Pharmaceutical Approval Update: Estradiol Gel 0.1% (Divigel)

Posted by James

Manufacturer: Upsher-Smith Laboratories, Inc., Maple Grove, MN

Indication: Estradiol gel 0.1% is indicated for the treatment of moderate-to-severe hot flashes associated with menopause.

Drug Class: The clear, colorless topical gel is odorless when dry. It is designed to deliver sustained circulating concentrations of estradiol when applied once daily to the skin. The gel is applied to a small area (200 cm²) of the thigh in a thin, quick-drying layer. The active component of the gel is estra-diol, chemically defined as estra-1,3,5(10)-triene-3,17f>-diol.

Uniqueness of Product: Estradiol, the major estrogenic hormone secreted by the human ovary, is delivered to the systemic circulation after topical application. The gel offers the lowest approved dose of estradiol available for women with menopausal vasomotor symptoms.

Boxed Warning: Estrogens increase the risk of endome-trial cancer. Close clinical surveillance of all women taking estrogens is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of “natural” estrogens results in a different endometrial risk profile than synthetic estrogens at equivalent estrogen doses.
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Cardiovascular and Other Risks. Estrogens with or without progestins should not be used to prevent cardiovascular disease or dementia. The estrogen-alone substudy of the Women’s Health Initiative (WHI) reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women 50 to 79 years of age during 6.8 years and 7.1 years, respectively, who used oral conjugated estrogens 0.625 mg alone per day, compared with placebo. Conjugated estrogens are derived from the urine of pregnant mares.

The estrogen-plus-progestin substudy of the WHI reported an increased risk of myocardial infarction (MI), stroke, invasive breast cancer, pulmonary emboli, and DVT in post-menopausal women during 5.6 years of treatment with oral conjugated estrogens 0.625 mg combined with medroxypro-gesterone acetate (MPA) 2.5 mg/day, compared with placebo.

The Women’s Health Initiative Memory Study (WHIMS), a substudy of the WHI, reported an increased risk of probable dementia in postmenopausal women 65 years of age or older during 5.2 years of treatment with conjugated estrogens 0.625 mg alone and during four years of taking conjugated estrogens 0.625 mg plus MPA 2.5 mg, compared with placebo. It is unknown whether this finding applies to younger post-menopausal women.

Other doses of oral conjugated estrogens with MPA and other combinations and dosage forms of estrogens and pro-gestins were not studied in the WHI clinical trials. In the absence of comparable data, these risks should be assumed to be similar. Because of these risks, estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration.

Warnings:

Cardiovascular Disorders. Estrogen-alone therapy has been associated with an increased risk of stroke and DVT. Estrogen-plus progestin therapy is associated with an increased risk of MI as well as stroke, venous thrombosis, and pulmonary embolism. If any of these occur or are suspected, estrogens should be discontinued immediately. Risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) or venous thromboembolism (VTE) (e.g., a personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately. online pharmacy prescription drugs

Stroke. In the estrogen-alone substudy, a statistically significant increased risk of stroke was observed with conjugated estrogens 0.625 mg daily (44 per 10,000 women-years), compared with placebo (32 per 10,000 women-years). The increased risk was observed in the first year and persisted.

In the estrogen-plus-progestin substudy, a statistically significant increased risk of stroke was reported with the same regimen, compared with placebo (31 vs. 24 per 10,000 women-years). The increase in risk was noted after the first year and persisted.

Coronary Heart Disease. In the estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (nonfatal MI, silent MI, or death from CHD) was reported in women receiving estrogen alone compared with those receiving placebo.

In the estrogen-plus-progestin substudy, no statistically significant increase of CHD events was reported with conjugated estrogens plus MPA, compared with placebo (39 vs. 33 per 10,000 women-years). An increase in relative risk was demonstrated in the first year and a trend of decreasing relative risk was reported in years two through five. cialis canadian pharmacy

In 2,763 postmenopausal women with documented heart disease (average age, 66.7 years), the Heart and Estrogen/ Progestin Replacement Study (HERS) demonstrated no cardiovascular benefit after treatment with conjugated estrogens 0.625 mg/day plus MPA 2.5 mg/day.

During an average follow-up of 4.1 years, this treatment did not reduce the overall rate of CHD events in postmenopausal women with established CHD. There were more CHD events in the hormone-treated group than in the placebo group in the first year but not during the subsequent years. In an open-label extension of the original HERS trial (HERS II), 2,321 women agreed to participate. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable between the hormone and placebo groups in HERS, HERS II, and overall.

In a large prospective clinical trial in men, large doses of conjugated estrogens at 5 mg/day, comparable to doses used to treat cancer of the prostate and breast, increased the risks of nonfatal MI, pulmonary embolism, and thrombophlebitis.