Estrogens, conjugated and Medroxyprogesterone

PREMPRO/PREMPHASE is an estrogen plus progestin indicated in a woman with a uterus for: • Treatment of Moderate to Severe Vasomotor Symptoms due to Menopause. • Treatment of Moderate to Severe Vulvar and Vaginal Atrophy due to Menopause. • 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, which is 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.

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. PREMPRO: one tablet containing conjugated estrogens (CE) plus medroxyprogesterone acetate (MPA) taken orally once daily. PREMPHASE: one maroon tablet containing 0.625 mg CE taken orally on days 1 through 14, and one light-blue tablet containing 0.625 mg CE plus 5.0 mg MPA taken orally on days 15 through 28.

PREMPRO and PREMPHASE are contraindicated in women with any of the following conditions: • Undiagnosed abnormal genital bleeding • Breast cancer or a history of breast cancer • 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 PREMPRO/PREMPHASE • Hepatic impairment or disease • Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders • Undiagnosed abnormal genital bleeding. • Breast cancer or history of breast cancer. • Estrogen-dependent neoplasia.

Boxed warning (cardiovascular disorders, breast cancer, endometrial cancer and probable dementia): Estrogen Plus Progestin Therapy Cardiovascular Disorders and Probable Dementia Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia. • 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 women on thyroid replacement therapy

The following serious adverse reactions are discussed elsewhere in the labeling: • Cardiovascular Disorders • Malignant Neoplasms In two prospective, randomized clinical studies, the most common adverse reactions >5% are abdominal pain, asthenia, back pain, headache, flatulence, nausea, depression, pruritus, breast pain, dysmenorrhea, and leukorrhea.

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 plus MPA. • Inducers and/or inhibitors of CYP3A4 may affect estrogen drug metabolism. • Aminoglutethimide administered concomitantly with MPA may significantly depress the bioavailability of medroxyprogesterone acetate

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