Intrarosa: Package Insert and Label Information

INTRAROSA- prasterone insert
Millicent US, Inc.

1 INDICATIONS AND USAGE

INTRAROSA ® is a steroid indicated for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy, due to menopause.

2 DOSAGE AND ADMINISTRATION

Administer one INTRAROSA vaginal insert once daily at bedtime, using the provided applicator.

3 DOSAGE FORMS AND STRENGTHS

Vaginal insert: 6.5 mg of prasterone, smooth, white to off-white solid fat bullet-shaped, measuring 28 mm in length, 9 mm in width at its wider end, and weighing 1.2 gram.

4 CONTRAINDICATIONS

Undiagnosed abnormal genital bleeding: Any postmenopausal woman with undiagnosed, persistent or recurring genital bleeding should be evaluated to determine the cause of the bleeding before consideration of treatment with INTRAROSA.

5 WARNINGS AND PRECAUTIONS

5.1 Current or Past History of Breast Cancer

Estrogen is a metabolite of prasterone. Use of exogenous estrogen is contraindicated in women with a known or suspected history of breast cancer. INTRAROSA has not been studied in women with a history of breast cancer.

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In four (4) placebo-controlled, 12-week clinical trials [91% — White Caucasian non-Hispanic women, 7% — Black or African American women, and 2% — “Other” women, average age 58.8 years of age (range 40 to 80 years of age)], vaginal discharge is the most frequently reported treatment-emergent adverse reaction in the INTRAROSA treatment group with an incidence of ≥ 2 percent and greater than reported in the placebo treatment group. There were 38 cases in 665 participating postmenopausal women (5.71 percent) in the INTRAROSA treatment group compared to 17 cases in 464 participating postmenopausal women (3.66 percent) in the placebo treatment group.

In a 52-week non-comparative clinical trial [92% — White Caucasian non-Hispanic women, 6% — Black or African American women, and 2% — “Other” women, average age 57.9 years of age (range 43 to 75 years of age)], vaginal discharge and abnormal Pap smear at 52 weeks were the most frequently reported treatment-emergent adverse reaction in women receiving INTRAROSA with an incidence of ≥ 2 percent. There were 74 cases of vaginal discharge (14.2 percent) and 11 cases of abnormal Pap smear (2.1 percent) in 521 participating postmenopausal women. The eleven (11) cases of abnormal Pap smear at 52 weeks include one (1) case of low-grade squamous intraepithelial lesion (LSIL), and ten (10) cases of atypical cells of undetermined significance (ASCUS).

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

INTRAROSA is indicated only in postmenopausal women. There are no data with INTRAROSA use in pregnant women regarding any drug-associated risks. Animal reproduction studies have not been conducted with prasterone.

8.2 Lactation

Risk Summary

INTRAROSA is indicated only in postmenopausal women. There is no information on the presence of prasterone in human milk, the effects on the breastfed infant, or the effects on milk production.

8.4 Pediatric Use

Safety and effectiveness have not been established in pediatric patients.

8.5 Geriatric Use

Of the 1522 prasterone-treated postmenopausal women enrolled in the four placebo-controlled 12-week and one open-label 52-week clinical trial, 19 and 11 percent, respectively, were 65 years of age or older.

8.6 Renal Impairment

The effect of renal impairment on the pharmacokinetics of prasterone has not been studied.

8.7 Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of prasterone has not been studied.

11 DESCRIPTION

INTRAROSA (prasterone) vaginal insert is a vaginally administered steroid. Prasterone is identified chemically as 3β-hydroxyandrost-5-en-17-one. It has the empirical formula C 19 H 28 O 2 with a molecular weight of 288.424 g/mol. Prasterone is a white to off-white crystalline powder insoluble in water and soluble in sodium lauryl sulfate (SLS). The structural formula is:

Prasterone
(click image for full-size original)

Each INTRAROSA (prasterone) vaginal insert contains 6.5 mg of prasterone in 1.3 ml of off-white hard fat (Witepsol).

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Prasterone is an inactive endogenous steroid and is converted into active androgens and/or estrogens. The mechanism of action of INTRAROSA in postmenopausal women with vulvar and vaginal atrophy is not fully established.

12.3 Pharmacokinetics

In a study conducted in postmenopausal women, administration of the INTRAROSA vaginal insert once daily for 7 days resulted in a mean prasterone C max and area under the curve from 0 to 24 hours (AUC 0-24 ) at Day 7 of 4.4 ng/mL and 56.2 ng·h/mL, respectively, which were significantly higher than those in the group treated with placebo (Table 1). The C max and AUC 0-24 of the metabolites testosterone and estradiol were also slightly higher in women treated with the INTRAROSA vaginal insert compared to those receiving placebo.

Table 1. C max and AUC 0-24 of Prasterone, Testosterone, and Estradiol on Day 7 Following Daily Administration of Placebo or INTRAROSA (mean ± SD).
1: N=8
Placebo (N=9) INTRAROSA (N=10)
Prasterone C max (ng/mL) 1.60 (±0.95)4.42 (±1.49)
AUC 0-24 (ng·h/mL) 24.82 (±14.31)56.17 (±28.27)
Testosterone C max (ng/mL) 0.12 (±0.04) 1 0.15 (±0.05)
AUC 0-24 (ng·h/mL) 2.58 (±0.94) 1 2.79 (±0.94)
Estradiol C max (pg/mL) 3.33 (±1.31)5.04 (±2.68)
AUC 0-24 (pg·h/mL) 66.49 (±20.70)96.93 (±52.06)

Figure 1. Serum Concentrations of Prasterone (A), Testosterone (B), and Estradiol (C) Measured Over a 24h Period on Day 7 Following Daily Administration of Placebo or INTRAROSA (mean ± SD).

Figure 1
(click image for full-size original)

In two primary efficacy trials, daily administration of INTRAROSA vaginal insert for 12 weeks increased mean serum C trough of prasterone and its metabolites testosterone and estradiol by 47%, 21% and 19% from baseline, respectively. This comparison based on C trough may underestimate the magnitude of increase in prasterone and metabolites’ exposure because it does not take into account the overall concentration-time profile following administration of INTRAROSA.

Metabolism

Exogenous prasterone is metabolized in the same manner as endogenous prasterone. Human steroidogenic enzymes such as hydroxysteroid dehydrogenases, 5α-reductases and aromatases transform prasterone into androgens and estrogens.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term studies in animals to evaluate carcinogenic potential have not been conducted with prasterone. Two metabolites of prasterone, testosterone and estradiol, are carcinogenic in animals.

Mutagenesis

Prasterone was not genotoxic in the in vitro bacterial mutagenesis assay (Ames test), the in vitro chromosomal aberrations assay with human peripheral blood lymphocytes, and in vivo in the mouse bone marrow micronucleus assay.

Fertility

Fertility studies were not conducted with prasterone.

14 CLINICAL STUDIES

The effectiveness of INTRAROSA on moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy, due to menopause was examined in two primary 12-week placebo-controlled efficacy trials.

The first clinical trial (Trial 1) was a 12-week randomized, double-blind and placebo-controlled trial that enrolled 255 generally healthy postmenopausal women between 40 to 75 years of age (mean 58.6 years) who, at baseline, identified moderate to severe dyspareunia as their most bothersome symptom of vulvar and vaginal atrophy. In addition to moderate to severe dyspareunia, women had ≤ 5% superficial cells on vaginal smear and a vaginal pH > 5. Women were randomized in a 1:1:1 ratio between three treatment groups who received daily INTRAROSA (n=87), one active comparator vaginal insert (n=87), or placebo (n=81). All women were assessed for improvement from Baseline to Week 12 for four co-primary efficacy endpoints: most bothersome moderate to severe symptom of dyspareunia, the percentage of vaginal superficial cells, the percentage of parabasal cells, and vaginal pH.

The second clinical trial (Trial 2) was a 12-week randomized, double-blind and placebo-controlled trial that enrolled 558 generally healthy postmenopausal women between 40 to 80 years of age (mean 59.5 years) who, at baseline, had identified moderate to severe dyspareunia as their most bothersome symptom of vulvar and vaginal atrophy. In addition to dyspareunia, women had ≤ 5% superficial cells on vaginal smear and a vaginal pH > 5. Women were randomized in a 2:1 ratio to receive once daily vaginal insert containing 6.5 mg INTRAROSA (n=376) or placebo (n=182). The primary endpoints and study conduct were the same or similar to those in Trial 1.

The primary efficacy results obtained in the Intent-to-Treat (ITT) population in Trial 1 are shown in Table 2.

Table 2: Efficacy Summary in Primary 12-Week Trial 1: ITT Population (LOCF)

1 Difference from placebo =INTRAROSA (Week 12 mean – Baseline mean) – Placebo (Week 12 mean – Baseline mean).
2 ANCOVA: Treatment as the main factor and Baseline value as the covariate.

Placebo

N = 77

INTRAROSA

N = 81

Dyspareunia

Baseline Mean Severity

Week 12 Mean Severity

Mean Change in Severity (SD)

Difference from Placebo 1

p-value 2

2.58

1.71

-0.87 (0.95)

2.63

1.36

-1.27 (0.99)

-0.40

0.0132

% Superficial Cells

Baseline Mean

Week 12 Mean

Mean Change (SD)

Difference from Placebo 1

p-value 2

0.73

1.64

0.91 (2.69)

0.68

6.30

5.62 (5.49)

4.71

<0.0001

% Parabasal Cells

Baseline Mean

Week 12 Mean

Mean Change (SD)

Difference from Placebo 1

p-value 2

68.48

66.86

-1.62 (28.22)

65.05

17.65

-47.40 (42.50)

-45.77

<0.0001

Vaginal pH

Baseline Mean

Week 12 Mean

Mean Change (SD)

Difference from Placebo 1

p-value 2

6.51

6.31

-0.21 (0.69)

6.47

5.43

-1.04 (1.00)

-0.83

<0.0001

The primary efficacy results obtained in the Intent-to-Treat (ITT) population in Trial 2 are shown in Table 3.

Table 3: Efficacy Summary in Primary 12-Week Trial 2: ITT Population (LOCF)

1 Difference from placebo =INTRAROSA (Week 12 mean – Baseline mean) – Placebo (Week 12 mean – Baseline mean).
2 ANCOVA: Treatment as the main factor and Baseline value as the covariate.

Placebo

N = 157

INTRAROSA

N = 325

Dyspareunia

Baseline Mean Severity

Week 12 Mean Severity

Mean Change in Severity (SD)

Difference from Placebo 1

p-value 2

2.56

1.50

-1.06 (1.02)

2.54

1.13

-1.42 (1.00)

-0.35

0.0002

% Superficial Cells

Baseline Mean

Week 12 Mean

Mean Change (SD)

Difference from Placebo 1

p-value 2

1.04

2.78

1.75 (3.33)

1.02

11.22

10.20 (10.35)

8.46

<0.0001

% Parabasal Cells

Baseline Mean

Week 12 Mean

Mean Change (SD)

Difference from Placebo 1

p-value 2

51.66

39.68

-11.98 (29.58)

54.25

12.74

-41.51 (36.26)

-29.53

<0.0001

Vaginal pH

Baseline Mean

Week 12 Mean

Mean Change (SD)

Difference from Placebo 1

p-value 2

6.32

6.05

-0.27 (0.74)

6.34

5.39

-0.94 (0.94)

-0.67

<0.0001

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