Estrogens, conjugated

PREMARIN is a mixture of estrogens indicated for: • Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause. • Treatment of Moderate to Severe Vulvar and Vaginal Atrophy due to Menopause. • Treatment of Hypoestrogenism due to Hypogonadism, Castration or Primary Ovarian Failure. • Treatment of Breast Cancer (for Palliation Only) in Appropriately Selected Women and Men with Metastatic Disease. • Treatment of Advanced Androgen-Dependent Carcinoma of the Prostate (for Palliation Only). • Prevention of Postmenopausal Osteoporosis

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 in the peripheral tissues. Thus, estrone and the sulfate-conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.

Generally, when estrogen therapy is prescribed for a postmenopausal woman with a uterus, a progestin should be considered to reduce the risk of endometrial cancer. A woman without a uterus does not need progestin. In some cases, however, hysterectomized women with a history of endometriosis may need a progestin. Use of estrogen-alone, or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary. PREMARIN may be taken without regard to meals. • Daily administration of 0.3, 0.45, 0.625, 0.9, and 1.25 mg. • Cyclic administration of 0.3, 0.625, and 1.25 mg

PREMARIN therapy is contraindicated in individuals with any of the following conditions: • Undiagnosed abnormal genital bleeding • Breast cancer or a history of breast cancer except in appropriately selected patients being treated for metastatic disease • Estrogen-dependent neoplasia • Active DVT, PE, or a history of these conditions • Active arterial thromboembolic disease (for example stroke and MI), or a history of these conditions • Known anaphylactic reaction or angioedema with PREMARIN • Hepatic impairment or disease • Protein C, protein S or antithrombin deficiency, or other known thrombophilic disorders. • Undiagnosed abnormal genital bleeding.

Boxed warning: Estrogen-Alone Therapy • There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. • Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia. • Women's Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT). • Estrogens increase the risk of gallbladder disease. • Discontinue estrogen if severe hypercalcemia, loss of vision, severe hypertriglyceridemia or cholestatic jaundice occurs. • Monitor thyroid function in patients on thyroid replacement therapy

The following serious adverse reactions are discussed elsewhere in labeling: • Cardiovascular Disorders • Malignant Neoplasms Most common adverse reactions (≥5%) are: abdominal pain, asthenia, pain, back pain, headache, flatulence, nausea, depression, insomnia, breast pain, endometrial hyperplasia, leucorrhea, vaginal hemorrhage, and vaginitis.

Data from a single-dose drug-drug interaction study involving CE and MPA indicate that the pharmacokinetic disposition of both drugs is not altered when the drugs are coadministered. No other clinical drug-drug interaction studies have been conducted with CE. Inducers and/or inhibitors of CYP3A4 may affect estrogen drug metabolism

Store at 20° to 25°C (68° to 77°F), excursions permitted to 15° to 30°C (59° to 86°F).