**Intrinsa**

**(Testosterone Transdermal System)**

**NDA 21-769**

Indication

"Treatment of hypoactive sexual desire disorder in surgically menopausal
women receiving concomitant estrogen therapy."

"Hypoactive sexual desire disorder (HSDD) is the persistent or recurrent
deficiency or absence of sexual thoughts, fantasies, and/or desire for
or receptivity for sexual activity, which causes personal distress or
interpersonal difficulties. Low sexual desire may be associated with low
sexual activity, sexual arousal problems or orgasm difficulty."

Dosing regimen:

One patch (300 mcg/day) applied to abdomen twice weekly on a continuous
basis. Patch should be replaced with a fresh patch every three to four
days.

Review by the Division of Reproductive and Urologic Drug Products

November 3, 2004

Table of Contents

1 baCKGROUND [5](#background)

1.1 Definition of FSD [5](#definition-of-fsd)

1.1.1 Hypoactive Sexual Desire Disorder
[5](#hypoactive-sexual-desire-disorder)

1.2 FDA Guidance [5](#fda-guidance)

1.3 Agreements with Applicant [5](#agreements-with-applicant)

2 Clinical development [5](#clinical-development)

2.1 Testosterone Therapy for HSDD [5](#testosterone-therapy-for-hsdd)

2.2 Applicant's Early Clinical Development Program
[5](#applicants-early-clinical-development-program)

2.3 Dose Selection [5](#dose-selection)

2.4 Instrument Development and Validation
[5](#instrument-development-and-validation)

2.5 Overview of Clinical Trials [5](#overview-of-clinical-trials)

3 Clinical Trial Design [5](#clinical-trial-design)

3.1 Description of Phase 2 Trial Protocols
[5](#description-of-phase-2-trial-protocols)

3.2 Description of Phase 3 Trial Protocols
[5](#description-of-phase-3-trial-protocols)

3.3 Inclusion/Exclusion Criteria [5](#inclusionexclusion-criteria)

3.3.1 Inclusion Criteria [5](#inclusion-criteria)

3.3.2 Exclusion Criteria [5](#exclusion-criteria)

3.4 Schedule of Assessments [5](#schedule-of-assessments)

3.5 Endpoints & Statistical Analysis
[5](#endpoints-statistical-analysis)

3.5.1 Primary Endpoint [5](#primary-endpoint)

3.5.2 Principal Secondary Endpoints [5](#principal-secondary-endpoints)

3.5.3 Primary Analysis [5](#primary-analysis)

4 Clinical Trial Outcomes [5](#clinical-trial-outcomes)

4.1 Enrollment [5](#enrollment)

4.2 Demographic Data - Combined Trials
[5](#demographic-data---combined-trials)

4.3 Discontinuation (withdrawal) Rates
[5](#discontinuation-withdrawal-rates)

4.4 Efficacy Outcomes [5](#efficacy-outcomes)

4.4.1 Baseline Findings [5](#baseline-findings)

4.5 Primary Efficacy Outcome (total SSEs at Week 24)
[5](#primary-efficacy-outcome-total-sses-at-week-24)

4.6 Principal Secondary Endpoints [5](#principal-secondary-endpoints-1)

4.6.1 Change in Personal Distress [5](#change-in-personal-distress)

4.6.2 Change in Sexual Desire [5](#change-in-sexual-desire)

4.7 Summary of Phase 3 Efficacy Findings
[5](#summary-of-phase-3-efficacy-findings)

4.8 Secondary Analyses of Primary and Principal Secondary Endpoints
[5](#secondary-analyses-of-primary-and-principal-secondary-endpoints)

4.8.1 Responder Analyses [5](#responder-analyses)

4.8.2 Onset of Treatment Effects: [5](#onset-of-treatment-effects)

4.9 Persistence of Treatment Effect
[5](#persistence-of-treatment-effect)

4.10 Study CMK#US030993 (Minimally Important Clinical Differences)
[5](#study-cmkus030993-minimally-important-clinical-differences)

4.11 Summary of Efficacy and Related Issues
[5](#summary-of-efficacy-and-related-issues)

5 Safety [5](#safety)

5.1 Overview of Safety Concerns with Testosterone
[5](#overview-of-safety-concerns-with-testosterone)

5.2 Overview of Safety Database [5](#overview-of-safety-database)

5.2.1 Studies Included [5](#studies-included)

5.2.2 Demographics of Safety Population
[5](#demographics-of-safety-population)

5.2.3 Safety Outcomes Evaluated [5](#safety-outcomes-evaluated)

5.3 Findings from Clinical Trials [5](#findings-from-clinical-trials)

5.3.1 Safety Findings --Testosterone vs. Placebo
[5](#safety-findings-testosterone-vs.-placebo)

5.3.2 Safety Findings with Increasing Duration of Testosterone Exposure
(Open Label and Extension Phases)
[5](#safety-findings-with-increasing-duration-of-testosterone-exposure-open-label-and-extension-phases)

5.3.3 Frequency and Incidence of Selected Adverse Events (Weeks 0-78)
[5](#frequency-and-incidence-of-selected-adverse-events-weeks-0-78)

5.3.4 Relationship of Serum Free Testosterone Levels to Androgenic
Adverse Events
[5](#relationship-of-serum-free-testosterone-levels-to-androgenic-adverse-events)

5.3.5 Pharmacokinetics of Free and Total Testosterone
[5](#pharmacokinetics-of-free-and-total-testosterone)

5.3.6 Special Safety Studies [5](#special-safety-studies)

5.4 Summary of Overall Safety [5](#summary-of-overall-safety)

5.4.1 Special Concerns [5](#special-concerns)

5.4.2 Unknown Risks [5](#unknown-risks)

6 Pharmacovigilance Program [5](#pharmacovigilance-program)

Appendices

**Appendix 1** FDA Draft Guidance for Industry: Female Sexual
Dysfunction -- Clinical Development of Drug Products for Treatment

**Appendix 2** Applicant\'s Instruments to Assess Sexual Desire and
Personal Distress

**Appendix 3** Listing of Limits for Markedly Abnormal Laboratory Values

**Appendix 4** Publications

Table of Tables

Table 1 Regulatory Activity [5](#__RefHeading___Toc87346450)

Table 2 Instruments Used to Measure Response to Treatment
[5](#_Ref87096983)

Table 3 List of Controlled, Blinded Efficacy Studies
[5](#__RefHeading___Toc87346452)

Table 4 Schedule of Visit Procedures: Phase 3 Trials
[5](#__RefHeading___Toc87346453)

Table 5 Phase 3 Trial Enrollment and Completion
[5](#__RefHeading___Toc87346454)

Table 6 Subject Disposition: Combined Data from Four Double Blind
Studies with 24 Weeks of Testosterone Exposure
[5](#__RefHeading___Toc87346455)

Table 7 Number of Satisfactory Sexual Events
[5](#__RefHeading___Toc87346456)

Table 8 Change in Personal Distress Scores
[5](#__RefHeading___Toc87346457)

Table 9 Change in Sexual Desire Score [5](#__RefHeading___Toc87346458)

Table 10 Changes in Frequency of SSEs, and Sexual Desire and Personal
Distress Scores [5](#__RefHeading___Toc87346459)

Table 11 Responder Analysis for Change in SSEs at Week 24
[5](#__RefHeading___Toc87346460)

Table 12 Responder Analysis for Change in Sexual Desire at Week 24
[5](#__RefHeading___Toc87346461)

Table 13 Distribution of Changes from Baseline in SSEs
[5](#__RefHeading___Toc87346462)

Table 14 Persistence of Treatment Effect
[5](#__RefHeading___Toc87346463)

Table 15 Changes from Baseline in TTS and Placebo Subjects Combined
Based on the Subject\'s Assessment of Clinical Benefit
[5](#__RefHeading___Toc87346464)

Table 16 Changes in Frequency of SSEs, and Sexual Desire and Personal
Distress Scores [5](#__RefHeading___Toc87346465)

Table 17 Demographic Data for Integrated Safety Population
[5](#__RefHeading___Toc87346466)

Table 18 Studies 068, 092, 133 & 134: Most Common Adverse Events (≥ 2%)
During Double Blind Phase [5](#__RefHeading___Toc87346467)

Table 19 Studies 068, 092, 133 & 134: Adverse Events Considered Possibly
or Probably Drug-Related in Double Blind Phase
[5](#__RefHeading___Toc87346468)

Table 20 Studies 068, 092, 133 & 134: Androgenic AEs in Double Blind
Phase [5](#__RefHeading___Toc87346469)

Table 21 Studies 133 & 134: Changes in Lipid Profile in Double Blind
Phase [5](#__RefHeading___Toc87346470)

Table 22 Studies 133 & 134: Proportion of Subjects with Markedly
Abnormal Values on Lipid Profiles in Double Blind Phase
[5](#__RefHeading___Toc87346471)

Table 23 Studies 133 & 134: Changes in Hepatic Function in Double Blind
Phase [5](#__RefHeading___Toc87346472)

Table 24 Studies 133 & 134: Changes in Carbohydrate Metabolism Markers
during Double Blind Phase [5](#__RefHeading___Toc87346473)

Table 25 Studies 133 & 134: Proportion of Subjects with Markedly
Abnormal Values on Carbohydrate Metabolism Markers in Double Blind Phase
[5](#__RefHeading___Toc87346474)

Table 26 Studies 133 & 134: Changes in Hemoglobin in Double Blind Phase
[5](#__RefHeading___Toc87346475)

Table 27 Study 133: Changes in Coagulation Parameters in Double Blind
Phase [5](#__RefHeading___Toc87346476)

Table 28 Study 133: Proportion of Subjects with Markedly Abnormal Values
on Coagulation Parameters in Double Blind Phase
[5](#__RefHeading___Toc87346477)

Table 29 Studies 133 & 134: Most Common Adverse Events (Incidence ≥ 2%)
During Open Label Phase [5](#__RefHeading___Toc87346478)

Table 30 Studies 133 & 134: Most Common Adverse Events (≥ 2% Incidence
Rate) During Extension Phase [5](#__RefHeading___Toc87346479)

Table 31 Studies 133 & 134: Changes in Lipid Profile in Open Label Phase
[5](#__RefHeading___Toc87346480)

Table 32 Studies 133 & 134: Proportion of Subjects with Markedly
Abnormal Values on Lipid Profiles in Open Label Phase
[5](#__RefHeading___Toc87346481)

Table 33 Studies 133 & 134: Changes in Lipid Profile in Extension Phase
[5](#__RefHeading___Toc87346482)

Table 34 Studies 133 & 134: Proportion of Subjects with Markedly
Abnormal Values on Lipid Profiles in Extension Phase
[5](#__RefHeading___Toc87346483)

Table 35 Studies 133 & 134: Changes in Hepatic Function in Open Label
Phase [5](#__RefHeading___Toc87346484)

Table 36 Studies 133 & 134: Changes in Hepatic Function in Extension
Phase [5](#__RefHeading___Toc87346485)

Table 37 Studies 133 & 134: Changes in Carbohydrate Metabolism Markers
in Open Label Phase [5](#__RefHeading___Toc87346486)

Table 38 Studies 133 & 134: Proportion of Subjects with Markedly
Abnormal Values in Carbohydrate Metabolism Markers in Open Label Phase
[5](#__RefHeading___Toc87346487)

Table 39 Studies 133 & 134: Changes in Carbohydrate Metabolism Markers
in Extension Phase [5](#__RefHeading___Toc87346488)

Table 40 Studies 133 & 134: Changes in Hemoglobin in Open Label Phase
[5](#__RefHeading___Toc87346489)

Table 41 Studies 133 & 134: Changes in Hemoglobin in Extension Phase
[5](#__RefHeading___Toc87346490)

Table 42 Study 133: Changes in Coagulation Parameters in Open Label
Phase [5](#__RefHeading___Toc87346491)

Table 43 Study 133: Proportion of Subjects with Markedly Abnormal Values
in Coagulation Parameters in Open Label Phase
[5](#__RefHeading___Toc87346492)

Table 44 Incidence of Adverse Events by Duration of Testosterone
Exposure [5](#__RefHeading___Toc87346493)

Table 45 Frequency of Adverse Events by Duration of Testosterone
Exposure [5](#__RefHeading___Toc87346494)

Table 46 Incidence of Androgenic AE by Serum Free Testosterone Quartiles
in Double Blind Phase [5](#__RefHeading___Toc87346495)

Table 47 Studies 133 & 134: Free and Total Testosterone Concentrations
[5](#__RefHeading___Toc87346496)

Table 48 Percent of Subjects with Free and Total Testosterone Levels
Beyond Normal Range for Reproductive Aged Women
[5](#__RefHeading___Toc87346497)

Table 49 Percent Ki67 Positive Cells in Subjects with Paired Samples
[5](#__RefHeading___Toc87346498)

Table 50 Change in Mammographic Breast Density
[5](#__RefHeading___Toc87346499)

Table 51 Mammographic Breast Density at Baseline
[5](#__RefHeading___Toc87346500)

Table of Figures

[Figure 1 Change from Baseline in 4-week Frequency of SSEs at Week 24
5](#__RefHeading___Toc87346501)

[Figure 2 Change from Baseline in Personal Distress Scale at Week 24
(LOCF) 5](#__RefHeading___Toc87346502)

[Figure 3 Change from Baseline in Sexual Desire at Week 24 (LOCF)
5](#__RefHeading___Toc87346503)

[Figure 4 Time Course of Mean Differences between TTS & placebo
5](#__RefHeading___Toc87346504)

# baCKGROUND

The proposed indication for the transdermal testosterone system is for
the "treatment of hypoactive sexual desire disorder in surgically
menopausal women receiving concomitant estrogen therapy."

## Definition of FSD

Over the years, there has been uncertainty as to exactly what
constitutes a female sexual disorder or dysfunction (FSD). The World
Health Organization\'s *International Statistical Classification of
Diseases and Related Problems* (ICD-10) suggests that sexual
dysfunctions are \"the various ways in which an individual is unable to
participate in a sexual relationship as he or she would wish.\" The main
categories of sexual dysfunction include lack of sexual desire, sexual
aversion disorder, failure of genital response (arousal disorder),
orgasmic dysfunction, dyspareunia, and excessive sexual drive. The
DSM-IV suggests that sexual dysfunctions are \"disturbances in sexual
desire and in the psychophysiologic changes that characterize the sexual
response cycle and cause marked distress and interpersonal difficulty.\"
The dysfunctions include hypoactive sexual desire, sexual aversion,
female arousal disorder, female orgasmic disorder, dyspareunia, and
vaginismus.

In 1999, the new American Foundation of Urologic Disease (AFUD) FSD
diagnostic and classification system was proposed. The AFUD definitions
state that disorders must be associated with personal distress, and may
be either acquired or lifelong (chronic). The many causes of FSD can be
broadly categorized into the following: vascular, neurological,
psychogenic, and hormonal-endocrine. The diagnosis of FSD, according to
AFUD, requires the clinician to obtain a detailed patient history that
defines the problem and identifies causative or confounding conditions
and important psychosocial information. The presence of more than one
dysfunction should be explored as considerable interdependence may
exist. The 4 major components of FSD according to the AFUD
classification are the following:

1.  Sexual desire disorder \[hypoactive sexual desire disorder, HSDD\]

2.  Sexual arousal disorder \[FSAD\]

3.  Orgasmic disorder \[FSOD\]

4.  Sexual pain disorder \[no common acronym\]

### Hypoactive Sexual Desire Disorder 

Hypoactive sexual desire disorder (HSDD), the proposed indication for
Intrinsa, is the persistent or recurring deficiency (or absence) of
sexual fantasies, thoughts and/or desire for, or receptivity to, sexual
activity, which causes personal distress. The cause may be either
physiological or psychological or a combination of both. Common
physiological etiologies include hormone deficiencies, medications, and
surgical interventions. Any disruption of the female hormonal milieu
caused by these etiologies can result in decreased sexual desire. The
lack of, or a decrease in, sexual desire may also be secondary to poor
sexual arousal and response, or to pain associated with sexual activity.
HSDD is sometimes a psychologically or emotionally based problem that
can result from a variety of reasons, including a history of sexual
abuse or trauma. For instance, depression and the treatment of
depression are common problems in women with low sexual desire. Another
factor may be difficulty with inability to attain or maintain sufficient
sexual excitement, a condition known as female sexual arousal disorder
(FSAD).

## FDA Guidance

In May 2000 the FDA distributed the first draft guidance for industry
for the \"Clinical Development of Drug Products for FSD\" (see Appendix
1). Although the definition of FSD was continuing to evolve at that time
(and still is evolving), emphasis was placed on clearly defining the
component or components of FSD that would be targeted for developing
therapies and the potential subgroups (e.g., age, premenopausal vs.
menopausal; different hormonal therapy) that might respond differently
to therapy. Relatively strict inclusion and exclusion criteria were
encouraged. The guidance states that personal distress should be
measured to ensure appropriate patient selection for trial participation
but should not serve as the primary endpoint for establishing
effectiveness.

**FDA Guidance recommendations for the clinical development program and
clinical trial design for FSD therapies included the following:**

1.  Instruments, questionnaires, scales that are used for diagnosis and
    endpoints should be developed, tested, and validated in women with
    FSD and should be able to differentiate between normal women and
    women with different components of FSD

2.  Primary endpoints should be statistically significant and
    [clinically meaningful]{.underline} over time and related to the
    components of FSD being studied

3.  The primary endpoint should include change in the number of
    satisfactory sexual events over time \[from baseline to end of
    treatment\] compared to placebo

4.  Sexual events or encounters include:\
    a) satisfactory sexual intercourse\
    b) sexual intercourse resulting in orgasm\
    c) oral sex resulting in orgasm\
    d) partner-initiated or self masturbation resulting in orgasm

5.  Endpoints based on health-related quality of life (HRQL) claims
    should be linked to clinically meaningful objective endpoints

6.  Two controlled Phase 3 trials of 6 months treatment duration should
    be conducted to support an NDA

7.  Pre-treatment baseline assessment period of 4-8 weeks

8.  Use of a daily diary to record all sexual activities

## Agreements with Applicant

Table 1 below is a brief tabular summary of the major interactions
between the Division and Procter and Gamble Pharmaceuticals, Inc.
(P&GP). Instrument development and validation were completed for the 3
most important endpoints in the Phase 3 trials. Issues that were raised
by the Division at the end-of-Phase 2 meeting, with the Phase 3
protocols, and at the pre-NDA meeting were addressed by the Applicant.
The Applicant conducted their development program consistent with the
Division\'s May 2000 draft guidance and subsequent advice from the
Division. The following were key issues that were raised in discussions
with the Applicant:

1.  Conducting the Phase 3 trials primarily in the U.S., because of the
    concern for major cultural differences in female sexuality in
    non-U.S. countries.

2.  Establishing and validating the diagnosis of HSDD separate from the
    other major components of FSD

3.  The importance of establishing a minimally important clinical
    difference (MICD) to support the primary endpoint and to help define
    the responder analysis

4.  Meeting the ICH guideline for long-term exposure; adding follow-up
    visits for safety after treatment ends

5.  Need for a responder analysis as a secondary analysis to support the
    primary endpoint analysis

6.  Handling missing data; the last observation carried forward (LOCF)
    method was changed to satisfy the Division

7.  Need for additional assessments of androgenic effects, including
    virilization and voice changes

[]{#__RefHeading___Toc87346450 .anchor}Table 1 Regulatory Activity

  ------------------ --------------------------------------------------------
  **IND #59, 232     
  (Procter & Gamble  
  Pharmaceuticals,   
  Applicant)**       

  **Date**           **Topic**

  16 Jul 99          Applicant Pre-IND meeting (IND #59,232)

  8 Dec 99           Telecon re instrument validation and Phase 2 protocol

  5 Dec 01           End-of Phase 2 (EOP2) meeting; fax to Applicant on 30
                     Nov 01

  3 Apr 02           FDA response to Applicant follow-up to EOP2 meeting
                     (letter)

  5 Aug 02           FDA comments on Phase 3 protocols (letter)

  11 Dec 02          FDA feedback on tradename and validation of diagnosis of
                     HSDD (letter)

  26 Jun 03          Pre-NDA meeting

  21 Jun 04          NDA received
  ------------------ --------------------------------------------------------

# Clinical development

It has been reported in several national U.S. surveys that the
proportion of menopausal women having low sexual desire (HSDD) ranges
from 7-33%. Testosterone levels in populations of menopausal women with
and without low libido have shown overlapping ranges of levels
regardless of the libido status. Testosterone levels alone have not been
shown to have a predictable value for diagnosing HSDD or characterizing
the severity of the condition. As noted earlier, HSDD is diagnosed by a
careful medical and psychosocial history, symptoms, and the associated
distress.

## Testosterone Therapy for HSDD 

In the 1980s and 1990s there were a few reports of small studies using
intramuscular or subcutaneous testosterone to treat HSDD in menopausal
women. Treatment resulting in increased sexual desire and sexual
activity as measured by non-validated instruments for sexual function
was often associated with supraphysiologic serum testosterone levels.

## Applicant's Early Clinical Development Program

Because there was no approved therapy available for this indication, the
Applicant embarked on a clinical program to develop a testosterone
transdermal system (TTS) for the treatment of HSDD in surgically
menopausal women. A transdermal delivery was selected for its ability to
deliver a relatively steady dose of testosterone that is not affected by
first pass effects of liver metabolism. The pharmacokinetics (PK) of
testosterone from the transdermal system were evaluated in single and
multiple dose studies, in standard PK and population PK studies, for
durations of 4 days to 12 months, at different application sites
(abdomen or buttocks), over a range of testosterone doses. Overall,
there were 3 bioavailability and 3 PK studies.

## Dose Selection

In Phase 2 studies, the Applicant investigated a range of doses. The 150
mcg/day dose was not effective, and the 450 mcg/day dose provided no
clear benefit beyond that of the 300 mcg/day dose. Based on these
observations, the Applicant selected a dose of 300 mcg/day for their
Phase 3 clinical trials.

## Instrument Development and Validation

Following the FDA's Guidance on FSD, which states it is important to use
validated instruments for assessing responses to FSD therapy in specific
target populations, the Applicant developed three psychometric
instruments for use in surgically menopausal women in the US, Canada,
Europe and Australia. These instruments were designed to measure
efficacy endpoints in women with HSDD in surgically and naturally
menopausal women. Table lists these 3 instruments.

[]{#_Ref87096983 .anchor}

Table 2 Instruments Used to Measure Response to Treatment

![](media/image1.png){width="5.990277777777778in"
height="0.4361111111111111in"}

![](media/image2.png){width="5.990277777777778in"
height="2.5770833333333334in"}

The FDA Draft Guidance stresses that the primary endpoint for assessing
the effectiveness of therapies for FSD is the number of satisfactory
sexual events. The number of satisfactory events, the primary endpoint
of the Applicant's two major Phase 3 trials, was assessed using the
Sexual Activity Log (SAL). The SAL is a record of sexual activity from
the previous 7 days. The determination of \"satisfaction\" was made by
the subject herself, rather than by her partner or a clinician. The
completed weekly diary was collected every 4 weeks (from the preceding 4
weeks) throughout the 24-week trials.

The Profile of Female Sexual Function (PFSF) contains 37 questions that
measure subjective aspects of HSDD in the 7 separate domains listed in
the table. The number of questions per domain ranges from 9 for Desire
to 3 for Arousal and Concerns. The Personal Distress Scale (PDS)
contains 9 items in a single domain and measures personal distress
associated with a patient\'s lack of interest in sex. Based on the
subject's experience and feelings over the preceding 30 days, subjects
filled out the PFSF and PDS at Weeks 0, 4, 8, 12, and 24 in the Phase 3
trials. The PFSF and PDS scores for each domain were then normalized so
that they ranged from 0-100. Scores of 0, 20, 40, 60, 80, and 100 for
each domain correspond, on average, to the following categories of
response: \"Never,\" \"Seldom,\" \"Sometimes,\" \"Often,\" \"Very
Often,\" and \"Always,\" respectively. A decrease in the PDS score
indicates a decrease in a subject\'s distress.

Based on their validation study, the Applicant believes that the 3
instruments were shown to be valid, consistent, and reliable for the
measurement of HSDD in both naturally and surgically menopausal women.
Appendix 2 contains the PDS and the items from the Desire domain of the
PFSF.

## Overview of Clinical Trials 

The clinical program to evaluate the efficacy of TTS in the treatment of
HSDD in surgically menopausal (SM) women consisted of seven trials (see
Table 2), two of which evaluated multiple dose levels. The two Phase 2b
and the two Phase 3 trials were similar in design and used the three
instruments developed by the Applicant in surgically menopausal women.
The two blinded, placebo-controlled Phase 3 studies (2001133 and
2001134) were the major studies submitted to support efficacy and
safety. They each enrolled over 500 women. These studies were conducted
utilizing the 300 microgram dose identified as the optimal dose in the
earlier Phase 2b studies.

There were two special studies linked to the Phase 3 trials. A subset of
132 subjects (68 placebo and 64 active treatment) from the Phase 3
24-week studies was evaluated in a clinical relevance study
(CMKUS030993) to determine whether they experienced meaningful benefits
during study participation. The goal of this sub-study was to determine
the minimally important clinical difference (MICD) for several
parameters. The open label extension studies each included a blinded
13-week \"withdrawal study\" from weeks 52-65 to evaluate the
persistence of treatment effect in a total of 205 women. All were
positive responders on active treatment during weeks 24-52 (see Section
4.9).

[]{#__RefHeading___Toc87346452 .anchor}Table 2 List of Controlled,
Blinded Efficacy Studies

+-------------+-------------+-----------+--------------+-------------+
| **Study**   | **N @       | **N @     | **Estrogen   | *           |
|             | T           | Placebo   | Therapy**    | *Comments** |
| **Phase/    | estosterone | dose**    |              |             |
| \#**        | dose**      |           |              |             |
|             | (mcg/day)   |           |              |             |
+-------------+-------------+-----------+--------------+-------------+
| **II a      | N= 75 @ 150 | N= 75     | Oral CEE     | 12 wk @     |
| T96006**    |             |           |              | each dose;  |
|             | N= 75 @ 300 |           |              | crossover   |
+-------------+-------------+-----------+--------------+-------------+
| **II b      | N= 107 @    | N= 119    | Oral only    | 300 mcg/day |
| 1999068**   | 150         |           |              | was the     |
|             |             |           |              | lowest,     |
|             | N= 110 @    |           |              | safest      |
|             | 300         |           |              | effective   |
|             |             |           |              | dose        |
|             | N= 111 @    |           |              |             |
|             | 450         |           |              |             |
+-------------+-------------+-----------+--------------+-------------+
| **II b      | N= 37 @ 300 | N= 39     | Transdermal  | Small       |
| 1999092**   |             |           | only         | European    |
|             |             |           |              | study       |
+-------------+-------------+-----------+--------------+-------------+
| **III       | N= 283 @    | N= 279    | Oral and     | 24-week     |
| 2001133**   | 300         |           | transdermal  | pivotal     |
+-------------+-------------+-----------+--------------+-------------+
| **III       | N= 266 @    | N= 266    | Oral and     | 24-week     |
| 2001134**   | 300         |           | transdermal  | pivotal     |
+-------------+-------------+-----------+--------------+-------------+
| **          |             |           |              |             |
| Sub-studies |             |           |              |             |
| of 2001133  |             |           |              |             |
| and         |             |           |              |             |
| 2001134**   |             |           |              |             |
+-------------+-------------+-----------+--------------+-------------+
| **CMK030993 | N= 64 @ 300 | N= 68     | Oral and     | Meaningful  |
| Exit        |             |           | transdermal  | Rx benefit  |
| interview   |             |           |              | (MICD)\*    |
| study**     |             |           |              |             |
+-------------+-------------+-----------+--------------+-------------+
| *           | N= 102 @    | N= 103    | Oral and     | Persistence |
| *Withdrawal | 300         |           | transdermal  | of Rx       |
| study**     |             |           |              | benefit-    |
|             |             |           |              | withdrawal  |
+-------------+-------------+-----------+--------------+-------------+
| **Total**   | N= 771@     | N= 778    |              |             |
|             | 300\*\*     |           |              |             |
+-------------+-------------+-----------+--------------+-------------+

\*MICD = minimally important clinical difference or minimally meaningful
clinical difference.

\*\* N= 771 [unique]{.underline} subjects using the TTS 300 mcg/day
dose; does not include the 64 exit interview and 102 withdrawal
subjects.

Safety of the testosterone transdermal system (TTS) was monitored in
clinical trials for periods of 6 months (957 subjects) and 12 months
(494 subjects) as described in the safety section of this review. After
the completion of the two Phase 3 12-month trials, P&G has elected to
conduct long-term safety surveillance (open-label) of subjects treated
with TTS for up to an additional 3 years. This surveillance is currently
on-going (321 women are enrolled beyond 12 months).

# Clinical Trial Design

## Description of Phase 2 Trial Protocols

Study 1999068 was a randomized, double blind, placebo-controlled
multicenter trial investigating the effects of three TTS doses on sexual
outcome measures using the SAL and PFSF. The 447 subjects had all
undergone a hysterectomy and oophorectomy and had low libido. The study
consisted of a 8-week pre-treatment period followed by a 24-week
efficacy period and a 28-week safety extension period. Routine
laboratory and androgen/estrogen hormonal levels were followed from
baseline through the 24 weeks.

Study 1999092 was a randomized, double blind, placebo-controlled
multicenter trial investigating the effects of 300 mcg/day on sexual
outcome measures using the SAL and PFSF. The 77 subjects had all
undergone a hysterectomy and oophorectomy, had low libido, and were on
transdermal estrogen therapy (ET). The study consisted of a 8-week
pre-treatment period followed by a 24-week efficacy period. Subjects
were stratified into 2 groups prior to randomization based on their dose
of ET (≤0.05 mg, \>0.05 mg). Routine laboratory and androgen/estrogen
hormonal levels were followed from baseline through the 24 weeks.

## Description of Phase 3 Trial Protocols

The two Phase 3 studies were nearly identical in design (clinical
laboratory tests differed slightly between the studies). Each was a
multicenter, multinational study conducted in SM women with HSDD. Each
was based on a 24-week, randomized, double-blind (DB),
placebo-controlled (PC), parallel-group design to assess efficacy and
safety. Each was followed by a 28-week open label (OL) extension period
to assess safety.

Subjects were stratified based on their use of oral or transdermal ET.
Within each stratum, subjects were randomly assigned in a 1:1 ratio to
receive 300 mcg/day TTS or a placebo patch. Subjects applied the
investigational TTS to their abdomen twice weekly (each patch was worn
for approximately 3-4 days). Upon completion of the 24-week DB efficacy
and safety period of the study, subjects receiving placebo were switched
to 300 mcg/day TTS, while the active cohort remained on active
treatment. [The subjects and study site personnel remained blinded to
the initial randomized treatment throughout the open label portion of
each study]{.underline}.

The [primary objective]{.underline} of each study was to assess the
efficacy of 300 mcg/day TTS in treating HSDD in SM women on concomitant
oral or transdermal estrogen therapy. Efficacy was assessed by the
change in the 4-week frequency of total satisfying sexual events (SSEs)
from baseline to Week 24. Key [secondary objectives]{.underline} were:

1.  personal distress as measured by the PDS score

2.  sexual desire as measured by the PFSF

The frequency of satisfactory sexual events was recorded on the SAL that
was completed by subjects at home on a weekly basis and returned to the
clinical sites at the next scheduled visit. The PFSF and PDS were
completed at the clinical sites at baseline (Week 0) and Weeks 4, 8, 12,
and 24. Safety was evaluated by monitoring adverse events (AEs), routine
clinical laboratory measurements, vital signs, and physical
examinations. Skin appearance at the most recent abdominal patch
application site was evaluated at each clinic visit for patch site
symptoms of irritation. Objective assessments of androgenic effects on
the skin (increases in hair growth at the lip and chin, facial
depilation, and degree of facial acne vulgaris) were also evaluated in
each study. Serum samples were analyzed in each study at baseline and
Weeks 12 and 24 for determination of free, total, and bioavailable
testosterone, SHBG, free and total estradiol, and estrone.

## Inclusion/Exclusion Criteria

### Inclusion Criteria 

[Inclusion criteria]{.underline} were developed to ensure that subjects
entering the study were surgically menopausal, satisfied major
diagnostic criteria for [acquired]{.underline} (not chronic) HSDD, and
were in stable relationships in which partner factors would not preclude
the possibility of demonstrating a treatment effect.

Women were screened for study participation according to the following
inclusion criteria at Week -8 (Visit 1) unless otherwise specified.
Eligible women must have:

1)  been 20 to 70 years old and in generally good health based on
    medical history, physical examination, and laboratory evaluation;

2)  undergone bilateral salpingo-oophorectomy and hysterectomy at least
    6 months prior to screening and had no physical impediment to sexual
    function for at least 3 months prior to screening (documented
    evidence of surgery had to be provided). If the surgical report was
    not available, a history consistent with removal of both ovaries was
    to be obtained. Attempts to obtain the surgical report were
    documented;

3)  been receiving a stable dose of ET for at least 3 months prior to
    screening with the intention of maintaining that regimen.

> •This treatment should have resulted in, on average, less than 3
> moderate to severe hot flashes per day.
>
> •Acceptable therapies included approved oral estrogens and approved
> transdermal estrogen patch regimens.
>
> •Compounded estrogen preparations, selective estrogen receptor
> modulators (SERMs), or phytoestrogens preparations were
> [not]{.underline} to be substituted for the ET requirement;

4)  been, in her own judgment, in a stable monogamous sexual
    relationship that was perceived to be secure and communicative, for
    at least 1 year prior to study entry. The relationship was to be
    with the same partner who was sexually functional, both
    psychologically and physically, and expected to be physically
    present (i.e., available for sexual activity at some time during a
    24-hour day) at least 50% of each month during the 8-week
    pretreatment and 24-week efficacy period of the study;

5)  answered affirmatively to ALL five of the following questions:

```{=html}
<!-- -->
```
1.  Before your ovaries were removed, would you say that in general,
    your sex life was good and satisfying?

2.  Since your ovaries were removed, do you feel you have experienced a
    meaningful loss in your level of desire for sex?

3.  Since your ovaries were removed, do you feel you have experienced a
    significant decrease in your sexual activity?

4.  Are you concerned about or bothered by your current level of desire
    for or interest in sex?

5.  Would you like to see an increase in your level of interest in or
    desire for sex and sexual activity?

```{=html}
<!-- -->
```
6)  if ≥ 40 years of age, had a clinically acceptable screening
    bilateral mammogram (no evidence of malignancy) as determined by the
    local radiologist (subjects could have submitted a mammogram done up
    to 2 months prior to screening). Subjects under 40 years of age at
    screening could have elected to have mammograms if they wished, but
    these were not required for study entry;

7)  had a clinically acceptable Pap smear as read by a central cytology
    facility (no evidence of malignancy or squamous intraepithelial
    lesions) if the cervix was present. A Pap smear at study entry could
    have been performed on subjects without a cervix at the discretion
    of the investigator;

### Exclusion Criteria 

[Exclusion criteria]{.underline} were developed to ensure that
psychological or physical factors, other than low testosterone, that
could cause hypoactive sexual desire were not present. Potential study
subjects with medical conditions that might cause them to be at
increased risk for adverse events (AEs) were also excluded, as were
subjects taking drugs or nutritional supplements that were likely to
affect sexual function.

Women were screened for study participation according to the following
exclusion criteria at Week -8 (Visit 1) or as specified. [Eligible women
must not]{.underline}:

1)  have had dyspareunia not alleviated by lubricants, any physical
    limitations, or sexual trauma since their oophorectomy that would
    have interfered with normal sexual function;

2)  have been experiencing any chronic or acute life stress relating to
    any major life change, such as recent loss of income or the death of
    a close family member, that could have, in the opinion of the
    investigator, significantly interfered with sexual activity;

3)  have had significant psychiatric disorder (including mild depressive
    disorder, as evidenced by a score of ≥ 14 on the Beck Depression
    Inventory-II \[BDI-II\]), or had a significant alcohol or drug
    dependency and/or been receiving pharmacologic treatment for such
    illness or disorder;

4)  have had evidence of clinically significant organic disease on the
    history and/or physical examination that would have, in the opinion
    of the investigator, prevented the patient from completing the
    study, or otherwise affected the outcome of the study. Subjects
    could not have had any major illness, active gallbladder disease,
    gynecological or breast surgery, including excisional biopsies,
    within the last 6 months;

5)  have used within the last 12 weeks any medications/preparations that
    could have affected sexual function or otherwise interfered with
    interpretation of study results.

6)  have used tablet or powder forms of phytoestrogens for less than 12
    weeks prior to Week -8 (Visit 1). No use or stable use of
    phytoestrogens for 12 weeks or longer was acceptable;

7)  have used (averaging more than once a week) in the past 30 days the
    following preparations: dehydroepiandrosterone (DHEA), melatonin, or
    other drugs or supplements that could have, in the opinion of the
    investigator, affected sexual function;

8)  have received marketed or investigational oral, sublingual, topical,
    transdermal, injectable, or vaginal androgen therapy at any time
    during the past 3 months, or investigational implantable androgen
    therapy at any time in the past 7 months;

9)  have had current severe dermatological problems (e.g., severe or
    cystic acne) or had a known or suspected hypersensitivity or allergy
    to any adhesive or any of the constituents of the transdermal
    systems;

10) have had a history of breast cancer or estrogen-dependent neoplasia
    (e.g., endometrial cancer) or any gynecological cancer at any time
    before study entry or other cancer (except basal or squamous cell
    carcinoma) within the last 5 years;

11) have had diabetes, a history of cerebrovascular disease,
    thromboembolic disorders, myocardial infarction, or angina at any
    time before study entry or thrombophlebitis within the last 5 years;

12) have had a thyroid-stimulating hormone (TSH) value at screening
    above the upper limit of normal confirmed by a free T4 outside the
    normal laboratory range (subjects with an abnormal TSH, normal free
    T4, and no clinical signs or symptoms of thyroid disease, with or
    without replacement treatment, could have been admitted to the
    study);

13) have had, in the opinion of the investigator, clinically significant
    abnormal pretreatment laboratory parameters (a single repeat assay
    was allowed if an assay result was questionable) that would have
    materially impacted the patient's ability to participate in the
    study;

14) have had the following laboratory values:

> • serum creatinine \> 2.5 mg/dL\
> • serum total bilirubin ≥ 2 times the upper limit of normal\
> • alanine aminotransferase (ALT) or aspartate aminotransferase (AST)
> \> 3 times the upper limit of normal; or

15) have previously participated in Study 1999068 or 1999092 or have
    participated in a clinical trial within 30 days or received an
    investigational medication within 30 days (women participating in
    observational studies, however, could have been included).

**[Division comment]{.underline}**:

-   In the Phase 2 studies T96006 and 1999068, per protocol, all the
    women had documented low serum testosterone levels \[free T \<3.5
    pg/mL; normal range is 0.9-7.3\]. This free T criterion was dropped
    in the Phase 3 studies because the Applicant's Phase 2b experience
    indicated that almost no potential study subject had baseline T
    levels exceeding the level set. Baseline serum testosterone
    parameters were obtained, however, as were testosterone levels at
    Weeks 12 and 24 during the 2 controlled Phase 3 trials.

## Schedule of Assessments

The Schedule of Visit Procedures for the Phase 3 clinical trials is
listed in Table 3.

[]{#__RefHeading___Toc87346453 .anchor}Table 3 Schedule of Visit
Procedures: Phase 3 Trials

<table>
<colgroup>
<col style="width: 42%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 0%" />
<col style="width: 5%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 6%" />
<col style="width: 6%" />
</colgroup>
<tbody>
<tr class="odd">
<td rowspan="3"><strong><br />
PROCEDURE</strong></td>
<td colspan="3"><strong>Screening Period</strong></td>
<td colspan="7"><strong>Efficacy Treatment Period</strong></td>
</tr>
<tr class="even">
<td><strong>Visit 1</strong></td>
<td><strong>Visit 2</strong></td>
<td colspan="2"><strong>Visit 3</strong></td>
<td><strong>Visit 4</strong></td>
<td><strong>Visit 5</strong></td>
<td><strong>Visit 6</strong></td>
<td><strong>Visit 7</strong></td>
<td><strong>Visit 8</strong></td>
<td><strong>Visit 9</strong></td>
</tr>
<tr class="odd">
<td><strong>Wk -8</strong></td>
<td><strong>Wk -4</strong></td>
<td colspan="2"><strong>Wk 0</strong></td>
<td><strong>Wk 4</strong></td>
<td><strong>Wk 8</strong></td>
<td><strong>Wk 12</strong></td>
<td><strong>Wk 16</strong></td>
<td><strong>Wk 20</strong></td>
<td><strong>Wk 24</strong></td>
</tr>
<tr class="even">
<td>Informed Consent</td>
<td>X</td>
<td></td>
<td colspan="2"></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Eligibility Criteria</td>
<td>X</td>
<td>X</td>
<td colspan="2">X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Personal/Demographic Data</td>
<td>X</td>
<td></td>
<td colspan="2"></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Medical, Gynecological and Drug History</td>
<td>X</td>
<td>X</td>
<td colspan="2">X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Physical Examination (including breast and pelvic exam)</td>
<td></td>
<td>X</td>
<td colspan="2"></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>X</td>
</tr>
<tr class="odd">
<td>Bilateral Mammogram</td>
<td></td>
<td>X</td>
<td colspan="2"></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Vital signs (BP, heart rate, temperature), weight</td>
<td>X</td>
<td></td>
<td colspan="2">X</td>
<td></td>
<td></td>
<td>X</td>
<td></td>
<td></td>
<td>X</td>
</tr>
<tr class="odd">
<td><blockquote>
<p>Cholesterol, triglycerides, LDL, HDL, glucose, hemoglobin
A1c<strong>,</strong> insulin, serum chemistry , liver function tests,
hematology</p>
</blockquote></td>
<td>X</td>
<td></td>
<td colspan="2"></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td>X</td>
</tr>
<tr class="even">
<td>Hormone measurements (Androgens, Estrogens and SHBG)</td>
<td></td>
<td>X</td>
<td colspan="2"></td>
<td></td>
<td></td>
<td>X</td>
<td></td>
<td></td>
<td>X</td>
</tr>
<tr class="odd">
<td>Hirsutism, Frequency of facial depilation, Acne score</td>
<td></td>
<td>X</td>
<td colspan="2"></td>
<td></td>
<td></td>
<td>X</td>
<td></td>
<td></td>
<td>X</td>
</tr>
<tr class="even">
<td>Randomize to treatment</td>
<td></td>
<td></td>
<td colspan="2">X</td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="odd">
<td>Review of inventories with patients</td>
<td>X</td>
<td>X</td>
<td colspan="2"></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
<td></td>
</tr>
<tr class="even">
<td>Collect completed SAL</td>
<td></td>
<td>X</td>
<td colspan="2">X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
</tr>
<tr class="odd">
<td>Complete PFSF, PDS</td>
<td></td>
<td></td>
<td colspan="2">X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td></td>
<td></td>
<td>X</td>
</tr>
<tr class="even">
<td>Concomitant Medications</td>
<td></td>
<td></td>
<td colspan="2"></td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
</tr>
<tr class="odd">
<td>AE Adverse Events</td>
<td>X</td>
<td>X</td>
<td colspan="2">X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
<td>X</td>
</tr>
</tbody>
</table>

## Endpoints & Statistical Analysis 

### Primary Endpoint

The [primary efficacy endpoint]{.underline} was the change from baseline
in the total frequency of satisfying sexual events at 24 weeks (sum of
the 4 consecutive weekly frequencies on SAL questions 3 and 6 during
Weeks 21-24). In this document, the frequency of satisfying sexual
events is presented as the total count over a 4-week period.

### Principal Secondary Endpoints

[Secondary endpoints]{.underline} were the sexual desire domain score of
the PFSF and the PDS Score (Distress) at 24 weeks. Each item within a
domain has 6 possible answers ranging from all of the time to none of
the time. Raw domain scores were computed by summing the scores for
items within a domain and transforming the score to a 0 to 100 scale.
(See Section 2.4.)

### Primary Analysis

The [primary analysis]{.underline} was based on the intent-to-treat
(ITT) population.

The change from baseline in the total frequency of satisfying sexual
activity, summed over Weeks 21-24, was regressed on treatment group,
pooled center, baseline average 4 week frequency of satisfying sexual
activity, age, and ET route in an ANCOVA analysis. Least squares
estimates of the mean 4 week frequency of satisfying sexual activity for
the 300 mcg/day testosterone arm and the placebo arm were computed, as
were 95% confidence intervals and a p-value testing the null hypothesis
of no treatment differences. Secondary models, including possible
interactions (e.g., pooled center by treatment), were explored to
evaluate consistency of treatment effects across other factors.

To account for subjects who did not complete the 24-week efficacy period
of the study and therefore had missing SAL weekly frequencies for Weeks
21-24, a last observation carried forward (LOCF) approach was used. For
each patient, the sexual activity corresponding to the last SAL and 3
preceding SALs was used in the analysis. For example, if the last SAL
returned from a patient is the Week 23 SAL, then the frequency of sexual
activity recorded for weeks 20-23 was used in the analysis. To account
for missing weekly assessments within any four-week interval of
follow-up, the average of non-missing assessments was imputed for the
missing assessment.

The prospectively defined analyses of the primary endpoint were not the
same in all studies. The Phase 2b studies used Poisson regression
analysis, and the Phase 3 studies used ANCOVA and Wilcox-rank sums
(WRS). The WRS was used in the Phase 3 studies to provide appropriate
comparisons between 300 mcg/day TTS and placebo in cases where the
ANCOVA assumptions were violated. Because a few influential outliers
occurred in Study 2001134, WRS was conducted for cross-study
comparisons, in addition to ANCOVA. All efficacy analyses are based on
the change from baseline in the total satisfying sexual activity at Week
24, using the ITT population and a LOCF approach.

# Clinical Trial Outcomes

## Enrollment

Phase 3 Study 2001133 enrolled 562 subjects in the U.S., Canada, and
Australia (52 clinical sites). A total of 451 (80%) subjects completed
the efficacy and safety period through Week 24. Of these subjects, 449
participated in the 28-week open label period and 380 (85%) completed
through Week 52. Phase 3 Study 2001134 enrolled 533 subjects in the
U.S., Canada, and Australia (51 clinical sites). A total of 418 (78%)
subjects completed through Week 24. Of these subjects, 388 (93%)
participated in the 28-week open label period and 261 (67%) of the 388
completed through Week 52 (see Table 4).

[]{#__RefHeading___Toc87346454 .anchor}Table 4 Phase 3 Trial Enrollment
and Completion

  --------------- --------- ----------- ----------- ----------- ------------
  Study Week      Study                 Study                   Totals
                  2001133               2001134                 

  Blinded Phase   N         \%          N           \%          

  0 (Enrollment)  526       100%        533         100%        1,059

  24 (Completion) 451       86%         418         78%         869 (82%)

  Open Label                                                    
  Phase                                                         

  24 (Enrollment) 449       100%        388         100%        837

  52 (Completion) 380       85%         261         67%         641 (77%)
  --------------- --------- ----------- ----------- ----------- ------------

## Demographic Data - Combined Trials 

Demographics were similar across between the placebo and TTS groups. In
the 4 trials combined (Phase 2b and 3 studies, see Table 2) the
following baseline demographic and anthropometric data were observed
among the 1,401 subjects:

1.  Age: mean 49 (7.5 SD); median 49; Min-Max 26-70

2.  Age distribution: 10% were 30-39; 41% were 40-49, 41% were 50-59; 6%
    60-64

3.  Race: 89% Caucasian; 6% African American; 3% Hispanic

4.  Geography: 89% U.S.; 3% Canada; 4% Europe; 4% Australia

5.  Marital status: 87% married to partner; 13% not married

6.  Duration of relationship with partner (years): mean 18.6 (11.35 SD);
    median 17; Min-Max 1-54

7.  Baseline weight (kg): mean 73.1 (15.3 SD); median 71; Min-Max
    40.6-153.6

8.  Baseline height (cm): mean 163.8 (6.38); median 163; Min-Max 132-183

9.  Body Mass Index: mean 27.2 (5.51); median 26; Min-Max 17-58

10. Estrogen therapy route: 77% oral; 23% transdermal

11. Age at hysterectomy: mean 39.6(7.9); median 40; Min-Max 17-66

12. Age at oophorectomy: mean 40.4 (7.8); median 41; Min-Max 17-66

13. Years since surgery: \~9 (7.2); median 7-8; Min-Max 0.5-42.5

14. Tobacco use: 53% never; 30% previously; 17% currently

15. Alcohol use: 22% never; 4% previously; 73% currently

Division comment:

-   The population in this study reflects the age group who has
    undergone hysterectomy in the U.S., but African American women are
    dramatically underrepresented in the study populations. Data from
    the MMWR Hysterectomy Surveillance -- United States, 1994-1999
    reported by Keshavarz H, et al, found that women aged 40-44 had the
    highest hysterectomy rate compared to other age groups -- 52% of
    hysterectomies were performed in women \<45 years of age. Fifty-five
    percent of women in the U. S. who had a hysterectomy had a bilateral
    oophorectomy. When age and race were examined together, the group
    with the highest rate of hysterectomy was African American women
    aged 40-44 years -- 16.8 per 1,000, compared to 10.8 per 1000 in the
    same age group of white women.

## Discontinuation (withdrawal) Rates

[Studies combined]{.underline}: A total of 1401 subjects (704 in the
placebo group; 697 in the 300 mcg/day TTS group) were enrolled in
Studies 2001133 (Phase 3), 2001134 (Phase 3), 1999068 and 1999092 (both
Phase 2). A similar percentage of subjects in the two treatment groups
completed these studies through Week 24. A total of 309 (22%) subjects
were discontinued during the 24-week double blind period. The most
common reasons for discontinuation were AEs (8% each) and voluntary
withdrawals (7% placebo, 9% TTS) (see Table 5). Discontinuation for
adverse events will be discussed in more detail in Section 5.3.1.1 of
this document.

[]{#__RefHeading___Toc87346455 .anchor}Table 5 Subject Disposition:
Combined Data from Four Double Blind Studies with 24 Weeks of
Testosterone Exposure

![](media/image3.wmf){width="5.844444444444444in"
height="2.058333333333333in"}

[Individual studies]{.underline}: When compared among the individual
studies, a similar percentage of subjects (within 1-2%) in each
treatment group in each trial withdrew due to the 6 reasons listed
above. The only exception was in Study 2001133 where a lower percentage
of subjects on placebo (12/279= 4%) voluntarily withdrew (not due to an
AE) as compared to the TTS subjects (26/283= 9%).

[Discontinuation over time]{.underline}: No increases in the rate of
patient withdrawals in the 4 combined studies were observed with
increased duration of exposure to 300 mcg/day TTS when comparing each
4-week time period during the 24-week studies. The percentage of
subjects who withdrew from each of the studies was similar between the
two treatment groups for each 4-week period. For each 4-week period, the
range was 3.1-5.5% for placebo and 3.0-4.3% for TTS. Similar results
were observed when time to withdrawal was compared between the two
individual Phase 3 studies.

## Efficacy Outcomes

### Baseline Findings

**Mean scores at baseline:** The overall mean scores at baseline in the
two phase 2 and two phase 3 studies for the SAL 4-week frequency of
total satisfying sexual events (3.0), PFSF sexual desire (21.2), and
personal distress (64.5) were consistent with mean scores from other
studies with women who considered themselves to have few satisfying
sexual activities, low sexual desire, and were distressed about their
lack of sexual desire. Baseline disease severity as judged by the three
main endpoints (satisfying sexual events, distress scores, and desire
scores) was similar between the active and placebo treatment groups
across the four studies.

Division comment:

-   Data collected by the Applicant early in the development program in
    2000 during the time of the initial 3 instrument validation studies
    showed on average 3-4 total satisfying sexual episodes (SSEs) per 4
    weeks in women with HSDD \[N= 347\] in Europe, the U.S. and Canada
    compared with \"normal\" age-matched controls \[N= 260\] who
    reported 10-12+ SSEs per 4 weeks. The sexual desire score associated
    with HSDD was 30 ± 5 (0-100 range) and with normal controls was 60
    ± 5. The personal distress score (0-100 range) was 55 ± 5 in women
    with HSDD and 5 ± 2 in age-matched controls.

-   It is of note that a PFSF sexual desire score of 21 corresponds, on
    average, to "seldom" having an interest in sexual activity, and that
    a PDS score of 65 corresponds, on average, to being "often"
    distressed about the lack of interest in sexual activity.

**Estrogen formulations used:** Overall, 77% of the subjects in the
combined studies were taking concomitant oral estrogen therapy (ET) and
23% were receiving concomitant transdermal ET. Subjects who participated
in Studies 2001133 and 2001134 used either oral or transdermal ET.
Subjects in Study 1999068 used concomitant oral ET, whereas subjects in
Study 1999092 used concomitant transdermal ET only. Of the 1,075
subjects on oral ET, the percentage of subjects taking higher dose oral
ET (defined by the Applicant as \>0.625 mg Premarin or its equivalent)
was 48% and those on higher dose transdermal ET (defined by the
Applicant as \>0.05 mg) was 54%. The remaining subjects were receiving
lower dose oral or transdermal ET. In the oral estrogen therapy group,
the percentage of subjects taking conjugated equine estrogen (63%) and
non-conjugated equine estrogen (37%) was also similar between the two
treatment groups in the 3 studies using oral ET. The next most commonly
used form of concomitant ET was estradiol.

Division comment:

-   A significant percentage of subjects were using higher doses of
    estrogen. Current guidelines recommend use of the lowest effective
    dose of estrogen. It is unclear whether women in these studies were
    on the lowest effective dose of estrogen for them as individuals.

## Primary Efficacy Outcome (total SSEs at Week 24)

The primary endpoint was the change in SSEs (sum of the SAL Question 3
and 6 - satisfying sexual activity with or without intercourse).

A discussion and analysis of the efficacy results follows, with results
from the 4 individual studies shown first, followed by Figures (bar
graphs) of the individual and combined results shown together.

Division comment:

-   The Division statistician found the analysis plan to be acceptable.

[]{#__RefHeading___Toc87346456 .anchor}Table 6 Number of Satisfactory
Sexual Events

<table>
<colgroup>
<col style="width: 18%" />
<col style="width: 0%" />
<col style="width: 17%" />
<col style="width: 0%" />
<col style="width: 11%" />
<col style="width: 0%" />
<col style="width: 18%" />
<col style="width: 0%" />
<col style="width: 16%" />
<col style="width: 0%" />
<col style="width: 16%" />
</colgroup>
<tbody>
<tr class="odd">
<td><p>Study Number</p>
<p>(Number of subjects)</p></td>
<td colspan="2">Testosterone dose (mcg/day)</td>
<td colspan="2">Baseline Mean<sup>a</sup></td>
<td colspan="2">Mean Change from Baseline at Week 24<sup>a,b</sup></td>
<td colspan="2">Efficacy Analysis Method</td>
<td colspan="2"><p>Results</p>
<p>p-value</p></td>
</tr>
<tr class="even">
<td colspan="11"><strong>Frequency of Total Satisfying Sexual Episodes
(SSEs)</strong></td>
</tr>
<tr class="odd">
<td colspan="11">Phase 3 trials</td>
</tr>
<tr class="even">
<td rowspan="2"><p>2001133</p>
<p>(N=562)</p></td>
<td colspan="2">0 (placebo)</td>
<td colspan="2">2.94</td>
<td colspan="2">0.98</td>
<td colspan="2" rowspan="2">ANCOVA</td>
<td colspan="2" rowspan="2">p=0.0003</td>
</tr>
<tr class="odd">
<td colspan="2">300</td>
<td colspan="2">2.82</td>
<td colspan="2">2.13</td>
</tr>
<tr class="even">
<td rowspan="2"><p>2001134</p>
<p>(N=532)</p></td>
<td colspan="2">0 (placebo)</td>
<td colspan="2">3.19</td>
<td colspan="2">0.73</td>
<td colspan="2" rowspan="2">Wilcoxon Rank Sum<sup>b</sup></td>
<td colspan="2" rowspan="2">p=0.0010</td>
</tr>
<tr class="odd">
<td colspan="2">300</td>
<td colspan="2">3.04</td>
<td colspan="2">1.56</td>
</tr>
<tr class="even">
<td colspan="11">Phase 2 trials</td>
</tr>
<tr class="odd">
<td colspan="2" rowspan="2"><p>1999068*</p>
<p>(N=229)</p></td>
<td colspan="2">0 (placebo)</td>
<td colspan="2">2.8</td>
<td colspan="2">1.20</td>
<td colspan="2" rowspan="2">Poisson Regression</td>
<td rowspan="2">p=0.0493</td>
</tr>
<tr class="even">
<td colspan="2">300</td>
<td colspan="2">2.92</td>
<td colspan="2">2.32</td>
</tr>
<tr class="odd">
<td colspan="2" rowspan="2"><p>1999092*</p>
<p>(N=76)</p></td>
<td colspan="2">0 (placebo)</td>
<td colspan="2">3.20</td>
<td colspan="2">1.12</td>
<td colspan="2" rowspan="2">Poisson Regression</td>
<td rowspan="2">p=0.0641</td>
</tr>
<tr class="even">
<td colspan="2">300</td>
<td colspan="2">2.08</td>
<td colspan="2">3.08</td>
</tr>
</tbody>
</table>

\* Source: E-Table 4, ISE.\
**^a^** The frequency of SSEs was based on data from the SAL from
baseline and the last 4 recorded weeks.\
**^b^** Mean change from baseline adjusted for age, estrogen therapy
route, pooled centers, and baseline value.

To be evaluable for efficacy, a subject had to receive at least 8 weeks
of blinded treatment. The table above shows the [mean change from
baseline]{.underline} in the SSEs for the last recorded 4-week period of
time. In both Phase 3 studies (2001133 and 2001134), compared with
placebo, subjects treated with 300 mcg/day TTS had an increase in the
frequency of total SSEs.

Mean changes from baseline on 300 mcg/day TTS and placebo are shown in
Figure 1.

[]{#__RefHeading___Toc87346501 .anchor}Figure 1 Change from Baseline in
4-week Frequency of SSEs at Week 24

![](media/image4.png){width="5.999305555555556in"
height="2.777083333333333in"}

Data for individual studies shown corresponds to the mean change from
baseline (±) 1 standard error (SE). Data for combined studies
corresponds to mean change from baseline adjusted for study (±) 1
standard error.

\*\* =p\<0.01; \*\*\*=p\<0.001 based on analysis of covariance (ANCOVA)
model for combined studies and Wilcoxon Rank-Sum (WRS) test for
individual studies.

Division comment:

-   The crucial question is the clinical significance of the change with
    active treatment yielding, on average, one more satisfying sexual
    event per 4 weeks compared to placebo.

## Principal Secondary Endpoints

The most important secondary endpoints were the decrease in the personal
distress score of the PDS and the increase in the sexual desire domain
of the PFSF.

Division comment:

-   Experts in the field consider that both an increase in sexual desire
    and a decrease in personal distress are necessary components of a
    clinically meaningful HSDD treatment.

### Change in Personal Distress 

The PDS measures personal distress associated with subjects' low desire
for, and lack of interest in, sex. The PDS instrument contains 9 items
in a single domain. Subjects filled out the questionnaire based on their
experiences and feelings over the preceding 30 days. (See Section 2.4.)
A [decrease in the PDS score indicates a decrease in a patient\'s
distress]{.underline}.

Across the two Phase 3 trials, the baseline score for distress ranged
from 62.57 to 66.38 for the placebo group and from 64.78 to 66.61 for
the TTS group, which corresponds to an average answer of \"often\" being
distressed for the 9 questions (see Table 7). The Least-Squares Means
difference between the change in placebo and TTS scores was
approximately 7.3.

Division comment:

-   The Applicant reports that women without HSDD have a score of 5 ± 2
    on this scale.

[]{#__RefHeading___Toc87346457 .anchor}Table 7 Change in Personal
Distress Scores

<table>
<colgroup>
<col style="width: 18%" />
<col style="width: 0%" />
<col style="width: 17%" />
<col style="width: 0%" />
<col style="width: 11%" />
<col style="width: 0%" />
<col style="width: 18%" />
<col style="width: 0%" />
<col style="width: 16%" />
<col style="width: 0%" />
<col style="width: 16%" />
</colgroup>
<tbody>
<tr class="odd">
<td>Study Number</td>
<td colspan="2">Testosterone dose (mcg/day)</td>
<td colspan="2">Baseline Mean<sup>a</sup></td>
<td colspan="2">Mean Change from Baseline at Week 24<sup>a,b</sup></td>
<td colspan="2">Efficacy Analysis Method</td>
<td colspan="2"><p>Results</p>
<p>p-value</p></td>
</tr>
<tr class="even">
<td colspan="11"><strong>Personal Distress Score</strong></td>
</tr>
<tr class="odd">
<td colspan="11">Phase 3 studies</td>
</tr>
<tr class="even">
<td rowspan="2"><p>2001133</p>
<p>(N=562)</p></td>
<td colspan="2">0</td>
<td colspan="2">62.57</td>
<td colspan="2">-16.31</td>
<td colspan="2" rowspan="2">ANCOVA</td>
<td colspan="2" rowspan="2">p=0.0006</td>
</tr>
<tr class="odd">
<td colspan="2">300</td>
<td colspan="2">64.78</td>
<td colspan="2">-23.55</td>
</tr>
<tr class="even">
<td rowspan="2"><p>2001134</p>
<p>(N=532)</p></td>
<td colspan="2">0</td>
<td colspan="2">66.38</td>
<td colspan="2">-18.27</td>
<td colspan="2" rowspan="2">ANCOVA</td>
<td colspan="2" rowspan="2">p=0.0091</td>
</tr>
<tr class="odd">
<td colspan="2">300</td>
<td colspan="2">66.61</td>
<td colspan="2">-24.34</td>
</tr>
<tr class="even">
<td colspan="11">Phase 2 trials</td>
</tr>
<tr class="odd">
<td colspan="2" rowspan="2"><p>1999068*</p>
<p>(N=229)</p></td>
<td colspan="2">0 (placebo)</td>
<td colspan="2">64.71</td>
<td colspan="2">-18.46</td>
<td colspan="2" rowspan="2">ANCOVA</td>
<td rowspan="2">p=0.1258</td>
</tr>
<tr class="even">
<td colspan="2">300</td>
<td colspan="2">65.39</td>
<td colspan="2">-23.76</td>
</tr>
<tr class="odd">
<td colspan="2" rowspan="2"><p>1999092*</p>
<p>(N=76)</p></td>
<td colspan="2">0 (placebo)</td>
<td colspan="2">56.73</td>
<td colspan="2">-2.11</td>
<td colspan="2" rowspan="2">ANCOVA</td>
<td rowspan="2">p=0.0025</td>
</tr>
<tr class="even">
<td colspan="2">300</td>
<td colspan="2">57.14</td>
<td colspan="2">-22.10</td>
</tr>
</tbody>
</table>

**^a^** Range for distress score is 0-100.\
**^b^** Mean change from baseline adjusted for age, estrogen therapy
route, pooled centers, and baseline value.

The changes from baseline in the PDS score at Week 24 for the four
individual studies and the studies combined are shown in Figure 2.

[]{#__RefHeading___Toc87346502 .anchor}Figure 2 Change from Baseline in
Personal Distress Scale at Week 24 (LOCF)

![](media/image5.png){width="5.997916666666667in"
height="2.7645833333333334in"}

Data for individual studies shown corresponds to the mean change from
baseline (**±**) 1 standard error.

Data for combined studies corresponds to mean change from baseline
adjusted for study (**±**) 1 standard error. \*\* = p\<0.01; \*\*\* =
p\<0.001 based on analysis of covariance (ANCOVA) model.

Division comment:

-   The difference in mean reduction in the distress scores in the TTS
    treated subjects compared to those in the placebo group correspond
    to less than an average change of one unit on the PDS
    questionnaire\'s response scale (range 1 to 6).

### Change in Sexual Desire

Change in desire was assessed using the Desire domain of the PFSF (see
Section 2.4). Subjects were instructed that feelings could be either
mental or physical and could occur in the absence of sexual activity.
Their responses were to reference the past 30 days.

Division comment:

-   The Applicant reported that women without HSDD had a score of 60 ± 5
    for this domain.

Across the two phase 3 trials, the baseline score for sexual desire
ranged from 20.82 to 23.37 for the placebo group and from 19.79 to 21.67
for the active treatment group. This generally corresponds with an
average answer of \"seldom\" for the 9 items in the desire domain.

[]{#__RefHeading___Toc87346458 .anchor}Table 8 Change in Sexual Desire
Score

+------------+-----------+-------+------------+-----------+-----------+
| Study      | Tes       | Bas   | Mean       | Efficacy  | Results   |
| Number     | tosterone | eline | Change     | Analysis  |           |
|            | dose      | Me    | from       | Method    | p-value   |
|            | (mcg/day) | an^a^ | Baseline   |           |           |
|            |           |       | at Week    |           |           |
|            |           |       | 24^a,b^    |           |           |
+------------+-----------+-------+------------+-----------+-----------+
| **Phase 3  |           |       |            |           |           |
| trials**   |           |       |            |           |           |
+------------+-----------+-------+------------+-----------+-----------+
| 2001133    | 0         | 20.82 | 6.90       | ANCOVA    | p=0.0006  |
|            | (placebo) |       |            |           |           |
| (N=562)    |           |       |            |           |           |
+------------+-----------+-------+------------+-----------+-----------+
|            | 300       | 19.79 | 11.85      |           |           |
+------------+-----------+-------+------------+-----------+-----------+
| 2001134    | 0         | 23.37 | 6.21       | ANCOVA    | p=0.0006  |
|            | (placebo) |       |            |           |           |
| (N=532)    |           |       |            |           |           |
+------------+-----------+-------+------------+-----------+-----------+
|            | 300       | 21.67 | 11.38      |           |           |
+------------+-----------+-------+------------+-----------+-----------+
| **Phase 2  |           |       |            |           |           |
| trials**   |           |       |            |           |           |
+------------+-----------+-------+------------+-----------+-----------+
| 1999068\*  | 0         | 20.14 | 8.38       | ANCOVA    | p=0.0498  |
|            | (placebo) |       |            |           |           |
| (N=229)    |           |       |            |           |           |
+------------+-----------+-------+------------+-----------+-----------+
|            | 300       | 20.94 | 13.67      |           |           |
+------------+-----------+-------+------------+-----------+-----------+
| 1999092\*  | 0         | 19.89 | 5.98       | ANCOVA    | p=0.0214  |
|            | (placebo) |       |            |           |           |
| (N=76)     |           |       |            |           |           |
+------------+-----------+-------+------------+-----------+-----------+
|            | 300       | 23.12 | 16.43      |           |           |
+------------+-----------+-------+------------+-----------+-----------+
| \*Source:  |           |       |            |           |           |
| E-Table 5, |           |       |            |           |           |
| ISE.       |           |       |            |           |           |
+------------+-----------+-------+------------+-----------+-----------+
| **^a^**    |           |       |            |           |           |
| Range for  |           |       |            |           |           |
| sexual     |           |       |            |           |           |
| desire     |           |       |            |           |           |
| score is   |           |       |            |           |           |
| 0-100.\    |           |       |            |           |           |
| **^b^**    |           |       |            |           |           |
| Mean       |           |       |            |           |           |
| change     |           |       |            |           |           |
| from       |           |       |            |           |           |
| baseline   |           |       |            |           |           |
| adjusted   |           |       |            |           |           |
| for age,   |           |       |            |           |           |
| estrogen   |           |       |            |           |           |
| therapy    |           |       |            |           |           |
| route,     |           |       |            |           |           |
| pooled     |           |       |            |           |           |
| centers,   |           |       |            |           |           |
| and        |           |       |            |           |           |
| baseline   |           |       |            |           |           |
| value.     |           |       |            |           |           |
+------------+-----------+-------+------------+-----------+-----------+

The changes from baseline in the PFSF Desire domain score at Week 24 for
the four individual studies and the studies combined are shown in Figure
3.

[]{#__RefHeading___Toc87346503 .anchor}Figure 3 Change from Baseline in
Sexual Desire at Week 24 (LOCF)

![](media/image6.png){width="6.423611111111111in"
height="3.2895833333333333in"}

Data for individual studies corresponds to mean change from baseline
(**±**) 1 standard error (SE).

Data for combined studies corresponds to mean change from baseline
adjusted for study (**±**) 1 standard error.  

\* = p\<0.05; \*\*\* = p\<0.001 based on analysis of covariance (ANCOVA)
model. LOCF= last observation carried forward.

Division comment:

-   The clinical significance of the increase with active treatment
    yielding, on average, an increase of only 5-6 points more than
    placebo on a scale of 100 is unknown.

## Summary of Phase 3 Efficacy Findings

An overview of the results for the primary and two most important
secondary efficacy endpoints for the two phase 3 clinical trials can be
found in Table 9.

[]{#__RefHeading___Toc87346459 .anchor}Table 9 Changes in Frequency of
SSEs, and Sexual Desire and Personal Distress Scores

+------------+-----------+-------+------------+-----------+-----------+
| **         | Tes       | Bas   | Mean       | Efficacy  | Results   |
| Endpoint** | tosterone | eline | Change     | Analysis  |           |
|            | dose      | Me    | from       | Method    | p-value   |
| Study      | (mcg/day) | an^a^ | Baseline   |           |           |
| Number     |           |       | at Week    |           |           |
|            |           |       | 24^a,b^    |           |           |
+------------+-----------+-------+------------+-----------+-----------+
| *          |           |       |            |           |           |
| *Frequency |           |       |            |           |           |
| of Total   |           |       |            |           |           |
| SSEs**     |           |       |            |           |           |
+------------+-----------+-------+------------+-----------+-----------+
| 2001133    | 0         | 2.94  | 0.98       | ANCOVA    | p=0.0003  |
+------------+-----------+-------+------------+-----------+-----------+
|            | 300       | 2.82  | 2.13       |           |           |
+------------+-----------+-------+------------+-----------+-----------+
| 2001134    | 0         | 3.19  | 0.73       | Wilcoxon  | p=0.0010  |
|            |           |       |            | Rank      |           |
|            |           |       |            | Sum^b^    |           |
+------------+-----------+-------+------------+-----------+-----------+
|            | 300       | 3.04  | 1.56       |           |           |
+------------+-----------+-------+------------+-----------+-----------+
| **Sexual   |           |       |            |           |           |
| Desire     |           |       |            |           |           |
| Score      |           |       |            |           |           |
| \[range 0  |           |       |            |           |           |
| to 100\]** |           |       |            |           |           |
+------------+-----------+-------+------------+-----------+-----------+
| 2001133    | 0         | 20.82 | 6.90       | ANCOVA    | p=0.0006  |
+------------+-----------+-------+------------+-----------+-----------+
|            | 300       | 19.79 | 11.85      |           |           |
+------------+-----------+-------+------------+-----------+-----------+
| 2001134    | 0         | 23.37 | 6.21       | ANCOVA    | p=0.0006  |
+------------+-----------+-------+------------+-----------+-----------+
|            | 300       | 21.67 | 11.38      |           |           |
+------------+-----------+-------+------------+-----------+-----------+
| **Personal |           |       |            |           |           |
| Distress   |           |       |            |           |           |
| Score      |           |       |            |           |           |
| \[range 0  |           |       |            |           |           |
| to 100\]** |           |       |            |           |           |
+------------+-----------+-------+------------+-----------+-----------+
| 2001133    | 0         | 62.57 | -16.31     |           |           |
+------------+-----------+-------+------------+-----------+-----------+
|            | 300       | 64.78 | -23.55     | ANCOVA    | p=0.0006  |
+------------+-----------+-------+------------+-----------+-----------+
| 2001134    | 0         | 66.38 | -18.27     |           |           |
+------------+-----------+-------+------------+-----------+-----------+
|            | 300       | 66.61 | -24.34     | ANCOVA    | p=0.0006  |
+------------+-----------+-------+------------+-----------+-----------+
| **^a^**    |           |       |            |           |           |
| For        |           |       |            |           |           |
| frequency  |           |       |            |           |           |
| of total   |           |       |            |           |           |
| satisfying |           |       |            |           |           |
| sexual     |           |       |            |           |           |
| episodes,  |           |       |            |           |           |
| baseline   |           |       |            |           |           |
| mean and   |           |       |            |           |           |
| mean       |           |       |            |           |           |
| change     |           |       |            |           |           |
| from       |           |       |            |           |           |
| baseline   |           |       |            |           |           |
| at Week 24 |           |       |            |           |           |
| refer to   |           |       |            |           |           |
| the        |           |       |            |           |           |
| average    |           |       |            |           |           |
| 4-week     |           |       |            |           |           |
| frequency. |           |       |            |           |           |
|            |           |       |            |           |           |
| **^b^**    |           |       |            |           |           |
| Mean       |           |       |            |           |           |
| change     |           |       |            |           |           |
| from       |           |       |            |           |           |
| baseline   |           |       |            |           |           |
| adjusted   |           |       |            |           |           |
| for age,   |           |       |            |           |           |
| estrogen   |           |       |            |           |           |
| therapy    |           |       |            |           |           |
| route,     |           |       |            |           |           |
| pooled     |           |       |            |           |           |
| centers,   |           |       |            |           |           |
| and        |           |       |            |           |           |
| baseline   |           |       |            |           |           |
| value. For |           |       |            |           |           |
| frequency  |           |       |            |           |           |
| of total   |           |       |            |           |           |
| satisfying |           |       |            |           |           |
| episodes   |           |       |            |           |           |
| in Study   |           |       |            |           |           |
| 2001134,   |           |       |            |           |           |
| the ANCOVA |           |       |            |           |           |
| model      |           |       |            |           |           |
| assumption |           |       |            |           |           |
| of         |           |       |            |           |           |
| normality  |           |       |            |           |           |
| was        |           |       |            |           |           |
| severely   |           |       |            |           |           |
| violated;  |           |       |            |           |           |
| therefore, |           |       |            |           |           |
| unadjusted |           |       |            |           |           |
| mean       |           |       |            |           |           |
| change     |           |       |            |           |           |
| from       |           |       |            |           |           |
| baseline   |           |       |            |           |           |
| (i.e. no   |           |       |            |           |           |
| covariate  |           |       |            |           |           |
| a          |           |       |            |           |           |
| djustment) |           |       |            |           |           |
| is shown   |           |       |            |           |           |
| and        |           |       |            |           |           |
| Wilcoxon   |           |       |            |           |           |
| rank sum   |           |       |            |           |           |
| analysis   |           |       |            |           |           |
| was        |           |       |            |           |           |
| conducted. |           |       |            |           |           |
+------------+-----------+-------+------------+-----------+-----------+

## Secondary Analyses of Primary and Principal Secondary Endpoints

### Responder Analyses 

The Applicant conducted a responder analysis for the primary efficacy
endpoint of SSEs and the secondary endpoint of change in the desire
score. The definition of a response was based upon the Applicant's
findings from Study CMK#US030993, which was designed to identify the
minimally important clinical difference (MICD) (see Section 4.10).

#### Applicant-Defined Responder Analyses

**Change in Satisfactory Sexual Events** Based on the findings of Study
CMK#US030993, the Applicant concluded that an increase of 1.1 events per
four weeks was the minimally important clinical difference. The
responder analysis based on this MICD value of \> 1 SSE per four weeks
is shown in Table 10 below. For each of the studies, a greater
proportion of subjects in the TTS groups were identified as having a
positive response to treatment. In the two phase 3 studies, the
difference in response rate between TTS and placebo groups ranged from
approximately 11 to 17%.

[]{#__RefHeading___Toc87346460 .anchor}Table 10 Responder Analysis for
Change in SSEs at Week 24

+-----------+----------------------------+----------------------------+
| Study     | Placebo                    | TTS                        |
|           |                            |                            |
|           | Sample/responders          | Sample/responders          |
|           |                            |                            |
|           | (% responders)^A^          | (% responders)             |
+-----------+----------------------------+----------------------------+
| 2001133   | 273/95 (34.8%)             | 276/126 (45.7%)            |
+-----------+----------------------------+----------------------------+
| 2001134   | 255/64 (25.1%)             | 258/109 (42.2%)            |
+-----------+----------------------------+----------------------------+
| 1999068   | 112/43 (38.4%)             | 108/55 (50.9%)             |
+-----------+----------------------------+----------------------------+
| 1999092   | 37/10 (27.0%)              | 35/22 (62.9%)              |
+-----------+----------------------------+----------------------------+
| **C       | **677/212 (31.3%)**        | **677/312 (46.1%)**        |
| ombined** |                            |                            |
+-----------+----------------------------+----------------------------+
| The LOCF  |                            |                            |
| analysis  |                            |                            |
| at Week   |                            |                            |
| 24 was    |                            |                            |
| based on  |                            |                            |
| responses |                            |                            |
| recorded  |                            |                            |
| on the    |                            |                            |
| last SAL  |                            |                            |
| e         |                            |                            |
| valuated. |                            |                            |
|           |                            |                            |
| The       |                            |                            |
| sample is |                            |                            |
| the       |                            |                            |
| number of |                            |                            |
| subjects  |                            |                            |
| with      |                            |                            |
| baseline  |                            |                            |
| and Week  |                            |                            |
| 24 (LOCF) |                            |                            |
| r         |                            |                            |
| esponses. |                            |                            |
|           |                            |                            |
| ^A^ A     |                            |                            |
| responder |                            |                            |
| is a      |                            |                            |
| patient   |                            |                            |
| with a    |                            |                            |
| change    |                            |                            |
| from      |                            |                            |
| baseline  |                            |                            |
| in their  |                            |                            |
| **total   |                            |                            |
| SSEs of   |                            |                            |
| \> 1      |                            |                            |
| e         |                            |                            |
| pisode.** |                            |                            |
+-----------+----------------------------+----------------------------+

**Change in Sexual Desire** Based on the findings of Study CMK#US030993,
the Applicant concluded that an increase of ≥ 8.9 points on a scale of 1
to 100 on the Desire domain of the PFSF was the minimally important
clinical difference. The responder analysis based on this MICD value of
≥ 8.9 points is shown in Table 11 below. For each of the studies, a
greater proportion of subjects in the TTS groups were identified as
having a positive response to treatment. In the two phase 3 studies, the
difference in response rate between TTS and placebo groups ranged from
approximately 15 to 17%

[]{#__RefHeading___Toc87346461 .anchor}Table 11 Responder Analysis for
Change in Sexual Desire at Week 24

+----------+-----------------------------+-----------------------------+
| Study    | Placebo                     | TTS                         |
|          |                             |                             |
|          | Sample/responders           | Sample/responders           |
|          |                             |                             |
|          | (% responders)^A^           | (% responders)              |
+----------+-----------------------------+-----------------------------+
| 200113   | 269/93 (34.6%)              | 269/138 (51.3%)             |
+----------+-----------------------------+-----------------------------+
| 200134   | 257/87 (33.9%)              | 252/124 (49.2%)             |
+----------+-----------------------------+-----------------------------+
| 1999068  | 101/40 (39.6%)              | 102/55 (53.9%)              |
+----------+-----------------------------+-----------------------------+
| 1999092  | 35/15 (42.9%)               | 34/18 (52.9%)               |
+----------+-----------------------------+-----------------------------+
| **Co     | **662/235 (35.5%)**         | **657/335 (51.0%)**         |
| mbined** |                             |                             |
+----------+-----------------------------+-----------------------------+
| The LOCF |                             |                             |
| analysis |                             |                             |
| at Week  |                             |                             |
| 24 was   |                             |                             |
| based on |                             |                             |
| r        |                             |                             |
| esponses |                             |                             |
| recorded |                             |                             |
| on the   |                             |                             |
| last     |                             |                             |
| PFSF     |                             |                             |
| ev       |                             |                             |
| aluated. |                             |                             |
|          |                             |                             |
| The      |                             |                             |
| sample   |                             |                             |
| is the   |                             |                             |
| number   |                             |                             |
| of       |                             |                             |
| subjects |                             |                             |
| with     |                             |                             |
| baseline |                             |                             |
| and Week |                             |                             |
| 24       |                             |                             |
| (LOCF)   |                             |                             |
| re       |                             |                             |
| sponses. |                             |                             |
|          |                             |                             |
| ^A^ A    |                             |                             |
| r        |                             |                             |
| esponder |                             |                             |
| is a     |                             |                             |
| patient  |                             |                             |
| with a   |                             |                             |
| change   |                             |                             |
| from     |                             |                             |
| baseline |                             |                             |
| in their |                             |                             |
| **sexual |                             |                             |
| desire   |                             |                             |
| score ≥  |                             |                             |
| 8.89**.  |                             |                             |
+----------+-----------------------------+-----------------------------+

#### FDA-Requested Responder Analysis

**Distribution of Changes from Baseline in SSEs** The Division requested
a post hoc analysis showing the distribution of changes from baseline in
SSEs in the placebo and TTS groups in the two Phase 3 trials. The
results are shown in Table 12.

[]{#__RefHeading___Toc87346462 .anchor}Table 12 Distribution of Changes
from Baseline in SSEs

+---------+--------------+--------------+--------------+--------------+
|         | Study        |              | Study        |              |
|         | 2001133      |              | 2001134      |              |
+---------+--------------+--------------+--------------+--------------+
| Change  | Placebo      | TTS\         | Placebo      | TTS\         |
| c       | (N=273)      | (N=276)      | (N=255)      | (N=258)      |
| ategory |              |              |              |              |
| (I      | n (%)        | n (%)        | n (%)        | n (%)        |
| ncrease |              |              |              |              |
| in      |              |              |              |              |
| SSEs)   |              |              |              |              |
+---------+--------------+--------------+--------------+--------------+
| \< 0    | 90 (33.0)    | 73 (26.4)    | 105 (41.2)   | 83 (32.2)    |
| SSE     |              |              |              |              |
+---------+--------------+--------------+--------------+--------------+
| 0 to    | 70 (25.6)    | 57 (20.7)    | 62 (24.3)    | 46 (17.8)    |
| \<1.0   |              |              |              |              |
+---------+--------------+--------------+--------------+--------------+
| 1 to    | 44 (16.1)    | 35 (12.7)    | 30 (11.8)    | 40 (15.5)    |
| \<2.0   |              |              |              |              |
+---------+--------------+--------------+--------------+--------------+
| 2 to    | 17 (6.2)     | 26 (9.4)     | 17 (6.7)     | 16 (6.2)     |
| \<3.0   |              |              |              |              |
+---------+--------------+--------------+--------------+--------------+
| 3 to    | 15 (5.5)     | 21 (7.6)     | 10 (3.9)     | 19 (7.4)     |
| \<4.0   |              |              |              |              |
+---------+--------------+--------------+--------------+--------------+
| 4 to    | 11 (4.0)     | 21 (7.6)     | 11 (4.3)     | 13 (5.0)     |
| \<5.0   |              |              |              |              |
+---------+--------------+--------------+--------------+--------------+
| ≥ 5     | 26 (9.5)     | 43 (15.6)    | 20 (7.8)     | 41 (15.9)    |
+---------+--------------+--------------+--------------+--------------+
| n (%) = |              |              |              |              |
| number  |              |              |              |              |
| and     |              |              |              |              |
| per     |              |              |              |              |
| centage |              |              |              |              |
| of      |              |              |              |              |
| women   |              |              |              |              |
| in      |              |              |              |              |
| ca      |              |              |              |              |
| tegory; |              |              |              |              |
| N =     |              |              |              |              |
| sample  |              |              |              |              |
| size    |              |              |              |              |
+---------+--------------+--------------+--------------+--------------+

### Onset of Treatment Effects:

Overall, maximal mean differences between placebo and TTS treated
subjects for SSEs and sexual desire were observed by 12 weeks and were
maintained to 24 weeks. Mean differences between placebo and TTS treated
subjects in distress continued to decline over the 24-week treatment
period. Figure 4 below combines findings from Studies 2001133 and
2001134.

[]{#__RefHeading___Toc87346504 .anchor}Figure 4 Time Course of Mean
Differences between TTS & placebo

![](media/image7.png){width="4.539583333333334in"
height="5.648611111111111in"}

## Persistence of Treatment Effect 

The persistence of treatment effects was assessed during a 13-week
double blind follow-up period (Weeks 53-65) of Studies 2001133 and
2001134. All subjects who completed both the 24 week double blind
placebo-controlled phase and the subsequent 28 week open label TTS phase
of the two phase 3 trials were offered the opportunity to participate in
a study to evaluate persistence of treatment effect. Subjects who agreed
to participate were asked a set of questions about their response to
treatment during the previous 28-week open label period. The subset of
subjects who responded positively to specific questions, including
having experienced an increase in desire for sexual activity and an
increase in satisfying sexual activity compared with before entering the
study, were randomized in a 1:1 ratio to receive placebo or TTS in a
double-blind manner for 13 weeks. Sex therapists conducted follow-up
telephone interviews with these subjects between Weeks 63 and 65 to
assess persistence of treatment effect. Of the 205 subjects enrolled,
199 (97%) completed interviews.

The primary endpoint in this study was the sex therapists' assessment of
a "noticeable decrease" in desire for sexual activity during the 13 week
treatment period. A higher percentage of women in the placebo group
compared with TTS \[62.7% vs. 43.3%\] reported a "noticeable decrease"
in desire for sexual activity during the 13 week study. In addition, a
higher percentage of women in the placebo group compared to the TTS
group \[47.1% vs. 25.8%\] reported experiencing a decrease in the
frequency of SSEs. (See Table 13.)

[]{#__RefHeading___Toc87346463 .anchor}Table 13 Persistence of Treatment
Effect

+---------------------------------------------+------+----+------+----+
| **Question**                                | **P  |    | **T  |    |
|                                             | lace |    | TS** |    |
|                                             | bo** |    |      |    |
+---------------------------------------------+------+----+------+----+
|                                             | **n  | *  | **n  | *  |
|                                             | /N** | *% | /N** | *% |
|                                             |      | ** |      | ** |
+---------------------------------------------+------+----+------+----+
| Noticeable Decrease in Desire for Sexual    | 64   | 62 | 4    | 43 |
| Activity (Therapist)                        | /102 | .7 | 2/97 | .3 |
+---------------------------------------------+------+----+------+----+
| Noticeable Decrease in Desire for Sexual    | 64   | 62 | 4    | 43 |
| Activity (Patient)                          | /102 | .7 | 2/97 | .3 |
+---------------------------------------------+------+----+------+----+
| Noticeable Decrease in Overall Clinical     | 62   | 60 | 4    | 46 |
| Benefit (Therapist)                         | /102 | .8 | 5/97 | .4 |
+---------------------------------------------+------+----+------+----+
| Noticeable Decrease in Overall Clinical     | 64   | 62 | 4    | 41 |
| Benefit (Patient)                           | /102 | .7 | 0/97 | .2 |
+---------------------------------------------+------+----+------+----+
| Noticeable Decrease in Satisfying Sexual    | 48   | 47 | 2    | 25 |
| Activity (Patient)                          | /102 | .1 | 5/97 | .8 |
+---------------------------------------------+------+----+------+----+
| Noticeable Decrease in Desire to Initiate   | 61   | 59 | 3    | 38 |
| Activity (Patient)                          | /102 | .8 | 7/97 | .1 |
+---------------------------------------------+------+----+------+----+
| Noticeable Decrease in Anticipation of      | 55   | 53 | 3    | 33 |
| Sexual Activity (Patient)                   | /102 | .9 | 2/97 | .0 |
+---------------------------------------------+------+----+------+----+
| N= number of subjects with interviews; n=   |      |    |      |    |
| number of subjects with noticeable decrease |      |    |      |    |
|                                             |      |    |      |    |
| \% = n/N, percentage of subjects with the   |      |    |      |    |
| finding                                     |      |    |      |    |
+---------------------------------------------+------+----+------+----+

Division comment:

-   The goal of the randomized discontinuation study was to assess the
    dependence of the apparent treatment effect upon continuation of
    active therapy. In order to assess this meaningfully, the same
    efficacy assessments should be employed as were used in the efficacy
    studies. Use of different assessment tools and endpoints by the
    Applicant makes interpretation of the results difficult.

## Study CMK#US030993 (Minimally Important Clinical Differences) 

A clinical relevance study was designed by the Applicant to investigate
the subjects' perspective on the results of their study treatment during
the blinded portion of studies 2001133 and 2001134. The primary
objectives of the clinical relevance study were to determine whether
subjects experienced benefits of study treatment that they considered
meaningful, and to define the magnitude of changes in selected clinical
endpoints that were associated with a meaningful treatment benefit as
defined by the women themselves.

The study data came from a subset of women from the two Phase 3 efficacy
studies. A series of 132 one-on-one patient interviews were conducted by
one trained, experienced female interviewer using a structured interview
guide that contained both open-ended and fixed-response (yes/no or
scaled-response) questions. All interviews were conducted no later than
2 weeks after subjects completed or exited double blind treatment. The
subjects, interviewer, study site personnel, and the Applicant
representatives who observed interviews or analyzed clinical data all
remained blinded to the treatment assignments (active or placebo).
Baseline demographics and disease severity in this subset were
representative of the entire group of women in the Phase 3 studies.

The primary assessment in the clinical relevance study was based on the
subjects' answers (yes or no) to the following question, which was asked
with reference to their experiences during the double-blind portion of
the studies:

> "Considering everything that we have talked about today, would you say
> that you experienced a meaningful benefit from the study patches?"

Subjects were dichotomized based on their answer to the above question.
For each of the two groups, the mean and median changes from baseline in
the three study endpoints (satisfying sexual activity \[SSEs\], personal
distress, and sexual desire) were determined (see Table 14). Of the 54
subjects reporting a meaningful benefit, 39% had received placebo and
61% TTS treatment. Among placebo subjects, 31% reported they had a
meaningful benefit; among TTS subjects, 52% reported a meaningful
benefit.

[]{#__RefHeading___Toc87346464 .anchor}Table 14 Changes from Baseline in
TTS and Placebo Subjects Combined Based on the Subject\'s Assessment of
Clinical Benefit

+---------+----------+----------+-------+---------+---------+---------+
| Pa      | Exp      | N (%)    | C     |         |         |         |
| rameter | erienced |          | hange |         |         |         |
|         | me       | 132      | from  |         |         |         |
|         | aningful | (100%)   | bas   |         |         |         |
|         | benefit? |          | eline |         |         |         |
|         |          |          | in    |         |         |         |
|         |          |          | 4     |         |         |         |
|         |          |          | -week |         |         |         |
|         |          |          | f     |         |         |         |
|         |          |          | reque |         |         |         |
|         |          |          | ncy\* |         |         |         |
+---------+----------+----------+-------+---------+---------+---------+
|         |          |          | Mean  | Median  | Minimum | Maximum |
+---------+----------+----------+-------+---------+---------+---------+
|         |          |          |       |         |         |         |
+---------+----------+----------+-------+---------+---------+---------+
| SSEs    | Yes      | 54       | 4.4   | 2.26    | -1.7    | 25.0    |
|         |          | (41.2%)  |       |         |         |         |
+---------+----------+----------+-------+---------+---------+---------+
|         | No       | 77       | 0.5   | 0.0     | -5.9    | 16.3    |
|         |          | (58.8%)  |       |         |         |         |
+---------+----------+----------+-------+---------+---------+---------+
| D       | Yes      | 54       | -36.5 | -34.3   | -100    | 28.6    |
| istress |          | (40.9%)  |       |         |         |         |
| Score   |          |          |       |         |         |         |
+---------+----------+----------+-------+---------+---------+---------+
|         | No       | 78       | -8.8  | -8.57   | -51.4   | 45.7    |
|         |          | (59.1%)  |       |         |         |         |
+---------+----------+----------+-------+---------+---------+---------+
| Desire  | Yes      | 54       | 21.0  | 16.7    | -17.8   | 66.7    |
| Score   |          | (40.9%)  |       |         |         |         |
+---------+----------+----------+-------+---------+---------+---------+
|         | No       | 78       | 2.9   | 2.22    | -33.3   | 44.4    |
|         |          | (59.1%)  |       |         |         |         |
+---------+----------+----------+-------+---------+---------+---------+
| \*In    |          |          |       |         |         |         |
| terview |          |          |       |         |         |         |
| pop     |          |          |       |         |         |         |
| ulation |          |          |       |         |         |         |
| (N=     |          |          |       |         |         |         |
| 132):   |          |          |       |         |         |         |
| change  |          |          |       |         |         |         |
| from    |          |          |       |         |         |         |
| b       |          |          |       |         |         |         |
| aseline |          |          |       |         |         |         |
| in      |          |          |       |         |         |         |
| given   |          |          |       |         |         |         |
| pa      |          |          |       |         |         |         |
| rameter |          |          |       |         |         |         |
| at Week |          |          |       |         |         |         |
| 24      |          |          |       |         |         |         |
|         |          |          |       |         |         |         |
| Mean    |          |          |       |         |         |         |
| b       |          |          |       |         |         |         |
| aseline |          |          |       |         |         |         |
| values  |          |          |       |         |         |         |
| for all |          |          |       |         |         |         |
| s       |          |          |       |         |         |         |
| ubjects |          |          |       |         |         |         |
| in the  |          |          |       |         |         |         |
| Phase 3 |          |          |       |         |         |         |
| trials  |          |          |       |         |         |         |
| were:   |          |          |       |         |         |         |
| SSEs=   |          |          |       |         |         |         |
| 3.0;    |          |          |       |         |         |         |
| D       |          |          |       |         |         |         |
| istress |          |          |       |         |         |         |
| scor    |          |          |       |         |         |         |
| e=65.1; |          |          |       |         |         |         |
| Desire  |          |          |       |         |         |         |
| score = |          |          |       |         |         |         |
| 21.4    |          |          |       |         |         |         |
+---------+----------+----------+-------+---------+---------+---------+

For the 3 endpoints examined, there was a range of changes from baseline
and there was overlap between subjects who reported a meaningful overall
benefit and subjects who reported no meaningful overall benefit.
However, all 3 endpoints in subjects who reported an overall meaningful
benefit showed mean and median changes from baseline that were
numerically greater than those in subjects who reported no meaningful
benefit.

Patient responses in this study were used to define a minimally
important clinical difference (MICD) from baseline in total satisfying
activity (SSEs) and desire scores. Using Receiver Operating
Characteristics (ROC) analysis, the MICDs were defined as the values
that best dichotomized subjects on the basis of reported meaningful
benefit. The MICDs determined by the Applicant were:

-   an increase of \> 1.0 in satisfying sexual events per 4 weeks

-   an increase of ≥8.9 in sexual desire score

-   a decrease of at least 20 points in distress score

These responder definitions were applied to the Phase 3 results to
examine the differences between the percentages of responders on TTS
treatment and placebo (see Section 4.8.1).

Division's comment:

-   Small differences in outcomes between active and placebo treatment
    groups may be statistically significant yet clinically unimportant.
    Making this distinction is particularly important, and often quite
    difficult, for outcomes based on health-related quality of life
    endpoints. The design and interpretation of studies to identify
    minimally important clinical difference (MICDs) can be difficult and
    fraught with problems. Experts in the development, validation, and
    interpretation of instruments to determine MICDs [may not
    agree]{.underline} with:

> \- **The appropriateness of the design of Study CMK#US030993,**
>
> **- The Applicant's interpretation of the study findings, and/or**
>
> **- The Applicant's values for the MICDs for the primary and principal
> secondary efficacy endpoints.**

## Summary of Efficacy and Related Issues

The clinical development program by the Applicant followed the May 2000
FDA Draft Guidance for industry for products being developed for a
female sexual dysfunction indication. Two Phase 3 trials were conducted
in a patient population of surgically menopausal women with HSDD. The
primary endpoint was the change in the number of satisfactory sexual
episodes (SSEs), and the two key secondary endpoints were the change in
sexual desire and personal distress scores. Three instruments were
developed to record and measure the efficacy endpoints.

Changes in the primary and secondary endpoints are summarized in Table
15.

[]{#__RefHeading___Toc87346465 .anchor}Table 15 Changes in Frequency of
SSEs, and Sexual Desire and Personal Distress Scores

+------------+-----------+-------+------------+-----------+-----------+
| **         | Tes       | Bas   | Mean       | Efficacy  | Results   |
| Endpoint** | tosterone | eline | Change     | Analysis  |           |
|            | dose      | Me    | from       | Method    | p-value   |
| Study      | (mcg/day) | an^a^ | Baseline   |           |           |
| Number     |           |       | at Week    |           |           |
|            |           |       | 24^a,b^    |           |           |
+------------+-----------+-------+------------+-----------+-----------+
| *          |           |       |            |           |           |
| *Frequency |           |       |            |           |           |
| of Total   |           |       |            |           |           |
| SSEs**     |           |       |            |           |           |
+------------+-----------+-------+------------+-----------+-----------+
| 2001133    | 0         | 2.94  | 0.98       | ANCOVA    | p=0.0003  |
+------------+-----------+-------+------------+-----------+-----------+
|            | 300       | 2.82  | 2.13       |           |           |
+------------+-----------+-------+------------+-----------+-----------+
| 2001134    | 0         | 3.19  | 0.73       | Wilcoxon  | p=0.0010  |
|            |           |       |            | Rank      |           |
|            |           |       |            | Sum^b^    |           |
+------------+-----------+-------+------------+-----------+-----------+
|            | 300       | 3.04  | 1.56       |           |           |
+------------+-----------+-------+------------+-----------+-----------+
| **Sexual   |           |       |            |           |           |
| Desire     |           |       |            |           |           |
| Score      |           |       |            |           |           |
| \[range 0  |           |       |            |           |           |
| to 100\]** |           |       |            |           |           |
+------------+-----------+-------+------------+-----------+-----------+
| 2001133    | 0         | 20.82 | 6.90       | ANCOVA    | p=0.0006  |
+------------+-----------+-------+------------+-----------+-----------+
|            | 300       | 19.79 | 11.85      |           |           |
+------------+-----------+-------+------------+-----------+-----------+
| 2001134    | 0         | 23.37 | 6.21       | ANCOVA    | p=0.0006  |
+------------+-----------+-------+------------+-----------+-----------+
|            | 300       | 21.67 | 11.38      |           |           |
+------------+-----------+-------+------------+-----------+-----------+
| **Personal |           |       |            |           |           |
| Distress   |           |       |            |           |           |
| Score      |           |       |            |           |           |
| \[range 0  |           |       |            |           |           |
| to 100\]** |           |       |            |           |           |
+------------+-----------+-------+------------+-----------+-----------+
| 2001133    | 0         | 62.57 | -16.31     |           |           |
+------------+-----------+-------+------------+-----------+-----------+
|            | 300       | 64.78 | -23.55     | ANCOVA    | p=0.0006  |
+------------+-----------+-------+------------+-----------+-----------+
| 2001134    | 0         | 66.38 | -18.27     |           |           |
+------------+-----------+-------+------------+-----------+-----------+
|            | 300       | 66.61 | -24.34     | ANCOVA    | p=0.0006  |
+------------+-----------+-------+------------+-----------+-----------+
| **^a^**    |           |       |            |           |           |
| For        |           |       |            |           |           |
| frequency  |           |       |            |           |           |
| of total   |           |       |            |           |           |
| satisfying |           |       |            |           |           |
| sexual     |           |       |            |           |           |
| episodes,  |           |       |            |           |           |
| baseline   |           |       |            |           |           |
| mean and   |           |       |            |           |           |
| mean       |           |       |            |           |           |
| change     |           |       |            |           |           |
| from       |           |       |            |           |           |
| baseline   |           |       |            |           |           |
| at Week 24 |           |       |            |           |           |
| refer to   |           |       |            |           |           |
| the        |           |       |            |           |           |
| average    |           |       |            |           |           |
| 4-week     |           |       |            |           |           |
| frequency. |           |       |            |           |           |
|            |           |       |            |           |           |
| **^b^**    |           |       |            |           |           |
| Mean       |           |       |            |           |           |
| change     |           |       |            |           |           |
| from       |           |       |            |           |           |
| baseline   |           |       |            |           |           |
| adjusted   |           |       |            |           |           |
| for age,   |           |       |            |           |           |
| estrogen   |           |       |            |           |           |
| therapy    |           |       |            |           |           |
| route,     |           |       |            |           |           |
| pooled     |           |       |            |           |           |
| centers,   |           |       |            |           |           |
| and        |           |       |            |           |           |
| baseline   |           |       |            |           |           |
| value. For |           |       |            |           |           |
| frequency  |           |       |            |           |           |
| of total   |           |       |            |           |           |
| satisfying |           |       |            |           |           |
| episodes   |           |       |            |           |           |
| in Study   |           |       |            |           |           |
| 2001134,   |           |       |            |           |           |
| the ANCOVA |           |       |            |           |           |
| model      |           |       |            |           |           |
| assumption |           |       |            |           |           |
| of         |           |       |            |           |           |
| normality  |           |       |            |           |           |
| was        |           |       |            |           |           |
| severely   |           |       |            |           |           |
| violated;  |           |       |            |           |           |
| therefore, |           |       |            |           |           |
| unadjusted |           |       |            |           |           |
| mean       |           |       |            |           |           |
| change     |           |       |            |           |           |
| from       |           |       |            |           |           |
| baseline   |           |       |            |           |           |
| (i.e. no   |           |       |            |           |           |
| covariate  |           |       |            |           |           |
| a          |           |       |            |           |           |
| djustment) |           |       |            |           |           |
| is shown   |           |       |            |           |           |
| and        |           |       |            |           |           |
| Wilcoxon   |           |       |            |           |           |
| rank sum   |           |       |            |           |           |
| analysis   |           |       |            |           |           |
| was        |           |       |            |           |           |
| conducted. |           |       |            |           |           |
+------------+-----------+-------+------------+-----------+-----------+

Division comment:

-   Although all these differences were statistically significant, it is
    unknown whether they are clinically meaningful.

# Safety

## Overview of Safety Concerns with Testosterone

In the aftermath of the Women's Health Initiative (WHI)
studies[^1]^,^[^2] of the risks and benefits of estrogen and combined
estrogen and progestin therapy in postmenopausal women, use of hormone
therapy in this population is subject to heightened scrutiny. The fact
that the results of these relatively long-term, randomized,
double-blind, placebo-controlled trials were at variance with data
provided by a number of observational studies suggests that short-term
or uncontrolled studies may not provide adequate estimates of the risks
of hormonal therapy in postmenopausal women.

The proposed indication, for use in surgically menopausal women
receiving concomitant estrogen therapy, raises two important issues that
should be considered:

1.  Women who take this product will be on estrogen, the duration and
    safety of which must be examined in light of the WHI estrogen-only
    study in women status post hysterectomy.

2.  Another hormone, testosterone, will be added to estrogen. In the
    second WHI study, the addition of progesterone to estrogen increased
    the risk of breast cancer and cardiovascular effects. It is unknown
    whether the addition of a different hormone, testosterone, might
    have similar or unanticipated adverse effects.

The literature provides little information about the safety of exposing
postmenopausal women to testosterone at doses that produce plasma
concentrations that are within or slightly above the range of those
normally observed in reproductive aged women. What data are available
often concern formulations or dose levels that differ from that achieved
by the TTS patch. Nonetheless, potential concerns that have been raised
in the literature include:

-   Cardiovascular safety -- potentially mediated by testosterone's
    effects on

    -   lipids

    -   vascular tone

    -   plasma viscosity

    -   coagulation

    -   polycythemia

    -   insulin resistance

-   Androgenic effects in women

    -   acne

    -   hirsutism

    -   alopecia

    -   voice deepening

    -   clitoromegaly

-   Hepatotoxicity

-   Effects on mood and behavior

-   Endometrial hyperplasia and cancer

-   Breast cancer

The safety database for subjects using TTS was examined for evidence of
these effects in women treated with testosterone and estrogen therapy.

## Overview of Safety Database

### Studies Included

Integrated safety data from two phase 2 studies (Studies 1999068 and
1999092, hereinafter referred to as 068 and 092, respectively) and two
pivotal phase 3 trials (Studies 2001133 and 2001134, hereinafter
referred to as 133 and 134, respectively) were reviewed. All four of
these studies were 24-week, randomized, double-blind, parallel-group,
placebo-controlled trials evaluating the safety and efficacy of a
testosterone transdermal delivery system (TTS) in surgically menopausal
women with HSDD. Study 068 compared patches that delivered doses of 0
(placebo), 150, 300 or 450 mcg/day when applied twice weekly. Studies
092, 133 and 134 utilized a TTS which administered a daily dose of 300
mcg when applied twice weekly.

Three of the studies continued on as safety extensions: Study 068 as a
double-blind, placebo-controlled trial for an additional 28 weeks, and
Studies 133 and 134 as open-label active treatment extensions for an
additional 28 weeks. Following completion of the first year of these
studies, limited additional open-label safety surveillance data have
been obtained from subjects from Studies 133 and 134 who continued to
use the TTS for an additional 26 weeks beyond the first year, in what is
planned to be a two year safety extension. Thus, the primary data
available for safety review include:

-   A 24 week placebo-controlled phase, which enrolled 1399 subjects
    (696 on TTS) in four studies

-   A 28 week open label phase, which enrolled 837 subjects (all on TTS)
    from the two phase 3 studies (of these, 418 had been on placebo in
    the double blind phase and 419 had been on active treatment)

-   An ongoing open label safety extension phase (for which data from
    weeks 52-78 is currently available), which enrolled 321 subjects
    (all on TTS) from the two phase 3 studies (of these, 167 previously
    had been treated with TTS for 28 weeks and 154 previously had been
    treated with TTS for 52 weeks)

An additional special safety study was also reviewed. Study 2003082 was
a 24-week, randomized, double-blind, placebo-controlled trial which
evaluated effects of the 300 mcg TTS on mammographic breast density and
breast epithelial proliferation in naturally menopausal women also
taking combined estrogen/progestogens hormone products.

### Demographics of Safety Population

Demographic information for subjects from the integrated safety
population comprising Studies 068, 092, 133 and 134 are presented in
Table 16. Demographic data for the subjects from Studies 133 and 134 who
continued into the open label and extension phases indicate that they
were representative of the safety population as a whole.

[]{#__RefHeading___Toc87346466 .anchor}Table 16 Demographic Data for
Integrated Safety Population

![](media/image8.wmf){width="5.979861111111111in"
height="6.538888888888889in"}

Source: E-Table 3, eff-sum.pdf, p 118-9

### Safety Outcomes Evaluated

The four studies provided data on the following safety parameters:

-   Adverse events -- deaths, serious adverse events, withdrawals due to
    adverse events, common adverse events

-   Androgenic effects -- acne, hirsutism, alopecia, voice deepening,
    clitoromegaly

-   Application site reactions (ASRs)

-   Impact on estrogen-related effects -- hot flushes, breast tenderness

-   Laboratory values -- serum chemistry, including lipid, renal and
    hepatic panels, carbohydrate metabolism, hematology and coagulation
    profile

-   Vital signs and weight

Subsets of subjects in Studies 068 and 092 also provided data on the
effects of testosterone on total body composition, bone mineral density
and markers of bone turnover, platelet aggregation, and vascular
reactivity and impedance of blood flow as measured by the vascular
pulsatility index. A study in naturally menopausal women provided data
on mammographic breast density and breast epithelial proliferation.

## Findings from Clinical Trials

### Safety Findings --Testosterone vs. Placebo 

#### Adverse Events

**[Deaths]{.underline}**

There was a single death, in a [placebo]{.underline} subject in Study
134 during the double blind phase of the study. Death was due to a basal
ganglia hemorrhage, which followed a transverse sinus thrombosis that
occurred five weeks after enrollment. The thrombosis was treated with
enoxaparin, heparin and warfarin, and the patient died suddenly five
days later. The transverse sinus thrombosis was judged possibly related
to study drug and the basal ganglia hemorrhage was judged doubtfully
related.

**[Serious Adverse Events]{.underline}**

The rate of serious adverse events (SAEs) was 2.2% in the TTS group and
2.1% in the placebo group. The most commonly reported SAEs in the TTS
group were application site reactions (1.3%) and nasopharyngitis and
headache (each 0.9%), and in the placebo group, application site
reactions, headache, migraine and back pain (each 0.6%).

**[Withdrawals due to Adverse Events]{.underline}**

Eight percent of subjects in each group withdrew due to adverse events
(AEs) in the double blind phase. The most common AEs associated with
withdrawal were application site reactions (ASRs) in both groups and
hirsutism in the TTS group. AEs in the overall categories of nervous
system and psychiatric disorders were also responsible for a number of
withdrawals in each group, each accounting for withdrawal of 1-2% of the
enrollees. Nervous system disorders resulting in withdrawals included
such MedDRA terms as headache, dysphonia, dizziness and transient
ischemic attack, and occurred in 14 TTS and 8 placebo subjects.
Psychiatric disorders that resulted in withdrawal included such MedDRA
terms as anxiety, agitation, aggression and depression, and occurred in
12 TTS and 13 placebo subjects.

**[Common Adverse Events]{.underline}**

Overall, AEs occurred in 76.1% of TTS subjects and 75.8% of placebo
subjects. Events occurring at \>2% frequency and with a numerically
greater incidence in the TTS group are listed in Table 17. Events that
occurred most commonly in the TTS group during the double blind phase
were acne, upper respiratory infections, hirsutism and headaches. The
TTS subjects had a higher proportion of overall AEs reported by the
Applicant to be possibly or probably drug-related (26.8% vs. 23.4%),
primarily due to greater occurrence of androgenic AEs. AEs that were
considered by the Applicant prior to unblinding to be potentially
drug-related and that occurred at \>2% frequency and with a numerically
greater incidence in the TTS group are listed in Table 18.

[]{#__RefHeading___Toc87346467 .anchor}Table 17 Studies 068, 092, 133 &
134: Most Common Adverse Events (≥ 2%) During Double Blind Phase

  ---------------------- ----------------------- ------------ ------------------- ------------
  **Adverse Event**      [Placebo]{.underline}                [TTS]{.underline}   

                         N                       \%           N                   \%

  **Total N**            703                                  696                 

  **N with at least one  533                     75.8         530                 76.1
  AE**                                                                            

                                                                                  

  Acne NOS               46                      6.5          61                  8.8

  URI NOS                51                      7.3          57                  8.2

  Hirsutism              35                      5.0          49                  7.0

  Headache               44                      6.3          48                  6.9

  Influenza              20                      2.8          20                  2.9

  UTI NOS                19                      2.7          20                  2.9

  Alopecia               15                      2.1          20                  2.9

  Gastrointestinal &     9                       1.3          19                  2.7
  abdominal pains (HLT)                                                           

  Cough                  15                      2.1          16                  2.3

  Migraine NOS           12                      1.7          16                  2.3

  Gastroenteritis viral  13                      1.8          15                  2.2
  NOS                                                                             

  Flushing               13                      1.8          15                  2.2

  Hypertension NOS       9                       1.3          14                  2.0

  Influenza-like illness 8                       1.1          14                  2.0
  ---------------------- ----------------------- ------------ ------------------- ------------

Note: HLT = Higher Level MedDRA Term, subsuming subheadings; NOS = Not
otherwise specified

Source: Based on Table 7, *safety-sum.pdf, pp 75-124*

[]{#__RefHeading___Toc87346468 .anchor}Table 18 Studies 068, 092, 133 &
134: Adverse Events Considered Possibly or Probably Drug-Related in
Double Blind Phase

  ---------------------- ----------------------- ------------ ------------------- ------------
  **Adverse Event**      [Placebo]{.underline}                [TTS]{.underline}   

                         N                       \%           N                   \%

  **Total N**            703                                  696                 

                                                                                  

  Acne NOS               41                      5.8          55                  7.9

  Hirsutism              33                      4.7          49                  7.0

  Alopecia               14                      2.0          17                  2.4
  ---------------------- ----------------------- ------------ ------------------- ------------

Note: HLT = Higher Level MedDRA Term, subsuming subheadings; NOS = Not
otherwise specified

ASRs are excluded from this listing.

Source: Based on Table 7, *safety-sum.pdf, pp 75-124*

Among cardiovascular, thrombotic and cancer-related events of interest,
there were no MIs in either group during the double blind phase,
although one placebo subject reported coronary artery disease as an AE
and two TTS subjects reported angina as AEs. There was a cerebral
hemorrhage and transverse sinus thrombosis in a placebo subject (the one
death in the trial) and a transient ischemic attack (TIA) in a single
TTS subject. There was a single DVT in a TTS subject, who had a past
history of DVT and Factor V Leiden. There was a single case of breast
cancer in the placebo group.

#### Androgenic Effects

In addition to assessing AE reports of androgenic effects, systematic
ascertainment was made of several individual androgenic effects. At
baseline, and Weeks 12, 24, 36 and 52, assessments at the lip and chin
for increased hair were made, with scoring done according to the facial
portion of the Lorenzo Pictorial Rating Scale (rated from 0-4), and
assessment of facial acne was assessed on a 0-3 scale developed by
Palatsi et al. Subjects were also asked at these visits about frequency
of depilation. In addition, subjects were queried about voice changes or
changes in scalp hair at Weeks 4, 24 and 52.

Hirsutism, acne and alopecia were the primary manifestations of
androgenic effects noted in the trial subjects. Other events of concern
include voice deepening (dysphonia or hoarseness), clitoromegaly and
potential psychiatric effects (increased aggression, agitation or
irritability).

The frequency of androgenic AEs during the double blind phase was higher
in the TTS group (17.7%) than the placebo group (14.4%), primarily due
to higher rates of acne and hirsutism (see Table 19). TTS subjects were
also more likely to experience multiple androgenic AEs and to withdraw
due to these AEs.

[]{#__RefHeading___Toc87346469 .anchor}Table 19 Studies 068, 092, 133 &
134: Androgenic AEs in Double Blind Phase

![](media/image9.wmf){width="5.990277777777778in"
height="5.061805555555556in"}

Source: S-Table 6, safety-sum.pdf, p 23

A single TTS subject reported clitoromegaly during the double blind
phase; this was confirmed on physical examination, and resolved a month
following study discontinuation. Her free testosterone level was 2.2
pg/ml (normal range 0.9 -- 7.3 pg/ml).

Psychiatric AEs of interest as possible androgenic effects were
specified by the Applicant as agitation, aggression or irritability.
Frequency of these events were assessed based on these MedDRA terms,
either from spontaneous subject reports or from AEs detected by
investigators or other site personnel, and they occurred in 2% of
subjects in each group. The rate of aggression was also identical, 0.9%,
in each group.

**[Acne]{.underline}**

AEs relating to acne were reported by 9.1% of TTS subjects and by 7.0%
of placebo subjects in the double blind phase.

On the objective assessment of acne using the Palatsi acne scale, the
TTS subjects showed greater frequency of increased acne scores, although
the inter-group differences were not statistically significant. At Week
24, 3.3% of TTS subjects experienced increases of one or more points on
the four-point Palatisi acne scale, as opposed to 2.4% of placebo
subjects.

**[Alopecia]{.underline}**

Alopecia was reported as an AE in 3.4% of TTS subjects and 2.7% of
placebo subjects, and withdrawal rates were similar.

**[Hirsutism]{.underline}**

Hirsutism was reported as an AE in 7.0% of TTS subjects and 5.0% of
placebo subjects.

On the objective assessment, the Lorenzo scale, the rating of chin
hirsutism increased from baseline in 6.1% of TTS subjects and 3.7% of
placebo subjects by Week 24, and upper lip hirsutism increased in 6.6%
of TTS subjects and 5.6% of placebo subjects by Week 24. Facial
depilation frequency increased in 13.2% of both TTS and placebo subjects
by the end of the double blind phase.

**[Voice Deepening]{.underline}**

Voice deepening (defined as dysphonia or hoarseness) was reported as an
adverse event in 2.3% of TTS subjects and 1.7% of placebo subjects in
the double blind phase. Two TTS subjects withdrew due to this AE. One of
these subjects rated her hoarseness severe, and it reportedly resolved
two months after discontinuation of testosterone.

#### Application Site Reactions

Data on application site reactions were pooled only over the two phase 3
trials, as the severity criteria differed between the phase 2 and phase
3 studies, and because the Study 068 subjects wore two patches
simultaneously to protect the blind. Rates were similar between the
phase 2 and phase 3 studies. Fewer than 5% of phase 2 subjects
discontinued participation due to application site reactions.
Application site reactions occurring during the double blind phase were
slightly higher in the placebo group (34.1% vs. 30.4%). Two subjects in
each group were reported as possible cases of sensitization, but no
confirmatory testing was performed. Three of these four subjects
withdrew from the study.

#### Impact on Estrogen-Related Effects

Effects of possible interaction between testosterone and the estrogen
therapy also administered to subjects were evaluated by assessing the
occurrence of hot flushes and breast tenderness. The rate of hot flushes
was numerically slightly greater in the TTS group (2.7% vs. 2.4%), and
slightly more TTS subjects experienced severe hot flushes in the double
blind phase (three vs. one placebo subject).

In the phase 2 studies, breast pain and tenderness was captured both by
spontaneous adverse event reports and by directed questioning about
breast tenderness at baseline and post-treatment. In the phase 3
studies, only spontaneous reports were used to count these events. Over
the four studies, 4.2% of TTS subjects had breast pain AEs as compared
to 4.8% of placebo subjects. Distributions of severity were similar
between the two groups.

#### Laboratory Values

The laboratory data were pooled separately for phase 2 and for phase 3
studies, as different clinical labs were used to run the tests in the
two phases. Only data from the phase 3 studies are reported below; the
results in the phase 2 studies were generally consistent with those
obtained in the phase 3 studies. Limits for markedly abnormal laboratory
values are found in Appendix 3.

Lipid Profile

Changes from baseline in lipid profile during the double blind phase
were small and not likely to be of clinical significance (Table 20). The
TTS group had a smaller mean increase in HDL at Week 24 than did the
placebo group (mean change 0.4 vs. 1.6 mg/dl in placebo). The frequency
of markedly abnormal values was low, and similar between groups (see
Table 21).

[]{#__RefHeading___Toc87346470 .anchor}Table 20 Studies 133 & 134:
Changes in Lipid Profile in Double Blind Phase

![](media/image10.wmf){width="5.979861111111111in"
height="2.0868055555555554in"}

Source: S-Table 14, *safety-sum.pdf, p 46*

[]{#__RefHeading___Toc87346471 .anchor}**Table 21 Studies 133 & 134:
Proportion of Subjects with** Markedly Abnormal Values on Lipid Profiles
in Double Blind Phase

+-----------------------+-----------+-----------+-----------+-----------+
| **Laboratory**        | **        |           | **TTS**   |           |
|                       | Placebo** |           |           |           |
| **Test**              |           |           | **N=549** |           |
|                       | **N=545** |           |           |           |
+-----------------------+-----------+-----------+-----------+-----------+
|                       | **\#      | **%**     | **\#      | **%**     |
|                       | abnl/**   |           | abnl/**   |           |
|                       |           |           |           |           |
|                       | **\# with |           | **\# with |           |
|                       | data**    |           | data**    |           |
+-----------------------+-----------+-----------+-----------+-----------+
| **Total Cholesterol** | 1/479     | 0.21      | 1/488     | 0.20      |
+-----------------------+-----------+-----------+-----------+-----------+
| **HDL**               | 0/479     | 0         | 0/488     | 0         |
+-----------------------+-----------+-----------+-----------+-----------+
| **LDL**               | 7/479     | 1.46      | 5/488     | 1.02      |
+-----------------------+-----------+-----------+-----------+-----------+
| **Triglycerides**     | 14/479    | 2.92      | 12/488    | 2.46      |
+-----------------------+-----------+-----------+-----------+-----------+

Source: Appendix 5.9, Table 4, *2001133.pdf, p 11154* and Appendix 5.9,
Table 4, *2001134.pdf, p 10113*

Hepatic Profile

Changes in hepatic function during the double blind phase are displayed
in Table 22. A single placebo subject had a markedly abnormal AST
(baseline of 28 U/L rose to 126 at Week 24). A single TTS subject had a
markedly abnormal ALT (baseline of 9 U/L rose to 191 at Week 24).

[]{#__RefHeading___Toc87346472 .anchor}Table 22 **Studies 133 & 134:**
Changes in Hepatic Function in Double Blind Phase

![](media/image11.wmf){width="5.979861111111111in"
height="2.066666666666667in"}

Source: S-Table 16, safety-sum.pdf, p 50

Carbohydrate Metabolism

Changes in carbohydrate metabolism during the double blind phase are
displayed in Table 23, with the frequency of markedly abnormal values in
each group shown in Table 24.

[]{#__RefHeading___Toc87346473 .anchor}Table 23 **Studies 133 & 134:**
Changes in Carbohydrate Metabolism Markers during Double Blind Phase

![](media/image12.wmf){width="5.979861111111111in"
height="1.6583333333333334in"}

Source: S-Table 18, safety-sum.pdf, p 53

[]{#__RefHeading___Toc87346474 .anchor}Table 24 Studies 133 & 134:
Proportion of Subjects with Markedly Abnormal Values on Carbohydrate
Metabolism Markers in Double Blind Phase

+-----------------------+-----------+-----------+-----------+-----------+
| **Laboratory**        | **        |           | **TTS**   |           |
|                       | Placebo** |           |           |           |
| **Test**              |           |           | **N=549** |           |
|                       | **N=545** |           |           |           |
+-----------------------+-----------+-----------+-----------+-----------+
|                       | **\#      | **%**     | **\#      | **%**     |
|                       | abnl/**   |           | abnl/**   |           |
|                       |           |           |           |           |
|                       | **\# with |           | **\# with |           |
|                       | data**    |           | data**    |           |
+-----------------------+-----------+-----------+-----------+-----------+
| **Glucose**           | 0/480     | 0         | 0/486     | 0         |
+-----------------------+-----------+-----------+-----------+-----------+
| **Hemoglobin A1c**    | 0/475     | 0         | 0/486     | 0         |
+-----------------------+-----------+-----------+-----------+-----------+
| **Insulin**           | 16/469    | 3.41      | 13/481    | 2.70      |
+-----------------------+-----------+-----------+-----------+-----------+

Source: Appendix 5.9, Table 13, *2001133.pdf, p 11167* and Appendix 5.9,
Table 13, *2001134.pdf, p 9868*

Hematology

Changes from baseline in hemoglobin during the double blind phase are
displayed in Table 25. The TTS group had a greater rise in hemoglobin
relative to placebo that was reported to be statistically significant. A
single placebo subject and two TTS subjects had markedly abnormal values
on white blood cell count.

[]{#__RefHeading___Toc87346475 .anchor}Table 25 Studies 133 & 134:
Changes in Hemoglobin in Double Blind Phase

![](media/image13.wmf){width="5.979861111111111in"
height="0.7486111111111111in"}

Source: S-Table 20, safety-sum.pdf, p 56

Coagulation Parameters

Coagulation parameters were only measured in Study 133. The changes in
coagulation parameters during the double blind phase are displayed in
Table 26. The frequency of markedly abnormal values in each group during
the double blind phase is shown in Table 27. The two TTS subjects with
prolonged prothrombin times were both being treated for prior
thromboses, one with warfarin.

[]{#__RefHeading___Toc87346476 .anchor}Table 26 Study 133: Changes in
Coagulation Parameters in Double Blind Phase

![](media/image14.wmf){width="6.620833333333334in"
height="2.1041666666666665in"}

Source: Appendix 5.9, Table 2, *2001133.pdf, p 11152*

[]{#__RefHeading___Toc87346477 .anchor}Table 27 Study 133: Proportion of
Subjects with Markedly Abnormal Values on Coagulation Parameters in
Double Blind Phase

![](media/image15.wmf){width="5.979861111111111in"
height="0.9666666666666667in"}

Source: Appendix 5.9, Table 19, *2001133.pdf, p 1*

#### Vital signs and Weight

There were no clinically relevant mean or median changes in systolic or
diastolic blood pressure nor differences between TTS and placebo groups
in the double blind phase. The mean (SD) and median changes from
baseline in systolic blood pressure were ‑0.9 (13.3) and 0 mm Hg in the
placebo group, and 0.2 (12.4) and 0 mm Hg in the TTS group. For
diastolic blood pressure, the mean (SD) and median changes from baseline
were -0.7 (9.0) and 0 mm Hg in the placebo group, and -0.3 (8.9) and 0
mm Hg in the TTS group. Shift tables were not provided.

The median weight change from baseline in the double blind phase was
greater in the TTS group at Week 24 and at all preceding weight
assessment periods. By the end of the double blind phase, TTS subjects
had gained a mean of 0.38 kg (median 0.35 kg) as compared to placebo
subjects, who had lost a mean of 0.25 kg (median change of 0).

### Safety Findings with Increasing Duration of Testosterone Exposure (Open Label and Extension Phases)

#### Adverse Events

**[Deaths]{.underline}**

There were no deaths in any TTS-exposed subjects, followed up to 18
months of exposure.

**[Serious Adverse Events]{.underline}**

In the 6 month open label phase, the rate of (SAEs) was 1.7%, regardless
of whether the subjects had received 28 or 52 weeks of testosterone. In
the extension phase, which followed the open label phase, the overall
rate of SAEs was 1.9%, but was higher in the group with a total of 12
months testosterone exposure (3%) than the group with a total of 18
months of testosterone exposure (0.6%). SAEs of concern in the open
label phase were cholecystitis/cholelithiasis (3 subjects, one of whom
was in the placebo-\>TTS group), pancreatitis (2 subjects, one of whom
was in the placebo-\>TTS group) and metastatic breast cancer (in a
placebo-\>TTS subject) and chest pain/dyspnea (in a TTS-\>TTS subject).
Reported SAEs of concern in the extension phase were irregular heart
rate, hypertension, chest pain, and ductal carcinoma in situ, each of
which occurred in a single placebo-\>TTS-\>TTS subject.

Division comment:

-   Although in the extension phase, the group with shorter testosterone
    exposure (12 months) appears to have a five-fold greater rate of
    SAEs (3.0 vs. 0.6%), this difference was not tested for statistical
    significance, and it is unlikely that this rate is affected by the
    initial randomization to placebo one year prior to this phase of the
    study. Overall, the SAE rate in subjects remaining on testosterone
    for 12-18 months is about 2%, which is equivalent to the SAE rates
    seen in testosterone-exposed subjects in the double blind and open
    label phases.

-   A placebo-\>TTS-\>TTS subject from Study 133, who was diagnosed with
    lobular breast cancer in the extension phase, was not reported by
    the Applicant as an SAE.

-   The incidence of SAEs must be viewed in light of the fact that all
    subjects were taking estrogen as well as testosterone.

**[Withdrawals due to Adverse Events]{.underline}**

Withdrawal due to adverse events occurred in 60 (7.2%) of the 837
subjects participating in the open label phase of Studies 133 and 134,
and in 17 (5.3%) of the 321 subjects in the extension phase up to 78
weeks. An additional four subjects withdrew due to AEs after completing
78 weeks of the study. The most common AEs resulting in withdrawal were
hirsutism, application site reactions, weight increase, acne and
alopecia in the open label phase and acne and alopecia in the extension
phase.

Division comments:

-   Acne and alopecia continued to result in AE-related withdrawals
    through 78 weeks of testosterone exposure and hirsutism continued to
    be a frequent cause of AE-related withdrawals through the first year
    of treatment with testosterone.

-   Subjects who continued into the extension phase tended to have AEs
    leading to withdrawal that differed from those noted in the double
    blind and open label phases. It is possible that the AEs that
    commonly led to withdrawal during the first year of the trials may
    also have limited the further participation of subjects in the
    extension phase. Events occurring uniquely in the extension phase
    and leading to withdrawal are concerning in aggregate, as they
    include palpitations, chest pain, fatigue, increased heart rate,
    dizziness, dyspnea and hypertension, all of which could reflect
    cardiovascular effects.

**[Common Adverse Events]{.underline}**

Overall AEs occurred in 57.1% of subjects in the open label phase and
52.6% of subjects in the extension phase. AEs that occurred with
incidence of at least 2% in the open label phase are displayed in Table
28.

[]{#__RefHeading___Toc87346478 .anchor}Table 28 Studies 133 & 134: Most
Common Adverse Events (Incidence ≥ 2%) During Open Label Phase

+----------------------------+----+---+---------+----+---+---------+
|                            | *  |   |         | *  |   |         |
|                            | *P |   |         | *T |   |         |
|                            | la |   |         | TS |   |         |
|                            | ce |   |         | -\ |   |         |
|                            | bo |   |         | >T |   |         |
|                            | -\ |   |         | TS |   |         |
|                            | >T |   |         | ** |   |         |
|                            | TS |   |         |    |   |         |
|                            | ** |   |         | *  |   |         |
|                            |    |   |         | *N |   |         |
|                            | *  |   |         | =4 |   |         |
|                            | *N |   |         | 19 |   |         |
|                            | =4 |   |         | ** |   |         |
|                            | 18 |   |         |    |   |         |
|                            | ** |   |         |    |   |         |
+----------------------------+----+---+---------+----+---+---------+
|                            | ** | * | **In    | ** | * | **In    |
|                            | \# | * | cidence | \# | * | cidence |
|                            | A  | % | Rat     | A  | % | Rat     |
|                            | Es | \ | e\*\*** | Es | \ | e\*\*** |
|                            | \* | * |         | \* | * |         |
|                            | ** | * |         | ** | * |         |
|                            |    | * |         |    | * |         |
+----------------------------+----+---+---------+----+---+---------+
| **Adverse Event**          |    |   |         |    |   |         |
+----------------------------+----+---+---------+----+---+---------+
| Hirsutism                  | 66 | 1 | 0.151   | 72 | 1 | 0.171   |
|                            |    | 5 |         |    | 7 |         |
|                            |    | . |         |    | . |         |
|                            |    | 8 |         |    | 2 |         |
+----------------------------+----+---+---------+----+---+---------+
| Acne NOS                   | 27 | 6 | 0.062   | 33 | 7 | 0.077   |
|                            |    | . |         |    | . |         |
|                            |    | 5 |         |    | 9 |         |
+----------------------------+----+---+---------+----+---+---------+
| ASRs                       | 23 | 5 | 0.055   | 24 | 5 | 0.049   |
|                            |    | . |         |    | . |         |
|                            |    | 5 |         |    | 7 |         |
+----------------------------+----+---+---------+----+---+---------+
| Alopecia                   | 8  | 1 | 0.018   | 14 | 3 | 0.033   |
|                            |    | . |         |    | . |         |
|                            |    | 9 |         |    | 3 |         |
+----------------------------+----+---+---------+----+---+---------+
| Weight increased           | 4  | 1 | 0.009   | 11 | 2 | 0.026   |
|                            |    | . |         |    | . |         |
|                            |    | 0 |         |    | 6 |         |
+----------------------------+----+---+---------+----+---+---------+
| URI tract sign & symptoms  | 11 | 2 | 0.025   | 10 | 2 | 0.020   |
| (HLT)                      |    | . |         |    | . |         |
|                            |    | 6 |         |    | 4 |         |
+----------------------------+----+---+---------+----+---+---------+
| Headache                   | 7  | 1 | 0.016   | 12 | 2 | 0.025   |
|                            |    | . |         |    | . |         |
|                            |    | 7 |         |    | 9 |         |
+----------------------------+----+---+---------+----+---+---------+
| Musculoskeletal &          | 10 | 2 | 0.023   | 12 | 2 | 0.024   |
| connective tissue signs &  |    | . |         |    | . |         |
| symptoms NEC (HLT)         |    | 4 |         |    | 9 |         |
+----------------------------+----+---+---------+----+---+---------+
| Sinusitis NOS              | 8  | 1 | 0.018   | 13 | 3 | 0.023   |
|                            |    | . |         |    | . |         |
|                            |    | 9 |         |    | 1 |         |
+----------------------------+----+---+---------+----+---+---------+
| Arthralgia                 | 10 | 2 | 0.023   | 7  | 1 | 0.017   |
|                            |    | . |         |    | . |         |
|                            |    | 4 |         |    | 7 |         |
+----------------------------+----+---+---------+----+---+---------+
| Breast disorders NEC (HLT) | 7  | 1 | 0.016   | 9  | 2 | 0.021   |
|                            |    | . |         |    | . |         |
|                            |    | 7 |         |    | 1 |         |
+----------------------------+----+---+---------+----+---+---------+
| UTI (HLT)                  | 9  | 2 | 0.021   | 5  | 1 | 0.007   |
|                            |    | . |         |    | . |         |
|                            |    | 2 |         |    | 2 |         |
+----------------------------+----+---+---------+----+---+---------+
| Limb injuries NEC (HLT)    | 2  | 0 | 0.005   | 9  | 2 | 0.021   |
|                            |    | . |         |    | . |         |
|                            |    | 5 |         |    | 1 |         |
+----------------------------+----+---+---------+----+---+---------+

Note: HLT = Higher Level MedDRA Term, subsuming subheadings; NOS = not
otherwise specified; NEC = not elsewhere classified

\* AEs counts and the % AEs are based on the total \# of AEs occurring
between Weeks 25-52, regardless of whether the subject had ever
previously reported that AE.

\*\*The incidence rate represents those AEs occurring for the first time
between Weeks 25-52 divided by the number of 28 patient-week units of
exposure time at risk during this period. Subjects who had previously
reported that AE as occurring during a period of testosterone exposure
were not considered at risk during the extension phase.

Source: Based on Table 11, *safety-sum.pdf, pp 130-81*

Rates of AEs occurring with at least 2% incidence in subjects in the
extension study to 78 weeks are presented in Table 29.

[]{#__RefHeading___Toc87346479 .anchor}Table 29 Studies 133 & 134: Most
Common Adverse Events (≥ 2% Incidence Rate) During Extension Phase

  ----------------------------- ------- ----- -------------- --------------
                                \#      %\*   \# Incident    Incidence
                                AEs\*         AEs\*\*        Rate\*\*

  **Adverse Event**                                          

  Hirsutism                     18      5.6   13             0.05

  Alopecia                      12      3.7   12             0.04

  URIs                          12      3.7   11             0.04

  ASRs                          12      3.7   8              0.03

  Headaches                     9       2.8   9              0.03

  Nasopharyngitis               8       2.5   7              0.02

  Bronchitis                    7       2.2   7              0.02

  Arthralgia                    7       2.2   6              0.02

  Acne                          7       2.2   5              0.02

  Hot flush                     6       1.9   6              0.02

  Pain & discomfort NEC         6       1.9   6              0.02

  Influenza                     6       1.9   4              0.01

  UTIs                          6       1.9   4              0.01

  Anxiety                       5       1.6   5              0.02

  Hypertension                  5       1.6   5              0.02

  Gastrointestinal and          4       1.2   3              0.01
  abdominal pain                                             
  ----------------------------- ------- ----- -------------- --------------

Note: HLT = Higher Level MedDRA Term, subsuming subheadings; NOS = not
otherwise specified; NEC = not elsewhere classified

\* AEs counts and the % AEs are based on the total \# of AEs occurring
between Weeks 53-78, regardless of whether the subject had ever
previously reported that AE.

Source: Table 7, *2001133-134addendum.pdf, pp 19-22*

Among cardiovascular, thrombotic and cancer-related events of interest,
there were no MIs, strokes or TIAs, DVTs or pulmonary emboli during the
open label or extension phases. There was a single case of metastatic
breast cancer in the placebo-\>TTS group. In the extension phase, there
was one case of breast cancer and one case of breast cancer in situ in
the placebo-\>TTS-\>TTS group.

#### Androgenic Effects

About 30% of subjects in the open label phase experienced androgenic
AEs. This rate was higher than that seen in the TTS-treated subjects in
the double blind phase, primarily because of a higher rate of hirsutism
in the open label portion of the studies. Withdrawals due to these AEs
were also higher in the open label phase. Androgenic AE rates, severity,
and rate of withdrawal due to these AEs were slightly higher in the
subjects who had 12 months exposure to testosterone as compared to those
exposed for only 6 months.

Division comment:

-   The number of subjects with androgenic AEs in the open label phase
    may be overestimated. The Applicant did not provide a summary
    comparable to those done for the double blind or extension phases;
    therefore, the reviewer summed the occurrence of the individual
    androgenic events, which would overestimate subjects who experienced
    androgenic AEs in two or more categories.

In the extension phase, androgenic AEs were reported in 12% of subjects;
these rates were similar to those seen in the TTS subjects in the double
blind phase.

Subgroup analyses of rates of androgenic adverse events by route of
estrogen therapy, age and race were conducted in the extension study,
and no subpopulations of increased risk were identified.

A case of clitoromegaly in a TTS-\>TTS subject began about five months
after starting testosterone, but was not reported until the open label
period. The finding was confirmed on physical exam at the Week 52 visit.
The subject continued into the extension phase with the event ongoing.
Her maximum free testosterone level was 6.8 pg/ml. There were no new
reports of clitoromegaly reported in the extension study.

The psychiatric events of interest as potential androgenic effects
(agitation, anxiety and irritability) occurred in 1.7% of subjects in
the open label phase, with an additional 0.7% experiencing aggression.

**[Acne]{.underline}**

In the open label phase, 7.2% of subjects reported acne as an AE, with a
higher frequency in the group with 12 months exposure to testosterone
(7.9%) as compared to the group with 6 months exposure (6.5%). Fewer
than 4% of subjects exposed for up to a year to testosterone experienced
worsening of acne as rated on the Palatsi scale as compared to the last
assessment before starting testosterone, and the rate was equal whether
the exposure was for 12 or 18 months.

In the extension phase, 2.2% of subjects reported acne as an AE, with a
higher frequency in the group with 12 months exposure to testosterone
(3.0%) as compared to the group with 18 months exposure (1.3%). Again,
fewer than 4% of subjects exposed for up to 78 weeks to testosterone
experienced worsening of acne as rated on the Palatsi scale as compared
to the last assessment before starting testosterone, and the rate was
equal whether the exposure was for 12 or 18 months.

Division comment:

-   Worsening of acne on the Palatsi scale used in the objective
    assessment does not appear to increase with increasing duration of
    testosterone exposure. Over the three phases of the studies,
    approximately 3-4% of testosterone-exposed subjects experienced
    worsening of acne compared to their baseline rating. This is
    corroborated by the observation that the frequency of acne as an AE
    does not appear to increase with increasing duration of testosterone
    treatment.

**[Alopecia]{.underline}**

In the open label phase, 4.2% of subjects reported alopecia as an AE.
The subjects with 12 months exposure to testosterone had higher rates of
this AE, more frequent withdrawal due to this AE, and greater
proportions of more severe alopecia than those exposed for only 6
months.

Alopecia was reported as an AE in 4.7% of subjects in the extension
phase. The 5.8% rate in subjects on testosterone from Weeks 0-78 was
greater than the 3.4% rate seen in subjects exposed to testosterone
during Weeks 0-24, the 5.0% rate in subjects exposed during Weeks 0-52,
and the 3.6% rate seen in subjects in the extension study who used
testosterone only from Weeks 25-78. All of the cases in the
TTS-\>TTS-\>TTS (18 month exposure) group were new onset cases, in
subjects who had not previously experienced alopecia. Four subjects in
this group withdrew due to alopecia, vs. none in the placebo-\>TTS-\>TTS
group.

Division comment:

-   Alopecia appears to increase in frequency with increasing duration
    of testosterone exposure. The majority of the cases occurring in the
    later phases of the study represented new incident cases, rather
    than recurrent or ongoing cases. While this AE was never rated by
    the investigator as severe, it was responsible for subject
    withdrawal in all three phases of the studies.

**[Hirsutism]{.underline}**

In the open label phase, 16.5% of subjects overall reported hirsutism as
an AE. This rate was numerically higher than that seen in placebo
subjects or than that of testosterone-exposed subjects in either the
double blind or the extension phase of the studies, as was the rate of
withdrawal due to hirsutism. Rates were slightly higher in subjects with
longer (12 months) exposure to testosterone, and their frequency of
withdrawal due to this AE was more than double that of subjects with
shorter (6 months) exposure to testosterone. Of subjects completing a
year of the trials, chin hirsutism increased from baseline in 8.3% of
subjects, and upper lip hirsutism increased in 10.6%. The frequency of
depilation increased from baseline in 17.3% of subjects in the open
label phase. On all three measures, the proportion of subjects with no
change or a decrease from baseline was similar between those with 6
months and those with 12 months of testosterone exposure.

Overall, 5.6% of subjects in the extension phase reported hirsutism as
an AE, with a greater frequency in subjects with 18 months exposure to
testosterone than those with 12 months exposure. On the Lorenzo scale,
the rating of chin hirsutism increased from baseline in 9% of subjects
in the extension study, with no difference between those exposed to
testosterone for 54 weeks and those exposed for 78 weeks. Upper lip
hirsutism increased from baseline in 10% of each group in the extension
study. Frequency of depilation increased in 19% of those exposed to
testosterone for 54 weeks and in 26% of those exposed for 78 weeks.

Division comment:

-   With longer duration of testosterone exposure, hirsutism does not
    seem to be reported more frequently as an AE, nor is it rated as
    more apparent on the Lorenzo scale. However, the increased frequency
    of depilation suggests that women are in fact experiencing greater
    facial hair growth with longer testosterone exposure.

**[Voice Deepening]{.underline}**

In the open label phase, 2.6% of subjects overall experienced voice
deepening, 2.4% of those receiving 6 months of testosterone, and 2.9% of
those receiving 12 months exposure.

Voice deepening was reported as an AE in 1.6% of subjects in the
extension phase; the rate was higher in subjects with 12 months exposure
to testosterone (2.4%) than those with 18 months exposure (0.6%) .

Division comment:

-   Voice deepening does not appear to occur more frequently with longer
    exposure to testosterone, but remains similar to the rate seen in
    placebo subjects.

#### Application Site Reactions

Application site reactions occurred in 5.6% of subjects in the open
label phase and 3.7% of subjects in the extension study. Rates were
similar regardless of whether subjects had initially been on placebo or
TTS. There were no reported cases of sensitization.

#### Impact on Estrogen-Related Effects

Rates of hot flushes were low in the open label (1.3%) and extension
phases (1.9%), and there were no consistent patterns regarding severity
of hot flushes with increasing duration of exposure to testosterone.

In the open label and extension phases, rates of breast pain and
tenderness were lower than in the double blind phase (1.8% and 1.2%
respectively). Severity was greater during the open label phase in those
subjects with longer testosterone exposure, although this pattern did
not continue in the extension phase, where all events were mild.

#### Laboratory Values

Lipid Profile

In the open label phase, changes in lab values at Week 52 were small,
but numerically more favorable in the TTS-\>TTS group (Table 30).
Markedly abnormal values developed in a small percentage of subjects in
both groups (range 0 to 4.4%) during the open label phase; abnormal LDL
and triglyceride levels were numerically more common in subjects with
longer exposure to testosterone (see Table 31).

[]{#__RefHeading___Toc87346480 .anchor}Table 30 Studies 133 & 134:
Changes in Lipid Profile in Open Label Phase

![](media/image16.wmf){width="6.374305555555556in"
height="1.632638888888889in"}

![](media/image17.wmf){width="6.374305555555556in"
height="0.4888888888888889in"}

Source: Table 50, safety-sum.pdf, pp 280-81

[]{#__RefHeading___Toc87346481 .anchor}**Table 31 Studies 133 & 134:
Proportion of Subjects with** Markedly Abnormal Values on Lipid Profiles
in Open Label Phase

+-----------------------+-----------+-----------+-----------+-----------+
| **Laboratory**        | **Placeb  |           | **TT      |           |
|                       | o-\>TTS** |           | S-\>TTS** |           |
| **Test**              |           |           |           |           |
|                       | **N=388** |           | **N=419** |           |
+-----------------------+-----------+-----------+-----------+-----------+
|                       | **\#      | **%**     | **\#      | **%**     |
|                       | abnl/**   |           | abnl/**   |           |
|                       |           |           |           |           |
|                       | **\# with |           | **\# with |           |
|                       | data**    |           | data**    |           |
+-----------------------+-----------+-----------+-----------+-----------+
| **Total Cholesterol** | 2/376     | 0.53      | 0/360     | 0         |
+-----------------------+-----------+-----------+-----------+-----------+
| **HDL**               | 0/376     | 0         | 0/360     | 0         |
+-----------------------+-----------+-----------+-----------+-----------+
| **LDL**               | 10/376    | 2.66      | 10/360    | 2.78      |
+-----------------------+-----------+-----------+-----------+-----------+
| **Triglycerides**     | 15/376    | 3.99      | 16/360    | 4.44      |
+-----------------------+-----------+-----------+-----------+-----------+

Source: Appendix 5.9, Table 25, *2001133.pdf, p 11184* and Appendix 5.9,
Table 20, *2001134.pdf, p 9880 []{.mark}*

Lipid values reported in subjects who remained in the study extension to
Week 78 are shown in Table 32 and proportions of subjects with markedly
abnormal values at Week 78 are displayed in Table 33. There was a
numerically greater decrease in triglycerides in those subjects with
shorter testosterone exposure. The occurrence of markedly abnormal
values was similar, regardless of the duration of exposure to
testosterone.

[]{#__RefHeading___Toc87346482 .anchor}Table 32 Studies 133 & 134:
Changes in Lipid Profile in Extension Phase

![](media/image18.wmf){width="5.979861111111111in"
height="1.9958333333333333in"}

Source: EOT Table 23, 2001133-134addendum.doc, p 101

[]{#__RefHeading___Toc87346483 .anchor}**Table** 33 **Studies 133 &
134:** Proportion of Subjects with **Markedly Abnormal Values on Lipid
Profiles in Extension Phase**

![](media/image19.wmf){width="5.979861111111111in"
height="0.9388888888888889in"}

Source: EOT Table 27, 2001133-134addendum.doc, p 105

Division comments:

-   On average, there were no clinically relevant changes in the lipid
    profile. It is notable, however, that as much as 3-4% of subjects
    exposed to testosterone for a year developed LDL or triglyceride
    levels more than 30% above baseline, although this does appear
    comparable to the rate seen in placebo subjects followed for six
    months.

-   Subjects exposed to testosterone for up to 78 weeks showed small
    decreases from baseline in total cholesterol and LDL, small
    increases in HDL and changes in triglycerides ranging from about a
    5% decrease to a small increase. None of these changes are likely to
    be of clinical significance.

Hepatic Profile

Table 34 shows the changes from baseline in hepatic function experienced
by subjects in the open label phase, which were of similarly small
magnitude to those seen in the double blind phase. A single subject in
the TTS-\>TTS group had a markedly abnormal value on ALT (baseline of 55
U/L rose to 104 at Week 24 and to 134 at Week 52). The subject
acknowledged significant and increased alcohol use over the course of
the study, to which the investigator attributed the ALT rise. An
additional TTS-\>TTS subject had a markedly abnormal AST (baseline of 36
UL rose to 153 at Week 52).

[]{#__RefHeading___Toc87346484 .anchor}Table 34 Studies 133 & 134:
Changes in Hepatic Function in Open Label Phase

![](media/image20.wmf){width="6.373611111111111in"
height="1.6520833333333333in"}

Source: Table 54, safety-sum.doc, p 285

Subjects with exposure to testosterone up to 78 weeks are displayed in
Table 35. None of these subjects experienced markedly abnormal values on
the four hepatic parameters evaluated.

[]{#__RefHeading___Toc87346485 .anchor}Table 35 Studies 133 & 134:
Changes in Hepatic Function in Extension Phase

![](media/image21.wmf){width="6.302083333333333in"
height="1.9965277777777777in"}

Source: EOT Table 25, 2001133-134addendum.doc, p 103

Carbohydrate Metabolism

Changes in the open label phase were of similarly small magnitude (Table
36). The slight increase in insulin at Week 52 was not felt to be
clinically meaningful. The proportion of subjects in the open label
phase who developed markedly abnormal values on measures of carbohydrate
metabolism is shown in Table 37. The change in glucose value for
subjects with up to 78 weeks of testosterone exposure is shown in Table
38. Only two subjects, one who initially received TTS and one who
initially received placebo, experienced markedly abnormal glucose levels
over Weeks 53-78.

[]{#__RefHeading___Toc87346486 .anchor}Table 36 Studies 133 & 134:
Changes in Carbohydrate Metabolism Markers in Open Label Phase

![](media/image22.wmf){width="5.990277777777778in"
height="1.6895833333333334in"}

Source: Table 58, safety-sum.pdf, p 290

[]{#__RefHeading___Toc87346487 .anchor}Table 37 Studies 133 & 134:
Proportion of Subjects with Markedly Abnormal Values in Carbohydrate
Metabolism Markers in Open Label Phase

+-----------------------+-----------+-----------+-----------+-----------+
| **Laboratory**        | **Placeb  |           | **TT      |           |
|                       | o-\>TTS** |           | S-\>TTS** |           |
| **Test**              |           |           |           |           |
|                       | **N=418** |           | **N=419   |           |
|                       |           |           | 220**     |           |
+-----------------------+-----------+-----------+-----------+-----------+
|                       | **\#      | **%**     | **\#      | **%**     |
|                       | abnl/**   |           | abnl/**   |           |
|                       |           |           |           |           |
|                       | **\# with |           | **\# with |           |
|                       | data**    |           | data**    |           |
+-----------------------+-----------+-----------+-----------+-----------+
| **Glucose**           | 0/374     | 0         | 1/361     | 0.28      |
+-----------------------+-----------+-----------+-----------+-----------+
| **Hemoglobin A1c**    | 0/372     | 0         | 0/359     | 0         |
+-----------------------+-----------+-----------+-----------+-----------+
| **Insulin**           | 7/371     | 1.89      | 14/357    | 3.92      |
+-----------------------+-----------+-----------+-----------+-----------+

Source: Appendix 5.9, Table 34, *2001133.pdf, p 11197* and Appendix 5.9,
Table 29, *2001134.pdf, p 9893*

[]{#__RefHeading___Toc87346488 .anchor}Table 38 Studies 133 & 134:
Changes in Carbohydrate Metabolism Markers in Extension Phase

![](media/image23.wmf){width="5.979861111111111in"
height="0.9430555555555555in"}

Source: EOT Table 24, 2001133-134addendum.doc, p 102

Division comment:

-   Overall, there were no clinically relevant changes in parameters of
    carbohydrate metabolism. The proportion of testosterone-exposed
    subjects who had markedly abnormal values for insulin after 12
    months of exposure is similar to the proportion of placebo subjects
    who displayed such changes.

Hematology

The change in hemoglobin during the open label phase was similar to that
seen among the TTS subjects during the double blind phase (see Table
39).

[]{#__RefHeading___Toc87346489 .anchor}Table 39 Studies 133 & 134:
Changes in Hemoglobin in Open Label Phase

![](media/image24.wmf){width="6.5in" height="0.7590277777777777in"}

Source: Table 62, safety-sum.pdf, p 294

At Week 78, hemoglobin declined slightly from baseline (Table 40); no
subjects had markedly abnormal hemoglobin values with 52-78 weeks of
testosterone exposure.

[]{#__RefHeading___Toc87346490 .anchor}Table 40 Studies 133 & 134:
Changes in Hemoglobin in Extension Phase

![](media/image25.wmf){width="6.500694444444444in"
height="0.8131944444444444in"}

Source: EOT Table 26, 2001133-134addendum.doc, p 104

Coagulation Parameters

Changes in the open label phase, displayed in Table 41, were generally
of greater magnitude, and the TTS-\>TTS group had a numerically greater
increase in fibrinogen than did the placebo-\>TTS group, with a mean
increase of almost 8% above baseline at Week 52. Markedly abnormal
values are summarized in Table 42.

[]{#__RefHeading___Toc87346491 .anchor}Table 41 Study 133: Changes in
Coagulation Parameters in Open Label Phase

![](media/image26.wmf){width="6.625in" height="1.6756944444444444in"}

![](media/image27.wmf){width="6.625in" height="0.4847222222222222in"}

Source: Appendix 5.9, Table 39, *2001133.pdf, pp 11205-6*

[]{#__RefHeading___Toc87346492 .anchor}Table 42 Study 133: Proportion of
Subjects with Markedly Abnormal Values in Coagulation Parameters in Open
Label Phase

![](media/image28.wmf){width="5.990277777777778in"
height="0.9423611111111111in"}

Source: Appendix 5.9, Table 40, *2001133.pdf, p 11207*

Data on coagulation parameters for subjects using testosterone for up to
78 weeks in the extension phase were not provided.

#### Vital signs and Weight

The open label and extension phases permitted assessment of changes from
baseline or differences in blood pressure based upon duration of
testosterone exposure. As some subjects had been exposed to placebo in
the first six months (double blind phase) of the clinical trials, their
baseline values were obtained from the visit just prior to their
initiation of testosterone therapy. In the open label phase, the mean
(SD) and median changes from baseline in systolic blood pressure were
1.6 (12.3) and 2.0 mm Hg in the placebo-\>TTS group, and 1.5 (14.0) and
0 mm Hg in the TTS‑\>TTS group. For diastolic blood pressure, the mean
(SD) and median changes from baseline were 0.9 (9.0) and 0 mm Hg in the
placebo-\>TTS group, and 0.5 (9.7) and 0 mm Hg in the TTS-\>TTS group.
In the extension phase, the mean (SD) and median changes from baseline
in systolic blood pressure were 1.0 (12.9) and 2.0 mm Hg in the
placebo-\>TTS-\>TTS group, and 0.2 (13.6) and 0 mm Hg in the
TTS-\>TTS-\>TTS group. For diastolic blood pressure, the mean (SD) and
median changes from baseline were 0.4 (9.1) and 0 mm Hg in the
placebo-\>TTS-\>TTS group, and -0.4 (8.6) and 0 mm Hg in the
TTS-\>TTS-\>TTS group.

In the open label phase, there was little further change in body weight;
the median change from baseline (the visit just before starting
testosterone) ranged from 0 to 0.05 kg, depending on the duration of
testosterone exposure.

Overall, subjects in the extension phase gained about 0.6 kg by Week 78.
One-third of subjects with 12 months exposure to testosterone gained
weight from baseline to Week 78, as did 40% of subjects with 18 months
of exposure. []{.mark}

Division comment:

-   Increases in systolic blood pressure as small as 1 mm Hg were
    observed in the WHI subjects on estrogen and progestin and were
    postulated as possible factors related to the increase in
    cardiovascular events in that arm.

-   It appears that testosterone is associated with a small increase in
    weight (mean 0.63 kg) over that seen with placebo. This weight gain
    persists in subjects treated up to 78 weeks.

### Frequency and Incidence of Selected Adverse Events (Weeks 0-78)

Data on the incidence (Table 43) and frequency (Table 44) of selected
adverse events are provided. The [incidence rate]{.underline} provides
information about the occurrence of new cases of a specific AE in the
population remaining at risk for that AE; subjects who have previously
experienced that AE are no longer considered at risk. Data on the
[frequency]{.underline} of AEs allows for the inclusion of an AE in a
given subject in every treatment phase in which it occurred. In this
analysis, the entire population remains at risk for AEs through all
three phases of the studies.

[]{#__RefHeading___Toc87346493 .anchor}Table 43 Incidence of Adverse
Events by Duration of Testosterone Exposure

+-------------+-------+------+-------+-------+----------+------------+
| **Duration  | **N   | **6  |       | **12  |          | **18       |
| of          | one** | mont |       | Mon   |          | Months**   |
| T           |       | hs** |       | ths** |          |            |
| estosterone |       |      |       |       |          |            |
| Exposure**  |       |      |       |       |          |            |
+-------------+-------+------+-------+-------+----------+------------+
| **Treatment | *     | **T  | *     | *     | *        | **TTS-\>T  |
| History**   | *Plac | TS** | *P-\> | *TTS- | *P-\>TTS | TS-\>TTS** |
|             | ebo** |      | TTS** | TTS** | -\>TTS** |            |
| *           |       | **   |       |       |          | **(        |
| *(Treatment | *     | (DB, | *     | *     | **(Ex    | Extension, |
| phase,      | *(DB, | Wks  | *(OL, | *(OL, | tension, | Wks        |
| length),**  | Wks   | 0-2  | Wks   | Wks   | Wks      | 53-78)**   |
|             | 0-    | 4)** | 25-   | 25-   | 53-78)** |            |
| **N**       | 24)** |      | 52)** | 52)** |          | **N        |
|             |       | **N  |       |       | **N=1    | =154\*\*** |
|             | *     | =696 | **N   | **N   | 67\*\*** |            |
|             | *N=70 | \*** | =418\ | =419\ |          |            |
|             | 3\*** |      | *\*** | *\*** |          |            |
+-------------+-------+------+-------+-------+----------+------------+
| **Incidence |       |      |       |       |          |            |
| Rate**      |       |      |       |       |          |            |
+-------------+-------+------+-------+-------+----------+------------+
| Death       | 0.001 | 0    | 0     | 0     | 0        | 0          |
+-------------+-------+------+-------+-------+----------+------------+
| SAE w/o     | 0.024 | 0    | N/A   | N/A   | N/A      | N/A        |
| ASRs        |       | .024 |       |       |          |            |
+-------------+-------+------+-------+-------+----------+------------+
| W/D due to  | 0.052 | 0    | NA    | N/A   | N/A      | N/A        |
| AE          |       | .057 |       |       |          |            |
+-------------+-------+------+-------+-------+----------+------------+
| Acne        | .     | 0    | 0.064 | 0.078 | N/A      | N/A        |
|             | 0.081 | .102 |       |       |          |            |
+-------------+-------+------+-------+-------+----------+------------+
| Alopecia    | 0.030 | 0    | 0.033 | 0.052 | 0.031    | 0.066      |
|             |       | .039 |       |       |          |            |
+-------------+-------+------+-------+-------+----------+------------+
| Hirsutism   | 0.056 | 0    | 0.164 | 0.189 | 0.036    | 0.068      |
|             |       | .079 |       |       |          |            |
+-------------+-------+------+-------+-------+----------+------------+
| Voice       | 0.019 | 0    | 0.023 | 0.029 | N/A      | N/A        |
| Deepening   |       | .026 |       |       |          |            |
+-------------+-------+------+-------+-------+----------+------------+
| ASRs\*\*    | 0.501 | 0    | 0.055 | 0.049 | N/A      | N/A        |
|             |       | .424 |       |       |          |            |
+-------------+-------+------+-------+-------+----------+------------+
| Hot Flushes | 0.027 | 0    | 0.014 | 0.012 | 0.031    | 0.007      |
|             |       | .031 |       |       |          |            |
+-------------+-------+------+-------+-------+----------+------------+
| Breast Pain | 0.056 | 0    | 0.019 | 0.017 | 0.006    | 0.021      |
|             |       | .047 |       |       |          |            |
+-------------+-------+------+-------+-------+----------+------------+
| Wt Gain ≥7% | 0.057 | 0    | 0.034 | 0.036 | N/A      | N/A        |
|             |       | .162 |       |       |          |            |
+-------------+-------+------+-------+-------+----------+------------+
| Laboratory  | 0.023 | 0    | 0.033 | 0.043 | 0.012    | 0.028      |
| AEs         |       | .036 |       |       |          |            |
+-------------+-------+------+-------+-------+----------+------------+

DB=Double Blind phase, OL=Open Label phase

\*Includes Studies 068, 092, 133 & 134

\*\* Includes Studies 133 & 134 only

Incidence rate is computed per 100 person-time units, where time unit is
the number of weeks in that phase of study

The incidence data provide the clearest assessment of the change in
occurrence over increasing duration of testosterone exposure. It can be
seen that the incidence of acne varies little with increasing duration
of exposure (i.e., there is no increase in new presentations over time),
up to one year, and remains similar to the rate observed in subjects on
placebo. In contrast, the incidence of alopecia increases in each
interval of testosterone exposure examined, and is more than double the
placebo rate by 18 months of testosterone treatment. The rate of voice
deepening remains relatively stable up to one year of exposure, and is
numerically slightly higher than that seen in placebo subjects.
Incidence data on the remaining AEs are too variable to suggest clear
trends with increasing length of exposure to testosterone.

[]{#__RefHeading___Toc87346494 .anchor}Table 44 Frequency of Adverse
Events by Duration of Testosterone Exposure

+---------------+-------+------+-------+-------+---------+------------+
| **Duration of | **N   | **6  |       | **12  |         | **18       |
| Testosterone  | one** | mont |       | mon   |         | months**   |
| Exposure**    |       | hs** |       | ths** |         |            |
+---------------+-------+------+-------+-------+---------+------------+
| **Time in     | **6   |      | **12  |       | **18    |            |
| Study**       | mon   |      | mon   |       | m       |            |
|               | ths** |      | ths** |       | onths** |            |
+---------------+-------+------+-------+-------+---------+------------+
| **Population  | *     | **T  | *     | *     | **P     | **TTS-\>T  |
| (Treatment    | *Plac | TS** | *P-\> | *TTS- | -\>TTS- | TS-\>TTS** |
| phase,        | ebo** |      | TTS** | TTS** | \>TTS** |            |
| length),**    |       | **   |       |       |         | **(        |
|               | *     | (DB, | *     | *     | **(Ext  | Extension, |
| **N**         | *(DB, | Wks  | *(OL, | *(OL, | ension, | Wks        |
|               | Wks   | 0-2  | Wks   | Wks   | Wks     | 53-78)**   |
|               | 0-    | 4)** | 25-   | 25-   | 5       |            |
|               | 24)** |      | 52)** | 52)** | 3-78)** | **N        |
|               |       | **N  |       |       |         | =154\*\*** |
|               | *     | =696 | **N   | **N   | **N=16  |            |
|               | *N=70 | \*** | =418\ | =419\ | 7\*\*** |            |
|               | 3\*** |      | *\*** | *\*** |         |            |
+---------------+-------+------+-------+-------+---------+------------+
| **% with      |       |      |       |       |         |            |
| Adverse       |       |      |       |       |         |            |
| Event**       |       |      |       |       |         |            |
+---------------+-------+------+-------+-------+---------+------------+
| Death         | **    | 0    | **0** | 0     | **0**   | 0          |
|               | 0.1** |      |       |       |         |            |
+---------------+-------+------+-------+-------+---------+------------+
| SAE           | **    | 2.2  | **    | 1.7   | **3.0** | 0.6        |
|               | 2.1** |      | 1.7** |       |         |            |
+---------------+-------+------+-------+-------+---------+------------+
| W/D due to AE | **    | 8.2  | **    | 8.4   | **5.4** | 5.2        |
|               | 8.4** |      | 6.0** |       |         |            |
+---------------+-------+------+-------+-------+---------+------------+
| All AEs       | **7   | 76.1 | **5   | 58.0  | *       | 51.3       |
|               | 5.8** |      | 6.2** |       | *53.9** |            |
+---------------+-------+------+-------+-------+---------+------------+
| Androgenic    | **1   | 17.7 | **    | N/A   | *       | 13.6       |
| AEs           | 4.4** |      | N/A** |       | *10.2** |            |
+---------------+-------+------+-------+-------+---------+------------+
| Acne          | **    | 6.7  | **    | 7.9   | **3.0** | 1.3        |
|               | 5.1** |      | 6.5** |       |         |            |
+---------------+-------+------+-------+-------+---------+------------+
| Alopecia      | **    | 4.2  | **    | 5.0   | **3.6** | 5.8        |
|               | 2.9** |      | 3.3** |       |         |            |
+---------------+-------+------+-------+-------+---------+------------+
| Hirsutism     | **    | 7.3  | **1   | 17.2  | **4.2** | 7.1        |
|               | 5.9** |      | 5.8** |       |         |            |
+---------------+-------+------+-------+-------+---------+------------+
| Voice         | **    | 2.7  | **    | 2.9   | **2.4** | 0.6        |
| Deepening     | 2.2** |      | 2.4** |       |         |            |
+---------------+-------+------+-------+-------+---------+------------+
| ASRs          | **3   | 30.4 | **    | 5.7   | **4.8** | 2.6        |
|               | 4.1** |      | 5.5** |       |         |            |
+---------------+-------+------+-------+-------+---------+------------+
| Hot Flushes   | **    | 2.7  | **    | 1.2   | **3.0** | 0.6        |
|               | 2.4** |      | 1.4** |       |         |            |
+---------------+-------+------+-------+-------+---------+------------+
| Breast Pain   | **    | 4.2  | **    | 1.7   | **0.6** | 1.9        |
|               | 4.8** |      | 1.9** |       |         |            |
+---------------+-------+------+-------+-------+---------+------------+
| Wt Gain\>=    | **1   | 20.2 | **    | N/A   | **      | 13.2#      |
| 3.5%          | 1.9** |      | N/A** |       | 15.5#** |            |
+---------------+-------+------+-------+-------+---------+------------+
| Laboratory    | **1   | 2.87 | **3   | 4.30  | *       | 2.60       |
| AEs           | .99** |      | .59** |       | *1.20** |            |
+---------------+-------+------+-------+-------+---------+------------+
| Markedly      | **4   | 3.68 | **7   | 7.22  | **4.5** | 6.2        |
| Abnormal      | .59** |      | .18** |       |         |            |
| Lipids\*\*    |       |      |       |       |         |            |
+---------------+-------+------+-------+-------+---------+------------+
| Markedly      | **3   | 2.70 | **1   | 4.20  | **0.7** | 0.8        |
| Abnormal      | .41** |      | .89** |       |         |            |
| Markers of    |       |      |       |       |         |            |
| Carbohydrate  |       |      |       |       |         |            |
| M             |       |      |       |       |         |            |
| etabolism\*\* |       |      |       |       |         |            |
+---------------+-------+------+-------+-------+---------+------------+
| Markedly      | **1   | 3.92 | **2   | 2.43  | **N/A** | N/A        |
| Abnormal      | .23** |      | .31** |       |         |            |
| Coagulation   |       |      |       |       |         |            |
| Labs##        |       |      |       |       |         |            |
+---------------+-------+------+-------+-------+---------+------------+
| Markedly      | **0   | 0.44 | **0** | 0.55  | **0**   | 0          |
| Abnormal      | .44** |      |       |       |         |            |
| Hepatic       |       |      |       |       |         |            |
| Labs\*\*      |       |      |       |       |         |            |
+---------------+-------+------+-------+-------+---------+------------+
| Markedly      | **0   | 0.90 | **0** | 0.66  | **0**   | 0          |
| Abnormal      | .41** |      |       |       |         |            |
| Hematology    |       |      |       |       |         |            |
| Labs\*\*      |       |      |       |       |         |            |
+---------------+-------+------+-------+-------+---------+------------+

**Bold rates** apply to subjects who initially received placebo, and are
used to help visually group them as they move through the different
phases of the trials; similarly, the unbolded rates apply to subjects
who were initially assigned to TTS.

DB=Double Blind phase, OL=Open Label phase

\*Includes Studies 068, 092, 133 & 134 \*\* Includes Studies 133 & 134
only

#Percent reported only for those gaining over 5% \## Includes Study 133
only

Division comment:

-   This frequency table allows for comparison of AE rates both by
    duration of testosterone exposure and by duration of study
    participation. Some AEs may be dependent upon time in study, (e.g.,
    application site reactions \[ASRs\]) rather than on duration of
    testosterone exposure (e.g., alopecia). As an example of a
    time-dependent AE, the frequency data on application site reactions
    suggests that the rate is highest (range 30-34%) in the first six
    months of exposure to the patch in general, rather than to
    testosterone specifically. Subjects continuing into the open label
    phase, who had already worn the patch for six months, reported a low
    rate (range 2.6-5.7%) of this AE. In contrast, a drug-dependent AE
    such as alopecia shows that the frequency rises with duration of
    testosterone exposure (rates in subjects who started the trials in
    the placebo arm rise from 2.9 to 3.3 to 3.6, while rates in subjects
    initially randomized to TTS rise from 4.2 to 5.0 to 5.8 as exposure
    to testosterone continues).

### Relationship of Serum Free Testosterone Levels to Androgenic Adverse Events

The association of androgenic AEs in the double blind phase with maximum
serum levels of total testosterone, free testosterone and DHT was
assessed by categorizing hormone levels into quartiles and evaluating
the rates of individual androgenic AEs within these quartiles (Table 45
shows data for free testosterone). The only association identified was
one of increasing hirsutism with increasing free testosterone. However,
a threshold free testosterone level reliably associated with hirsutism
could not be defined by the Applicant.

[]{#__RefHeading___Toc87346495 .anchor}Table 45 Incidence of Androgenic
AE by Serum Free Testosterone Quartiles in Double Blind Phase

![](media/image29.wmf){width="5.667361111111111in"
height="1.207638888888889in"}

Source: Table 43, safety-sum.pdf, p 273

Division comment:

-   The incidence of acne appears to show a trend when comparison is
    made between rates in the lower two quartiles (7%) and those in the
    upper two quartiles (11-13%).

Four TTS subjects attained free testosterone levels above 20 pg/ml
during the double blind phase (normal range for reproductive age women
0.9-7.3 pg/ml). Two, with maximal levels of 32.1 pg/ml and 25.3 pg/ml,
had no androgenic AEs. Another subject with a maximal level of 61.8
pg/ml at Week 12 and 16.5 pg/ml at Week 24 reported mild facial hair
growth and mild acne with onset three and four months, respectively,
after randomization. She continued into the extension phase with a Week
52 free testosterone level of 3.2 pg/ml. The fourth subject developed
mild chin hirsutism at three months and withdrew three months later due
to lack of efficacy. Her Week 12 free testosterone level was 6.2 pg/ml
and her exit level about six months after starting testosterone was 30.4
pg/ml. She reported resolution of the hirsutism one month after
discontinuation of testosterone.

In the open label phase, seven subjects developed free testosterone
levels above 20 pg/ml. Two, with maximal values of 21.5 pg/ml and 45.7
pg/ml, had no androgenic AEs. A subject who had a level of 107.7 pg/ml
at Week 52 reported mild acne, which was ongoing at the end of the open
label phase; she did not continue into the extension study. A subject
with mild hirsutism had a maximal level of 24.2 pg/ml, and entered the
extension study with the side effect ongoing. A third subject
experienced mild acne with a maximal free testosterone level of 24.1 at
Week 52; the acne resolved shortly after she began the extension phase.
A subject experienced mild hoarseness after 11 months on testosterone
and had a Week 52 level of 63.1 pg/ml. She did not continue in the
extension phase, but reported resolution one month after discontinuing
the drug. The final subject had mild acne, mildly increased fasting
insulin and experienced a DVT during the double blind phase. Her Week 52
testosterone level was 23.7 pg/ml. Both the acne and the laboratory
abnormality resolved shortly after her entry into the extension phase.

Division comment:

-   There does appear to be an increased risk of hirsutism and possibly
    acne with rising free testosterone levels. Review of outliers on
    serum free testosterone levels does not identify any additional
    patterns of adverse events associated with attainment of
    supraphysiological free testosterone levels in a small number of
    subjects.

### Pharmacokinetics of Free and Total Testosterone

The Applicant submitted data descriptive of the normal range of free and
total testosterone in reproductive aged women (ages 18-49 years). The
reference range for free testosterone in this population was 0.9-7.3
pg/ml, and the reference range for total testosterone was 12-50 ng/dl.

The serum concentrations of free and total testosterone in participants
on testosterone in Studies 133 and 134 who had blood samples collected
within 5 days of applying the last patch prior to the scheduled study
visit are presented in Table 46. While mean concentrations of total
testosterone exceeded the upper limit of normal for reproductive-aged
women at all treatment visits, mean concentrations of free testosterone
remained at the upper of the normal range throughout treatment.

[]{#__RefHeading___Toc87346496 .anchor}Table 46 Studies 133 & 134: Free
and Total Testosterone Concentrations

![](media/image30.wmf){width="5.979861111111111in"
height="3.734722222222222in"}

Source: EOT Table 34, 2001133-134.pdf, p 114

Percentages of subjects in the double blind and open label phases whose
maximal free or total testosterone level exceeded the normal range in
reproductive age women are presented in Table 47.

[]{#__RefHeading___Toc87346497 .anchor}Table 47 Percent of Subjects with
Free and Total Testosterone Levels Beyond Normal Range for Reproductive
Aged Women

  ----------------- --------- ------- ------- ------- --------------- ------- ----------- -------
  **Maximal Free                                                                          
  Testosterone\                                                                           
  **(Normal range                                                                         
  0.9-7.3 pg/ml)                                                                          

                    Double                            Open Label                          
                    Blind                             Phase                               
                    Phase                                                                 

  Testosterone      Placebo           TTS             Placebo-\>TTS           TTS-\>TTS   
  Values                                                                                  

                    N         \%      N       \%      N               \%      N           \%

  Within normal     434       99.8    351     80.0    272             87.7    256         85.9
  range                                                                                   

  Above normal      1         0.2     88      20.0    38              12.3    42          14.1
  range                                                                                   

                                                                                          

  **Maximal Total                                                                         
  Testosterone**\                                                                         
  (Normal range                                                                           
  12-50 ng/dl)                                                                            

                    Double                            Open Label                          
                    Blind                             Phase                               
                    Phase                                                                 

  Testosterone      Placebo           TTS             Placebo-\>TTS           TTS-\>TTS   
  Values                                                                                  

                    N         \%      N       \%      N               \%      N           \%

  Within normal     434       99.3    91      20.7    109             35.0    118         39.5
  range                                                                                   

  Above normal      3         0.7     349     79.3    202             65.0    181         60.5
  range                                                                                   
  ----------------- --------- ------- ------- ------- --------------- ------- ----------- -------

Division comment:

-   The proportion of TTS treated subjects experiencing above normal
    values of total testosterone was much greater than the proportion
    with elevated free testosterone levels. The increased total
    testosterone levels may not reflect bioactive testosterone because
    of increased levels of sex hormone binding globulin (SHBG).

### Special Safety Studies

#### Mammographic Study

Study 2003082 was a 24-week, randomized (1:1), double-blind,
placebo-controlled trial designed to evaluate the effects of the 300 mcg
TTS on mammographic breast density and breast epithelial proliferation
in 99 naturally menopausal women who were also taking combined
estrogen/progestogen hormone products. Entry criteria for this study
included amenorrhea for at least 12 months or FSH \>40 IU/L, no sex
hormone treatment for three months before enrollment, and no prior
history of breast disease, cancer or abnormal mammogram. Subjects
received mammograms and fine needle aspirations (FNA) at baseline and
after 6 months of treatment.

Proliferation of breast epithelium was assessed by immunostaining of
epithelial breast cells obtained by FNA with Ki67, a monoclonal antibody
that reacts with a human nuclear antigen that is only present in
proliferating cells. Mammographic breast density was classified into
four categories according to the Wolfe classification:

-   N1 -- essentially normal breast

-   P1 -- prominent ductal pattern in up to ¼ of breast volume

-   P2 - prominent ductal pattern in more than ¼ of breast volume

-   DY -- extremely dense parenchyma, usually denoting connective tissue
    hyperplasia

Mammograms were also classified into one of five categories of
percentage of dense parenchymal tissue, ranging from 0-20, 21-40, 41-60,
61-80 and 81-100%.

The average exposure of the testosterone-exposed subjects was 171 days;
99% of subjects were compliant with dosing, defined as application of
80% of assigned patches. Eighty-eight subjects (47 on TTS) completed the
study.

FNA biopsies were obtained on two occasions from all 88 subjects
completing the study; however, only 125 biopsies were evaluable based on
sufficient number of cells in the aspirate. Just over half (45/88) of
the subjects had paired samples available for pre- and post-treatment
comparison. Mean and median percent of Ki67 positive cells for each
group are displayed in Table 48. The difference in change from baseline
between TTS and placebo groups, which was not significant, suggested a
trend toward reduced epithelial proliferation in the TTS group, but this
difference disappeared when results were adjusted for the higher percent
of Ki67 positive cells at baseline in the TTS group. When all evaluable
biopsies were evaluated (not just paired samples), there were no
statistically significant differences between placebo and TTS subjects
at either baseline or end of treatment.

[]{#__RefHeading___Toc87346498 .anchor}Table 48 Percent Ki67 Positive
Cells in Subjects with Paired Samples

![](media/image31.wmf){width="5.979861111111111in"
height="3.1618055555555555in"}

Source: Table 4, Karolinska.pdf, p 17

There were no mammographic abnormalities detected in any subjects in
this study. A total of 87 subjects had mammograms evaluable for change
in density. Changes from baseline in Wolfe classification and percent
change are presented in Table 49. No subjects in either treatment arm
experienced a decrease in breast density, and the proportions
experiencing an increase by either classification did not differ
significantly between the two groups. Actual scores on each
classification at baseline and at the end of treatment are displayed in
Table 50. Both groups showed shifts toward denser breast tissue, with
neither reaching the highest categories of density.

[]{#__RefHeading___Toc87346499 .anchor}Table 49 Change in Mammographic
Breast Density

![](media/image32.wmf){width="5.979861111111111in"
height="2.2465277777777777in"}

Source: Table 6, Karolinska.pdf, p 19

[]{#__RefHeading___Toc87346500 .anchor}Table 50 Mammographic Breast
Density at Baseline

![](media/image33.wmf){width="5.979861111111111in"
height="3.395138888888889in"}

**Mammographic Breast Density at End of Treatment**

![](media/image34.wmf){width="5.979861111111111in"
height="3.3555555555555556in"}

Source: EoT Tables 3&4, *Karolinska.pdf, p 24-5*

Division comments:

-   Although the proposed indication is for use in surgically menopausal
    women, who would only be using estrogen therapy, the Applicant
    provided data comparing testosterone to placebo in women using
    [combined estrogen/progestin]{.underline} therapy. It is known that
    progesterone itself increases breast density, and thus any effect of
    testosterone may be obscured by the progesterone effect in this
    study.

-   No formal power or sample size calculations are provided for this
    study. It is unclear whether the power was sufficient to detect
    differences between placebo and TTS-exposed subjects in breast
    epithelial proliferation or mammographic density that may be of
    clinical relevance.

-   The duration of this study was relatively short. With regard to
    detection of breast cancer itself, data from the WHI studies on
    estrogen plus progestin found that rates of breast cancer did not
    diverge from those found in placebo subjects until 2-4 years
    following randomization.

An additional anecdotal report arose in Study 133, where a subject in
the Placebo-\>TTS-\>TTS group was diagnosed with breast cancer during
the extension study. Her baseline mammogram had shown fibroglandular
densities bilaterally and a six-month follow-up was recommended. She
continued into the open label and extension phases, not obtaining a
repeat mammogram until she had had 37 weeks exposure to testosterone.
The follow-up mammogram showed microcalcifications in the left breast,
and a biopsy revealed an infiltrating breast cancer with marked lobular
features, which was ER and PR positive. The subject was discontinued
from both testosterone and estrogen therapy.

#### Bone Mineral Density and Bone Turnover

Bone mineral density measurements were made of the lumbar spine at
baseline and Week 24 in a subset of 120 subjects from Study 068
(Subgroup 1) and from 60 subjects in Study 092 (Subset 1), and markers
of bone turnover (serum N-telopeptide, serum type 1 C-terminal
procollagen peptide and serum bone specific alkaline phosphatase) were
drawn at baseline and Weeks 4, 12 and 24 in the same subsets.

Although the differences were not statistically significant, the 300 mcg
group increased lumbar BMD slightly from baseline to Week 24 (0.52%),
while the placebo group decreased slightly from baseline (-0.11%) in
Study 068. In Study 092, the difference in the change from baseline
between testosterone and placebo subjects was statistically significant.
Testosterone subjects showed a 0.5% increase in lumbar BMD at Week 24,
compared to a 0.9% decrease seen in the placebo subjects.

In Study 068, the only statistically significant difference in markers
of bone turnover between subjects receiving placebo and those taking 300
mcg testosterone was on serum N-telopeptide, a marker of bone
resorption. Testosterone subjects showed a 10.1% decrease from baseline
in this marker, while placebo subjects decreased by 5.7%. There were no
statistically significant differences between placebo and testosterone
groups in any bone markers in Study 092.

Division comment:

-   The effect of testosterone on bone mineral density appears to be
    neutral to slightly favorable.

#### Vascular Pulsatility Study

A second 120-subject subgroup (Subgroup 2) from Study 068 and a
9-subject subset (Subset 2) from Study 092 were used for the measurement
of the vascular pulsatility index by Doppler ultrasound of internal
carotid artery blood flow. This was conducted at baseline and Week 24.
Measurements were reported for right and left internal carotids, for the
average of the two and for the worst (most increased from baseline)
index for the two arteries. There were no significant changes from
baseline seen in the vascular pulsatility index in the 300 mcg
testosterone group vs. the placebo group in Study 068. Due to the small
number of subjects (9) from Study 092, their data were not analyzed.

Division comment:

-   The effect of testosterone on vascular reactivity and impedance to
    blood flow appears minimal in this small exploratory analysis.

#### Platelet Aggregation

Subgroup 2 from Study 068 and Subset 2 from Study 092 were also used for
platelet aggregation tests, done at baseline and Week 24. Subjects were
instructed to avoid aspirin for seven days prior to this test. No
statistically significant changes or percent changes from baseline were
seen in platelet aggregation in the 300 mcg testosterone group vs. the
placebo group in Study 068. Due to the small number of subjects from
Study 092, their data were not analyzed.

#### Total Body Composition

In Studies 068 and 092, a dual energy x-ray absorptiometry evaluation
for total body composition (lean body mass and fat content) was
conducted in Subgroup 1 and Subset 1 at baseline and Weeks 12 and 24. No
statistically significant changes or percent changes from baseline were
seen in total lean body mass, percent total body fat, trunk fat or trunk
lean body mass in the 300 mcg testosterone group vs. the placebo group
in Study 068. In Study 092, total lean body mass increased from baseline
by 865 gm (2.4%) in the TTS group, as compared to a 226 gm (0.7%)
increase in the placebo group; this difference was statistically
significant. There were no significant differences in other parameters
measured.

#### Local Tolerance

Local tolerance was evaluated in three phase 2 studies (T96002, 1999098
and T96001), which were designed to evaluate the incidence of contact
sensitization and dermal irritation following repetitive applications
over three weeks of active and placebo patches. Study T96002 found no
evidence of contact sensitization to either the active or the placebo
patch. Study 1999098 used 5 cm^2^ patches cut from 14 cm^2^ and 18 cm^2^
patches delivering 150 mcg of testosterone per day, smaller than that
used in the phase 3 trials. This cumulative irritation study found that
these smaller patches showed evidence of irritation ranging from " a
slight potential for very mild cumulative irritation" for samples cut
from the 14 cm^2^ patch to "a moderate potential for mild cumulative
irritation" for the samples cut from the 18 cm^2^ patch. Study T96001,
which also used 5 cm^2^ patch samples, found that the testosterone patch
was a "probably mild" irritant in normal use, and was not a cumulative
skin irritant.

Division comment:

-   These data appear to be borne out in the phase 3 trials, where the
    incidence of application site reactions was greatest upon initial
    exposure, and did not appear to increase with cumulative exposure to
    the patch (see Table 44).

## Summary of Overall Safety 

One overarching concern in evaluating the safety of the proposed
testosterone patch for use in surgically menopausal women is that the
proposed labeled indication is for use in women "receiving concomitant
estrogen therapy." Risks associated with use of estrogen alone in
surgically menopausal women, as documented in the WHI study, include
increased incidence of nonfatal stroke and deep vein thrombosis. While
there appears to be a reduction in hip and vertebral fracture risk in
estrogen users, estrogen alone has a neutral effect on the incidence of
coronary heart disease, breast and colorectal cancer, and death.

Current black box warnings on estrogen and combined estrogen/progestin
products used for treatment of vasomotor symptoms and vulvovaginal
atrophy associated with menopause state that these products "should be
prescribed at the lowest effective doses and for the shortest duration
consistent with treatment goals and risks for the individual woman." The
American College of Obstetrics and Gynecology[^3] recommends that women
review their decision to use hormonal products annually with their
physician. However, Intrinsa is a product that will potentially be used
on a chronic, long-term basis, and thus, might induce women to continue
use of estrogen well beyond the duration that would be recommended for
management of menopausal symptoms.

### Special Concerns

Areas of special concern regarding the use of testosterone in surgically
menopausal women include the unknown risks of cardiovascular disease and
breast malignancy potentially arising from chronic use of this hormone.

### Unknown Risks

The primary trials reviewed enrolled surgically menopausal women, who
had had a hysterectomy and bilateral salpingo-oophorectomy prior to
enrollment. Thus, in this population, there is no concern about
potential effects of testosterone on the endometrium. The product
however, has the potential for off-label use, either in naturally
menopausal women or even in pre- and perimenopausal women with intact
uteri, who may be at risk for endometrial hyperplasia, cancer and
pregnancy.

The proposed label notes the potential for edema as a serious
complication of high doses of testosterone administered to women with
preexisting cardiac, renal or hepatic dysfunction. The current trials
were conducted in generally healthy women, with a mean age of 49;
therefore the potential for this adverse event arising from use of
Intrinsa has not been evaluated.

The major areas of unknown risk, however, concern the long-term impact
of chronic use of testosterone, especially when combined with estrogen
treatment. While the short-term effects of testosterone treatment appear
relatively benign and easy to monitor, long-term effects cannot be
appreciated from the clinical trial data available to date. The alarm
generated by the publication of the WHI results following decades of
widespread use of estrogen/progestin therapy highlights the need for
proactive assessment of the risks of chronic use of testosterone in
women.

# Pharmacovigilance Program

The Applicant has proposed a Pharmacovigilance plan utilizing a
pharmaceutical claims-based database. The proposed plan is detailed
below.

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Division comment:

-   The Office of Drug Safety (ODS) was asked to provide consultation on
    the potential utility of this pharmacovigilance plan. They concluded
    that the proposed retrospective cohort study was unlikely to provide
    adequate information about potential risks of the product and
    recommended that a prospective, long-term randomized, controlled
    study of sufficient power, which incorporates prespecified endpoints
    of particular concern, would be most likely to provide meaningful
    answers about the long-term risks of treatment with TTS (Intrinsa).
    Specific comments from the ODS epidemiologist regarding the
    Applicant's proposed pharmacovigilance study included a concern that
    drug use and hospitalizations might cease to be captured by the
    proposed pharmacovigilance study when postmenopausal women treated
    with TTS shifted to Medicare as their primary health insurer at
    age 65. The ODS epidemiologist also had concerns that the sample
    size and duration of the proposed study might not provide adequate
    power to detect an increase over the background rate of potential
    adverse events of interest in women of the age group for whom TTS
    would be indicated.

[^1]: The Women's Health Initiative Steering Committee, Effects of
    Conjugated Equine Estrogen in Postmenopausal Women with
    Hysterectomy, [JAMA]{.underline}, 291: 1701-12, 2004

[^2]: Writing Group for the Women's Health Initiative Investigators,
    Risks and Benefits of Estrogen plus Progestin in Healthy Menopausal
    Women, [JAMA]{.underline}, 288: 321-33, 2002

[^3]: ACOG Task Force on Hormone Therapy, Hormone Therapy -- Vasomotor
    Symptoms, [Obstet & Gynecol]{.underline}, 104 (4S): 106S-117S, 2004