Drug Monograph

DHEA Vaginal Cream

DESCRIPTION

DHEA Vaginal Cream is a vaginally administered steroid.

HOW SUPPLIED

DHEA vaginal cream is available in a hypoallergenic base in following strengths:

  • 5mg/ml
  • 10mg/ml
CLINICAL PHARMACOLOGY

DHEA (Dehydroepiandosterone) is a naturally occurring steroid produced by the adrenal glands. It is a precursor of steroid hormones like testosterone and estradiol. DHEA has weak androgenic activity, weak estrogenic activity and neurosteroid activity, and acts as a prohormone of androgens and estrogens depending on its dosage and route of administration. Levels of these steroids decrease throughout life and are 70-80% lower in the elderly relative to levels in young adults.

As a medication, DHEA may be used to restore or increase DHEA levels in deficiency or old age, for menopausal women as a weak androgen or to treat virginal atrophy and sexual dysfunction, and, in its sulfate form, for cervical dilation during childbirth.

PHARMACOKINETICS

In a study conducted in postmenopausal women, administration of the DHEA vaginal suppository once daily for 7 days resulted in a mean DHEA Cmax and area under the curve from 0 to 24 hours (AUC0-24) 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. The Cmax and AUC0-24 of the metabolites testosterone and estradiol were also slightly higher in women treated with the DHEA vaginal suppository compared to those receiving placebo.

In two primary efficacy trials, daily administration of DHEA vaginal suppositories for 12 weeks increased mean serum Ctrough of DHEA and its metabolites testosterone and estradiol by 47%, 21% and 19% from baseline, respectively.

This comparison based on Ctrough may underestimate the magnitude of increase in DHEA and metabolites’ exposure because it does not take into account the overall concentration-time profile following administration of DHEA Vaginal Suppositories.

CLINICAL STUDIES

In 2009, Labrie et al1 conducted a randomized, double-blind, and placebo-controlled phase III clinical trial which was published in the journal Menopause. The study included 216 participants. Inclusion criteria included post-menopausal women between the ages of 40 and 75 years of age who were experiencing either vaginal dryness, vaginal or vulvar irritation, or dyspareunia.

After 12 weeks of the study, the group administered a 1% (13mg) DHEA vaginal ovule nightly at bedtime showed a 49% improvement in sexual desire according to the MENQOL questionnaire and a 23% improvement in sexual desire according to the ASF questionnaire. The 1% DHEA group showed an improvement in sexual arousal by 68%, sexual lubrication by 39 %, ability to achieve orgasm by 75%, and vaginal dryness by 57 % according to the ASF questionnaire when compared to the placebo.

Another Phase III, open-label study published in the Journal of Hormone Molecular Biology and Clinical Investigations, Bouchard2 took a closer look at the use of intravaginal DHEA as a treatment for sexual function. The study took place over the course of a year, and 154 post-menopausal women with vaginal atrophy were administered intravaginal 0.5% (6.5mg) DHEA on a daily basis.

When the study concluded, the women showed marked improvements in multiple parameters of sexual function examined by the questionnaire, including increased desire by 28%, arousal by 49%, lubrication by 115%, ability to orgasm by 51%, satisfaction by 41% and improvements in pain by 108%.

In both studies, the application of intravaginal DHEA demonstrated benefits for the sexual function of post-menopausal women. At the doses of DHEA 0.5% and 1%, the levels of DHEA metabolites, estradiol and testosterone, in the serum remained well within safe limits.

INDICATIONS AND USAGE

DHEA has been studied for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy, due to menopause.1,2

Clinical studies indicate that DHEA has been shown to increase sexual desire, sexual arousal, sexual lubrication, orgasm, and vaginal dryness when treating women suffering from severe dyspareunia.1,2

DOSAGE AND ADMINISTRATION

Administer 5-10mg DHEA vaginal cream daily at bedtime.

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 DHEA.

WARNINGS AND PRECAUTIONS

Current or Past History of Breast Cancer. Estrogen is a metabolite of DHEA. Use of exogenous estrogen is contraindicated in women with a known or suspected history of breast cancer. DHEA Suppositories have not been studied in women with a history of breast cancer.

ADVERSE REACTIONS

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 DHEA Suppository 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 DHEA suppository 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 DHEA suppositories 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).

USE IN SPECIFIC POPULATION
Pregnancy

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

Lactation

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

Pediatric Use

Safety and effectiveness have not been established in pediatric patients.

Geriatric Use

Of the 1522 DHEA-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.

Renal Impairment

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

Hepatic Impairment

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

NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis. Long-term studies in animals to evaluate carcinogenic potential have not been conducted with DHEA.

Mutagenesis. DHEA 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 DHEA.

REFERENCES
  1. Labrie F, Archer D, Bouchard C, Fortier M, Cusan L, Gomez JL, Girard G, Baron M, Ayotte N, Moreau M, Dube R, Cote I, Labrie C, Lavoie L, Berger L, Gilbert L, Martel C, Balser J. Effect of intravaginal dehydroepiandrosterone (Prasterone) on libido and sexual dysfunction in postmenopausal women. Menopause. 2009 Sep-Oct;16(5):923-31.
  2. Bouchard C, Labrie F, Derogatis L, Girard G, Ayotte N, Gallagher J, Cusan L, Archer DF, Portman D, Lavoie L, Beauregard A, Cote I, Martel C, Vaillancourt M, Balser J, Moyneur E; VVA Prasterone Group.. Effect of intravaginal dehydroepiandrosterone (DHEA) on the female sexual function in postmenopausal women: ERC-230 open-label study. Horm Mol Biol Clin Investig. 2016 Mar;25(3):181-90.
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