⛔ FDA Black Box Warning
WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, AND PROBABLE DEMENTIA • Women taking DUAVEE should not take additional estrogens [see Warnings and Precautions (5.1) ] • 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. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding [see Warnings and Precautions (5.3) ] • Estrogen therapy should not be used for the prevention of cardiovascular disease or dementia [see Warnings and Precautions (5.2 , 5.4) ] • The Women's Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral conjugated estrogens (0.625 mg)-alone, relative to placebo [see Warnings and Precautions (5.2) ] • The WHI Memory Study (WHIMS) estrogen-alone ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women 65 years of age and older during 5.2 years of treatment with daily conjugated estrogens (0.625 mg)-alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions (5.4) ] Only daily oral 0.625 mg CE was studied in the estrogen-alone substudy of the WHI. Therefore, the relevance of the WHI findings regarding adverse cardiovascular events and dementia to lower CE doses, other routes of administration, or other estrogen-alone products is not known. Without such data, it is not possible to definitively exclude these risks or determine the extent of these risks for other products. Discuss with your patient the benefits and risks of estrogen-alone therapy, taking
Contraindications
4 CONTRAINDICATIONS 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 [see pregnancy (8.1) ] . • Undiagnosed abnormal uterine bleeding ( 4 , 5.3 ) • Known, suspected, or past history of breast cancer ( 4 , 5.3 ) • Known or suspected estrogen-dependent neoplasia ( 4 , 5.3 ) • Active or past history of venous thromboembolism ( 4 , 5.2 ) • Active or past history of arterial thromboembolism ( 4 , 5.2 ) • Hypersensitivity (angioedema, anaphylaxis) to estrogens, bazedoxifene, or any ingredients ( 4 ) • Known hepatic impairment or disease ( 4 , 5.9 , 8.7, 12.3 ) • Known protein C, protein S, or antithrombin deficiency or other known thrombophilic disorders ( 4 ) • Pregnancy ( 1 , 4 , 8.1 )
Pregnancy & Breastfeeding
8.1 Pregnancy Risk Summary DUAVEE is contraindicated for use in pregnant women and is not indicated for use in females of reproductive potential [see Contraindications (4) , Warnings and Precautions (5.15) ]. Conjugated Estrogens (CE) There are no data with the use of conjugated estrogens in pregnant women; however, epidemiologic studies and meta-analyses have not found an increased risk of genital and non-genital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to combined hormonal contraceptives before conception or during early pregnancy. Bazedoxifene There are no available data on bazedoxifene use in pregnant women to inform a drug associated risk of adverse developmental outcomes. Animal studies have shown that oral bazedoxifene administered during the period of organogenesis to pregnant rats or rabbits at 0.3 and 2 times, respectively, the exposure at the maximum recommended dose, can cause fetal harm [see Data ]. Based on mechanism of action, bazedoxifene may block the important functions that estrogen has during all stages of pregnancy [see Clinical Pharmacology (12.1) ] . Data Animal data Bazedoxifene Administration of bazedoxifene to rats at maternally toxic dosages ≥1 mg/kg/day (≥ 0.3 times the human area under the curve (AUC) at the 20 mg dose) resulted in reduced numbers of live fetuses and/or reductions in fetal body weights. No fetal developmental anomalies were observed. In studies conducted with pregnant rabbits treated with bazedoxifene, abortion and an increased incidence of heart (ventricular septal defect) and skeletal system (ossification delays, misshapen or misaligned bones, primarily of the spine and skull) anomalies in the fetuses were present at maternally toxic dosages of ≥ 0.5 mg/kg/day (≥ 2 times the human AUC at the 20 mg dose).