Bazedoxifene and Estrogens, conjugated

DUAVEE is indicated in women with a uterus for: DUAVEE is a combination of conjugated estrogens with an estrogen agonist/antagonist indicated for treatment of the following conditions in women with a uterus: • Treatment of moderate to severe vasomotor symptoms associated with menopause. • Prevention of postmenopausal osteoporosis. Limitation of Use: DUAVEE should be used for the shortest duration consistent with treatment goals and risks for the individual woman

DUAVEE pairs conjugated estrogens with bazedoxifene. Conjugated estrogens and bazedoxifene function by binding to and activating estrogen receptors (ER) α and β, which vary in proportion from tissue to tissue. Conjugated estrogens are composed of multiple estrogens and are agonists of ER- α and β. Bazedoxifene is an estrogen agonist/antagonist that acts as an agonist in some estrogen-sensitive tissues and an antagonist in others (e.g., uterus). The pairing of conjugated estrogens with bazedoxifene produces a composite effect that is specific to each target tissue. The bazedoxifene component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component.

• Take one tablet orally once daily Treatment of Moderate to Severe Vasomotor Symptoms Associated with Menopause The recommended dosage is one DUAVEE tablet daily.

DUAVEE is contraindicated in women with any of the following conditions: • Undiagnosed abnormal uterine bleeding • Known, suspected, or past history of breast cancer • Known or suspected estrogen-dependent neoplasia • Active deep venous thrombosis, pulmonary embolism, or history of these conditions • Active arterial thromboembolic disease (for example, stroke, myocardial infarction) or history of these conditions • Hypersensitivity (for example, anaphylaxis, angioedema) to estrogens, bazedoxifene, or any ingredients • Known hepatic impairment or disease • Known protein C, protein S, or antithrombin deficiency or other known thrombophilic disorders • Pregnancy, as DUAVEE may cause fetal harm.

Boxed warning (endometrial cancer, cardiovascular disorders, and probable dementia •): Women taking DUAVEE should not take additional estrogens • There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. DUAVEE has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. • Women taking DUAVEE should not take progestins, additional estrogens or additional estrogen agonist/antagonists. • Cardiovascular disorders, including venous thromboembolism, pulmonary embolism, stroke, and retinal vascular thrombosis. • Malignant neoplasms, including endometrial cancer, breast cancer, and ovarian cancer. • Estrogens increase the risk of gallbladder disease. • Discontinue estrogen if loss of vision, severe hypertriglyceridemia or cholestatic jaundice occurs.

The following adverse reactions are discussed in greater detail in other sections of the label: • Cardiovascular Disorders • Malignant Neoplasms • Gallbladder Disease • Hypertriglyceridemia In four prospective, randomized, placebo-controlled trials the common adverse reactions (incidence ≥ 5%) were muscle spasms, nausea, diarrhea, dyspepsia, abdominal pain upper, oropharyngeal pain, dizziness, and neck pain

Cytochrome P450 (CYP) In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Concomitant administration of itraconazole, a strong CYP3A4 inhibitor, with DUAVEE, resulted in increases in bazedoxifene exposure (40%) and, to a lesser extent, conjugated estrogens exposure (9% for baseline-adjusted total estrone, 5% for total equilin), compared to DUAVEE alone. Inducers of CYP3A4, such as St. John's Wort (Hypericum perforatum) preparations, phenobarbital, carbamazepine, and rifampin, may reduce plasma concentrations of some estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Bazedoxifene does not induce or inhibit the activities of major CYP isoenzymes. In vitro data suggest that bazedoxifene is unlikely to interact with co-administered drugs via CYP-mediated metabolism.

Blisters DUAVEE tablets should be stored at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F). See USP Controlled Room Temperature. Protect from moisture.