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).
Risk Summary
DUAVEE is not indicated for use in females of reproductive potential [see Warnings and Precautions (5.15)].
Conjugated Estrogens
Estrogens are present in human milk and can reduce milk production in breast-feeding females. This reduction can occur at any time but is less likely to occur once breast-feeding is well-established.
Bazedoxifene
There are no data on the presence of bazedoxifene in either human or animal breast milk, the effect on the breastfed infant, or the effects on milk production. Based on mechanism of action, bazedoxifene may block the important functions that estrogen has in mammary tissue during lactation [see Clinical Pharmacology (12.1)].
Infertility
Bazedoxifene
Based on animal data, bazedoxifene administration may adversely affect female fertility. However, clinical fertility studies with bazedoxifene have not been conducted [see Nonclinical Toxicology (13.1)].
DUAVEE is not recommended for use in women greater than 75 years of age [see Dosage and Administration (2.7) and Clinical Pharmacology 12.3)].
Of the total number of women in phase 3 clinical studies who received DUAVEE, 4.60% (n=224) were 65 years and over. DUAVEE was not studied in women aged 75 and over. No overall differences in safety or effectiveness were observed between women 65–74 years of age and younger women, and other reported clinical experience has not identified differences in responses between the elderly and younger women, but greater sensitivity of some older women cannot be ruled out.
An increased risk of probable dementia in women over 65 years of age was reported in the Women's Health Initiative Memory ancillary studies of the Women's Health Initiative using daily conjugated estrogens (0.625 mg) [see Clinical Studies (14.6)].
DUAVEE is not recommended for use in patients with renal impairment [see Dosage and Administration (2.6) and Clinical Pharmacology (12.3)].
The pharmacokinetics, safety, and efficacy of DUAVEE have not been evaluated in women with renal impairment.
DUAVEE is contraindicated in patients with hepatic impairment [see Contraindications (4) and Clinical Pharmacology (12.3)].
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 Cmax and AUC of bazedoxifene increased 67% and 143%, respectively, in women with mild hepatic impairment (Child Pugh Class A), compared to healthy women. The Cmax and AUC of bazedoxifene increased 32% and 109%, respectively, in women with moderate hepatic impairment (Child Pugh Class B). The Cmax 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.
Following DUAVEE administration, the systemic exposures of conjugated estrogens and bazedoxifene were lower in obese subjects, compared to non-obese subjects [see Pharmacokinetics (12.3)].
A single dose of DUAVEE (conjugated estrogens 0.45 mg/bazedoxifene 20 mg) was administered to 12 obese BMI ≥ 30 [mean (SD) = 32.7 (2.7) kg/m2] and 12 non-obese BMI < 30 [mean (SD) 25.3 (2.6) kg/m2] postmenopausal women. In obese subjects, systemic exposures of total estrone, total equilin, and bazedoxifene were 2%, 32%, and 13% lower, respectively, compared to non-obese subjects.
A greater reduction in bazedoxifene exposure compared to conjugated estrogens may be associated with decreased protection from endometrial hyperplasia. Monitor and evaluate women with postmenopausal or unexplained genital bleeding for possible endometrial hyperplasia or malignancy [see Warnings and Precautions (5.3)].
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).
Risk Summary
DUAVEE is not indicated for use in females of reproductive potential [see Warnings and Precautions (5.15)].
Conjugated Estrogens
Estrogens are present in human milk and can reduce milk production in breast-feeding females. This reduction can occur at any time but is less likely to occur once breast-feeding is well-established.
Bazedoxifene
There are no data on the presence of bazedoxifene in either human or animal breast milk, the effect on the breastfed infant, or the effects on milk production. Based on mechanism of action, bazedoxifene may block the important functions that estrogen has in mammary tissue during lactation [see Clinical Pharmacology (12.1)].
Infertility
Bazedoxifene
Based on animal data, bazedoxifene administration may adversely affect female fertility. However, clinical fertility studies with bazedoxifene have not been conducted [see Nonclinical Toxicology (13.1)].
DUAVEE is not recommended for use in women greater than 75 years of age [see Dosage and Administration (2.7) and Clinical Pharmacology 12.3)].
Of the total number of women in phase 3 clinical studies who received DUAVEE, 4.60% (n=224) were 65 years and over. DUAVEE was not studied in women aged 75 and over. No overall differences in safety or effectiveness were observed between women 65–74 years of age and younger women, and other reported clinical experience has not identified differences in responses between the elderly and younger women, but greater sensitivity of some older women cannot be ruled out.
An increased risk of probable dementia in women over 65 years of age was reported in the Women's Health Initiative Memory ancillary studies of the Women's Health Initiative using daily conjugated estrogens (0.625 mg) [see Clinical Studies (14.6)].
DUAVEE is not recommended for use in patients with renal impairment [see Dosage and Administration (2.6) and Clinical Pharmacology (12.3)].
The pharmacokinetics, safety, and efficacy of DUAVEE have not been evaluated in women with renal impairment.
DUAVEE is contraindicated in patients with hepatic impairment [see Contraindications (4) and Clinical Pharmacology (12.3)].
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 Cmax and AUC of bazedoxifene increased 67% and 143%, respectively, in women with mild hepatic impairment (Child Pugh Class A), compared to healthy women. The Cmax and AUC of bazedoxifene increased 32% and 109%, respectively, in women with moderate hepatic impairment (Child Pugh Class B). The Cmax 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.
Following DUAVEE administration, the systemic exposures of conjugated estrogens and bazedoxifene were lower in obese subjects, compared to non-obese subjects [see Pharmacokinetics (12.3)].
A single dose of DUAVEE (conjugated estrogens 0.45 mg/bazedoxifene 20 mg) was administered to 12 obese BMI ≥ 30 [mean (SD) = 32.7 (2.7) kg/m2] and 12 non-obese BMI < 30 [mean (SD) 25.3 (2.6) kg/m2] postmenopausal women. In obese subjects, systemic exposures of total estrone, total equilin, and bazedoxifene were 2%, 32%, and 13% lower, respectively, compared to non-obese subjects.
A greater reduction in bazedoxifene exposure compared to conjugated estrogens may be associated with decreased protection from endometrial hyperplasia. Monitor and evaluate women with postmenopausal or unexplained genital bleeding for possible endometrial hyperplasia or malignancy [see Warnings and Precautions (5.3)].
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