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Drug Monograph

DHEA Vaginal Cream

DESCRIPTION

DHEA Vaginal Cream is a vaginally administered steroid.

HOW SUPPLIED

DHEA vaginal cream is compounded in a hypoallergenic cream base in the following strengths.

DHEA Vaginal Cream 2.5mg/ml, 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 vaginal 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 of 4.4 ng/mL and mean DHEA AUC of 56.2 ng/mL, 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 al 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% DHEA vaginal dose 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, Bouchard 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% 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 is a steroid which has been studied for the treatment of moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy, due to menopause.

Studies involving DHEA have shown increases in sexual desire, sexual arousal, sexual lubrication, orgasm, and vaginal dryness.

DOSAGE AND ADMINISTRATION

Administer 1 gram intravaginally daily at bedtime.

STORAGE

May be stored at room temperature or refrigerated; 41-86oF (5-30oC).

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 placebo-controlled, 12-week clinical trials, 665 women ages ranging from 40 to 80 years, vaginal discharge was the most frequently reported emergent adverse reaction in the DHEA Suppository treatment group with an incidence of 5.71% compared to 3.66% in the placebo group.

In a 52-week non-comparative clinical trial, women ages ranging from 43 to 75 years, vaginal discharge and abnormal Pap smear were the most frequently reported treatment-emergent adverse reaction in women receiving DHEA suppositories with an incidence of ≥ 2%. There were 74 cases of vaginal discharge (14.2%) and 11 cases of abnormal Pap smear (2.1%) in 521 participating postmenopausal women.

USE IN SPECIFIC POPULATIONS
Pregnancy and Lactation

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

The effect of renal and 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.

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