Ethinyl estradiol and Norethindrone

Norethindrone acetate and ethinyl estradiol tablets are a combination of an estrogen and progestin indicated in a woman with a uterus for: • Treatment of Moderate to Severe Vasomotor Symptoms 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 estrogen, alone or in combination with a progestogen, at the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Re-evaluate postmenopausal women periodically as clinically appropriate to determine whether treatment is still necessary. • One tablet orally once daily

Norethindrone acetate and ethinyl estradiol tablets 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, angioedema, or hypersensitivity to norethindrone acetate and ethinyl estradiol tablets. • Hepatic impairment or disease. • Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders. • Undiagnosed abnormal genital bleeding.

Boxed warning (cardiovascular disorders, probable dementia, breast cancer, and endometrial cancer): Estrogen Plus Progestin Therapy Cardiovascular Disorders and Probable Dementia The Women’s Health Initiative (WHI) estrogen plus progestin substudy reported increased risks of pulmonary embolism (PE), deep vein thrombosis (DVT), stroke, and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg] combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo. • 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. Most common adverse reactions with norethindrone acetate and ethinyl estradiol tablets (incidence greater than or equal to 5 percent) are: headache, abdominal pain, breast pain, and edema (generalized).

In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen and progestin drug metabolism. Inducers of CYP3A4 such as St. John’s wort (Hypericum perforatum) preparations, phenobarbital, carbamazepine and rifampin may decrease the plasma concentration of estrogens and progestins, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase the plasma concentration of the estrogen or the progestin or both and may result in adverse reactions. Co-administration of atorvastatin and certain hormonal products containing ethinyl estradiol increase AUC values for ethinyl estradiol approximately 20 percent.

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