ESTROGEL � estradiol gel, metered
ASCEND Therapeutics, Inc.
Rx only
5000718-1137
E01306 ARev2 01/2008
WARNINGS
ENDOMETRIAL CANCER
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. (See WARNINGS, Malignant neoplasms, Endometrial cancer.)
CARDIOVASCULAR AND OTHER RISKS
Estrogens with or without progestins should not be used for the prevention of cardiovascular disease or dementia. (See CLINICAL STUDIES and WARNINGS, Cardiovascular disorders and Dementia.)
The Women�s Health Initiative (WHI) estrogen alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50-79 years of age) during 6.8 and 7.1 years, respectively, of treatment with daily oral conjugated estrogens (CE 0.625 mg), relative to placebo. (See CLINICAL STUDIES and WARNINGS, Cardiovascular disorders.)
The estrogen plus progestin WHI substudy reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and DVT in postmenopausal women (50-79 years of age) during 5.6 years of treatment with daily oral CE 0.625 mg combined with medroxyprogesterone acetate (MPA 2.5 mg), relative to placebo. (See CLINICAL STUDIES and WARNINGS, Cardiovascular disorders and Malignant neoplasms, Breast cancer.)
The Women�s Health Initiative Memory Study (WHIMS), a substudy of WHI, reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years of treatment with daily CE 0.625 mg alone and during 4 years of treatment with daily CE 0.625 mg combined with MPA 2.5 mg, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. (See CLINICAL STUDIES and WARNINGS, Dementia, and PRECAUTIONS, Geriatric Use.)
In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA and other combinations and dosage forms of estrogens and progestins. Because of these risks, estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.
DESCRIPTION
EstroGel� (estradiol gel) contains 0.06% estradiol in an absorptive hydroalcoholic gel base formulated to provide a controlled release of the active ingredient. It is a clear, colorless gel, which is odorless when dry. The gel is applied over a large area (750 cm2) of the skin in a thin layer. The recommended area of application is the arm, from wrist to shoulder. An EstroGel unit dose of 1.25 g contains 0.75 mg of estradiol.
Estradiol is a white crystalline powder, chemically described as estra-1,3,5(10)-triene-3,17?-diol. It has an empirical formula of C18 H24 O2 and molecular weight of 272.39. The structural formula is:
Estradiol Structural Formula
The active component of the transdermal gel is estradiol. The remaining components of the gel (purified water, alcohol, triethanolamine and carbomer 934P) are pharmacologically inactive.
CLINICAL PHARMACOLOGY
EstroGel provides systemic estrogen replacement therapy by releasing estradiol, the major estrogenic hormone secreted by the human ovary.
Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level.
The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate-conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.
Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue.
Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) through a negative feedback mechanism. Estrogens act to reduce elevated levels of these hormones seen in postmenopausal women.
