Bazedoxifene and estrogens, conjugated
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Boxed 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 into account her individual risk profile. Estrogens should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. WARNING: ENDOMETRIAL CANCER, CARDIOVASCULAR DISORDERS, AND PROBABLE DEMENTIA See full prescribing information for complete Boxed Warning. • Women taking DUAVEE should not take additional estrogens ( 5.1 ) • There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens ( 5.1 , 5.3 ) • Estrogen therapy should not be used for the prevention of cardiovascular…
Handling and access
NIOSH hazardous drug
Table 1This product contains estrogens, conjugated, which NIOSH lists as a hazardous drug. AHFS class: 68:16.04 estrogens; 92:24 bone resorption inhibitors.
- Listed in Table 1 because it meets the NIOSH definition of a hazardous drug and is classified as a carcinogen.
- Carcinogen classification: NTP “known to be a human carcinogen”.
Handle with the precautions your facility uses for hazardous drugs (USP <800>). NIOSH's Managing Hazardous Drug Exposures lists controls by drug form and activity.
Estrogen
Dosing in kidney impairment
Use in Patients with Renal Impairment The pharmacokinetics of DUAVEE have not been evaluated in patients with renal impairment. Use in patients with renal impairment is not recommended [see Use in Specific Populations and Clinical Pharmacology ] .
Dosing in liver impairment
Hepatic Impairment DUAVEE is contraindicated in patients with hepatic impairment [see Contraindications and Clinical Pharmacology] . The pharmacokinetics, safety, and efficacy of DUAVEE have not been evaluated in women with hepatic impairment. In a pharmacokinetics study of bazedoxifene 20 mg alone, the C max and AUC of bazedoxifene increased 67% and 143%, respectively, in women with mild hepatic impairment (Child Pugh Class A), compared to healthy women.
The C max and AUC of bazedoxifene increased 32% and 109%, respectively, in women with moderate hepatic impairment (Child Pugh Class B). The C max and AUC of bazedoxifene increased 20% and 268%, respectively, in women with severe hepatic impairment (Child Pugh Class C). No pharmacokinetic studies with conjugated estrogens were conducted in women with hepatic impairment.
Preparation and administration
Administration Instructions for Missed Doses If a dose of DUAVEE is missed, instruct patients to take it as soon as remembered unless it is almost time for the next scheduled dose. They should not take two doses at the same time.
Drug interactions
Check bazedoxifene and estrogens, conjugated against a medication listLabel text (5 paragraphs)
7 DRUG INTERACTIONS
7.1 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 [see Pharmacokinetics (12.3) ] . 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.
7.2 Uridine Diphosphate Glucuronosyltransferase (UGT) Bazedoxifene undergoes metabolism by UGT enzymes in the intestinal tract and liver. The metabolism of bazedoxifene may be increased by concomitant use of substances known to induce UGTs, such as rifampin, phenobarbital, carbamazepine, and phenytoin. A reduction in bazedoxifene exposure may be associated with an increase risk of endometrial hyperplasia. 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.
7.3 Atorvastatin Concomitant administration of bazedoxifene (40 mg daily) and atorvastatin (20 mg, single-dose) to healthy postmenopausal women did not affect the pharmacokinetics of bazedoxifene, atorvastatin or its active metabolites.
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 )
Safety data
Reported adverse events (FAERS)
Liver injury (LiverTox)
LiverTox has no chapter for bazedoxifene and estrogens, conjugated. Check the label's hepatic warnings.
Pregnancy and lactation
Pregnancy
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).
For breastfeeding, also see LactMed (National Library of Medicine), which summarizes milk levels and infant effects.
Supply and cost
Drug shortage status
Recalls (last 24 months)
Therapeutic equivalence (Orange Book)
Price ladder
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