -4.89) at 12 weeks.  This also 
THE 
BY 
needs to be considered in light of the 24 week mean change being -14.52 for study 
99270. In all three studies and the meta-analysis at both 12 and 24 weeks, a difference 
in mean improvement of –10 on the LSAS fell within the 95% CIs for this outcome, 
providing a high level of confidence that a clinically meaningful result was obtained. 
In Study 99279, 17 to 27% more patients responded to therapy, based on the LSAS 
responders definition (risk difference 17.2%, 95% CI 7.0%, 27.5% with escitalopram 
10mg daily; risk difference 27.3%, 95% CI 17.1%, 37.6% with escitalopram 20mg 
daily), both compared with placebo at Week 24. 
 
The further improvement in the response to treatment on the LSAS scale between 12 
and 24 weeks seen in these studies suggest that the 12 weeks short-term efficacy 
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SECTION B 
 
results underestimate the fuller response to treatment observed with prolonged 
treatment to six months.  Other available clinical trial evidence indicates that further 
mean improvement in the symptoms of SAD as measured on the LSAS total score 
beyond six months is likely13.  Thus it would be expected that improvement much 
greater than a 10 point change on the LSAS scale would be seen if treatment duration 
was extended, given that statistically and clinically significant improvements of 11 
points (Study 99269) and 15 points (escitalopram 20mg daily, Study 99270) were 
seen in the 24 week studies.  
 
 
Clinical Global Impression– Improvement (CGI-I) and Severity (CGI-S) 
CGI-I score results are secondary study outcomes in all the studies.  The CGI-I scale 
UNDER 
has been used to identify responders to therapy, specifically patients reporting a score 
1982 
of 1 or 2 (very much or much improved) on the CGI-I scale have been defined as 
ACT 
responding to therapy.  Patients reporting a CGI-S score of <2 have been defined as 
RELEASED 
remitters (i.e achieving disease remission).  While these global scales are not 
recommended as primary scales, they may be use
BEEN  ful as a secondary scale to help 
HEALTH 
judge the clinical relevance of the finding13.   
HAS INFORMATION 
OF 
 
OF 
The percentage of patients with CGI-I<2 was greater with escitalopram than placebo 
in the two treatment studies in which it was measured.  In the meta-analysis of Study 
DOCUMENT 
DEPARTMENT 
99270 and 99012 there was a 46%
FREEDOM  improvement with escitalopram compared with 
THIS 
placebo (RR 1.46, 95% CI 1.24, 1.71)
THE 
.  Significant improvement in response beyond 
THE 
BY 
12 weeks did not occur.  In Study 99270 remission based on the CGI-S scale was also 
assessed, with significantly more patients achieving remission at Weeks 12 and 24 
with both 10mg and 20mg escitalopram daily.  The improvement was 83-92% greater 
from Weeks 12-24 with escitalopram 10mg compared with placebo (Week 12: RR 
1.83, 95% CI 1.14, 2.94; Week 24: RR 1.92, 95% CI 1.33, 2.77).  A 103-137% greater 
improvement was seen with escitalopram 20mg daily (Week 12: RR 2.03, 95% CI 
1.27, 3.22; Week 24: 2.37, 95% CI 1.67, 3.38; both versus placebo) 
 
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SECTION B 
 
 
s22
UNDER 
1982 
 
ACT 
The impact of co-morbidities on the effectiveness of treatment 
RELEASED 
The clinical trials excluded patients with co-morbidities, as recommended in clinical 
trials guidelines for SAD13.  However approxim
BEEN  ately 50%-82.3% of patients with 
HEALTH 
social phobia have comorbid mental, drug or alcohol problems.28 29  Up to 23.6% of 
HAS INFORMATION 
OF 
patients who present with social phobia have alcohol abuse problems; conversely, 
OF 
many patients presenting for treatment of substance abuse problems meet the criteria 
for social phobia.30  Studies have shown that alcohol-related disorders occur twice as 
DOCUMENT 
DEPARTMENT 
often in those affected by SAD than in those w
FREEDOM 
ithout.18 31  Social phobia usually 
THIS 
precedes alcohol abuse and a
THE bout 20% of those treated for alcohol-related disorders 
THE 
BY 
have SAD.32  If undetected, the risk of rapid relapse is high, since psychosocial 
treatments that are often a central aspect of treating alcohol abuse may be difficult or 
impossible to attend. Importantly, when SAD is treated in alcohol abusers, both social 
anxiety and alcohol use appear to improve.  
 
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SECTION B 
 
Longitudinal data show that: 
•  Social phobia precedes approximately 70 percent of these comorbid 
conditions, suggesting that some comorbid conditions arise in response to 
the phobia18 33 
•  Social phobia may be a risk factor for other mental health issues16 34 and is 
also associated with a more severe course and character of subsequent 
depressive illness35 
•  The presence of comorbidity in social phobia has been associated with an 
increased lifetime incidence of suicidal ideation and suicide attempts.18  
•  Comorbid disorders, particularly major depression, tend to be more 
prevalent in patients with an earlier onset of SAD and are associated with 
exacerbated disability and lower quality of life36. 
UNDER 
 
1982 
In an Australian study 21% of the people who met criteria for any mental disorder met 
ACT 
criteria for three or more current disorders, and they accounted for 33% of the 
RELEASED 
disability days and for 37% of the service use.37 Comorbidity has serious 
BEEN 
consequences and, because of the linear nature of the relationships, is unlikely to be 
HEALTH 
an artefact of the method of inquiry. 
HAS INFORMATION 
OF 
 
OF 
The co-occurrence of SAD and MDD is associated with greater impairment than SAD 
alone.38  In a study that compared patients with SAD alone, patients with SAD and 
DOCUMENT 
FREEDOM 
DEPARTMENT 
depression (MDD, dysthymia, or depressive disorder not otherwise specified (NOS)), 
THIS  THE 
and patients with SAD
THE  and comorbid anxiety disorders, those with SAD and 
BY 
depression had poorer overall functioning.39  Furthermore, patients in the SAD and 
depression group reported an earlier age of onset of their SAD than did patients in the 
other two groups and had more severe social anxiety symptoms than patients in the 
SAD alone group. 
 
Attachment 8 presents the clinical trial evidence (1 trial) regarding escitalopram 
treating people with SAD and comorbidities (with depression being the largest co-
morbidity). Many of the symptoms of SAD overlap with those of depression and other 
anxiety disorders40.  Individuals who present with anxiety, depression, alcohol- or 
substance-related disorders should be considered at high risk of undetected SAD.  The 
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UNDER 
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ACT 
RELEASED 
BEEN  HEALTH 
HAS INFORMATION 
OF 
OF 
DOCUMENT 
FREEDOM 
DEPARTMENT 
THIS 
THE  THE 
BY 

---

UNDER 
1982 
ACT 
RELEASED 
BEEN  HEALTH 
HAS INFORMATION 
OF 
OF 
DOCUMENT 
FREEDOM 
DEPARTMENT 
THIS 
THE  THE 
BY 

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SECTION B 
 
 
B.8.2.6 
The consistency of results over the three trials presented 
The results in the three studies presented were generally consistent.  All efficacy 
outcomes improved with escitalopram therapy, with most results achieving statistical 
significance.  This was particularly evident with the primary outcome, difference in 
mean change in LSAS Total Score.  There was generally a greater improvement with 
escitalopram 20mg daily compared with 10mg daily (Study 99270).  Results achieved 
at 24 weeks were generally greater than those achieved after 12 weeks of therapy 
(Study 99270 and 99012).   
 
Study 99012 was a relapse prevention study and thus the study design differed from 
the other two treatment studies.  Prior to randomisation into this study, patients had 
received open-label escitalopram for 12 weeks, with responders then randomised to 
UNDER 
receive either escitalopram or placebo.  Despite this difference in study design, the 
1982 
results occurring in this study were generally consistent with the other two studies (in 
ACT 
which all patients were randomised to therapy, not specifically responders). 
RELEASED 
 
BEEN 
 
HEALTH 
HAS 
OF 
 
 
B.8.2.7  Classification of the therapeutic profile of escitalopram  
INFORMATION 
OF 
Escitalopram has been demonstrated to be therapeutically superior to the comparator 
placebo, in Section B.6 and B.8, due to greater comparative effectiveness.  The 
DOCUMENT 
comparative safety is considered similar/non-inferior.  While treatment-emergent 
FREEDOM 
DEPARTMENT 
adverse events are gr
THIS eater with escitalopram than placebo (as would be expected of an 
THE  THE 
active treatment), total patient withdrawals and withdrawals due to adverse events are 
BY 
similar in the treatment studies.  Withdrawals due to lack of efficacy were statistically 
significantly greater with placebo in the two longer term studies, in the 12 week meta-
analysis and there was a strong trend towards significance in the 12 week study. 
s22
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FOI 4150 - Document 8
Lexapro® Product Information 07/2007 
 
 
PRODUCT INFORMATION 
 
LEXAPRO® FILM-COATED TABLETS 
LEXAPRO® ORAL SOLUTION 
 
 
NAME OF THE MEDICINE 
 
Escitalopram oxalate 
 
Chemical name: 
S(+)-1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile 
hydrogen oxalate.   
 
CAS number: 
UNDER 
219861-08-2 
 
1982 
Molecular formula: 
ACT 
C20H21FN2O, C2H2O4 
RELEASED 
 
Molecular weight: 
414.42 
BEEN  HEALTH 
 
Structural formula: 
HAS INFORMATION 
OF 
 
OF 
 
NC
O
DOCUMENT 
CH2CH2CH2N(CH3)2     , HOOCCOOH
FREEDOM 
DEPARTMENT 
THIS 
THE  THE 
BY 
F
 
 
 
DESCRIPTION 
 
Escitalopram is the active enantiomer (S-enantiomer) of citalopram.  Escitalopram oxalate 
is a fine white to yellow, crystalline material. 
 
Escitalopram  oxalate  is  sparingly  soluble  in  water,  slightly  soluble  in  acetone,  soluble  in 
ethanol and freely soluble in methanol.  No polymorphic forms have been detected. 
 
Lexapro 10 mg tablets are oval, white, scored, film-coated tablets marked with "E” and “L" 
on one side.  
 
Lexapro 20 mg tablets are oval, white, scored, film-coated tablets marked with "E” and “N" 
on one side. 
 
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FOI 4150 - Document 8
Lexapro® Product Information 07/2007 
Lexapro  tablets  contain  the  following  excipients:  cellulose  -  microcrystalline,  silica  - 
colloidal  anhydrous,  talc  -  purified,  croscarmellose  sodium,  magnesium  stearate, 
hypromellose, macrogol 400 and titanium dioxide. 
Lexapro  oral  solution  is  a  clear,  nearly  colourless  to  yellowish  solution.    It  contains  the 
following excipients: sodium hydroxide and purified water. 
PHARMACOLOGY 
Pharmacological actions 
Biochemical and behavioural studies have shown that escitalopram is a potent inhibitor of 
serotonin (5-HT)-uptake (in vitro IC50 2nM). 
The  antidepressant  action  of  escitalopram  is  presumably  linked  to  the  potentiation  of 
serotonergic activity in the central nervous system (CNS) resulting from its inhibitory effect 
on the reuptake of 5-HT from the synaptic cleft. 
UNDER 
Escitalopram  is  a  highly  selective  Serotonin  Reuptake  Inhibitor  (SSRI).  On  the  basis  of 
1982 
in vitro  studies,  escitalopram  had  no,  or  minimal  effect  on  noradrenaline  (NA),  dopamine 
(DA) and gamma aminobutyric acid (GABA) uptake. 
ACT 
RELEASED 
In contrast to many tricyclic antidepressants and some of the SSRIs, escitalopram has no 
or  very  low  affinity  for  a  series  of  receptors  including  5-HT1A,  5-HT2,  DA  D1  and  DA  D2 
BEEN 
receptors, 1-, 2-, -adrenoceptors, histamine H1, musca
HEALTH rine cholinergic, benzodiazepine, 
and  opioid  receptors.    A  series  of  functional  in  vitro  tests  in  isolated  organs  as  well  as 
HAS 
OF 
functional in vivo tests have confirmed the lack of recep
INFORMATION  tor affinity. 
OF 
Escitalopram  has  high  affinity  for  the  primary  binding  site  and  an  allosteric  modulating 
effect on the serotonin transporter. 
DOCUMENT 
Allosteric modulation of the serotonin transporter enhances binding of escitalopram to the 
FREEDOM 
DEPARTMENT 
primary binding site, resulting in more complete serotonin reuptake inhibition. 
THIS 
THE  THE 
Escitalopram  is  the  S-enantiomer  of  the  racemate  (citalopram)  and  is  the  enantiomer  to 
BY 
which  the  therapeutic activity  is  attributed.   Pharmacological  studies  have  shown  that  the 
R-enantiomer  is  not  inert  but  counteracts  the  serotonin-enhancing  properties  of  the  S-
enantiomer in citalopram.
In  healthy  volunteers  and  in  patients  escitalopram  did  not  cause  clinically  significant 
changes in vital signs, ECGs, or laboratory parameters. 
S-demethylcitalopram, the main plasma metabolite, attains about 30% of parent compound
levels  after  oral  dosing  and  is  about  5-fold  less  potent  at  inhibiting  5-HT  reuptake  than
escitalopram  in  vitro.  It  is  therefore  unlikely  to  contribute  significantly  to  the  overall
antidepressant effect.
Pharmacokinetics 
Absorption 
Data  specific  to  escitalopram  are  unavailable.  Absorption  is  expected  to  be  almost 
complete  and  independent  of  food  intake  (mean  Tmax  is  4  hours  after  multiple  dosing). 
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Lexapro® Product Information 07/2007 
 
While the absolute bioavailability of escitalopram has not been studied, it is unlikely to differ 
significantly from that of racemic citalopram (about 80%). 
 
Distribution 
The apparent volume of distribution (Vd,/F) after oral administration is about 12 to 26 L/kg. 
The  binding  of  escitalopram  to  human  plasma  proteins  is  independent  of  drug  plasma 
levels and averages 55%. 
 
Metabolism 
Escitalopram  is  metabolised  in  the  liver  to  the  demethylated  and  didemethylated 
metabolites.  Alternatively,  the  nitrogen  may  be  oxidised  to  form  the  N-oxide  metabolite. 
Both parent and metabolites are partly excreted as glucuronides. Unchanged escitalopram 
is the predominant compound in plasma. After multiple dosing the mean concentrations of 
the  demethyl  and  didemethyl  metabolites  are  usually  28  -  31%  and  <  5%  of  the 
escitalopram  concentration,  respectively.  Biotransformation  of  escitalopram  to  the 
demethylated  metabolite  is  mediated  by  a  combination  of  CYP2C19,  CYP3A4  and 
CYP2D6. 
 
UNDER 
Elimination 
1982 
The  elimination  half-life  (t½)  after  multiple  dosing  is  about  30  hours  and  the  oral  plasma 
clearance (Cloral) is about 0.6 L/min.  
ACT 
 
RELEASED 
Escitalopram and major metabolites are, like racemic citalopram, assumed to be eliminated 
both  by  the  hepatic  (metabolic)  and  the  renal  routes  with  the  major  part  of  the  dose 
BEEN 
excreted  as  metabolites  in  urine.  Approximately  8.0% 
HEALTH  of  escitalopram  is  eliminated 
unchanged  in  urine  and  9.6%  as  the  S-demethylcitalopram  metabolite  based  on  20  mg 
HAS 
OF 
escitalopram data. Hepatic clearance is mainly by the P
INFORMATION  450 enzyme system. 
 
OF 
The  pharmacokinetics  of  escitalopram  are  linear  over  the  clinical  dosage  range.  Steady 
state plasma levels are achieved in about 1 week.  Average steady state concentrations of 
50 nmol/L (range 20 to 125 nmol/L) are achieved at a daily dose of 10 mg. 
DOCUMENT 
 
FREEDOM 
DEPARTMENT 
Reduced hepatic function 
THIS 
In  patients  with  mild  or  moderate
THE   hepatic impairment (Child-Pugh Criteria A and B), the 
THE 
half-life of escitalopram was about twice as long and the exposure was about 60% higher 
BY 
than  in  subjects  with  normal  liver  function  (see  PRECAUTIONS  and  DOSAGE  AND 
ADMINISTRATION). 
 
Reduced renal function 
While there is no specific data,  the use of  escitalopram in  reduced renal function may be 
extrapolated  from  that  of  racemic  citalopram.  Escitalopram  is  expected  to  be  eliminated 
more  slowly  in  patients  with  mild  to  moderate  reduction  of  renal  function  with  no  major 
impact on the escitalopram concentrations in serum. At present no information is available 
for  the  treatment  of  patients  with  severely  reduced  renal  function  (creatinine  clearance 
< 20 mL/min). 
 
Elderly patients (> 65 years) 
Escitalopram  pharmacokinetics  in  subjects  >  65  years  of  age  were  compared  to  younger 
subjects in  a single-dose and a multiple-dose study.  Escitalopram AUC and half-life were 
increased  by  approximately  50%  in  elderly  subjects,  and  Cmax  was  unchanged.  10  mg  is 
the recommended dose for elderly patients.  
 
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FOI 4150 - Document 8
Lexapro® Product Information 07/2007 
 
Gender  
In a multiple-dose study of escitalopram (10 mg/day for 3 weeks) in 18 male (9 elderly and 
9  young)  and  18  female  (9  elderly  and  9  young)  subjects,  there  were  no  differences  in 
AUC,  Cmax  and half-life  between  the  male  and  female  subjects.  No  adjustment  of  dosage 
on the basis of gender is needed. 
 
Polymorphism 
It has been observed that poor metabolisers with respect to CYP2C19 have twice as high a 
plasma  concentration of escitalopram as extensive metabolisers. No  significant change in 
exposure was observed in poor metabolisers with respect to CYP2D6 (see DOSAGE AND 
ADMINISTRATION). 
 
 
CLINICAL TRIALS 
 
Lexapro  should  not  be  used  for  the  treatment  of  major  depression,  generalised 
anxiety  disorder,  social  anxiety  disorder  and  obsessive-compulsive  disorder  in 
children and adolescents under the age of 18 years since the safety and  efficacy in 
UNDER 
this population have not been established. 
 
1982 
Major Depression 
ACT 
Lexapro should not be used in the treatment of children an
RELEASED  d adolescents under the age of 
18 years. 
 
BEEN 
Two fixed-dose studies and one flexible-dose study have
HEALTH  shown escitalopram in the dose 
range 10 - 20 mg/day to be more efficacious than 
OF  placebo in the treatment of depression.  
HAS INFORMATION 
 
All  three  studies  were  randomised, 
OF  double-blind,  parallel-group,  placebo-controlled, 
multicentre studies. Two of the studies included an active reference (citalopram). All three 
studies  consisted  of  a  1-week  single-blind  placebo  lead-in  period  followed  by  an  8-week 
double-blind treatment period. 
DOCUMENT 
 
FREEDOM 
DEPARTMENT 
Patients  were  required
THIS    to  have  depression  with  a  minimum  score  of  22  on  the 
THE 
Montgomery-Åsberg  Dep
THE  ression  Rating  Scale  (MADRS)  at  both  the  screening  and 
baseline  visits.  The  MADR
BY  S  consists  of  10  items  that  measure  core  symptoms  of 
depression, such as sadness, tension, pessimism and suicidal thoughts. Each item is rated 
on  a  scale  of  0  (no  abnormality)  to  6  (severe).  The  populations  studied  were  therefore 
defined as suffering from moderate to severe depression (mean MADRS score 29). A total 
of 591 patients received escitalopram in these studies.  
 
All three studies showed escitalopram to be statistically significantly superior to placebo on 
the  ITT  LOCF  analysis  of  the  mean  change  from  baseline  in  the  MADRS  total  score 
(p≤0.01).  The  magnitude  of  the  difference  between  escitalopram  and  placebo  in  the 
MADRS change score ranged from 2.7 to 4.6 (mean of these values: 3.6). The magnitude 
of  the  difference  for  citalopram  ranged  from  1.5  to  2.5  (mean  of  these  values:  2.0).  The 
magnitude of the difference is larger with escitalopram than with citalopram. 
 
Escitalopram demonstrated a significant early difference compared to placebo from week 2 
onwards on the MADRS (week 1 in observed cases analysis). Likewise, the Clinical Global 
Impression–Improvement  items  (CGI-I)  differed  significantly  from  placebo  from  week  1 
onwards. These early differences were not seen with racemic citalopram. 
 
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FOI 4150 - Document 8
Lexapro® Product Information 07/2007 
 
In the study with two parallel escitalopram dose groups, analysis of subgroups of patients 
showed  a  trend  towards  greater  improvement  in  patients  with  severe  major  depressive 
disorder  (HAM-D  >  25)  receiving  20  mg/day  as  compared  to  10  mg/day.  The  Hamilton 
Rating Scale for Depression (HAM-D) consists of 17 to 24 items reflecting core symptoms 
of depression. Each item is scored on a 3, 4, or 5 point scale with 0 reflecting no symptoms 
and higher scores reflecting increasing symptom severity. 
 
In a fourth flexible-dose study with a similar design, the primary analysis did not distinguish 
a significant drug/placebo difference for either escitalopram or citalopram over 8 weeks on 
the MADRS change score in the LOCF dataset. However, on the basis of the OC analysis, 
both escitalopram and citalopram were significantly better than placebo (p≤0.05; difference 
between escitalopram and placebo: 2.9). 
 
Escitalopram demonstrated efficacy in the treatment of anxiety symptoms associated with 
depression. In the three positive double-blind placebo-controlled studies escitalopram was 
shown to be effective compared to placebo on the MADRS anxiety items; inner tension and 
sleep  disturbances.  Furthermore,  in  the  one  study  where  the  Hamilton  Anxiety  Scale 
(HAM-A)  and  the  anxiety  factor  of  the  Hamilton  Depression  Ratin
UNDER  g Scale (HAM-D scale) 
were used, results have shown that escitalopram was significantly better than placebo. 
1982 
 
In  a  relapse  prevention  trial,  274  patients  meeting  (DSM-IV)  criteria  for  major  depressive 
ACT 
disorder,  who  had  responded  during  an  initial  8-week  open-label  treatment  phase  with 
RELEASED 
escitalopram  10  or  20  mg/day,  were  randomised  to  continuation  of  escitalopram  at  the 
same dose, or to placebo, for up to 36 weeks of observation for relapse. Response during 
BEEN 
the open-label phase was defined as a decrease of the MADRS total score to ≤ 12.  
HEALTH 
 
HAS 
OF 
Relapse  during  the  double-blind  phase  was  defined  a
INFORMATION  s an increase of the MADRS total 
score  to  ≥  22,  or  discontinuation  due  to  insufficient  clinical  response.  Patients  receiving 
OF 
continued  escitalopram  experienced  a  significantly  longer  time  to  relapse  over  the 
subsequent  36  weeks  compared  to  those  receiving  placebo  (26%  vs.  40%;  hazard 
ratio=0.56, p=0.013).   DOCUMENT 
 
FREEDOM 
DEPARTMENT 
Further  evidence  of  long-term  efficacy  is  provided  in  a  6-month  study  which  compared 
THIS 
escitalopram  10  mg/day  to  cita
THE  lopram  20  mg/day  over  a  6-month  treatment  period.  
THE 
Analysis  of  the  primary  endpoint  (the  development  of  the  MADRS  total  scores  over 
BY 
24 weeks)  demonstrated  escitalopram  to  be  at  least  as  efficacious  as  citalopram  in  the 
long-term  treatment  of  depression.    Secondary  analyses  showed  that,  while  both 
treatments  resulted  in  numerical  improvements  in  ratings  in  the  MADRS,  HAM-A  and  the 
CGI, escitalopram was statistically superior to citalopram in several analyses, both during 
and at the end of the study. 
 
Additional  supportive  evidence  of  the  sustained  efficacy  of  escitalopram  treatment  is 
demonstrated  in  an  open-label  12-month  study.  The  efficacy  of  escitalopram  was 
maintained  throughout  the  study,  as  measured  by  the  MADRS  total  score  and  CGI-S 
score. Patients showed continued improvement, with total MADRS scores falling from 14.2 
at baseline to 5.8 at last assessment, and CGI-scores falling from 2.7 at baseline to 1.6 at 
last assessment.  
 
A  study  in  the  elderly  did  not  provide  conclusive  efficacy  results  for  escitalopram,  as  the 
reference  drug  (fluoxetine)  failed  to  differentiate from  placebo.  However,  safety  data  from 
this study showed escitalopram to be well tolerated.  
 
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FOI 4150 - Document 8
Lexapro® Product Information 07/2007 
 
Generalised Anxiety Disorder (GAD) 
Lexapro should not be used in the treatment of children and adolescents under the age of 
18 years. 
 
The  efficacy  of  escitalopram  in  the  treatment  of  Generalised  Anxiety  Disorder  was 
demonstrated  in  three  8-week  placebo-controlled  flexible-dose  studies  (10  to  20  mg  per 
day)  and  one  12-week  fixed-dose,  active-reference  (paroxetine  20  mg/day),  study  (5,  10 
and 20 mg per day).   
 
In the four studies, the mean HAM-A total scores at baseline ranged from 22.1 to 27.7 and 
the CGI-S scores were 4.2 or higher, indicating significant GAD symptomatology. 
 
In  all  three  placebo-controlled,  flexible-dose  studies,  escitalopram  was  significantly  better 
than placebo at endpoint on the primary efficacy measure (mean change from baseline to 
endpoint  in  HAM-A  total  score),  and  the  results  were  supported  by  secondary  efficacy 
measures.   
 
UNDER 
In the fixed-dose study, over a 12-week period, escitalopram in doses of 10 and 20 mg/day 
was  statistically  significantly  more  effective  than  placebo  on
1982   the  primary  measure  of 
efficacy, with an effect size at least as high as that of the reference treatment paroxetine.  
The 5 mg dose of escitalopram was numerically, but not sta
ACT  tistically significantly, superior 
to  placebo.  10  mg  escitalopram  was  statistically  significan
RELEASED  tly  superior  to  the  reference 
treatment paroxetine (LOCF) based on the HAM-A and CGI-I.   
 
BEEN 
Table 1 
HEALTH 
HAS 
OF 
Study 
Mean Treatment Difference in Change from Baseline in  
INFORMATION 
HAM-A Total Scores (LOCF)  
OF 
[95% CI] 
 
8 weeks 
12 weeks 
Flexible-dose 
DOCUMENT   
 
FREEDOM 
DEPARTMENT 
ESC to PBO 
                    -1.6*      [-3.2  ; -0.0] 
- 
THIS  THE 
Flexible-dose 
 
 
THE 
BY 
ESC to PBO 
                    -1.48*    [-2.83; -0.13] 
- 
Flexible-dose 
 
 
ESC to PBO 
                    -3.49*** [-4.93; -2.04] 
- 
Fixed-dose 
 
 
ESC5 to PBO 
- 
                      -1.29    [-3.13;  0.54] 
ESC10 to PBO 
- 
                      -2.56** [-4.40; -0.73] 
ESC20 to PBO 
- 
                      -2.15*  [-3.99; -0.31] 
PAR20 to PBO 
- 
                      -0.51   [-2.33;  1.32] 
ESC20 to PAR20 
- 
                     -1.65#   [-3.49;  0.20] 
*p0.05; **p0.01; ***p0.001; #p0.05 versus PAR 
ESC = escitalopram; ESC5 = escitalopram 5 mg; ESC10 = escitalopram 10 mg; ESC20 = escitalopram 20 mg;  
PAR20 = paroxetine 20 mg; PBO = placebo 
 
 
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FOI 4150 - Document 8
Lexapro® Product Information 07/2007 
 
In  the  pooled  analysis  of  these  three  placebo-controlled,  flexible-dose  studies  of  similar 
design,  the  mean  change  from  baseline  in  HAM-A  total  score  improved  statistically 
significantly (LOCF) over time in the escitalopram group relative to the placebo group. The 
separation from placebo was first observed at week 1 and continued through to the end of 
the  study  (week  8).  The  treatment  difference  to  placebo  at  week  8  was  –2.3  in  favour  of 
escitalopram (p0.01). 
 
The  results  of  the  primary  analysis  (pooled  data)  were  supported  by  secondary  LOCF 
analyses  (pooled  data),  where  escitalopram  was  statistically  significantly  superior  to 
placebo  on  the  HAM-A  psychic  anxiety  subscale  score  (p0.001),  the  HAM-A  item  1 
(anxious  mood)  score  (p0.001),  and  the  HAM-A  item  2  (tension)  score  (p0.01). 
Escitalopram was also more effective than placebo on the CGI-S score (p0.01) and on the 
CGI-I  score  at  week  8  (p0.001).  The  results  on  the  HAD  anxiety  subscale,  the  HAM-A 
somatic  subscale,  the  HAM-D  anxiety  scale,  the  Covi  Anxiety  Scale  (OC),  and  the  QoL 
(OC) also showed superior efficacy of escitalopram relative to placebo at week 8 (p0.05). 
 
The long-term efficacy of escitalopram in the treatment of GAD is based on the results from 
UNDER 
the  double-blind  active  comparator  study,  an  open-label  extension  study  and  a  double-
blind, randomised, placebo-controlled relapse prevention study.  
1982 
 
The  active  comparator  study  demonstrated  numerically  su
ACT  perior efficacy  of escitalopram 
over  paroxetine  both  on  the  primary  efficacy  measure  (m
RELEASED  ean  change  from  baseline  in 
HAM-A total score) and on the secondary efficacy measures (mean change from baseline 
in  HAM-A  psychic  anxiety,  CGI-S,  QoL,  HAM-A  somatic  anxiety,  HAM-A  item  1  (anxious 
BEEN 
mood), HAM-A item 2 (tension), HAM-D anxiety and Covi sc
HEALTH  ores, and mean CGI-I score) at 
week 24. For all but one (QoL) of the efficacy measures, a further improvement was seen 
HAS INFORMATION 
OF 
from week 8 to week 24. In the primary efficacy analysis, the extra improvement in mean 
HAM-A  total  score  over  the  last  16  wee
OF  ks of treatment was 2.3 points for escitalopram 
compared with 1.6 points for paroxetine. 
 
Further evidence of long-term efficacy 
DOCUMENT  is provided by an open-label extension study, which 
showed  a  beneficial  effect  of  continued  tre
DEPARTMENT  atment  with  escitalopram.  In  this  study, 
FREEDOM 
escitalopram treatment 
THIS was associated with additional improvement beyond the response 
THE 
observed during the initial 
THE  8 weeks of treatment in the lead-in studies. The mean change in 
HAM-A  total  score  from  ba
BY  seline (final visit of the lead-in study) to week 24 (LOCF) was     
-3.8, with greater improvement observed in patients who were switched from placebo in the 
lead-in study to escitalopram in the extension study (4.9 points versus 2.7 points for those 
previously treated with escitalopram). Similar positive results were seen in the analyses of 
secondary efficacy measures. 
 
Escitalopram  20  mg/day  significantly  reduced  the  risk  of  relapse  in  a  24-  to  76-week 
randomised  continuation  study  in  373  patients  who  had  responded  during  the  initial  12-
week open-label treatment. 
 
Social Anxiety Disorder (SAD) 
Lexapro should not be used in the treatment of children and adolescents under the age of 
18 years. 
 
The efficacy of escitalopram in the treatment of SAD  was demonstrated in three placebo-
controlled clinical studies. A short-term, flexible-dose (10 to 20 mg/day) study, a long-term, 
 
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FOI 4150 - Document 8
Lexapro® Product Information 07/2007 
 
fixed-dose  (5,  10,  and  20  mg/day),  active-reference  (paroxetine  20 mg/day)  study,  and  a 
relapse prevention study.   
 
Approximately two-thirds of patients in the studies were markedly or severely ill (score of 5 
or 6 on the CGI-S) and one-third were moderately ill (score of 4 or less on the CGI-S).  The 
mean baseline LSAS total score ranged from 92 to 96 in the three studies. 
 
In the short-term, flexible-dose study, over a 12-week period, escitalopram was statistically 
significantly better than placebo on the primary, and almost all the secondary measures of 
efficacy (see Table 2).   
 
In  the  placebo-controlled,  active-reference  study,  escitalopram  was  effective  both  in  the 
short- and in the long-term (see Table 2), with an effect size at least as high as that of the 
reference  treatment  paroxetine  (escitalopram  20  mg/day  was  significantly  superior  to  the 
reference  treatment  paroxetine  20  mg/day  from  week  16  and  onwards  (OC)).  Thus, 
continued  treatment  with  escitalopram  improves  treatment  response.  At  week  24  of  the 
study, all three doses of escitalopram also produced significant improvements in the LSAS 
subscale scores for fear/anxiety and avoidance, the CGI-I score (e
UNDER xcept for the 10 mg dose 
of escitalopram), the CGI-S score, and the SDS subscale scores for work, social life, and 
1982 
family life.  
 
ACT 
Table 2 
RELEASED 
Study 
Mean Treatment Difference in Change from Baseline in  
LSAS Total Scores (LOCF) 
BEEN 
[95% CI] 
HEALTH 
 
12 wee
HAS  ks  OF 
24 weeks 
INFORMATION 
Short-term, flexible-dose 
 
 
OF 
ESC to PBO 
                  -7.29**  [-12.37; -2.21] 
- 
Long-term, fixed-dose 
 
 
DOCUMENT 
ESC5 to PBO 
                  -9.18*** [-14.40; -3.95] 
              -10.46*** [-16.27; -4.66] 
FREEDOM 
DEPARTMENT 
ESC10 to PBO 
THIS                    -5.07†   [-10.32;   0.18] 
                -7.45**  [-13.29; -1.62] 
THE  THE 
ESC20 to PBO 
                -10.31*** [-15.56; -5.06] 
              -15.09*** [-20.92; -9.25] 
BY 
PAR20 to PBO 
                 -9.83***  [-15.04; -4.61] 
              -11.82*** [-17.62; -6.03] 
ESC20 to PAR20 
- 
                -3.26     [  -9.07;  2.54] 
*p0.05; **p0.01; ***p0.001; †p=0.059 
ESC = escitalopram; ESC5 = escitalopram 5 mg; ESC10 = escitalopram 10 mg; ESC20 = escitalopram 20 mg;  
PAR20 = paroxetine 20 mg; PBO = placebo 
 
 
The  beneficial  effect  of  long-term  treatment  with  escitalopram  was  also  reflected  in  the 
analyses of responders and remitters in this study. The analyses showed a further increase 
both  in  the  proportion  of  responders  and  in  the  proportion  of  remitters  from  week  12  to 
week  24,  especially  in  the  escitalopram  20  mg  group.  At  week  24,  a  statistically 
significantly  greater  proportion  of  responders  and  remitters  were  seen  in  all  three 
escitalopram  dose  groups  (except  for  the  proportion  of  responders  in  the  10  mg  group) 
than in the placebo group (p0.01) (see Tables 3 and 4). 
 
 
 
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FOI 4150 - Document 8
Lexapro® Product Information 07/2007 
 
Table 3 
Long-term, fixed-dose 
Responders (CGI-I  2) (LOCF) (%) 
study 
 
12 weeks 
24 weeks 
PBO 
41 
50 
ESC5  
   61*** 
   67** 
ESC10 
55* 
58 
ESC20 
   62*** 
   70*** 
*p0.05; **p0.01; ***p0.001 
ESC5 = escitalopram 5 mg; ESC10 = escitalopram 10 mg; ESC20 = escitalopram 20 mg; PBO = placebo 
 
Table 4 
Long-term, fixed-dose 
Remitters (CGI-S  2) (LOCF) (%) 
study 
 
12 weeks 
24 weeks 
UNDER 
PBO 
13 
19 
1982 
ESC5  
    29*** 
    39*** 
ACT 
ESC10 
 24* 
     37*** 
RELEASED 
ESC20 
   27** 
    46*** 
*p0.05; **p0.01; ***p0.001 
BEEN  HEALTH 
ESC5 = escitalopram 5 mg; ESC10 = escitalopram 10 mg; ESC20 = escitalopram 20 mg; PBO = placebo 
 
HAS 
OF 
In  the  relapse  prevention  study,  the  primary  effica
INFORMATION  cy  analysis  showed  a  statistically 
significantly  superior  effect  of  escitalopram  relative  to  placebo  on  the  time  to  relapse  of 
OF 
SAD  (log-rank  test,  p0.001).  Furthermore,  patients  treated  with  escitalopram  had  fewer 
protocol-defined relapses than those treated with placebo.  In addition, patients treated with 
escitalopram showed a further improve
DOCUMENT  ment in mean LSAS total score during the double-
blind  period,  while  patients  treated  with  place
DEPARTMENT  bo showed deterioration. Escitalopram was 
FREEDOM 
also  statistically significan
THIS  tly superior to placebo at week 24 on all the secondary efficacy 
THE 
measures  in  this  study:  th
THE  e LSAS total score, the LSAS subscale scores for fear/anxiety 
and  avoidance,  the  CGI-S
BY  score, and the SDS subscale scores for work, social life, and 
family life (p0.001). 
 
Obsessive-Compulsive Disorder (OCD) 
Lexapro should not be used in the treatment of children and adolescents under the age of 
18 years. 
 
Efficacy  of  escitalopram  in  the  treatment  of  OCD  was  investigated  in  two  clinical  trials,  a 
24-week  placebo-controlled,  fixed-dose  study  (with  efficacy  assessments  at  week 12  and 
week 24) and a 16 + 24-week placebo-controlled relapse prevention study. 
 
Patients  included  in  these  studies  were  male  and  female  outpatients  aged 18  –  65  years 
with  a  diagnosis  of  OCD  according  to  the  Diagnostic  and  Statistical  Manual  of  Mental 
Disorders (DSM-IV-TR) criteria and a pre-defined minimum score of 20 on the Yale-Brown 
Obsessive-Compulsive Scale (Y-BOCS).  Patients had actual baseline Y-BOCS scores of 
approx. 27, indicating significant OCD symptomatology.  A structured clinical interview, the 
 
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FOI 4150 - Document 8
Lexapro® Product Information 07/2007 
 
Mini  International  Neuropsychiatric  Interview  (MINI),  was  used  to  assist  in  the  diagnosis 
and  to  exclude  relevant  psychiatric  comorbidities.    In  order  to  avoid  the  confounding 
variable  of  significant  concomitant  depression,  patients  with  more  than  mild  depressive 
symptoms, i.e. a score of 22 or more on the Montgomery-Åsberg Depression Rating Scale 
(MADRS),  were  excluded.    To  ensure  a  relatively  homogenous  population  with  OCD, 
patients currently diagnosed with any other psychiatric disorders as per Axis I of DSM-IV-
TR or any clinically significant unstable medical illness were also excluded. 
 
Results  at  week  12  of  the  24-week  placebo-controlled,  fixed-dose  study  are  shown  in 
Tables  5  and  6.    In  the  short-term  (12 weeks),  20  mg/day  escitalopram  separated  from 
placebo on the Y-BOCS total score.  
 
Table 5 
Long-term (24 weeks) fixed-
Mean Change from Baseline to Week 12 in  
dose study  
Y-BOCS Total Score (FAS, LOCF, ANCOVA)   
[95% CI] 
ESC10 to PBO 
-1.97  [-3.97; 0.02] 
UNDER 
ESC20 to PBO 
-3.21*  [-5.19; -1.23] 
1982 
*p0.01 
ACT 
ESC10 = escitalopram 10 mg; ESC20 = escitalopram 20 mg; PBO = placebo 
 
RELEASED 
Furthermore,  escitalopram  20  mg/day  was  significantly  more  efficacious  than  placebo  on 
the  Y-BOCS  subscale  of  rituals  at  week  12.    Both  escitalopram  10 mg/day  and 
BEEN 
escitalopram  20 mg/day  were  significantly  more  efficaciou
HEALTH  s than placebo on the Y-BOCS 
subscale  of  obsessions  as  well  as  on  the  NIMH-OCS  total  score,  CGI-I  score  and  CGI-S 
HAS INFORMATION 
OF 
score.  
 
OF 
Table 6 
Long-term 
Mean Change from Baseline to Week 12 (FAS, LOCF, ANCOVA)   
DOCUMENT 
(24 weeks) fixed-
[95% CI] 
DEPARTMENT 
dose study  
FREEDOM 
Y-BOCS 
Y-BOCS 
NIMH-OCS 
CGI-I Score  
CGI-S Score  
THIS 
Obsessional  Compulsive 
Score  
THE  THE 
Subscore  
Subscore  
BY 
ESC10 to PBO 
-1.15* 
-1.01 
-1.01** 
-0.36* 
-0.41* 
[-2.20; -0.10] 
[-2.04; 0.01] 
[-1.70; -0.33] 
[-0.66; -0.06] 
[-0.72; -0.09] 
ESC20 to PBO 
-2.05*** 
-1.34** 
-1.40*** 
-0.53*** 
-0.64*** 
[-3.10; -1.01] 
[-2.37; -0.32] 
[-2.08; -0.72] 
[-0.83; -0.23] 
[-0.95; -0.33] 
*p0.05; **p0.01; ***p0.001 
ESC10 = escitalopram 10 mg; ESC20 = escitalopram 20 mg; PBO = placebo 
 
Results  after  24  weeks  showed  that  both  escitalopram  10  mg/day  (p<0.05)  and 
escitalopram  20  mg/day  (p<0.01)  were  significantly  more  efficacious  than  placebo  as 
measured  by  the  primary  outcome  measure,  the  Y-BOCS  total  score,  as  well  as  on  the 
secondary  subscales  of  Y-BOCS  (obsessions  and  rituals)  and  the  NIMH-OCS  score 
(escitalopram 10 mg/day (p<0.01) and escitalopram 20 mg/day (p<0.001)). 
 
 
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FOI 4150 - Document 8
Lexapro® Product Information 07/2007 
 
Table 7 
Long-term (24 weeks) fixed-
Mean Change from Baseline to Week 24 in  
dose study  
Y-BOCS Total Score (FAS, LOCF, ANCOVA)  
[95% CI] 
ESC10 to PBO 
-2.56*  [-4.93; -0.20] 
ESC20 to PBO 
-3.55** [-5.90; -1.20] 
ESC (10 or 20 mg) vs PBO: *p0.05; **p0.01 
ESC10 = escitalopram 10 mg; ESC20 = escitalopram 20 mg; PBO = placebo 
 
The beneficial efficacy of long-term treatment with escitalopram was also demonstrated by 
the analyses of responders and remitters in this study as shown in Tables 8 and 9. 
 
Table 8 
Long-term (24 weeks) fixed-
Responders (CGI-I  2) (LOCF) (%)  
dose study 
12 weeks 
24 weeks 
PBO 
38.9 
38.1 
UNDER 
ESC10 
50 
58* 
ESC20 
57.9* 
1982  56.1* 
ESC (10 or 20 mg) vs PBO: *p0.01 
ACT 
ESC10 = escitalopram 10 mg; ESC20 = escitalopram 20 mg; PBO = placebo 
 
RELEASED 
Table 9 
Long-term (24 weeks) fixed-
Remitters (CGI-S  2) (LOCF) (%) 
BEEN  HEALTH 
dose study 
12 weeks 
24 weeks 
HAS INFORMATION 
OF 
PBO 
11.5 
26.5 
OF 
ESC10 
24.1* 
41.1* 
ESC20 
28.1** 
38.6 
ESC (10 or 20 mg) vs PBO: *p0.05; **p0.01 
DOCUMENT 
ESC10 = escitalopram 10 mg; ESC20 = escitalopram 20 mg; PBO = placebo 
FREEDOM 
DEPARTMENT 
 
THIS 
Maintenance  of  efficacy  and  prevention  of  relapse  were  investigated  in  the  relapse 
THE  THE 
prevention  study.  This  24-week  relapse  prevention  study  was  preceded  by  a  16-week 
BY 
open-label period with patients initially receiving escitalopram 10 mg/day.  In case of lack of 
efficacy  (as  judged  by  the  investigator),  the  dose  could  be  increased  to  a  maximum  of 
20 mg/day.    If  dose-limiting  adverse  effects  occurred,  it  was  permissible  to  decrease  the 
dose  to  10 mg/day.    Thus  the  dose  of  escitalopram  was  flexible  at  10  -  20  mg/day  from 
week 2 to 12.  Subsequently, the dose was fixed at the dose received at the end of week 
12 until week 16 to allow stabilisation of the patient on this dose.  Responders to treatment 
were defined as patients with a decrease in Y-BOCS total score from baseline by  25% at 
week  16,  and  remitters  were  defined  as  Y-BOCS  ≤ 10.    See  Table  10  for  responder  and 
remitter rates at the end of the 16-week open-label phase. 
 
Table 10 
Relapse prevention study 
Responders 
Remitters 
(Reduction of Y-BOCS ≥ 25%) 
(Y-BOCS  10)  
(16-week open-label, flexible-
(APTS I, LOCF) 
(APTS I, LOCF) 
dose phase) 
(%) 
(%) 
ESC 
74.4 
34.0 
ESC = escitalopram 10 & 20 mg 
 
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FOI 4150 - Document 8
Lexapro® Product Information 07/2007 
 
Responders  at  the  end  of  the  above  16-week  open-label  treatment  phase  (escitalopram 
10 mg:  30  responders;  escitalopram  20  mg:  133  responders)  entered  the  24-week 
randomised, double-blind placebo-controlled relapse prevention phase.  Both escitalopram 
10 mg/day  (p=0.014)  and  20  mg/day  (p<0.001)  showed  significantly  fewer  relapses  as 
seen in Table 11.  
 
Table 11 
Relapse prevention study 
n 
Number of relapses 
% relapsed 
(24-week double-blind phase) 
10 mg dose group 
ESC10 
30 
3 
10.00* 
PBO 
20 
7 
35.00 
20 mg dose group 
ESC20 
133 
35 
  26.32** 
PBO 
137 
74 
54.01 
10 - 20 mg dose group 
ESC 
163 
38 
  23.31** 
PBO 
157 
81 
51.59 
UNDER 
ESC (10 or 20 mg) vs PBO: *p0.05; **p0.001 
1982 
ESC10 = escitalopram 10 mg; ESC20 = escitalopram 20 mg; ESC = escitalopram 10 & 20 mg; PBO = placebo 
 
ACT 
 
RELEASED 
INDICATIONS 
 
Treatment of major depression. 
BEEN  HEALTH 
Treatment of social anxiety disorder (social phobia). 
Treatment of generalised anxiety disorde
HAS r. 
INFORMATION 
OF 
Treatment of obsessive-compulsive disorder. 
OF 
 
 
CONTRAINDICATIONS 
DOCUMENT 
 
FREEDOM 
DEPARTMENT 
Hypersensitivity  to  citalopram,  escitalopram  and  any  excipients  in  Lexapro  (see 
THIS 
DESCRIPTION).  
THE  THE 
 
BY 
Monoamine  Oxidase  Inhibitors  -  Cases  of  serious  reactions  have  been  reported  in 
patients  receiving  an  SSRI  in  combination  with  a  monoamine  oxidase  inhibitor  (MAOI)  or 
the reversible MAOI (RIMA), moclobemide, and in patients who have recently discontinued 
an SSRI and have been started on a MAOI (see Interactions with other medicines). Some 
cases presented with features resembling serotonin syndrome (see ADVERSE EFFECTS). 
 
Escitalopram should not be used in combination with a MAOI. Escitalopram may be started 
14 days after discontinuing treatment with an irreversible MAOI and at least one day after 
discontinuing  treatment  with  the  reversible  MAOI  (RIMA),  moclobemide.  At  least  14  days 
should elapse after discontinuing escitalopram treatment before starting a MAOI or RIMA. 
 
Pimozide  -  Concomitant  use  in  patients  taking  pimozide  is  contraindicated  (see 
Interactions with other medicines). 
 
Page 12 of 28 
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FOI 4150 - Document 8
Lexapro® Product Information 07/2007 
 
PRECAUTIONS 
 
Clinical worsening and suicide risk - The risk of suicide attempt is inherent in depression 
and  may  persist  until  significant  remission  occurs.    This  risk  must  be  considered  in  all 
depressed patients. 
 
Patients  with  depression may  experience  worsening  of  their  depressive  symptoms  and/or 
the  emergence  of  suicidal  ideation  and  behaviours  (suicidality)  whether  or  not  they  are 
taking  antidepressant  medications,  and  this  risk  may  persist  until  significant  remission 
occurs.  As  improvement  may  not  occur  during  the  first  few  weeks  or  more  of  treatment, 
patients should be closely monitored for clinical worsening and suicidality, especially at the 
beginning  of  a  course  of  treatment,  or  at  the  time  of  dose  changes,  either  increases  or 
decreases.  Consideration should be given to changing the therapeutic regimen, including 
possibly  discontinuing  the  medication,  in  patients  whose  depression  is  persistently  worse 
or  whose emergent  suicidality  is  severe,  abrupt  in  onset,  or  was not  part  of  the  patient’s 
presenting symptoms.  
 
Patients  (and  caregivers  of  patients)  should be  alerted about  the 
UNDER  need to monitor for any 
worsening  of  their  condition  and/or  the  emergence  of  suicidal  ideation/behaviour  or 
1982 
thoughts  of  harming  themselves  and  to  seek  medical  advice  immediately  if  these 
symptoms are present.  
ACT 
 
RELEASED 
Patients  with  comorbid  depression  associated  with  other  psychiatric  disorders  being 
treated  with  antidepressants  should  be  similarly  observed  for  clinical  worsening  and 
BEEN 
suicidality. 
HEALTH 
 
HAS 
OF 
Patients with a history of suicide-related events, or tho
INFORMATION  se exhibiting a significant degree of 
suicidal  ideation  prior  to  commencement  of  treatment,  are  at  greater  risk  of  suicidal 
OF 
thoughts or suicide attempts, and should receive careful monitoring during treatment.  
 
Pooled  analyses  of  24  short-term  (4  to  16-week),  placebo-controlled  trials  of  nine 
DOCUMENT 
antidepressant medicines (SSRIs and others) in 4,400 children and adolescents with major 
FREEDOM 
DEPARTMENT 
depressive disorder (16 trials), obsessive-compulsive disorder (4 trials), or other psychiatric 
THIS 
disorders  (4  trials)  have  revea
THE led a greater risk of adverse events representing suicidal 
THE 
behaviour or thinking (suicidality) during the first few months of treatment in those receiving 
BY 
antidepressants. The average risk of such events in patients treated with an antidepressant 
was 4%, compared with 2% of patients given placebo.  There was considerable variation in 
risk among the antidepressants, but there was a tendency towards an increase for almost 
all  antidepressants  studied.    The  risk  of  suicidality  was  most  consistently  observed  in  the 
major  depressive  disorder  trials,  but  there  were  signals  of  risk  arising  from  trials  in  other 
psychiatric indications (obsessive-compulsive disorder and social anxiety disorder) as well.  
No  suicides occurred in these trials.  It is unknown whether the suicidality  risk in  children 
and adolescent patients extends to use beyond several months.  The nine antidepressant 
medicines in the pooled analyses included five SSRIs (citalopram, fluoxetine, fluvoxamine, 
paroxetine,  sertraline)  and  four  non-SSRIs  (buproprion,  mirtazapine,  nefazodone, 
venlafaxine). 
 
Pooled analyses of short-term studies of  antidepressant medications have also shown an 
increased  risk  of  suicidal  thinking  and  behaviour,  known  as  suicidality,  in  young  adults 
aged 18 to 24 years during initial treatment (generally the first one to two months). Short-
term  studies  did  not  show  an  increase  in  the  risk  of  suicidality  with  antidepressants 
 
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compared to placebo in adults beyond the age of 24 years, and there was a reduction with 
antidepressants compared to placebo in adults aged 65 years and older. 
 
Symptoms 
of  anxiety,  agitation, 
panic 
attacks, 
insomnia, 
irritability,  hostility 
(aggressiveness),  impulsivity,  akathisia  (psychomotor  restlessness),  hypomania,  and 
mania,  have  been  reported  in  adults,  adolescents  and  children  being  treated  with 
antidepressants  for  major  depressive  disorder  as  well  as  for  other  indications,  both 
psychiatric  and  nonpsychiatric.    Although  a  causal  link  between  the  emergence  of  such 
symptoms and either worsening of depression and/or emergence of suicidal impulses has 
not been established, there is concern that such symptoms may be precursors of emerging 
suicidality. 
 
Families and caregivers of children and adolescents being treated with antidepressants for 
major depressive disorder or for any other condition (psychiatric or non psychiatric) should 
be  informed  about  the  need  to  monitor  these  patients  for  the  emergence  of  agitation, 
irritability, unusual changes in behaviour, and other symptoms described above, as well as 
the  emergence  of  suicidality,  and  to  report  such  symptoms  to  health  care  providers 
immediately.  It is particularly important that monitoring be underta
UNDER ken during the initial few 
months of antidepressant treatment or at times of dose increase or decrease.  
1982 
 
Prescriptions  for  Lexapro  should  be  written  for  the  smallest  quantity  of  tablets  consistent 
ACT 
with good patient management, in order to reduce the risk of overdose. 
RELEASED 
 
Akathisia/psychomotor  restlessness  -  The  use  of  SSRIs/SNRIs  has  been  associated 
BEEN 
with the development of akathisia, characterised by a subjectively unpleasant or distressing 
HEALTH 
restlessness and need to move often accompanied by an inability to sit or stand still. This is 
HAS 
OF 
most likely to occur within the first few weeks of treatme
INFORMATION  nt. In patients who develop these 
symptoms, increasing the dose may be detrimental. 
OF 
 
Haemorrhage  -  Bleeding  abnormalities  of  the  skin  and  mucous  membranes  have  been 
reported  with  the  use  of  SSRIs  (including  purpura,  ecchymoses,  haematoma,  epistaxis, 
DOCUMENT 
vaginal  bleeding  and  gastrointestinal  bleeding).    Lexapro  should  therefore  be  used  with 
FREEDOM 
DEPARTMENT 
caution  in  patients  concomitantly  treated  with  oral  anticoagulants,  medicinal  products 
THIS 
known  to  affect  platelet  functio
THE  n  (e.g.  atypical  antipsychotics  and  phenothiazines,  most 
THE 
tricyclic antidepressants, acetylsalicylic acid and non-steroidal anti-inflammatory medicinal 
BY 
products (NSAIDs), ticlopidine and dipyridamole) as well as  in patients with a past history 
of  abnormal  bleeding  or  those  with  predisposing  conditions.    Pharmacological 
gastroprotection should be considered for high risk patients. 
 
Hyponatraemia  -  Probably  due  to  inappropriate  antidiuretic  hormone  secretion  (SIADH), 
hyponatraemia  has  been  reported  as  a  rare  adverse  reaction  with  the  use  of  SSRIs. 
Especially elderly patients seem to be a risk group. 
 
Seizures - The drug should be discontinued in any patient who develops seizures. SSRIs 
should be avoided in patients  with unstable epilepsy and patients with controlled epilepsy 
should  be  carefully  monitored.  SSRIs  should  be  discontinued  if  there  is  an  increase  in 
seizure frequency (see Preclinical safety). 
 
Diabetes - In patients with diabetes, treatment with an SSRI may alter glycaemic control, 
possibly  due  to  improvement  of  depressive  symptoms.  Insulin  and/or  oral  hypoglycaemic 
dosage may need to be adjusted. 
 
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FOI 4150 - Document 8
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Mania - SSRIs should be used with caution in patients with a history of mania/hypomania. 
SSRIs should be discontinued in any patient entering a manic phase. 
 
ECT  (electroconvulsive  therapy)  -  There  is  limited  published  clinical  experience  of 
concurrent administration of SSRIs and ECT, therefore caution is advised. 
 
Effects on ability to drive and use machines - Escitalopram does not impair intellectual 
function  and  psychomotor  performance.    However,  as  with  other  psychoactive  drugs, 
patients should be cautioned about their ability to drive a car and operate machinery. 
 
Discontinuation  -  Discontinuation  symptoms  when  stopping  treatment  are  common, 
particularly if discontinuation is abrupt.  
 
The  risk  of  discontinuation  symptoms  may  be  dependent  on  several  factors  including  the 
duration  and  dose  of  therapy  and  the  rate  of  dose  reduction.  Dizziness,  sensory 
disturbances  (including  paraesthesia  and  electric  shock  sensations),  sleep  disturbances 
(including  insomnia  and  intense  dreams),  agitation  or  anxiety,  nausea  and/or  vomiting, 
tremor,  confusion,  sweating,  headache,  diarrhoea,  palpitations,  emotional  instability, 
UNDER 
irritability,  and  visual  disturbances  are  the  most  commonly  reported  reactions.  Generally 
these  symptoms  are mild  to moderate,  however,  in  some  patien
1982  ts they may be severe in 
intensity.  
ACT 
 
They usually occur within the first few days of discontinuing
RELEASED   treatment, but there have been 
very rare reports of such symptoms in patients who have inadvertently missed a dose. 
 
BEEN  HEALTH 
Generally  these  symptoms  are  self-limiting  and  usually  resolve  within  2  weeks,  though  in 
some individuals they may be prolonged 
HAS (2 - 3 mo
OF  nths or more). It is therefore advised that 
INFORMATION 
escitalopram  should  be  gradually  tapered  when  discontinuing  treatment  over  a  period  of 
several  weeks  or  months,  according
OF    to  the  patient’s  needs  (see  DOSAGE  AND 
ADMINISTRATION). 
 
Cardiac disease - Escitalopram has 
DOCUMENT  not been evaluated or used to any appreciable extent 
in  patients  with  a  recent  history  of  m
FREEDOM  yocardia
DEPARTMENT  l infarction or unstable heart disease.  Like 
other SSRIs,  escitalopram
THIS   causes a small decrease in heart rate.  Consequently, caution 
THE 
should  be observed when
THE   escitalopram is initiated in patients with pre-existing slow heart 
rate. 
BY 
 
Impaired  hepatic  function  -  In  subjects  with  hepatic  impairment,  clearance  of 
escitalopram  was  decreased  and  plasma  concentrations  were  increased.    The  dose  of 
escitalopram  in  hepatically  impaired  patients  should  therefore  be  reduced  (see 
Pharmacokinetics and DOSAGE AND ADMINISTRATION). 
 
Impaired  renal  function  -  Escitalopram  is  extensively  metabolised  and  excretion  of 
unchanged  drug  in  urine  is  a  minor  route  of  elimination.    At  present  no  information  is 
available  for  the  treatment  of  patients  with  severely  reduced  renal  function  (creatinine 
clearance  <  20  mL/min)  and  escitalopram  should  be  used  with  caution  in  such  patients 
(see DOSAGE AND ADMINISTRATION). 
  
Preclinical  safety  -  High  doses  of  escitalopram,  which  resulted  in  plasma  Cmax  for 
escitalopram and metabolites  at  least  8-fold  greater  than  anticipated  clinically, have  been 
associated  with  convulsions,  ECG  abnormalities  and  cardiovascular  changes  in 
experimental  animals.  Of  the  cardiovascular  changes,  cardiotoxicity  (including  congestive 
 
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FOI 4150 - Document 8
Lexapro® Product Information 07/2007 
 
heart  failure)  was  observed  in  comparative  toxicological  studies  in  rats  following  oral 
escitalopram or citalopram administration for 4 to 13 weeks and appears to correlate with 
peak  plasma  concentrations  although  its  exact  mechanism  is  not  clear.  Clinical 
experiences  with  citalopram,  and  the  clinical  trial  experience  with  escitalopram,  do  not 
indicate that these findings have a clinical correlate. 
 
Effects on fertility 
No  fertility  studies  were  performed  with  escitalopram.    However,  other  nonclinical  studies 
suggest  that  the  effects  of  escitalopram  can  be  directly  predicted  from  those  of  the 
citalopram racemate. 
 
In  rats,  female  fertility  was  unaffected  by  oral  treatment  with  citalopram  doses  which 
achieved plasma drug concentrations slightly in excess of  those expected in humans, but 
effects on male rat fertility have not been tested with adequate oral doses. 
 
Use in pregnancy 
Category C. 
No  relevant  epidemiological  data  or  well  controlled  studies  in
UNDER    pregnant  women  are 
available  for  escitalopram.  SSRIs  have  had  limited  use  in  pregnancy  without  a  reported 
1982 
increase in birth defects.  
 
ACT 
Neonates should be observed if maternal use of Lexapro continues into the later stages of 
RELEASED 
pregnancy,  particularly  in  the  third  trimester.  Abrupt  discontinuation  should  be  avoided 
during pregnancy. 
BEEN 
 
HEALTH 
Neonates  exposed  to  Lexapro,  other  SSRIs  (Selective  Serotonin  Reuptake  Inhibitors),  or 
HAS 
OF 
SNRIs  (Serotonin  Norepinephrine  Reuptake  Inhibitors)
INFORMATION  ,  late  in  the  third  trimester  have 
developed complications requiring prolonged  hospitalisation, respiratory support, and tube 
OF 
feeding.    Such  complications  can  arise  immediately  upon  delivery.    Reported  clinical 
findings  have  included  respiratory  distress,  cyanosis,  apnoea,  seizures,  temperature 
instability, feeding difficulty, vomiting, hypoglycaemia, hypotonia, hypertonia, hyperreflexia, 
DOCUMENT 
tremor, jitteriness, irritability, lethargy, constant crying, somnolence and difficulty sleeping.  
FREEDOM 
DEPARTMENT 
These  features  are  consistent  with  either  a  direct  toxic  effect  of  SSRIs  and  SNRIs  or, 
THIS 
possibly,  a  drug  discontinuatio
THE n  syndrome.    In  the  majority  of  cases  the  complications 
THE 
begin immediately or soon (< 24 hours) after delivery. 
BY 
 
Oral treatment of rats with escitalopram during organogenesis at maternotoxic doses led to 
increased  post-implantation  loss  and  reduced  foetal  weight  at  systemic  exposure  levels 
(based  on  AUC)  ca.  11-fold  that  anticipated  clinically,  with  no  effects  seen  at  6-fold.  No 
teratogenicity  was  evident  in  this  study  at  relative  systemic  exposure  levels  of  ca.  15 
(based on AUC). 
 
There were no peri/postnatal effects of escitalopram following oral dosing of pregnant rats 
(conception  through  to  weaning)  at  systemic  exposure  levels  (based  on  AUC)  ca.  2-fold 
that  anticipated  clinically.  However,  the  number  of  stillbirths  was  increased  and  the  size, 
weight and postnatal survival of offspring  were decreased at a relative systemic exposure 
level ca. 5. 
 
Because  animal  reproduction  studies  are  not  always  predictive  of  human  response,  this 
drug  should  be  used  during  pregnancy  only  if  clearly  needed  and  only  after  careful 
consideration of the risk/benefit. 
 
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Use in lactation 
It  is  expected  that  escitalopram,  like  citalopram,  will  be  excreted  into  human  breast  milk. 
Studies  in  nursing  mothers  have  shown  that  the  mean  combined  dose  of  citalopram  and 
demethylcitalopram transmitted to infants via breast milk (expressed as a percentage of the 
weight-adjusted maternal dose) is 4.4 - 5.1% (below the notional 10% level of concern).  
 
Plasma concentrations of these drugs in infants were very low or absent and there were no 
adverse  effects.  Whilst  the  citalopram  data  support  the  safety  of  use  of  escitalopram  in 
breast-feeding women, the decision to breast-feed should always be made as an individual 
risk/benefit analysis. 
 
Paediatric use (children and adolescents < 18 years) 
The  efficacy  and  safety  of  escitalopram  has  not  been  established  in  children  and 
adolescents less than 18 years of age. Consequently, escitalopram should not be used in 
children and adolescents less than 18 years of age. 
 
Use in the elderly (> 65 years) 
Escitalopram AUC and half-life were increased in subjects  65 ye
UNDER  ars of age compared to 
younger subjects in a single-dose and a multiple-dose pharmacokinetic study.  The dose of 
1982 
escitalopram  in  elderly  patients  should  therefore  be  reduced  (see  DOSAGE  AND 
ADMINISTRATION). 
ACT 
 
RELEASED 
Carcinogenicity 
No  carcinogenicity  studies  were performed with escitalopram.  However, other  nonclinical 
BEEN 
studies suggest that the effects of escitalopram can be directly predicted from those of the 
HEALTH 
citalopram racemate. 
HAS 
OF 
 
INFORMATION 
Citalopram did not show any carcinogenic activity in long-term oral studies using mice and 
OF 
rats at doses up to 240 and 80 mg/kg/day, respectively. 
 
Genotoxicity 
DOCUMENT 
No  genotoxicity  studies  were  performed  with  escitalopram.    However,  other  nonclinical 
FREEDOM 
DEPARTMENT 
studies suggest that the effects of escitalopram can be directly predicted from those of the 
THIS 
citalopram racemate. THE  THE 
 
BY 
In assays of genotoxic activity, citalopram showed no evidence of mutagenic or clastogenic 
activity. 
 
Interactions with other medicines 
MAOIs  -  Co-administration  with  MAO  inhibitors  may  cause  serotonin  syndrome  (see 
CONTRAINDICATIONS). 
 
Pimozide  -  Co-administration  of  a  single  dose  of  pimozide  2  mg  to  subjects  treated  with 
racemic  citalopram  40  mg/day  for  11  days  caused  an  increase  in  AUC  and  Cmax  of 
pimozide,  although  not  consistently  throughout  the  study.  The  co-administration  of 
pimozide and citalopram resulted in a mean increase in the QTc interval of approximately 
10  msec.    Due  to  the  interaction  with  citalopram  noted  at  a  low  dose  of  pimozide, 
concomitant  administration  of  escitalopram  and  pimozide  is  contraindicated  (see 
CONTRAINDICATIONS). 
 
 
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Serotonergic  drugs  -  Co-administration  with  serotonergic  drugs  (e.g.  tramadol, 
sumatriptan)  may  lead  to  an  enhancement  of  serotonergic  effects.  Similarly,  Hypericum 
perforatum (St John’s Wort) should be avoided as adverse interactions have been reported 
with a range of drugs including antidepressants. 
 
Lithium and tryptophan - There have been reports of enhanced effects when SSRIs have 
been  given  with  lithium  or  tryptophan  and  therefore  concomitant  use  of  SSRIs  with  these 
drugs should be undertaken with caution. 
 
Medicines  affecting  the  central  nervous  system  -  Given  the  primary  CNS  effects  of 
escitalopram,  caution  should  be  used  when it  is  taken  in  combination  with  other  centrally 
acting drugs. 
 
Medicines  lowering  the  seizure  threshold  -  SSRIs  can  lower  the  seizure  threshold. 
Caution is advised when concomitantly using other medicinal products capable of lowering 
the 
seizure 
threshold 
(e.g. 
antidepressants 
(tricyclics, 
SSRIs), 
neuroleptics 
(phenothiazines, thioxanthenes, butyrophenones), mefloquine, bupropion and tramadol). 
 
UNDER 
Hepatic  enzymes  -  Escitalopram  has  a  low  potential  for  clinically  significant  drug 
1982 
interactions.  In  vitro  studies  have  shown  that  the  biotransformation  of  escitalopram  to  its 
demethylated  metabolites  depends  on  three  parallel  pathways  (cytochrome  P450  (CYP) 
ACT 
2C19,  3A4  and  2D6).  Escitalopram  is  a  very  weak  inhibitor  of  isoenzyme  CYP1A2,  2C9, 
RELEASED 
2C19, 2E1, and 3A4, and a weak inhibitor of 2D6. 
 
Effects of other drugs on escitalopram in vivo 
BEEN  HEALTH 
The pharmacokinetics of escitalopram was not changed by co-administration with ritonavir 
HAS 
OF 
(CYP3A4  inhibitor).  Furthermore,  co-administration  wi
INFORMATION  th  ketoconazole  (potent  CYP3A4 
inhibitor) did not change the pharmacokinetics of racemic citalopram. 
OF 
 
Co-administration  of  escitalopram  with  omeprazole  (a  CYP2C19  inhibitor)  resulted  in  a 
moderate  (approximately  50%)  increase  in  plasma  concentrations  of  escitalopram  and  a 
DOCUMENT 
small but statistically significant increase (31%) in the terminal half-life of escitalopram (see 
DEPARTMENT 
also Poor metabolisers of CYP2C19 u
FREEDOM  nder DOSAGE AND ADMINISTRATION). 
 
THIS  THE 
Co-administration  of  escita
THE  lopram  with  cimetidine  (moderately  potent  general  enzyme 
inhibitor)  resulted  in  a 
BY  moderate  (approximately  70%)  increase  in  the  plasma 
concentrations of escitalopram.  
 
Thus,  caution  should  be  exercised  at  the  upper  end  of  the  dose  range  of  escitalopram 
when  used  concomitantly  with  CYP2C19  inhibitors  (e.g.  omeprazole,  esomeprazole, 
fluoxetine,  fluvoxamine,  lansoprazole,  and  ticlopidine)  or  cimetidine.    A  reduction  in  the 
dose  of  escitalopram  may  be  necessary  based  on  clinical  judgement  (see  also  Poor 
metabolisers of CYP2C19 under DOSAGE AND ADMINISTRATION). 
 
Effects of escitalopram on other drugs in vivo 
Escitalopram  is  an  inhibitor  of  the  enzyme  CYP2D6.  Caution  is  recommended  when 
escitalopram  is  co-administered  with  medicinal  products  that  are  mainly  metabolised  by 
this  enzyme,  and  that  have  a  narrow  therapeutic  index,  e.g.  flecainide,  propafenone  and 
metoprolol (when used in cardiac failure), or some CNS acting medicinal products that are 
mainly metabolised by CYP2D6, e.g. antidepressants  such as desipramine,  clomipramine 
and  nortriptyline  or  antipsychotics  like  risperidone,  thioridazine  and  haloperidol.  Dosage 
adjustment may be warranted. 
 
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FOI 4150 - Document 8
Lexapro® Product Information 07/2007 
 
Co-administration with desipramine (a CYP2D6 substrate) resulted in a twofold increase in 
plasma  levels  of  desipramine.  Therefore,  caution  is  advised  when  escitalopram  and 
desipramine are co-administered. A similar increase in plasma levels of desipramine, after 
administration of imipramine, was seen when given together with racemic citalopram.  
 
Co-administration  with  metoprolol  (a  CYP2D6  substrate)  resulted  in  a  twofold  increase  in 
the  plasma  levels  of  metoprolol.  However,  the  combination  had  no  clinically  significant 
effects on blood pressure and heart rate. 
 
The pharmacokinetics of ritonavir (CYP3A4 inhibitor) was not changed by co-administration 
with escitalopram.  
 
Furthermore,  pharmacokinetic  interaction  studies  with  racemic  citalopram  have 
demonstrated no clinically important interactions with carbamazepine (CYP3A4 substrate), 
triazolam  (CYP3A4  substrate),  theophylline  (CYP1A2  substrate),  warfarin  (CYP3A4  and 
CYP2C9 substrate), levomepromazine (CYP2D6 inhibitor), lithium and digoxin. 
 
Medicines that interfere with haemostasis (NSAIDs, aspirin, warfarin, etc) – Serotonin 
release  by  platelets  plays  an  important  role  in  haemostasis.    Th
UNDER  ere  is  an  association 
between  use  of  psychotropic  drugs  that  interfere  with  serotonin  reuptake  and  the 
1982 
occurrence  of  abnormal  bleeding.    Concurrent  use  of  an  NSAID,  aspirin  or  warfarin 
potentiates  this  risk.    Thus,  patients  should  be  cautioned  about  using  such  medicines 
ACT 
concurrently with Lexapro. 
RELEASED 
 
Alcohol - The combination of SSRIs and alcohol is not advisable. 
BEEN 
 
HEALTH 
 
HAS 
OF 
ADVERSE EFFECTS 
INFORMATION 
 
OF 
Adverse reactions observed with escitalopram are in general mild and  transient. They are 
most  frequent  during  the  first  one  or  two  weeks  of  treatment  and  usually  decrease  in 
intensity and frequency with continued treatment and generally  do not lead to a cessation 
DOCUMENT 
of  therapy.  Data  from  short-term  placebo-controlled  studies  are  presented  below.  The 
FREEDOM 
DEPARTMENT 
safety data from the long-term studies showed a similar profile. 
THIS 
 
THE  THE 
Treatment Emergent Adverse Events with an Incidence of ≥ 1% in placebo-controlled 
BY 
trials 
 
Figures marked with * in the table below indicate adverse reactions where the incidence with escitalopram is 
statistically significantly different from placebo (p<0.05). 
 
PLACEBO 
ESCITALOPRAM 
 System Organ Class and Preferred Term 
n    (%) 
 n    (%) 
 Patients Treated 
1795 
2632 
 Patients with Treatment Emergent Adverse Event 
1135 (63.2) 
1891 (71.8) 
 GASTROINTESTINAL SYSTEM DISORDERS 
   nausea 
151 (  8.4) 
481 (18.3)* 
   diarrhoea 
91  (  5.1) 
207 (  7.9)* 
   mouth dry 
74  (  4.1) 
152 (  5.8)* 
   constipation 
42  (  2.3) 
71  ( 2.7) 
* = Statistically significant difference escitalopram vs placebo (p<0.05)   
[gs] = gender specific 
 
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FOI 4150 - Document 8
Lexapro® Product Information 07/2007 
 
 
PLACEBO 
ESCITALOPRAM 
 System Organ Class and Preferred Term 
n    (%) 
 n    (%) 
   abdominal pain 
47  (  2.6) 
68  ( 2.6) 
   vomiting 
29  (  1.6) 
54  ( 2.1) 
   dyspepsia 
30  (  1.7) 
33 (  1.3) 
   flatulence 
15  (  0.8) 
31  ( 1.2) 
 CENTRAL AND PERIPHERAL NERVOUS SYSTEM DISORDERS   
   headache 
305  (17.0) 
506  (19.2) 
   dizziness 
64  (  3.6) 
147 (  5.6)* 
   paraesthesia 
13  (  0.7) 
35  (  1.3) 
   migraine 
17  (  0.9) 
23  (  0.8) 
   tremor 
15  (  0.8) 
33  (  1.3) 
  PSYCHIATRIC DISORDERS 
   insomnia 
82   (  4.6) 
245  (  9.3)* 
UNDER 
   somnolence 
62   (  3.5) 
217   (  8.2)* 
1982 
   anorexia 
12  (  0.7) 
56   (  2.1)* 
   libido decreased 
21   (  1.2) 
102   (  3.9)* 
ACT 
   anxiety 
44   (  2
RELEASED .5) 
77   (  2.9) 
   appetite decreased 
8   (  0.5) 
35   (  1.3)* 
   agitation 
BEEN 
6   (  0.3) 
33   (  1.3)* 
HEALTH 
   nervousness 
13   (  0.7) 
25   (  1.0) 
HAS INFORMATION 
OF 
   dreaming abnormal 
18   (  1.0) 
41   (  1.6) 
OF 
   impotence [gs] 
4   (  0.6) 
22   (  2.2)* 
 RESPIRATORY SYSTEM DISORDERS 
   upper respiratory tract infection 
91   (  5.1) 
96   (  3.6) 
DOCUMENT 
   coughing 
18    (  1.1) 
24   (  0.9) 
FREEDOM 
DEPARTMENT 
   rhinitis 
THIS 
81    (  4.8) 
146   (  5.5) 
THE  THE 
   sinusitis 
24    (  1.3) 
46   (  1.7) 
BY 
   pharyngitis 
44    (  2.5) 
57   (  2.2) 
   yawning 
3    (  0.2) 
58   (  2.2)* 
   bronchitis 
31    (  1.7)* 
26  (  0.9) 
 BODY AS A WHOLE - GENERAL DISORDERS 
   influenza-like symptoms 
65    (  3.6) 
87    ( 3.3) 
   fatigue 
62     (  3.5) 
230    ( 8.7)* 
   back pain 
61     (  3.4) 
74    ( 2.8) 
 SKIN AND APPENDAGES DISORDERS 
   sweating increased 
27     (  1.5) 
145    ( 5.5)* 
 MUSCULOSKELETAL SYSTEM DISORDERS 
 
 
   arthralgia 
22     (  1.2) 
27    ( 1.0) 
* = Statistically significant difference escitalopram vs placebo (p<0.05)   
[gs] = gender specific 
 
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FOI 4150 - Document 8
Lexapro® Product Information 07/2007 
 
 
PLACEBO 
ESCITALOPRAM 
 System Organ Class and Preferred Term 
n    (%) 
 n    (%) 
 REPRODUCTIVE DISORDERS, FEMALE 
   anorgasmia [gs] 
3     (  0.3) 
47    (  2.9)* 
 METABOLIC AND NUTRITIONAL DISORDERS 
 
 
   weight increase 
20     (  1.1) 
45    (  1.7) 
 REPRODUCTIVE DISORDERS, MALE 
 
 
   ejaculation disorder [gs] 
3     (  0.5) 
48    (   4.7)* 
  ejaculation failure [gs] 
1     (  0.2) 
27    (   2.7)* 
 CARDIOVASCULAR DISORDERS 
 
 
   hypertension 
24     (  1.3)* 
13    (   0.5) 
 HEART RATE AND RHYTHM DISORDERS 
 
 
   palpitation 
15     (  0.8) 
30    (   1.1) 
 SECONDARY TERMS 
 
 
UNDER 
   inflicted injury (unintended injury) 
22     (  1.2) 
23    (  0.8) 
1982 
* = Statistically significant difference escitalopram vs placebo (p<0.05)   
[gs] = gender specific 
 
ACT 
Adverse Events in Relation to Dose 
RELEASED 
 
The potential dose dependency of  common adverse events (defined as an incidence rate 
of ≥ 5% in either the 10 mg or 20 mg escitalopram groups) was examined on the basis of 
BEEN 
the  combined  incidence  of  adverse  events  in  two  fixed-d
HEALTH  ose trials. The overall incidence 
rates of adverse events in 10 mg escitalopram treated patients (66%) was similar to that of 
HAS INFORMATION 
OF 
the  placebo  treated  patients  (61%),  while  the  incidence  rate  in  20  mg/day  escitalopram 
treated  patients  was  greater  (86%). 
OF  Common  adverse  events  that  occurred  in  the 
20 mg/day escitalopram group with an incidence approximately twice that of the 10 mg/day 
escitalopram group and approximately twice that of the placebo group are shown below. 
DOCUMENT 
 
DEPARTMENT 
Incidence of common adverse ev
FREEDOM  ents* in patients with major depression receiving  
plac
THIS  ebo, 10 mg/day Lexapro, or 20 mg/day Lexapro 
THE  THE 
Adverse Event 
Placebo 
10 mg/day Lexapro 
20 mg/day Lexapro 
BY  (n=311) 
(n=310) 
(n=125) 
Insomnia 
4% 
7% 
14% 
Diarrhoea 
5% 
6% 
14% 
Dry mouth 
3% 
4% 
9% 
Somnolence 
1% 
4% 
9% 
Dizziness 
2% 
4% 
7% 
Sweating increased 
< 1% 
3% 
8% 
Constipation 
1% 
3% 
6% 
Fatigue 
2% 
2% 
6% 
Indigestion 
1% 
2% 
6% 
*adverse events with an incidence rate of at least 5% in either escitalopram group and with an incidence rate in the 
20  mg/day  escitalopram  group  that  was  approximately  twice  that  of  the  10  mg/day  escitalopram  group  and  the 
placebo group. 
 
 
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FOI 4150 - Document 8
Lexapro® Product Information 07/2007 
 
Vital Sign Changes 
Escitalopram  and  placebo  groups  were  compared  with  respect  to  (1)  mean  change  from 
baseline in vital signs (pulse, systolic blood pressure, and diastolic blood pressure) and (2) 
the  incidence  of  patients  meeting  criteria  for  potentially  clinically  significant  changes  from 
baseline in these variables.  These analyses did not reveal any clinically important changes 
in vital signs associated with escitalopram treatment. 
 
ECG Changes 
Electrocardiograms  from  escitalopram,  racemic  citalopram,  and  placebo  groups  were 
compared with respect to (1) mean change from baseline in various ECG parameters and 
(2)  the  incidence  of  patients  meeting  criteria  for  potentially  clinically  significant  changes 
from baseline in these variables. There were no clinically relevant changes in pulse rate for 
any  one  treatment  group.  In  all  treatment  groups  (including  placebo),  there  was  a  small 
increase in the mean adjusted QTcB interval: 1.8 msec for escitalopram and 2.0 msec for 
racemic  citalopram,  compared  to 1.7  msec  for  placebo.  Neither  escitalopram  nor  racemic 
citalopram  were  associated  with  the  development  of  clinically  significant  ECG 
abnormalities.  
 
UNDER 
Weight Changes 
1982 
Patients  treated  with  escitalopram  in  controlled  trials  did  not  differ  from  placebo-treated 
patients with regard to clinically important change in body weight. 
ACT 
 
RELEASED 
Laboratory Changes 
In  clinical  studies,  there  were  no  signals  of  clinically  important  changes  in  either  various 
BEEN 
serum  chemistry,  haematology,  and  urinalysis  parameters  associated  with  escitalopram 
HEALTH 
treatment  compared  to  placebo  or  in  the  incidence  of  patients  meeting  the  criteria  for 
HAS 
OF 
potentially clinically significant changes from baseline in
INFORMATION   these variables.  
 
OF 
For  abnormal  laboratory  changes  registered  as  either  uncommon  events  or  serious 
adverse  events  from  ongoing  trials  and  observed  during  (but  not  necessarily  caused  by) 
treatment  with  Lexapro,  please  see  Other  Events  Observed  during  the  Premarketing 
DOCUMENT 
Evaluation of Lexapro. 
FREEDOM 
DEPARTMENT 
 
THIS 
Other Events Observed during the 
THE 
Premarketing Evaluation of Lexapro 
THE 
 
BY 
Following  is  a  list  of  WHO  terms  that  reflect  adverse  events  occurring  at  an  incidence  of 
< 1%  and  serious  adverse  events  from  ongoing  trials.    All  reported  events  are  included 
except  those  already  listed  in  the  table  or  elsewhere  in  the  Adverse  Effects  section,  and 
those occurring in only one patient.  It is important to emphasise that, although the events 
reported occurred during treatment with Lexapro, they were not necessarily caused by it. 
 
Events are further categorised by body system and are listed below. Uncommon adverse 
events are those occurring in less than 1/100 patients but at least 1/1,000 patients.  
 
Application Site Disorders 
Uncommon: otitis externa, cellulitis. 
 
Body as a Whole 
Uncommon:  allergy,  aggravated  allergy,  allergic  reactions,  asthenia,  carpal  tunnel 
syndrome,  chest  pain,  chest  tightness,  fever,  hernia,  leg  pain,  limb  pain,  neck  pain, 
oedema, oedema of extremities, peripheral oedema, rigors, malaise, syncope, scar. 
 
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FOI 4150 - Document 8
Lexapro® Product Information 07/2007 
 
Cardiovascular Disorders, General  
Uncommon: hypertension aggravated, hypotension, hypertension, abnormal ECG.  
 
Central and Peripheral Nervous System Disorders 
Uncommon:  ataxia,  dysaesthesia,  dysequilibrium,  dysgeusia,  dystonia,    hyperkinesia, 
hyperreflexia,  hypertonia,  hypoaesthesia,  leg  cramps,  lightheadedness,  muscle 
contractions,  nerve  root  lesion,  neuralgia,  neuropathy,  paralysis,  sedation,  tetany,  tics, 
twitching, vertigo. 
 
Gastrointestinal System Disorders  
Uncommon:  abdominal  cramp,  abdominal  discomfort, belching,  bloating,  change  in  bowel 
habit,  colitis,  colitis  ulcerative,  enteritis,  epigastric  discomfort,  gastritis,  gastroesophageal 
reflux,  haemorrhoids,  heartburn,  increased  stool  frequency,  irritable  bowel  syndrome, 
melaena, periodontal destruction, rectal haemorrhage, tooth disorder, toothache, ulcerative 
stomatitis. 
 
Hearing and Vestibular Disorders  
Uncommon: deafness, earache, ear disorder, otosalpingitis, tinnitu
UNDER s. 
 
1982 
Heart Rate and Rhythm Disorders 
Uncommon: bradycardia, tachycardia.  
ACT 
 
RELEASED 
Liver and Biliary System Disorders 
Uncommon: bilirubinaemia, hepatic enzymes increased. 
BEEN 
 
HEALTH 
Metabolic and Nutritional Disorders  
HAS 
OF 
Uncommon:  abnormal  glucose  tolerance,  diabetes  me
INFORMATION  llitus, gout, hypercholesterolaemia, 
hyperglycaemia, hyperlipaemia, thirst, weight decrease, xerophthalmia. 
OF 
 
Musculoskeletal System Disorders 
Uncommon:  arthritis,  arthropathy,  arthrosis,  bursitis,  costochondritis,  fascitis  plantar, 
DOCUMENT 
fibromyalgia,  ischial  neuralgia,  jaw  stiffness,  muscle  cramp,  muscle  spasms,  muscle 
FREEDOM 
DEPARTMENT 
stiffness,  muscle  tightness,  muscle  weakness,  myalgia,  myopathy,  osteoporosis,  pain 
THIS 
neck/shoulder, tendinitis, tenosyn
THE  ovitis. 
THE 
 
BY 
Myo-, Endo- and Pericardial and Valve Disorders 
Uncommon: myocardial infarction, myocardial ischaemia, myocarditis, angina pectoris. 
 
Neoplasm 
Uncommon: female breast neoplasm, ovarian cyst, uterine fibroid. 
 
Platelet, Bleeding and Clotting Disorders 
Uncommon:  abnormal  bleeding,  predominantly  of  the  skin  and  mucous  membranes, 
including purpura, epistaxis, haematomas, vaginal bleeding and gastrointestinal bleeding.   
 
Poison Specific Terms 
Uncommon: sting. 
 
Psychiatric Disorders 
Uncommon:  aggressive  reaction,  amnesia,  apathy,  bruxism,  carbohydrate  craving, 
concentration 
impairment, 
confusion, 
depersonalisation, 
depression, 
depression 
 
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FOI 4150 - Document 8
Lexapro® Product Information 07/2007 
 
aggravated,  emotional  lability,  excitability,  feeling  unreal,  forgetfulness,  hallucination, 
hypomania,  increased  appetite,  irritability,  jitteriness,  lethargy,  loss  of  libido,  obsessive-
compulsive  disorder,  panic  reaction,  paroniria,  restlessness  aggravated,  sleep  disorder, 
snoring, suicide attempt, thinking abnormal. 
 
Red Blood Cell Disorders 
Uncommon: anaemia hypochromic, anaemia. 
 
Reproductive Disorders / Female  
Uncommon:  amenorrhoea,  atrophic  vaginitis,  breast  pain,  genital  infection,  intermenstrual 
bleeding,  menopausal  symptoms,  menorrhagia,  menstrual  cramps,  menstrual  disorder, 
premenstrual  tension,  postmenopausal  bleeding,  sexual  function  abnormality,  unintended 
pregnancy, dysmenorrhoea, vaginal haemorrhage, vaginal candidiasis, vaginitis. 
 
Reproductive Disorders / Male  
Uncommon: ejaculation delayed, prostatic disorder. 
 
Resistance Mechanism Disorders 
UNDER 
Uncommon: moniliasis genital, abscess, infection, herpes simplex, herpes zoster, infection 
1982 
bacterial, infection parasitic, infection (tuberculosis), moniliasis. 
 
ACT 
Respiratory System Disorders 
RELEASED 
Uncommon:  asthma, dyspnoea,  laryngitis, nasal congestion,  nasopharyngitis,  pneumonia, 
respiratory  tract  infection,  shortness  of  breath,  sinus  congestion,  sinus  headache,  sleep 
BEEN 
apnoea, tracheitis, throat tightness.   
HEALTH 
 
HAS 
OF 
Skin and Appendages Disorders 
INFORMATION 
Uncommon:  acne,  alopecia,  dermatitis,  dermatitis  fungal,  dermatitis  lichenoid,  dry  skin, 
OF 
eczema,  erythematous  rash,  furunculosis,  onychomycosis,  pruritus,  psoriasis  aggravated, 
rash, rash pustular, skin disorder, urticaria, verruca.  
 
DOCUMENT 
Secondary Terms 
FREEDOM 
DEPARTMENT 
Uncommon:  accidental  injury,  bite,  burn,  fall,  fractured  neck  of  femur,  alcohol  problem, 
THIS 
traumatic haematoma, cyst, foo
THE d poisoning, lumbar disc lesion, surgical intervention.    
THE 
 
BY 
Special Senses Other, Disorders 
Uncommon:  dry  eyes,  eye  irritation,  taste  alteration,  taste  perversion,  visual  disturbance, 
ear infection NOS, vision blurred.  
 
Urinary System Disorders  
Uncommon:  cystitis,  dysuria,  facial  oedema,  micturition  frequency,  micturition  disorder, 
nocturia,  polyuria,  pyelonephritis,  renal  calculus,  urinary  frequency,  urinary  incontinence, 
urinary tract infection. 
 
Vascular (Extracardiac) Disorders  
Uncommon:  cerebrovascular  disorder,  flushing,  hot  flush  [gs],  ocular  haemorrhage, 
peripheral ischaemia, varicose vein, vein disorder, vein distended. 
 
Vision Disorders  
Uncommon: accommodation abnormal, blepharospasm, eye infection, eye pain, mydriasis, 
vision abnormal, vision blurred, visual disturbance.  
 
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FOI 4150 - Document 8
Lexapro® Product Information 07/2007 
 
White Cell and Reticuloendothelial System Disorders 
Uncommon: leucopenia. 
 
In addition the following adverse reactions have been reported with racemic citalopram (all 
of which have also been reported for other SSRIs):  
 
Disorders of metabolism and nutrition – hyponatraemia, inappropriate ADH secretion (both 
especially in elderly women). 
 
Neurological disorders – convulsions, convulsions grand mal and extrapyramidal disorder, 
serotonin  syndrome  (typically  characterised  by  a  rapid  onset  of  changes  in  mental  state, 
with confusion, mania, agitation, hyperactivity, shivering, fever, tremor, ocular movements, 
myoclonus, hyperreflexia, and inco-ordination). 
 
Skin disorders - ecchymoses, angioedema. 
 
Furthermore  a  number  of  adverse  reactions  have  been  listed  for  other  SSRIs.  Although 
these  are  not  listed  as  adverse  reactions  for  escitalopram  or  citalopram,  it  cannot  be 
UNDER 
excluded  that  these  adverse  reactions  may  occur  with  escitalopram.  These  SSRI  class 
reactions are listed below: 
1982 
 
Cardiovascular disorders - postural hypotension. 
ACT 
 
RELEASED 
Hepatobiliary disorders - abnormal liver function tests. 
 
BEEN 
Neurological disorders - movement disorders.  
HEALTH 
 
HAS 
OF 
Psychiatric disorders - mania, panic attacks.  
INFORMATION 
 
OF 
Renal and urinary disorders - urinary retention. 
 
Reproductive disorders - galactorrhoea.  
DOCUMENT 
 
DEPARTMENT 
Other Events Observed During the
FREEDOM   Postmarketing Evaluation of Escitalopram 
THIS 
 
THE 
Although  no  causal  relation
THE  ship to escitalopram treatment has been found, the following 
adverse  events  have been
BY   reported in association with escitalopram treatment in at least 
3 patients  (unless  otherwise  noted)  and  not  described  elsewhere  in  the  Adverse  Effects 
section:  
 
Stomatitis,  drug  interaction  NOS,  feeling  abnormal,  hypersensitivity  NOS,  non-accidental 
overdose, injury NOS. 
 
In  addition,  although  no  causal  relationship  to  racemic  citalopram  treatment  has  been 
found,  the  following adverse  events  have  been  reported to  be  temporally  associated  with 
racemic citalopram treatment subsequent to the marketing of racemic citalopram and were 
not observed during the premarketing evaluation of escitalopram or citalopram: acute renal 
failure, akathisia, anaphylaxis, choreoathetosis, delirium, dyskinesia, epidermal necrolysis, 
erythema multiforme, gastrointestinal haemorrhage, haemolytic anaemia, hepatic necrosis, 
myoclonus,  neuroleptic  malignant  syndrome,  nystagmus,  pancreatitis,  priapism, 
prolactinaemia,  prothrombin  decreased,  QT  prolonged,  rhabdomyolysis,  spontaneous 
abortion,  thrombocytopenia,  thrombosis,  Torsades de pointes,  ventricular  arrhythmia,  and 
withdrawal syndrome. 
 
Page 25 of 28 
Page 25 of  28

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FOI 4150 - Document 8
Lexapro® Product Information 07/2007 
 
DOSAGE AND ADMINISTRATION 
 
Adults 
Escitalopram is administered as a single oral dose and may be taken with or without food.  
The oral solution can be mixed with water, orange juice or apple juice. 
Major depression 
The  recommended  dose  is  10  mg  (one  10  mg  tablet  or  1  mL  of  the  oral  solution)  once 
daily. Depending on individual patient response, the dose may be increased to a maximum 
of 20 mg (one 20 mg tablet or 2 mL of the oral solution) daily.  
 
Usually  2  -  4  weeks  are  necessary  for  antidepressant  response,  although  the  onset  of 
therapeutic  effect  may  be  seen  earlier.  The  treatment  of  a  single  episode  of  depression 
requires treatment over the acute and the medium term. After the symptoms resolve during 
acute treatment, a period of consolidation of the response is required. Therefore, treatment 
of a depressive episode should be continued for a minimum of 6 months. 
Social anxiety disorder 
The  recommended  dose  is  10  mg  (one  10  mg  tablet  or  1  mL  o
UNDER f the oral solution) once 
daily. Depending on individual patient response, the dose may be increased to a maximum 
1982 
of 20 mg (one 20 mg tablet or 2 mL of the oral solution) daily. Social anxiety disorder is a 
disease  with  a  chronic  course  and  long-term  treatment  is  therefore  warranted  to 
ACT 
consolidate response and prevent relapse. 
RELEASED 
Generalised anxiety disorder 
The  recommended  dose  is  10  mg  (one  10  mg  tablet  or  1  mL  of  the  oral  solution)  once 
BEEN 
daily. Depending on individual patient response, the dose 
HEALTH may be increased to a maximum 
of 20 mg (one 20 mg tablet or 2 mL of the oral solution) daily. Generalised anxiety disorder 
HAS INFORMATION 
OF 
is  a  disease  with  a  chronic  course  and  long-term  treatment  is  therefore  warranted  to 
consolidate response and prevent relapse
OF  . 
Obsessive-compulsive disorder 
The recommended starting dose is 10 mg (one 10 mg tablet or 1 mL of the oral solution) 
DOCUMENT 
once daily. Depending on individual patient response, the dose may be increased to 20 mg 
DEPARTMENT 
(one 20 mg tablet or 2 mL of the oral so
FREEDOM  lution) daily.  
THIS 
 
THE 
Long-term treatment has b
THE  een studied for a maximum of 40 weeks.  Patients responding to 
a 16-week open-label trea
BY tment phase were randomised to a 24-week placebo-controlled 
relapse prevention phase, receiving 10 or 20 mg escitalopram daily.  As OCD is a chronic 
disease, patients should be treated for a sufficient period to ensure that they are symptom 
free. This period may be several months or even longer. 
 
Elderly patients (> 65 years of age) 
A longer half-life and a decreased clearance have been demonstrated in the elderly. 10 mg 
(one 10 mg tablet or 1 mL of the oral solution) is the recommended maximum maintenance 
dose in the elderly (see Pharmacokinetics and PRECAUTIONS). 
 
Children and adolescents (< 18 years of age) 
Safety and efficacy have not been established in this population. Escitalopram should not 
be used in children and adolescents under 18 years of age (see PRECAUTIONS). 
 
Reduced hepatic function 
An initial dose of 5 mg (half a 10 mg tablet or 0.5 mL of the oral solution) daily for the first 
two  weeks  of  treatment  is  recommended.  Depending  on  individual  patient  response,  the 
 
Page 26 of 28 
Page 26 of  28

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FOI 4150 - Document 8
Lexapro® Product Information 07/2007 
 
dose  may  be  increased  to  10  mg  (one  10  mg  tablet  or  1  mL  of  the  oral  solution)  (see 
PRECAUTIONS). 
 
Reduced renal function 
Dosage adjustment is not necessary in patients with mild or moderate renal impairment. No 
information  is  available  on  the  treatment  of  patients  with  severely  reduced  renal  function 
(creatinine clearance < 20 mL/min) (see PRECAUTIONS). 
 
Poor metabolisers of CYP2C19 
For  patients  who  are  known  to  be  poor  metabolisers  with  respect  to  CYP2C19,  an  initial 
dose of 5 mg (half a 10 mg tablet or 0.5 mL of the oral solution) daily during the first two 
weeks of  treatment  is recommended.  Depending on individual patient response, the dose 
may  be  increased  to  10  mg  (one  10  mg  tablet  or  1  mL  of  the  oral  solution)  (see 
Pharmacokinetics and Interactions with other medicines under PRECAUTIONS). 
 
Discontinuation 
Significant numbers of discontinuation symptoms may occur with abrupt discontinuation of 
escitalopram. To minimise discontinuation reactions, tapered disco
UNDER  ntinuation over a period 
of  at  least  one  to  two weeks  is  recommended.  If  unacceptable  discontinuation  symptoms 
1982 
occur following a decrease in the dose or upon discontinuation of treatment then resuming 
the  previously  prescribed  dose  may  be  considered.  Subsequently,  the  dose  may  be 
ACT 
decreased but at a more gradual rate. 
RELEASED 
 
 
BEEN 
OVERDOSAGE 
HEALTH 
 
HAS 
OF 
In general, the main therapy for all overdoses is supporti
INFORMATION  ve and symptomatic care. 
 
OF 
Toxicity 
Clinical  data  on  escitalopram  overdose  are  limited  and  many  cases  involve  concomitant 
overdoses  of  other  drugs.    In  the  majority  of  cases  mild  or  no  symptoms  have  been 
DOCUMENT 
reported.  Doses between 400 and 800 mg of escitalopram alone have been taken without 
FREEDOM 
DEPARTMENT 
any  severe  symptoms.    No  fatalities  or  sequelae  were  reported  in  the  few  cases  with  a 
THIS 
higher dose (one patient survive
THE  d ingestion of either 2,400 or 4,800 mg). 
THE 
 
BY 
Symptoms 
Symptoms seen in reported overdose of escitalopram include symptoms mainly related to 
the central nervous system (ranging from dizziness,  tremor and agitation to rare  cases of 
serotonin syndrome, convulsion and coma), the gastrointestinal system (nausea/vomiting), 
the  cardiovascular  system  (hypotension,  tachycardia,  arrhythmia  and  ECG  changes 
(including QT prolongation)), and electrolyte/fluid balance conditions. 
 
Treatment 
There  is  no  specific  antidote.    Establish  and  maintain  an  airway,  ensure  adequate 
oxygenation and respiratory function.  The use of activated charcoal should be considered.  
Activated charcoal may reduce absorption of the drug if given within one or two hours after 
ingestion.    In  patients  who  are  not  fully  conscious  or  have  impaired  gag  reflex, 
consideration  should  be  given  to  administering  activated  charcoal  via  a  nasogastric  tube, 
once the airway is protected.  Cardiac and vital signs monitoring are recommended along 
with general symptomatic supportive measures. 
 
 
Page 27 of 28 
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FOI 4150 - Document 8
Lexapro® Product Information 07/2007 
 
For  further  advice  on  management  of  overdose  please  contact  the  Poisons  Information 
Centre (Tel: 13 11 26 for Australia and Tel: 0800 764 766 for New Zealand). 
 
 
PRESENTATION AND STORAGE CONDITIONS 
 
Lexapro tablets 
o  Film-coated tablets containing 10 mg or 20 mg escitalopram (as oxalate). 
o  Blister packs of 28 tablets. 
 
Lexapro solution 
o  Oral solution containing 10 mg/mL escitalopram (as oxalate). 
o  28  mL  solution  in  brown  glass  bottle  with  a  screw  cap  with  childproof  closure  and 
syringe. 
 
Storage conditions 
 
Lexapro tablets: 
Store below 30°C. 
UNDER 
Lexapro solution: 
Store below 25°C.   
1982 
 
Store  the  opened  oral  solution  below  25°C.    Discard  after 
3 months. 
ACT 
 
RELEASED 
 
NAME AND ADDRESS OF THE SPONSOR 
BEEN 
 
HEALTH 
Lundbeck Australia Pty Ltd 
HAS 
OF 
1/10 Inglewood Place 
INFORMATION 
Norwest Business Park 
OF 
Baulkham Hills  NSW  2153 
Ph: +61 2 9836 1655 
 
DOCUMENT 
 
FREEDOM 
DEPARTMENT 
POISON SCHEDULE OF THE MEDICINE 
THIS 
 
THE  THE 
Prescription only medicine 
BY 
 
 
DATE OF APPROVAL 
 
Date of TGA approval:  27 April 2007 
 
Date of most recent amendment:  09 July 2007 
 
 
 
”Lexapro” is the registered trademark of H. Lundbeck A/S. 
 
Page 28 of 28 
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FOI 4150 - Document 9
ESCITALOPRAM (LEXAPRO®): GAD – Attachment 2 
ATTACHMENT 2 
EPIDEMIOLOGY OF GENERALISED 
UNDER 
1982 
ANXIETY DISORDER (GA
ACT 
RELEASED 
D) 
BEEN  HEALTH 
HAS INFORMATION 
OF 
OF 
DOCUMENT 
FREEDOM 
DEPARTMENT 
THIS 
THE  THE 
BY 
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FOI 4150 - Document 9
ESCITALOPRAM (LEXAPRO®): GAD – Attachment 2 
 
Table of Contents 
Table of Contents ............................................................................................................ 2 
List of Tables .................................................................................................................. 3 
List of Figures ................................................................................................................. 3 
Abbreviations .................................................................................................................. 4 
GAD Overview ............................................................................................................... 5 
Clinical Features ............................................................................................................. 6 
Aetiology of GAD and worry ......................................................................................... 8 
Epidemiology ................................................................................................................ 10 
Prevalence ..................................................................................................................... 12 
Co-morbidity ................................................................................................................. 18 
Impact on Impairment ................................................................................................... 22 
Diagnosis ....................................................................................................................... 23 
Treatment ...................................................................................................................... 24 
UNDER 
Treatment Outcomes ..................................................................................................... 32 
Duration of Treatment ................................................................................................
1982 
... 36 
Defining Response and Remission ............................................................................... 36 
ACT 
 
RELEASED 
BEEN  HEALTH 
HAS INFORMATION 
OF 
OF 
DOCUMENT 
FREEDOM 
DEPARTMENT 
THIS 
THE  THE 
BY 
9. D16-1012942  GAD Att 2 Lexapro Oct 07 v1.doc 
 
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FOI 4150 - Document 9
ESCITALOPRAM (LEXAPRO®): GAD – Attachment 2 
 
List of Tables 
Table 1 
Diagnostic Criteria for Generalised Anxiety Disorder ................................... 7 
Table 2 
Shift in Criteria to Diagnose GAD ................................................................ 15 
Table 3 
Lifetime Prevalence of GAD ........................................................................ 16 
Table 4 
Lifetime Co-morbidities with GAD .............................................................. 19 
Table 5 
Guidelines for Social Anxiety Disorder or Social Phobia ............................ 28 
Table 6 
Correlation of Response/Treatment Between Scales .................................... 36 
 
 
 
UNDER 
1982 
List of Figures 
ACT 
Figure 1 
Process of anxious apprehension12 .................................................................. 9 
RELEASED 
Figure 2 
 Course of patients with generalized anxiety disorder. ................................ 11 
Figure 3 
 Prevalence and Comorbidity of Generalized Anxiety Disorder and Major 
BEEN 
Depression at 12 Months in Two National General Population Surveys ......................... 21 
HEALTH 
Figure 4 
 Diagnostic algorithm for exploring anxiety disorders ................................. 24 
HAS 
OF 
Figure 5 
Onset of effect of different anxiolytic drugs
INFORMATION  ................................................. 27 
OF 
 
 
DOCUMENT 
FREEDOM 
DEPARTMENT 
THIS 
THE  THE 
BY 
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FOI 4150 - Document 9
ESCITALOPRAM (LEXAPRO®): GAD – Attachment 2 
 
 Abbreviations 
 
Abbreviation 
 
GAD 
Generalized Anxiety Disorder 
EDSP 
Early Developmental Stages of 
Psychopathology 
ESEMed 
European Study of the Epidemiology of 
Mental Disorders 
GHS 
German Health Interview and Examination 
Survey 
HARP 
The Harvard/Brown Anxiety Research 
Program 
ICPE  
International Consortium in Psychiatric 
Epidemiology UNDER 
LASA 
Longitudinal Aging Study Amsterdam 
MDD 
Major Depressive Disord
1982 
er 
NCS 
National Comorbidity Study 
ACT 
NCS-R 
National Comorbidity Survey Replication 
RELEASED 
NEMESIS 
Netherlands 
Mental Health Survey and Incidence Study 
NESARC 
Na
BEEN  tional Epidemiologic Survey on Alcohol 
HEALTH 
and Related Conditions 
NSMHW 
HAS 
Nati
OF onal Survey of mental Health and 
INFORMATION 
Well-being 
OF 
US 
United States 
 
DOCUMENT 
FREEDOM 
DEPARTMENT 
THIS 
THE  THE 
BY 
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ESCITALOPRAM (LEXAPRO®): GAD – Attachment 2 
 
GAD Overview 
Generalized anxiety disorder (GAD) is characterized by chronic and uncontrollable 
worrying and somatic anxiety, such as tension, hypervigilance and insomnia 1  The 
sufferer knows that the worry is excessive or unrealistic but feels unable to control it. The 
worry is associated with symptoms such as restlessness, fatigue, difficulty concentrating, 
irritability, muscle tension or sleep disturbance.2  GAD is highly associated with other 
psychiatric disorders, and this comorbidity increases the economic and personal burden 
and severity of the disorder1 3 4. 
 
A re-analysis of the National Comorbidity Survey Replication that introduced a measure 
UNDER 
of severity, showed that GAD severity predicts the onset of secondary disorders, with 
1982 
more severe GAD associated with a higher risk of secondary disorders (comorbidities).5 
ACT 
 
RELEASED 
Some of the symptoms associated with GAD are as follows (3 of these symptoms. Of at 
BEEN 
least moderate severity, should be present for a diagnosis)6: 
HEALTH 
•  Restlessness or feeling ‘on edge’ HAS INFORMATION 
OF 
•  Easily tired 
OF 
•  Concentration difficulties or mind going blank 
•  Irritability 
DOCUMENT 
DEPARTMENT 
•
FREEDOM 
  Muscle tension 
THIS 
•
THE 
  Sleep disturbance (di
THE fficulty falling or staying asleep or unsatisfying sleep) 
BY 
 
These symptoms were also commonly reported in a Hong Kong study7,  where the three 
most commonly reported symptoms were: 
•  ‘‘easily tired’’,  
•  ‘‘easily irritable’’ and 
•  ‘‘difficult to concentrate’’. 
 
Over half of the GAD subjects reported palpitations and bowel problems.7 GAD subjects 
were more likely than sub-threshold GAD subjects to report ten of the eleven symptoms 
9. D16-1012942  GAD Att 2 Lexapro Oct 07 v1.doc 
 
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FOI 4150 - Document 9
ESCITALOPRAM (LEXAPRO®): GAD – Attachment 2 
 
examined, depressed mood for two or more weeks, suicidal ideation, cigarette smoking 
and alcohol use7.  Other concerns were over finances, work performance and studies. 
 
An American study8 found that in a sample of primary care patients (N=1,029), 
approximately 1 in 10 met the criteria for GAD (DSM-IV) and these patients were more 
likely to suffer from somatic pain. 
 
The following case study describes a GAD patient: 
 
“The patient is a 54-year-old man who has been worrying excessively about activities of 
daily living in general and his health in particular for several years.  He recently read 
UNDER 
about leukaemia and asked his primary physician to perform a bone marrow aspiration 
1982 
to rule out the disease.  A hypochondriac, he fears that his minor physical ailments (such 
ACT 
as headaches, coughing and sneezing) are masking a deadly disease.  He is also 
RELEASED 
convinced that his 33 year old son, who is mildly overweight, is going to die soon of heart 
BEEN 
disease, and he is doing his utmost to convince his son to lose the excess weight. 
HEALTH 
 
HAS INFORMATION 
OF 
The patient is a successful businessman, husband and father of several children; an 
OF 
athlete; a pointer –even a decorated war veteran.  Despite his achievements, however, 
the patient feels “miserable” and “tortured” by his persistent worries.  He anticipates 
DOCUMENT 
DEPARTMENT 
and dreads poor outcomes of even rout
FREEDOM  ine activities.  He feels he cannot go to the movies 
THIS 
because he might be unable to ge
THE  t a parking spot.  He is convinces that people disregard 
THE 
BY 
him because he is short.  He believes his wife is entirely unsympathetic to his plight.  He 
now seeks medical advice.’9 
 
 
Clinical Features 
GAD is categorised as an independent disorder.10  The clinical diagnostic criteria for 
GAD are provided in Table 1. 
 
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FOI 4150 - Document 9
ESCITALOPRAM (LEXAPRO®): GAD – Attachment 2 
 
Table 1  Diagnostic Criteria for Generalised Anxiety Disorder11 
DSM IV Criteria for the Anxiety Disorders: Generalized Anxiety Disorder 
A. Excessive anxiety and worry (apprehensive expectation), occurring more days than 
not, for at least 6 months, about a number of events or activities (such as work or school 
performance). 
B. The person finds it difficult to control the worry. 
C. The anxiety and worry are associated with three (or more) of the following six 
symptoms (with at least some symptoms present for more days than not, for the past 6 
months). Note: Only one item is required in children. 
•  restlessness or feeling keyed up or on edge  
•  being easily fatigued  
UNDER 
•  difficulty concentrating or mind going blank  
1982 
•  irritability  
ACT 
•  muscle tension  
RELEASED 
•  sleep disturbance (difficulty falling or staying asleep, or restless, unsatisfying sleep)  
BEEN 
D. The focus of the anxiety and worry is not confined to fea
HEALTH tures of an Axis I disorder, 
OF 
eg, the anxiety or worry is not about having a
HAS 
 panic attack (as in Panic Disorder), being 
INFORMATION 
embarrassed in public (as in social phobia)
OF  , being contaminated (as in obsessive-
compulsive disorder), being away from home or close relatives (as in separation anxiety 
disorder), gaining weight (as in anor
DOCUMENT  exia nervosa), having multiple physical complaints 
FREEDOM 
DEPARTMENT 
(as in somatization disorder), or having a serious illness (as in hypochondriasis), and the 
THIS  THE 
anxiety and worry do not occ
THE 
ur exclusively during post-traumatic stress disorder. 
BY 
E. The anxiety, worry or physical symptoms cause clinically significant distress or 
impairment in social, occupational or other important areas of functioning. 
F. The disturbance is not due to the direct physiological effects of a substance (eg, a drug 
of abuse, a medication) or a general medical condition (eg, hyperthyroidism) and does 
not occur exclusively during a mood disorder, a psychotic disorder, or a Pervasive 
Developmental Disorder. 
 
 
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Aetiology of GAD and worry 
A generic model of GAD proposed by Barlow incorporates biological, psychological and 
environmental factors (an abridged version of the model is presented in Figure 1).12 
Barlow conceptualizes GAD as anxious apprehension and, suggests that it is the ‘basic’ 
anxiety disorder. 
 
The model suggests that an individual has biological and psychological vulnerabilities 
which, if triggered will result in negative affect.12  The negative affect is characterized by 
a sense of uncontrollability and is accompanied by supportive physiology and activation 
of specific brain circuits (e.g. the behavioural inhibition system).  The individual becomes 
self-focused (e.g. on their physiological arousal) and hypervigilant for
UNDER   threat, which 
results in attempts to cope with the anxiety.  Predominant coping stra
1982  tegies are 
behavioural avoidance or worry in an attempt to solve problems and reduce negative 
ACT 
affect.  It is important to note that behavioural avoidance is qu
RELEASED  ite common in GAD: one 
study reported that 65% of patients avoided specific triggering stimuli, with social 
BEEN  HEALTH 
situations being most common.13  HAS 
OF 
 
INFORMATION 
OF 
Results from the twin studies suggest a modest role for genetics with an estimated 
heritability of approximately 30–40% for both men and women (vs 70% heritability for 
DOCUMENT 
major depression).14 It should be noted that the largest proportion of the variance in 
FREEDOM 
DEPARTMENT 
liability for GAD is due to individual environmental factors. 
THIS 
THE  THE 
 
BY 
Early environmental factors that are considered to be important in the development of 
GAD are:6 
•  Insecure attachment in childhood which is adulthood develop into beliegs that the 
world is a dangerous place, worry becomes an effective coping strategy. 
•  A traumatic childhood experience 
•  Parental separation 
•  Lack of opportunity for social interactions 
•  Modeling of a relative who has an anxiety disorder. 
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HAS INFORMATION 
OF 
OF 
DOCUMENT 
FREEDOM 
DEPARTMENT 
THIS 
THE  THE 
BY 

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Epidemiology 
In general, anxiety disorders develop relatively early in life.15 In 80–90% of cases, the 
disorder manifests before the age of 35, and the time between 10 and 25 years seems to 
be a high-risk period for the development of anxiety disorders.  With GAD, the average 
first manifestation is between 25 and 30 years. GAD is the only anxiety disorder to show 
increased prevalence in the elderly. 
 
In a 40 year longitudinal study of GAD patients (DSM-II-R) the course of the disorder 
was followed.16  Between 1950-61, 512 people were admitted to the Lopez 
Neuropsychiatric Research Institute in Spain.  A total of 370 of the original patients were 
UNDER 
contacted in 1984-2000 and of those 209 agreed to participate in the study.  They were 
1982 
interviewed and 65 were diagnosed with GAD during the period of 1984-88.  These 
ACT 
patients were followed up during 1997-2000 (n=59). 
RELEASED 
 
BEEN 
The mean age of onset of GAD was 25.6 years and the mean episode length was 7.4 
HEALTH 
months; periods of remission or total remission of a
OF  nxiety symptoms was uncommon.16  
HAS INFORMATION 
There is however evidence to suggest that unlike other anxiety disorders, GAD is most 
OF 
common among older age groups.17  See Figure 2 which shows that the majority of cases 
are in the 25-35 age group. 
DOCUMENT 
DEPARTMENT 
 
FREEDOM 
THIS 
Social phobia (12%) and simple phobia
THE 
 (70%) were present before the appearance eof 
THE 
GAD, whilst the rest of the
BY   comorbid disorders usually emerged afterwards.16  The course 
of development is presented in Figure 2.16  It can be seen that, anxiety disorders peaked 
during the third and fourth decades of life and decreased thereafter. From age 30 the 
somatoform disorders emerged, together with major depression and alcohol dependence; 
finally, from age 50, dysthymia appeared. USD (undifferentiated somatoform disorder) 
was very frequent as a chronic clinical condition. The main symptoms recorded were 
somatic complaints about pain, and gastrointestinal and cardiopulmonary symptoms. 
These complaints had caused patients to see a doctor, and their worry about symptoms 
was not considered uncontrolled. 
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Figure 2 
Course of patients with generalized anxiety disorder.16 
UNDER 
 
1982 
(*) Percentage of patients with episodes or exacerbations of psychiatric disorders 
Notes: 
ACT 
Affective disorders: major depression or dysthymia 
RELEASED 
Somatoform disorders: somatization disorder, hypochondria or undifferentiated somatoform disorder 
(USD) 
BEEN  HEALTH 
 
HAS INFORMATION 
OF 
The study found that :  
OF 
(i) 
a low percentage of subjects were chronically affected by GAD after age 50; 
(ii) 
with age, GAD tends to be replaced by somatizations (USD); and  
DOCUMENT 
(iii) 
worse prognosis was determined by lac
DEPARTMENT  k of regular compliance, gender (female) 
FREEDOM 
THIS 
and early onset of GAD. 
THE  THE 
 
BY 
In relation to the natural history of the disorder and the replacement, with age, of GAD by 
somatoform disorders, these results are in line with those of classic works. 18  The 
replacement of GAD by undifferentiated somatization disorder (USD) could be 
interpreted from two different points of view.19 USD in these patients could reflect a 
change in the way they cope with anxiety. It has been suggested that in addition to the 
classic fight-or-flight reaction to chronic stress, the aged respond in a way that is more 
adaptative (freeze-reaction). The freeze response would not necessarily produce anxiety, 
but the elderly would be more likely to focus on their somatic state.20  From an alternative 
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point of view, USD may constitute a minor form of GAD in older subjects .  Older adults 
report more worries about health and fewer concerns about work compared with younger 
adults. Also, habituation to anxiety can decrease the number and severity of anxiety 
symptoms. Therefore, GAD in older patients could be characterized by vague and 
persistent complaints about health with mild levels of anxiety. These clinical symptoms 
could lead to a diagnosis of undifferentiated somatization disorder in older subjects 21 22. 
 
Generally GAD has been associated with various medical conditions.23 24  The 
susceptibility to comorbid conditions differs between male and female sufferers. Among 
males, particularly high rates were found for dermatologic (75%), arthritic (27%), and 
cardiac problems (20%), and among females, gastrointestinal problems (63%), allergies 
UNDER 
(52%), back pain (50%), migraine (42%), metabolic disorders (27%), and neurologic 
1982 
disorders (8%).23 24 Similar results were observed in a French study though the rates were 
ACT 
lower25.  To secure successful remission, therefore, physician treatment choices must 
RELEASED 
address not only the symptoms of GAD, but also current or probable comorbidities and 
BEEN 
any underlying causality. 
HEALTH 
HAS INFORMATION 
OF 
 
OF 
 
Prevalence 
DOCUMENT 
FREEDOM 
DEPARTMENT 
Interpreting the epi
THIS  demiological evidence26 
THE  THE 
 
BY 
Stage 1 
Many of the earliest studies were based on DSM-III criteria (APA, 1980).  DSM-III 
defined GAD as 1 month of persistent anxiety accompanied by associated symptoms 
from three of four categories.5 DSM-III allowed GAD to be diagnosed only if patients did 
not meet the criteria for any other anxiety or affective disorder. It also separated 
generalised anxiety disorder from panic disorder. This was considered to create confusion 
because GAD was a residual category.27 
 
 
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Stage 2 
DSM-III-R changed the requirements to 6 months of worry along with 6 of 18 associated 
symptoms to improve the validity of separation from normal anxiety and from anxiety 
that occurs secondary to other mental disorders (American Psychiatric Association, 
1987).5  An example of how this change has impacted on the estimation of the prevalence 
of GAD is shown by relaxing the requirement of excessive worry more days than not 
occurring for at least 6 months (requirement for DSM-III-R) to 1 month (requirement for 
DSM-III).  A re-analysis of the National Comorbidity Survey Replication using this 
change showed that prevalence increased by about 50-60%.5 
 
UNDER 
Stage 3 
1982 
DSM-IV made further changes aimed at sharpening the characterization of GAD by 
ACT 
requiring that worry be excessive and uncontrollable (American Psychiatric Association, 
RELEASED 
1994). DSM-IV also stipulated that the worry in GAD must be associated with at least 
three of six symptoms of tension and vigilance, a
BEEN  nd cause significant distress or 
HEALTH 
impairment.5  An example of how this change has impacted on the estimation of the 
HAS INFORMATION 
OF 
prevalence of GAD is shown by relaxing the requirement of excessiveness of worry in 
OF 
DSM-IV, re-analysis of the National Comorbidity Survey Replication showed that 
prevalence increased by about 40%.5  The authors also found that increasingly broader 
DOCUMENT 
definitions of GAD are associated w
FREEDOM  ith decreasing
DEPARTMENT   rates of co-morbidity.  One of the 
THIS 
criticisms levelled at DSM-IV is t
THE  hat the 6-month duration and excessive-worry 
THE 
requirements, appear to mi
BY  ss individuals who suffer from significant generalized anxiety, 
and who also have an elevated risk of developing additional disorders.  This has been 
found in other studies, with concerns that patients suffering from symptoms of GAD are 
being excluded inappropriately.28 29  
 
The changes seen in the classification of GAD and the epidemiologic evidence that 
eventuated suggest that GAD is a common disorder that, although often comorbid with 
other mental disorders, does not have a rate of comorbidity that is higher than those found 
in most other anxiety or mood disorders.30 
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The above description of the changes in DSM from III to IV, leave little doubt that GAD 
is now classified as a severe disorder that produces significant distress or impairment. 
 
Table 2 summarises the key features of DSM-III, DSM-III-R and DSM-VI.  The key 
differences in DSM changes from DSM-III-R to DSM-VI being31: 
 
•  "unrealistic/excessive anxiety and worry about two or more life circumstances" in the 
DSM-III-R to "excessive (but not unrealistic) anxiety and worry about more than one 
life circumstance" in the DSM-IV to which "difficulties to control the worry" was 
added.  
UNDER 
•  In the DSM-IV, the ancillary symptoms were further reduced and involve only 3 of 6 
1982 
symptoms, selected from the categories of motor tension and vigilance, whereas the 
ACT 
autonomic category was deleted.  
RELEASED 
•  With associative features, "mild depressive symptoms are common," according to the 
BEEN 
DSM-III and DSM-III-R, whereas in the DSM-IV, in additi
HEALTH  on to depressive 
HAS 
OF 
symptoms, the severity of which is unspecified, symptoms of muscle tension and 
INFORMATION 
somatic symptoms were added.  OF 
•  Finally, impairment, which in the DSM-III and DSM-III-R was considered "only 
mild," is considered in the DSM-
DOCUMENT  IV as "producing significant distress or impairment". 
FREEDOM 
DEPARTMENT 
 
THIS  THE 
 
THE 
BY 
Therefore it is clear from this evidence that DSM-IV defined GAD patients are a severe 
group of GAD patients.  Further DSM-IV defined patients are a more restrictive group of 
patients that would not include a large proportion of DSM-III-R patients.  This is the key 
reason why the submission will look at DSM-IV patients alone, given that these were the 
basis of the Escitalopram trial. 
 
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OF 
OF 
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FREEDOM 
DEPARTMENT 
THIS 
THE  THE 
BY 

---

UNDER 
1982 
ACT 
RELEASED 
BEEN  HEALTH 
HAS INFORMATION 
OF 
OF 
DOCUMENT 
FREEDOM 
DEPARTMENT 
THIS 
THE  THE 
BY 

---

UNDER 
1982 
ACT 
RELEASED 
BEEN  HEALTH 
HAS INFORMATION 
OF 
OF 
DOCUMENT 
FREEDOM 
DEPARTMENT 
THIS 
THE  THE 
BY 

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Co-morbidity 
A New Zealand study found that of those followed from 1972 till 2005, 42% of those 
diagnosed with GAD, had co-morbid depression, where GAD preceded the depression.53  
They conclude that this comorbidity seemed to be associated with substantial health 
burden, as indicted by recurrent course, mental health service use and suicide attempt. 
 
The ESEMeD study showed that patients with GAD were 32.7 times more likely to 
develop depression, 12.5 times more likely to have SAD and 1.5 times more likely to 
abuse alcohol (10.2 times more likely to be alcohol dependant).54 
 
 
UNDER 
 
1982 
 
ACT 
RELEASED 
BEEN  HEALTH 
HAS INFORMATION 
OF 
OF 
DOCUMENT 
FREEDOM 
DEPARTMENT 
THIS 
THE  THE 
BY 
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ACT 
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HAS INFORMATION 
OF 
OF 
DOCUMENT 
FREEDOM 
DEPARTMENT 
THIS 
THE  THE 
BY 

---

UNDER 
1982 
ACT 
RELEASED 
BEEN  HEALTH 
HAS INFORMATION 
OF 
OF 
DOCUMENT 
FREEDOM 
DEPARTMENT 
THIS 
THE  THE 
BY 

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Figure 3 shows the rate of comorbidities based on two studies and the overlap that 
exists.41 
Figure 3 
Prevalence and Comorbidity of Generalized Anxiety Disorder and Major 
Depression at 12 Months in Two National General Population Surveys41 
 
UNDER 
1982 
ACT 
RELEASED 
BEEN  HEALTH 
HAS INFORMATION 
OF 
OF 
DOCUMENT 
FREEDOM 
DEPARTMENT 
THIS 
THE  THE 
BY 
 
 
 
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Impact on Impairment 
A central issue of debate is whether generalized anxiety is itself associated with 
impairment or disability, or whether the impairment in individuals with GAD is due 
entirely to other co-morbid disorders.43  Epidemiological studies have addressed this 
question by assessing the comparative disability of GAD and major depressive episodes 
(MDE). In these studies39 41 the separate and joint effects of GAD and MDE were 
evaluated by comparing the disability of pure GAD, pure MDE, and the two conditions 
when co-morbid. No significant differences in disability were found between pure GAD 
and pure MDE, and two of the three surveys found that individuals with co-morbid GAD-
MDE had significantly greater disability than those with either pure GAD or pure MDE.   
 
UNDER 
These findings have led researchers to conclude that the status of GAD
1982 
 as an 
independent disorder is at least as strongly supported as it is for MDE.30 43 
ACT 
RELEASED 
 
It used to be thought that GAD, in the absence of other disorders, was associated with a 
BEEN  HEALTH 
low level of disability.58 However, the chronic nature of GAD means that the condition 
HAS INFORMATION 
OF 
imposes a substantial individual burden. This may manifest in the quality and level of 
OF 
functioning in social and occupational interactions, resulting in significant though indirect 
costs to society. This burden is most notable in terms of substantial impairments resulting 
DOCUMENT 
in days where a sufferer is restricted from or unable to carry out daily activities, causing a 
FREEDOM 
DEPARTMENT 
reduction in the patient's 
THIS  quality of life and well-being.10 The NCS and the “Midlife 
THE  THE 
Development in the United States Survey” both state that the level of impairment related 
BY 
to GAD is considerable and equivalent to that of MD. 41  In fact, a combined analysis of 
these two surveys revealed that even GAD with no comorbidity is associated with marked 
impairments in psychosocial functioning equivalent to those caused by MD. 41 
 
A similar conclusion was arrived at in the analysis of the Australian NSMHWH. 57  In 
functional terms, persons with pure GAD had been unable to engage in their usual 
activities on an average of 6 days in the previous month, and their disability score on the 
SF-12 mental health scale fell more than one standard below the population average.  The 
authors conclude that the Australian data support that GAD, as a single disorder is 
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significantly disabling.  Consequently, the data supported that patients with GAD have a 
use of health services. 
 
 
Diagnosis 
Some useful questions to ask in establishing a diagnosis of GAD59 
•  Are you a worrier? 
•  Do you think that you worry excessively? 
•  When things are going well do you still find things to worry about? 
•  Once you start to worry do you find it hard to stop? 
UNDER 
•  How much does worry interfere with your life?  1982 
•  How long has worrying like this been a problem? 
ACT 
 
RELEASED 
Excessive worry accompanied by significant symptoms of muscle tension, autonomic 
BEEN 
arousal and hypervigilance must be present for at least 6 months
HEALTH 
 for a diagnosis of GAD 
HAS 
OF 
to be made. 
INFORMATION 
 
OF 
The following (Figure 4) depicts the latest diagnostic algorithm for exploring anxiety 
disorder issued by the British Associa
DOCUMENT  tion for Psychopharmacology:60 
FREEDOM 
DEPARTMENT 
THIS 
THE  THE 
BY 
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Figure 4 
Diagnostic algorithm for exploring anxiety disorders60 
 
UNDER 
1982 
ACT 
 
RELEASED 
 
 
BEEN  HEALTH 
HAS 
OF 
Treatment 
INFORMATION 
OF 
GAD follows a chronic course and may be either constant or fluctuating. Patients 
typically suffer symptoms for a number of years before being diagnosed and effectively 
DOCUMENT 
treated, with retrospective studies suggesting symptoms may wax and wane for up to 20 
FREEDOM 
DEPARTMENT 
years.61-63 The Harvard/Brow
THIS 
n Anxiety Research Program (HARP), a naturalistic, 
THE  THE 
longitudinal study that assessed patients, with PD, PDA, SP, and GAD, at 6–12- month 
BY 
intervals for of 8 years, showed that the likelihood of these anxiety patients experiencing 
full remission was modest and more likely to occur during the first 2 years of the study. 
In addition, this study indicated that GAD patients continued remitting late into the study 
period.64  This tends to support the idea of GAD having an episodic pattern in which 
periods of remission and recurrence are evident for many years.65 
 
Results from the National Epidemiologic Survey on Alcohol and Related Conditions 
(NESARC) indicated a continued lack of treatment for many individuals with GAD.43  
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Approximately 50-59% of individuals with GAD received no treatment, 7 43 with an 
average 2-year lag between onset and first treatment.43 
 
A New Zealand study that followed a birth cohort to the age of 32 found that of the 
patients diagnosed as having pure GAD, 35% only had received mental health services 
and 19% psychiatric medication66.  For patients with GAD and comorbid MDD these 
figures were higher with 57% accessing mental health services and 39% psychiatric 
medication.66  Similar results were found in the ESEMeD study where for any anxiety 
around 36% of individuals had consulted any type of formal health services in the 
previous 12 months.67  Overall approximately 30-39% of GAD patients receive 
appropriate treatment,67 58 66 this was as low as 11% in the UK National Surveys of 
UNDER 
Psychiatric Morbidity.68 
1982 
 
ACT 
In summary, having examined all the evidence the data shows that 11-50% of patients  
RELEASED 
diagnosed with GAD are treated. 
BEEN 
 
HEALTH 
HAS 
OF 
 
INFORMATION 
The UK National Surveys of Psychiatric Mor
OF 
bidity study also identified that the factors 
influencing treatment with antidepressants are the number of psychiatric symptoms, 
marital status, age and employment st
DOCUMENT  atus. It is clear that by far the strongest influence is 
FREEDOM 
DEPARTMENT 
that of symptomatic severity, with the most severe category over four times as likely as 
THIS  THE 
the least severe to receiv
THE  e antidepressants.67  
BY 
 
There are a variety of agents that can be used to treat GAD.  Figure 1 shows the onset of 
effect of different anxiolytic drugs (benzodiazepines, buspirone and antidepressants).69  It 
can be seen that although benzodiazepines have a rapid anxiolytic effect (without onset 
worsening) there are major concerns surrounding long-term use of these.  Indeed some 
argue for the theory that antidepressants affect predominantly psychological 
symptoms whereas benzodiazepines affect predominantly somatic symptoms in 
patients with GAD.70  
 
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Adverse effects on discontinuation with benzodiazepines are more frequent than with 
other drugs, and these may be caused by recurrence or rebound (recurrence with 
increased intensity) of the original anxiety symptoms, or by drug withdrawal effects.71 72 
The benzodiazepine withdrawal syndrome is potentially serious, but is generally mild and 
self-limiting (up to 6 weeks).  As a guide benzodiazepines may be used for 2–4 weeks to 
cover the onset worsening caused by some antidepressants, or on an occasional basis 
before exposure to a feared situation. 59 60 73 74 
 
In order to assess the magnitude of the withdrawal syndrome some evidence is provided 
by a Canadian study which examined 30 consecutive inpatients admitted for assistance 
from their benzodiazepine detoxification.75  These patients were long-term users of 
UNDER 
benzodiazepines (≥1 months,  =86 months).  Of all patients 20% were diagnosed with 
1982 
GAD.  These patients were assessed as above therapeutic dose users.  Another study 
ACT 
assessed 131 long-term, therapeutic dose users (daily use >3 mont
RELEASED 
hs;  =3 years) who had 
entered an outpatient treatment program for discontinuations of benzodiazepines.75  These 
BEEN 
patients tended to shift their use of medication from an as-pre
HEALTH  scribed to an as-needed 
HAS 
OF 
pattern.  The majority of patients (91%) had made at least one attempt to decrease their 
INFORMATION 
dose or stop their use of benzodiazepines, a
OF  nd all who had done so reported experiencing 
symptoms upon attempting to discontinuation. Of the patients admitted 33% had GAD. 
 
DOCUMENT 
FREEDOM 
DEPARTMENT 
Studies of the long-term efficacy of benzodiazepines have reported the development of 
THIS  THE 
tolerance or loss of effec
THE  t over time in the treatment of anxiety.  Additionally, a high 
BY 
relapse rate (65%) is observed in the 6-month period following benzodiazepine 
discontinuation after short-term treatment.76 
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Figure 5 Onset of effect of different anxiolytic drugs69 
 
UNDER 
1982 
ACT 
 
RELEASED 
 
BEEN 
 
HEALTH 
HAS INFORMATION 
OF 
OF 
DOCUMENT 
FREEDOM 
DEPARTMENT 
THIS 
THE  THE 
BY 
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Table 5  Guidelines for Social Anxiety Disorder or Social Phobia 
 
British Guidelines60 73 
Australian Guidelines77 
NICE Guidelines74 
Recognition 
Although generalized anxiety disorder (GAD) is  Some of the symptoms associated with GAD 
The accurate diagnosis of panic disorder or 
and diagnosis 
amongst the most common mental disorders in  are as follows (3 of these symptoms. Of at least  generalised anxiety disorder is central to the 
primary care, and is associated with increased 
moderate severity, should be present for a 
effective management of these conditions. It is 
use of health services, it is often not 
diagnosis): 
acknowledged that frequently there are other 
recognized: possibly because only a minority of  •  Restlessness or feeling ‘keyed up’ or ‘on 
conditions present, such as depression, that 
patients present with anxiety symptoms (most 
edge’ 
can make the presentation and diagnosis 
patients with present with physical symptoms), 
•
UNDER 
  Being easily fatigued 
confusing. An algorithm has been developed to 
and doctors tend to overlook anxiety unless it is  •  Difficulty concentrating or mind ‘going blank’  aid the clinician in the diagnostic process, and 
1982 
a presenting complaint . 
•  Irritability 
to identify which guideline is most appropriate 
 
•  Muscle tension 
to support the clinician in the management of 
ACT 
The disability associated with GAD is similar to  •
the individual patient. 
  Sleep disturbance (difficulty falling or 
that with major depression.78  Patients with 
RELEASED 
staying asleep or restless unsatisfying 
'comorbid' depression and GAD have a more 
sleep) 
severe and prolonged course of illness and 
BEEN 
greater functional impairment,41 and a greater 
HEALTH 
chance of being recognized as having mental 
HAS 
OF 
health problems, though not necessarily as 
INFORMATION 
having GAD10 79. 
OF 
Acute 
Systematic reviews and placebo-controlled 
• Treatment with benzopiazepine for up to 2 
•  support and information  
Treatment 
RCTs indicate that some SSRIs (escitalopram, 
weeks followed by a gradual reduction of 
•  problem solving  
paroxetine and sertraline), the SNRI 
dose to zero within 6 weeks.  Subsequent 
•  benzodiazepines 2-4 weeks 
DOCUMENT 
venlafaxine, some benzodiazepines 
use should be on an ‘as required basis’. 
•  sedating antihistamines 
DEPARTMENT 
(alprazolam and diazepam), the tricyclic 
•
FREEDOM   Diazepam 2-5mg orally up to twice a  •  self help 
imipramine, and the [5-HT.sub.1A] partia
THIS  l 
day 
THE 
 
agonist buspirone are all efficacious in ac
THE  ute 
or 
Note level of evidence differs 
treatment. 
BY 
•  Diazepam 5-10mg at night 
or 
Other compounds with proven efficacy include 
•  Oxazepam 15-30mg orally, as a single 
the antipsychotic trifluoperazine, the 
dose, up to twice a day 
antihistamine hydroxyzine, the anticonvulsant 
 
pregabalin, and the sigma-site ligand 
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British Guidelines60 73 
Australian Guidelines77 
NICE Guidelines74 
opipramol. Treatments with unproven efficacy 
in GAD include the beta-blocker.  
There have been few comparator-controlled 
studies, and most reveal no significant 
differences in efficacy between active 
compounds: however, escitalopram (20 
mg/day) has been found significantly superior 
UNDER 
to paroxetine (20 mg/day), and venlafaxine (75-
225 mg/day) superior to fluoxetine (20-60 
1982 
mg/day) on some outcome measures in 
patients with comorbid GAD and major 
ACT 
depression. 
RELEASED 
Psychological symptoms of anxiety may 
BEEN 
respond better to antidepressant drugs than to 
HEALTH 
benzodiazepines.  
HAS 
OF 
Long-term 
Double-blind studies indicate that continuing 
These should be nonpharmac
INFORMATION  ological as 
•  psychological therapy – CBT, conditions 
treatment 
with SSRI or SNRI treatment is associated with  pharmacological treatments have statistically 
apply 
OF 
an increase in overall response rates: from 8 to  significant, but clinically modest effects.  Some  •  pharmacological therapy (antidepressant 
24 weeks with escitalopram or paroxetine; from  agents used: 
medication) 
4 to 12 weeks with sertraline and from 8 to 24 
•  Venlafaxine 
•  SSRIs should be offered 
DOCUMENT 
weeks with venlafaxine.  
•  Buspirone 
•  reviewed at 2, 4, 6 and 12 weeks 
DEPARTMENT 
•
FREEDOM 
  paroxetine 
•  duration - 12 weeks 
Placebo-controlled relapse-prevention s
THIS  tudies 
•  if not responding at 12 weeks switch to 
THE 
in patients who have responded to previo
THE us 
other SSRI, conditions apply 
acute treatment reveal a significant advantage 
BY 
•  if responding at 12 weeks continue 
for staying on active medication (escitalopram 
treatment for another 6 months 
or paroxetine), compared to switching to 
•  venlafaxine initiated only by specialist 
placebo, for up to six months. 
mental health practitioners, including GPs 
with a special interest in mental health 
•  self-help 
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British Guidelines60 73 
Australian Guidelines77 
NICE Guidelines74 
•   
Comparative 
Drug or psychological treatments, delivered 
Recommended primary treatments for GAD are  •  Cognitive and behavioural techniques 
efficacy of 
singly, have broadly similar efficacy in acute 
nonpharmacological.  Initial treatment should 
combined had greater effect sizes than the 
pharmacologica treatment. Relapse rates are lower with 
include listening to the patient, counselling and 
individual interventions. 
l, psychological  cognitive behaviour therapy than with other 
the teaching of relaxation techniques, personal  •  In the short term, cognitive and behavioural 
and 
forms of psychological treatment, but the 
and interpersonal strategies and coping skills. 
techniques were as effective as 
combination 
comparative efficacy of drug and psychological 
pharmacological therapies, but evidence is 
treatments 
approaches over the long term is not 
UNDER 
lacking for long term effectiveness.  
established. It is uncertain whether combining 
•  The Gould meta-analysis found no 
drug and psychological treatments is 
1982 
difference in treatment outcomes for men 
associated with greater overall efficacy than 
and women. 
with either treatment, given alone.  
ACT 
 
RELEASED 
 
When initial 
There is no clear evidence for an increase in 
 
Switching to another SSRI 
BEEN 
treatments 
response with dose escalation after an initial 
HEALTH 
prove unhelpful  non-response to a lower dose. Switching 
HAS 
OF 
between treatments with proven efficacy may 
INFORMATION 
be helpful. 
OF 
Duration of 
12 weeks initial response, if responding at least   
12 weeks initial response, if responding at least 
Treatment 
another 6 months. 
another 6 months. 
 
DOCUMENT 
FREEDOM 
DEPARTMENT 
THIS 
THE  THE 
BY 
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Effects of Treatment with co-morbidities 
For a full analysis of treatment with comorbid GAD refer to Attachment 8.  Recent 
epidemiological data suggests that the impact of comorbidity in clinical outcomes is no 
greater in GAD than in other anxiety disorders.80  Moreover, comorbidities such as major 
depression do not appear to change the course of GAD.80  There are also data supporting 
the notion that psychotherapy may have an additional impact in the comorbid conditions 
associated with GAD.81 
 
Epidemiologic studies have demonstrated the negative implications of comorbidity for 
course of illness.82 83  Studies have found that the best predictors in cases of GAD and 
UNDER 
panic were severity and duration of symptoms, as well as comorbid depression. 15  The 
1982 
HARP study similarly found that the likelihood of remission of GAD and any other 
ACT 
comorbid condition after one year was half the annual rate for GAD alone.84  In a recent 
RELEASED 
prospective study with nortriptyline or interpersonal psychotherapy, it was shown that 
while both treatments were effective, patients wi
BEEN  th comorbid GAD had a longer time to 
HEALTH 
recovery.85 
HAS INFORMATION 
OF 
 
OF 
Evidence presented in this Attachment, regarding the impact of treatment in co-
morbidities, is sparse and certainly does not meet Level 1 evidence.  When 
DOCUMENT 
pharmacotherapy is considered, upon examinati
DEPARTMENT  on of the two trials utilising escitalopram, 
FREEDOM 
THIS 
it would seem that patients with at least one anxiety disorder and comorbid depression 
THE  THE 
has a greater improvement i
BY  n HAM-A score than those without comorbid anxiety.  This 
would seem to indicated that at worst comorbid patients would respond similarly to those 
with pure depression and at best would show an improved outcome, when measured in 
terms of HAM-A.  Response to both depression and anxiety has been shown in younger 
and elderly cohorts. 
 
The conclusions from two open-label studies that examined patients with comorbidities 
are reported below: :86 87 
a)  The use of anxiolytics had no impact on the outcome 
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b)  Of the 61% of patients experiencing a co-morbidity, results showed that anxiety 
symptoms as measured with the HAM-A, improved in parallel to the improvement 
in depressive symptoms, with escitalopram treatment. 
c)  Patients with at least one anxiety disorder had a greater improvement in HAM-A 
score than those without comorbid anxiety, but there was no statistically significant 
difference in the improvement in HAM-A scores as a function of baseline severity 
of depression, indicating that comorbid depression did not affect response to 
treatment of anxiety. 
d)  The remission rate for anxiety symptoms (38.1%) is very close to the 36% 
reported in a randomized, double-blind clinical trial of escitalopram in patients with 
pure GAD.88 Patients with a comorbid anxiety disorder responded well to treatment, 
UNDER 
particularly those with GAD, SAD, or obsessive–compulsive disorder. 
1982 
e)  In a small study in elderly patients with comorbid GAD and MDD Escitalopram 
ACT 
was associated with significant improvements in symptoms of anxiety and 
RELEASED 
depression. 
BEEN  HEALTH 
 
HAS INFORMATION 
OF 
 
OF 
Treatment Outcomes 
DOCUMENT 
DEPARTMENT 
Like other mental disorders, the plac
FREEDOM  ebo response rate may range from 20% to over 50% 
THIS  THE 
and what contributes to t
THE  his is not always clear from study reports.74 
BY 
 
Hamilton Anxiety Scale (HAMA) 
This scale rates the patient’s level of anxiety based on feelings of anxiousness, tension 
and depression; any phobias, sleep disturbance, or difficulty in concentrating, the 
presence of genitourinary, cardiovascular, respiratory, autonomic or somatic symptoms, 
and the interviewer’s assessment of the patient’s appearance and behaviour during the 
interview are also rated. 
 
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The HAMA was developed to quantify the severity of symptoms of anxiety and is widely 
used to evaluate anxiety in clinical studies. 
The Hamilton Anxiety Scale consists of 14 items, each defined by a series of symptoms; 
1) anxious mood, 2) tension, 3) fears, 4) insomnia, 5) intellectual, 6) depressed mood, 7) 
somatic complaints: muscular, 8) somatic complaints: sensory, 9) cardiovascular 
symptoms, 10) respiratory symptoms, 11) gastrointestinal symptoms, 12) genitourinary 
symptoms, 13) autonomic symptoms, and 14) behaviour at interview. 
 
Each item is rated on a 5-point scale, ranging from 0 (not present) to 4 (very severe). The 
sum (total score) indicates the severity of anxiety; less than 12 is normal, 18 mild anxiety 
(and the lowest threshold at which medication is usually prescribed), 25 moderate 
UNDER 
anxiety, and 30 severe anxiety.89 
1982 
 
ACT 
Typically in clinical trials response is determined for a ≥50% reduction in HAM-A and 
RELEASED 
remission is defined by patients with a HAM-A<10 or a HAM-A<890,  both of which is 
BEEN 
within the range of normal anxiety as determined by HAM-A<
HEALTH  12.89 
HAS 
OF 
 
INFORMATION 
Consensus conferences proposed that for G
OF  AD, remission is defined as HAM-A≤7-10 
functional impairment is SDS≤1 on each item and a HAM-D score of ≤7.91 92 
 
DOCUMENT 
FREEDOM 
DEPARTMENT 
HAMA Psychic Anxiety Subscale 
THIS  THE 
The HAMA psychic anxi
THE  ety subscale is derived from the HAMA scale and consists of 
BY 
the sum of the following items:  item 1 (anxious mood), item 2 (tension), item 3 (fears), 
item 4 (insomnia), item 5 (intellectual), item 6 (depressed mood), and item 14 (behaviour 
at the interview). 
 
 
HAMA Somatic Anxiety Subscale 
The HAMA somatic anxiety subscale is derived from the HAMA scale and consists of 
the sum of the following items:  item 7 (somatic, muscular), item 8 (somatic, sensory), 
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item 9 (cardiovascular), item 10 (respiratory), item 11 (gastrointestinal), item 12 
(genitourinary) and item 13 (other autonomic symptoms). 
 
 
Hamilton Depression Rating Scale 
This 17-item scale rated the patient’s depressive state based on feelings of depression, 
guilt, suicidality, anxiety (psychic and somatic), and agitation; level of insight; patterns of 
insomnia (early, middle, late); loss of interest in work and other activities; weight loss, 
hypochondriasis psychomotor retardation; genital symptoms, gastrointestinal somatic 
symptoms and general somatic symptoms.  Each item was scored on 3-, 4- or 5-point 
scale with 0 reflecting no symptoms and higher scores reflecting increasing symptom 
UNDER 
severity.   
1982 
(Source: SCT-MD-05 Study Report p. 16) 
ACT 
 
RELEASED 
 
BEEN 
Hospital Anxiety and Depression Scale (HAD)  HEALTH 
The HAD scale is completed by the patie
HAS nt and comprises two subsc
OF 
ales: one which 
INFORMATION 
measures depression (D-scale) and one which measures anxiety (A-scale).  Each subscale 
OF 
consists of seven items, with four possible response alternatives (scored from 0 to 3, with 
0 reflecting the most enjoyment/least anxiety).  The D-scale consists of HAD items 1, 3, 
DOCUMENT 
DEPARTMENT 
5, 8, 10, 11 and 13, and the A-scale c
FREEDOM  onsists of HAD items 2, 4, 6, 7, 9, 12 and 14.  
THIS 
Patients fill in the scores that m
THE  ost accurately reflect the way they had felt over the 
THE 
BY 
previous days.  Scores for the depression and anxiety subscales are calculated separately. 
(Source: Study Report for 99815 p.33)  
 
 
Clinical Global Impression (CGI) 
The CGI93 are categorical scales used as both primary (though they are not recommended 
as primary and are most useful as secondary scales to help judge the clinical relevance of 
the finding) and secondary efficacy scales and as categorical scales to define 
responders.90  CGI consists of two subscales: 
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•  Clinical Global Impressions – Improvement scale (CGI-I): 
This scale evaluates a patient’s total improvement from baseline I on a 7 point-
scale, regardless of whether the improvement is related to the study product.  The 
assessor rates the patient from 1 (very much improved) to 7 (very much worse) 
•  Clinical Global Impressions – Severity scale (CGI-S): 
This scale evaluates a patient’s severity of disease on a 7-point scale based on the 
investigators total clinical experience with this population.  The assessor rates the 
patient from 1 (normal, not at all ill) to 7 (among the most extremely ill patients). 
 
Responders and Remitters on the CGI scale are classified as:  
 
UNDER 
Responders: CGI-I≤ 2 (much or very much improved)90 or CGI-I ≥50% reduction94. 
1982 
These patients have improved but are usually not considered as having reached remission. 
ACT 
 
RELEASED 
Remission:90 CGI-S≤ 2 (normal, not at all ill, or borderline illness). This has been used to 
BEEN 
define remitters but the level of remission represented by the
HEALTH  se scores remains 
controversial. 
HAS INFORMATION 
OF 
 
OF 
 
Quality of Life Questionnaire (QOL
DOCUMENT  ) 
FREEDOM 
DEPARTMENT 
This 16-item patient-rated questionnaire is derived from the Quality of Life, Enjoyment, 
THIS  THE 
and Satisfaction Questio
THE  nnaire.  Patients answered questions based on their satisfaction 
BY 
during the previous two weeks regarding mood, health, activities of daily living, and 
interpersonal relationships on a 5-point scale.  Unlike the other efficacy ratings, higher 
scores on this scale reflect improved function. 
(Source: SCT-MD-05 Study Report p. 16) 
 
 
Sheehan Disability Scale (SDS) 
The SDS1 is a 3-item scale to measure impairment.  The items address the impact of 
symptoms of SAD on work, social life, and family life, within the last 7 days.  The rating 
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is based up an interview with the patient.  This scale may also be helpful in indicating the 
relevance of improvement.  It has been shown to be efficient in demonstrating significant 
differences in improvement in function from the patients’ perspective. Since GAD is 
associated with considerable impairment of function the SDS may provide a useful 
comment on the functional relevance of the treatment.90 
 
 
Duration of Treatment 
Acute Treatment: 12 weeks, this is also the period required to determine efficacy of a 
medication aiming to treat GAD.60 74 
UNDER 
 
1982 
Long –Term Treatment: for patients responding at 12 weeks, an additional 6 months, at 
least, is recommended.60 74 
ACT 
RELEASED 
 
 
BEEN  HEALTH 
Defining Response and Remissi
HAS  on 
INFORMATION 
OF 
When defining ‘response’ to a treatment on a standard rating scale, a score which equates 
OF 
to ≥50% reduction on the scale has been found to be too conservative, with a clinically 
measurable difference being seen at a smaller reduction from baseline as can be seen in 
DOCUMENT 
DEPARTMENT 
Table 6. 
FREEDOM 
THIS 
 
THE  THE 
BY 
Table 6  Correlation of Response/Treatment Between Scales94 
CGI Defined 
Corresponding Reductions 
 
MADRS 
HAM-A 
LSAS 
Response 
 
 
 
CGI-I ≥50% reduction  
≥39% 
≥42% 
≥31% 
Remission 
 
 
 
CGI-S ≤2  
≤11 points 
≤ 9points 
≤36 points 
 
The HAM-A of ≤ 9points full well within the range arrived at the consensus 
conferences.91 92  
 
 
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List of References 
 
1. Nutt DJ, Ballenger JC, Sheehan D, Wittchen HU. Generalized anxiety disorder: 
Comorbidity, comparative biology and treatment. International Journal of 
Neuropsychopharmacology 2002;5(4):315-325. 
2. McManus FV. Assessment of anxiety. Psychiatry 2007;6(4):149-155. 
3. Kessler RC MK, Zhao S, et al. . Lifetime and 12-month prevalence of DSM-III-R 
psychiatric disorders in the United States. Results from the National Comorbidity 
Survey. . Arch Gen Psychiatry 1994;51:8-19. 
4. Ormel J, Vonkorff, M., Ustun, T. B., Pini, S., Korten, A. & Oldehinkel, T. Common 
mental disorders and disability across cultures: results from the WHO 
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Document Outline

• Document 7 D16-1013278 - Mar 2008 main submission body - clinical evaluation for 7.3
• Document 8 D16-1012938 Att 1 Lexapro PI (marketed) 09 July 2007
• Document 9 D16-1012942  GAD Att 2 Lexapro Oct 07 

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