Duavee

• •
  Women taking DUAVEE should not take additional estrogens

  [see

  5.1 Drugs Containing Progestins, Estrogens or Estrogen Agonist/Antagonists

  DUAVEE contains conjugated estrogens and bazedoxifene, an estrogen agonist/antagonist. Women taking DUAVEE should not take progestins, additional estrogens or additional estrogen agonist/antagonists.

  ]
• •
  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

  5.3 Malignant Neoplasms

  Endometrial Cancer

  An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in women with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12 times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more of treatment. This risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.

  DUAVEE contains an estrogen agonist/antagonist. This component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component. Endometrial hyperplasia may be a precursor to endometrial cancer. Women taking DUAVEE should not take additional estrogens as this may increase the risk of endometrial hyperplasia.

  Clinical surveillance of all women taking DUAVEE is important. 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.

  Breast Cancer

  The WHI substudy of daily conjugated estrogens (0.625 mg)-alone provided information about breast cancer in estrogen‑alone users. In the WHI estrogen-alone substudy, after an average follow-up of 7.1 years, daily conjugated estrogen (0.625 mg)-alone was not associated with an increased risk of invasive breast cancer (relative risk [RR] 0.80).

  The use of estrogen-alone has been reported to result in an increase in abnormal mammograms requiring further evaluation. The effect of treatment with DUAVEE on the risk of breast cancer is unknown.

  All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.

  Ovarian Cancer

  A meta-analysis of 17 prospective and 35 retrospective epidemiology studies found that women who used hormonal therapy for menopausal symptoms had an increased risk for ovarian cancer. The primary analysis, using case-control comparisons, included 12,110 cancer cases from the 17 prospective studies. The relative risks associated with current use of hormonal therapy was 1.41 (95% confidence interval [CI] 1.32 to 1.50); there was no difference in the risk estimates by duration of the exposure (less than 5 years [median of 3 years] vs. greater than 5 years [median of 10 years] of use before the cancer diagnosis). The relative risk associated with combined current and recent use (discontinued use within 5 years before cancer diagnosis) was 1.37 (95% CI 1.27–1.48), and the elevated risk was significant for both estrogen-alone and estrogen plus progestin products. The exact duration of hormone therapy use associated with an increased risk of ovarian cancer, however, is unknown.

  The effect of treatment with DUAVEE on the risk of ovarian cancer is unknown.

  ]
• •
  Estrogen therapy should not be used for the prevention of cardiovascular disease or dementia

  [see

  5.2 Cardiovascular Disorders

  Estrogen agonist/antagonists (including bazedoxifene, a component of DUAVEE) and estrogens individually are known to increase the risk of VTE.

  An increased risk of stroke and DVT has been reported with estrogen-alone therapy. Should any of these occur or be suspected, DUAVEE should be discontinued immediately.

  Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or VTE (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately.

  Stroke

  In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily conjugated estrogens (CE) (0.625 mg)-alone compared to women in the same age group receiving placebo (45 versus 33 per 10,000 women-years). The increase in risk was demonstrated in year 1 and persisted

  [see Clinical Studies (14.5)]

  .

  Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving conjugated estrogens (0.625 mg)-alone versus those receiving placebo (18 versus 21 per 10,000 women-years).

  Should a stroke occur or be suspected, DUAVEE should be discontinued immediately

  [see Contraindications (4)].

  Coronary Heart Disease

  In the WHI estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as nonfatal myocardial infarction, silent myocardial infarction, or CHD death) was reported in women receiving estrogen-alone compared to placebo

  [see Clinical Studies (14.5)]

  .

  Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant reduction in CHD events (CE [0.625 mg]-alone compared to placebo) in women with less than 10 years since menopause (8 versus 16 per 10,000 women-years).

  Venous Thromboembolism (VTE)

  In the WHI estrogen-alone substudy, the risk of VTE [DVT and pulmonary embolism (PE)] was increased for women receiving daily conjugated estrogens (0.625 mg)-alone compared to placebo (30 versus 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 versus 15 per 10,000 women-years). The increase in VTE risk was demonstrated during the first 2 years

  [see Clinical Studies (14.5)]

  .

  If feasible, DUAVEE should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. Because immobilization increases the risk for venous thromboembolic events independent of therapy, DUAVEE should be discontinued prior to and during prolonged immobilization (e.g., post-surgical recovery, prolonged bed rest) and DUAVEE therapy should be resumed only after the patient is fully ambulatory. In addition, women taking DUAVEE should be advised to move about periodically during travel involving prolonged immobilization.

  ,

  5.4 Probable Dementia

  In the WHIMS estrogen-alone ancillary study of WHI, a population of 2,947 hysterectomized women 65 to 79 years of age was randomized to daily CE (0.625 mg)-alone or placebo.

  After an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83–2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years

  [see Use in Specific Populations (8.5)and Clinical Studies (14.6)]

  .

  ]
• •
  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

  5.2 Cardiovascular Disorders

  Estrogen agonist/antagonists (including bazedoxifene, a component of DUAVEE) and estrogens individually are known to increase the risk of VTE.

  An increased risk of stroke and DVT has been reported with estrogen-alone therapy. Should any of these occur or be suspected, DUAVEE should be discontinued immediately.

  Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or VTE (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately.

  Stroke

  In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily conjugated estrogens (CE) (0.625 mg)-alone compared to women in the same age group receiving placebo (45 versus 33 per 10,000 women-years). The increase in risk was demonstrated in year 1 and persisted

  [see Clinical Studies (14.5)]

  .

  Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving conjugated estrogens (0.625 mg)-alone versus those receiving placebo (18 versus 21 per 10,000 women-years).

  Should a stroke occur or be suspected, DUAVEE should be discontinued immediately

  [see Contraindications (4)].

  Coronary Heart Disease

  In the WHI estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as nonfatal myocardial infarction, silent myocardial infarction, or CHD death) was reported in women receiving estrogen-alone compared to placebo

  [see Clinical Studies (14.5)]

  .

  Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant reduction in CHD events (CE [0.625 mg]-alone compared to placebo) in women with less than 10 years since menopause (8 versus 16 per 10,000 women-years).

  Venous Thromboembolism (VTE)

  In the WHI estrogen-alone substudy, the risk of VTE [DVT and pulmonary embolism (PE)] was increased for women receiving daily conjugated estrogens (0.625 mg)-alone compared to placebo (30 versus 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 versus 15 per 10,000 women-years). The increase in VTE risk was demonstrated during the first 2 years

  [see Clinical Studies (14.5)]

  .

  If feasible, DUAVEE should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. Because immobilization increases the risk for venous thromboembolic events independent of therapy, DUAVEE should be discontinued prior to and during prolonged immobilization (e.g., post-surgical recovery, prolonged bed rest) and DUAVEE therapy should be resumed only after the patient is fully ambulatory. In addition, women taking DUAVEE should be advised to move about periodically during travel involving prolonged immobilization.

  ]
• •
  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

  5.4 Probable Dementia

  In the WHIMS estrogen-alone ancillary study of WHI, a population of 2,947 hysterectomized women 65 to 79 years of age was randomized to daily CE (0.625 mg)-alone or placebo.

  After an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83–2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years

  [see Use in Specific Populations (8.5)and Clinical Studies (14.6)]

  .

  ]

DUAVEE is indicated in women with a uterus for:

• •Take one tablet orally once daily (
  2 DOSAGE AND ADMINISTRATION

  • •Take one tablet orally once daily

  2.1 Treatment of Moderate to Severe Vasomotor Symptoms Associated with Menopause

  The recommended dosage is one DUAVEE tablet daily.

  2.2 Prevention of Postmenopausal Osteoporosis

  The recommended dosage is one DUAVEE tablet daily.

  2.3 General Dosing Information

  Take DUAVEE once daily, without regard to meals. Tablets should be swallowed whole.

  2.4 Recommendations for Calcium and Vitamin D Supplementation

  Women taking DUAVEE for prevention of postmenopausal osteoporosis should add supplemental calcium and/or vitamin D to their diet if daily intake is inadequate.

  2.5 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.

  2.6 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 (8.6)and Clinical Pharmacology (12.3)]

  .

  2.7 Use in the Elderly

  DUAVEE has not been studied in women over 75 years of age. Use in women over 75 years of age is not recommended.
  )

DUAVEE (conjugated estrogens/bazedoxifene) tablets, 0.45 mg/20 mg are oval, biconvex, pink tablets, branded with "0.45/20" in black ink on one side.

• •Geriatric Use: DUAVEE was not studied in women aged 75 or older (
  8.5 Geriatric Use

  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)].
  ,
  12.3 Pharmacokinetics

  Absorption

  Following administration of multiple doses of conjugated estrogens 0.45 mg/bazedoxifene 20 mg to healthy women who were naturally postmenopausal or who had undergone bilateral oophorectomy, the mean steady state pharmacokinetic parameters at Day 10 for conjugated estrogens (baseline adjusted for total estrone) and bazedoxifene are summarized in Table 2.

  Table 2: Mean ± SD Steady-State Pharmacokinetic Parameters (n=24)

  	Cmax (ng/mL)	Tmax (hr)	AUCss (ng∙hr/mL)
  Baseline-Adjusted Total Estrone	2.6 ± 0.8	6.5 ± 1.6	35 ± 12
  Bazedoxifene	6.9 ± 3.9	2.5 ± 2.1	71 ± 34

  Results from monotherapy studies with conjugated estrogens or bazedoxifene components of DUAVEE, are noted below:

  Conjugated estrogens are soluble in water and are well-absorbed from the gastrointestinal tract after release from the drug formulation.

  Bazedoxifene exhibits a linear increase in plasma concentrations for single doses from 0.5 mg up to 120 mg and multiple daily doses from 1 mg to 80 mg. The absolute bioavailability of bazedoxifene is approximately 6%.

  Food Effect

  In a single-dose, crossover study in 23 postmenopausal women given conjugated estrogens 0.625 mg/bazedoxifene 20 mg with a high fat/high calorie meal, food increased AUC_0–infof bazedoxifene by 25%. The C_maxof bazedoxifene was unchanged.

  Distribution

  The distribution of conjugated estrogens and bazedoxifene after administration of DUAVEE has not been studied.

  Results from monotherapy studies with conjugated estrogens or bazedoxifene, components of DUAVEE, are noted below:

  The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin.

  Following intravenous (IV) administration of a 3 mg dose of bazedoxifene, the volume of distribution is 14.7 ± 3.9 L/kg. Bazedoxifene is highly bound (98%–99%) to plasma proteins

  in vitro,

  but does not bind to SHBG.

  Metabolism

  The metabolic disposition of conjugated estrogens and bazedoxifene, after administration of DUAVEE, has not been studied.

  Results from monotherapy studies with conjugated estrogens or bazedoxifene, components of DUAVEE, are noted below:

  Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. 17-β estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. In postmenopausal women, a significant proportion of the circulating estrogens exists as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.

  The metabolic disposition of bazedoxifene has been determined following oral administration of 20 mg of radiolabeled bazedoxifene. Bazedoxifene is extensively metabolized in women. Glucuronidation is the major metabolic pathway. Little or no cytochrome P450-mediated metabolism is evident. Bazedoxifene-5-glucuronide is the major circulating metabolite. The concentrations of this glucuronide are approximately 10-fold higher than those of unchanged drug in plasma.

  Excretion

  After administration of a single dose of conjugated estrogens/bazedoxifene, baseline-adjusted total estrone (representing conjugated estrogens) is eliminated with a half-life of approximately 17 hours. Bazedoxifene is eliminated with a half-life of approximately 30 hours. Steady-state concentrations are achieved by the second week of once-daily administration.

  Results from monotherapy studies with conjugated estrogens or bazedoxifene, components of DUAVEE, are noted below:

  The conjugated estrogens components, 17β-estradiol, estrone, and estriol are excreted in the urine, along with glucuronide and sulfate conjugates.

  The clearance of bazedoxifene is 0.4 ± 0.1 L/h/kg based on intravenous administration. The major route of excretion after oral administration of 20 mg of radiolabeled bazedoxifene is via biliary excretion, followed by elimination in the feces (~85%), with < 1% of the radioactive dose eliminated in the urine. Based on these results, it is expected that bazedoxifene undergoes entero-hepatic recycling from the gut back to the systemic circulation, therefore, some drugs may potentially interfere with bazedoxifene recycling process in the gut by various mechanisms resulting in a decrease in its systemic exposure.

  Use in Specific Populations

  Pediatric

  The pharmacokinetics of conjugated estrogens/bazedoxifene tablets have not been evaluated in a pediatric population

  [see Use in Specific Populations (8.4)].

  Geriatric

  The effect of age on the pharmacokinetics of conjugated estrogens/bazedoxifene tablets have not been evaluated

  [see Use in Specific Populations (8.5)]

  .

  No pharmacokinetic studies with conjugated estrogens were conducted in specific populations, including women over 75 years of age.

  The pharmacokinetics of a 20 mg single-dose of bazedoxifene, were evaluated in postmenopausal women. On average, compared to women 51 to 64 years of age (n=8), women 65 to 74 years of age (n=8) showed a 1.5-fold increase in AUC, and women ≥ 75 years of age (n=8) showed a 2.6-fold increase in AUC.

  Renal Impairment

  The pharmacokinetics of conjugated estrogens/bazedoxifene tablets have not been evaluated in women with renal impairment

  [see Dosage and Administration (2.6)and Use in Specific Populations (8.6)]

  .

  Hepatic Impairment

  The pharmacokinetics of conjugated estrogens/bazedoxifene tablets have not been evaluated in women with hepatic impairment

  [see Contraindications (4), Warnings and Precautions (5.5), and Use in Specific Populations (8.7)].

  No pharmacokinetic studies with conjugated estrogens were conducted in specific populations, including women with hepatic impairment.

  A single dose of bazedoxifene 20 mg was given to fasted, healthy (N=18) and hepatically impaired postmenopausal women. In six mild hepatic impairment patients (Child Pugh Class A), C_maxand AUC of bazedoxifene increased 67% and 143%, respectively, compared to healthy subjects. In six moderate hepatic impairment patients (Child Pugh Class B), C_maxand AUC of bazedoxifene increased 32% and 109%, respectively, compared to healthy subjects. In six severe hepatic impairment patients (Child Pugh Class C), C_maxand AUC of bazedoxifene increased 20% and 268%, respectively, compared to healthy subjects. Half-life was prolonged from 32 to 50 hrs in patients with severe hepatic impairment, compared to healthy subjects.

  Body Mass Index

  In a clinical study, a single dose of DUAVEE (conjugated estrogens 0.45 mg/bazedoxifene 20 mg) was administered to 12 obese [mean (SD) BMI = 32.7 (2.7) kg/m²] and 12 non-obese [mean (SD) BMI = 25.3 (2.6) kg/m²] postmenopausal women. In obese subjects, systemic exposure (AUC_0–72) of total estrone was 2% lower and systemic exposures (AUC_0–inf) of total equilin and bazedoxifene were 32% and 13% lower, respectively, compared to non-obese subjects.

  Drug Interactions

  Effect of Co-Administered Drugs on the Pharmacokinetics of Conjugated Estrogens/Bazedoxifene

  In a drug-drug interaction study, itraconazole 200 mg, a strong CYP3A4 inhibitor, was administered with breakfast to 24 postmenopausal women for 4 days, followed by a fifth dose of itraconazole 200 mg with breakfast and DUAVEE on Day 5 (3 hours after itraconazole). Itraconazole 200 mg was continued for 2 additional days after the co-administration of itraconazole 200 mg and DUAVEE. Following co-administration of DUAVEE and itraconazole, baseline-adjusted total estrone C_maxand AUC_0–72increased 9% and 9%, respectively, total equilin C_maxand AUC_0–72increased 11% and 5%, respectively, and bazedoxifene C_maxand AUC_0–infincreased 11% and 40%, respectively, compared to subjects treated with DUAVEE alone.

  Effect of Co-Administered Drugs on the Pharmacokinetics of Bazedoxifene

  Conjugated Estrogens

  Conjugated estrogens 0.625 mg were administered alone for 6 consecutive days prior to the co-administration of a single dose of 20 mg bazedoxifene and conjugated estrogens 0.625 mg in thirty postmenopausal women. Conjugated estrogens 0.625 mg were continued for 2 additional days after the co-administration of bazedoxifene and conjugated estrogens. The C_maxof bazedoxifene increased by 3% and AUC of bazedoxifene decreased by 6%.

  Ibuprofen

  A single dose of ibuprofen 600 mg was given with a bazedoxifene 20 mg capsule in twelve postmenopausal women after an overnight fast. Co-administration of ibuprofen and bazedoxifene increased C_maxand AUC of bazedoxifene by 18% and 7%, respectively.

  Atorvastatin

  Atorvastatin 20 mg was given once with bazedoxifene 40 mg in thirty postmenopausal women. Co-administration of atorvastatin and bazedoxifene decreased C_maxof bazedoxifene by 3% and increased AUC of bazedoxifene by 6%.

  Azithromycin

  Azithromycin 500 mg was given once daily for 8 consecutive days in thirty postmenopausal women. Azithromycin 500 mg and a bazedoxifene 40 mg tablet were co-administered on Day 9. Azithromycin 250 mg administration once daily continued on Days 10 to 13. Co-administration of azithromycin and bazedoxifene increased C_maxof bazedoxifene by 6% and decreased AUC of bazedoxifene by 15%.

  Aluminum and Magnesium Hydroxide

  A single dose of 460 mg aluminum hydroxide and 400 mg magnesium hydroxide was given with a bazedoxifene 40 mg tablet in thirty postmenopausal women after an overnight fast. Co-administration of aluminum/magnesium hydroxide and bazedoxifene decreased C_maxof bazedoxifene by 8% and increased AUC of bazedoxifene by 7%.

  Effect of Bazedoxifene on the Pharmacokinetics of Co-Administered Drugs

  Conjugated Estrogens

  Bazedoxifene 20 mg was administered alone for 8 consecutive days prior to co-administration of a single dose of conjugated estrogens 0.625 mg and bazedoxifene 20 mg in twenty-six postmenopausal women. Bazedoxifene 20 mg was continued for 2 additional days after co-administration of bazedoxifene and conjugated estrogens. The C_maxand AUC of unconjugated estrone increased by 11% and 3%, respectively. The C_maxand AUC of unconjugated equilin increased by 17% and 14%, respectively.

  Ibuprofen

  A single dose of bazedoxifene 20 mg capsule was given with a single dose of ibuprofen 600 mg in twelve fasted, postmenopausal women. Co-administration of bazedoxifene and ibuprofen increased the C_maxof ibuprofen by 6%. The AUC of ibuprofen was unchanged.

  Atorvastatin

  Bazedoxifene 40 mg was given for 8 consecutive days prior to co-administration of bazedoxifene 40 mg and atorvastatin 20 mg. Co-administration of bazedoxifene and atorvastatin decreased C_maxof atorvastatin by 14%. The AUC of atorvastatin was unchanged. The C_maxand AUC of 2-OH atorvastatin were decreased by 18% and 8%, respectively.
  ); use in this population is not recommended (
  2.7 Use in the Elderly

  DUAVEE has not been studied in women over 75 years of age. Use in women over 75 years of age is not recommended.
  ,
  8.5 Geriatric Use

  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)].
  )
• •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 (
  5.4 Probable Dementia

  In the WHIMS estrogen-alone ancillary study of WHI, a population of 2,947 hysterectomized women 65 to 79 years of age was randomized to daily CE (0.625 mg)-alone or placebo.

  After an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83–2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years

  [see Use in Specific Populations (8.5)and Clinical Studies (14.6)]

  .
  ,
  8.5 Geriatric Use

  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)].
  ,
  14.6 Women's Health Initiative Memory Study

  The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominantly healthy hysterectomized postmenopausal women 65 to 79 years of age (45 percent were 65 to 69 years of age, 36 percent were 70 to 74 years of age, and 19 percent were 75 years of age and older) to evaluate the effects of daily conjugated estrogens (0.625 mg)-alone on the incidence of probable dementia (primary outcome) compared to placebo.

  After an average follow-up of 5.2 years, the relative risk of probable dementia for conjugated estrogens-alone versus placebo was 1.49 (95 percent CI, 0.83–2.66). The absolute risk of probable dementia for conjugated estrogens-alone versus placebo was 37 versus 25 cases per 10,000 women-years. Probable dementia as defined in this study included Alzheimer's disease (AD), vascular dementia (VaD) and mixed type (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women

  [see Warnings and Precautions (5.4)and Use in Specific Populations (8.5)]

  .
  )
• •Renal Impairment: DUAVEE was not studied in women with renal impairment; use in this population is not recommended (
  2.6 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 (8.6)and Clinical Pharmacology (12.3)]

  .
  ,
  8.6 Renal Impairment

  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

  .
  ,
  12.3 Pharmacokinetics

  Absorption

  Following administration of multiple doses of conjugated estrogens 0.45 mg/bazedoxifene 20 mg to healthy women who were naturally postmenopausal or who had undergone bilateral oophorectomy, the mean steady state pharmacokinetic parameters at Day 10 for conjugated estrogens (baseline adjusted for total estrone) and bazedoxifene are summarized in Table 2.

  Table 2: Mean ± SD Steady-State Pharmacokinetic Parameters (n=24)

  	Cmax (ng/mL)	Tmax (hr)	AUCss (ng∙hr/mL)
  Baseline-Adjusted Total Estrone	2.6 ± 0.8	6.5 ± 1.6	35 ± 12
  Bazedoxifene	6.9 ± 3.9	2.5 ± 2.1	71 ± 34

  Results from monotherapy studies with conjugated estrogens or bazedoxifene components of DUAVEE, are noted below:

  Conjugated estrogens are soluble in water and are well-absorbed from the gastrointestinal tract after release from the drug formulation.

  Bazedoxifene exhibits a linear increase in plasma concentrations for single doses from 0.5 mg up to 120 mg and multiple daily doses from 1 mg to 80 mg. The absolute bioavailability of bazedoxifene is approximately 6%.

  Food Effect

  In a single-dose, crossover study in 23 postmenopausal women given conjugated estrogens 0.625 mg/bazedoxifene 20 mg with a high fat/high calorie meal, food increased AUC_0–infof bazedoxifene by 25%. The C_maxof bazedoxifene was unchanged.

  Distribution

  The distribution of conjugated estrogens and bazedoxifene after administration of DUAVEE has not been studied.

  Results from monotherapy studies with conjugated estrogens or bazedoxifene, components of DUAVEE, are noted below:

  The distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin.

  Following intravenous (IV) administration of a 3 mg dose of bazedoxifene, the volume of distribution is 14.7 ± 3.9 L/kg. Bazedoxifene is highly bound (98%–99%) to plasma proteins

  in vitro,

  but does not bind to SHBG.

  Metabolism

  The metabolic disposition of conjugated estrogens and bazedoxifene, after administration of DUAVEE, has not been studied.

  Results from monotherapy studies with conjugated estrogens or bazedoxifene, components of DUAVEE, are noted below:

  Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. 17-β estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. In postmenopausal women, a significant proportion of the circulating estrogens exists as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens.

  The metabolic disposition of bazedoxifene has been determined following oral administration of 20 mg of radiolabeled bazedoxifene. Bazedoxifene is extensively metabolized in women. Glucuronidation is the major metabolic pathway. Little or no cytochrome P450-mediated metabolism is evident. Bazedoxifene-5-glucuronide is the major circulating metabolite. The concentrations of this glucuronide are approximately 10-fold higher than those of unchanged drug in plasma.

  Excretion

  After administration of a single dose of conjugated estrogens/bazedoxifene, baseline-adjusted total estrone (representing conjugated estrogens) is eliminated with a half-life of approximately 17 hours. Bazedoxifene is eliminated with a half-life of approximately 30 hours. Steady-state concentrations are achieved by the second week of once-daily administration.

  Results from monotherapy studies with conjugated estrogens or bazedoxifene, components of DUAVEE, are noted below:

  The conjugated estrogens components, 17β-estradiol, estrone, and estriol are excreted in the urine, along with glucuronide and sulfate conjugates.

  The clearance of bazedoxifene is 0.4 ± 0.1 L/h/kg based on intravenous administration. The major route of excretion after oral administration of 20 mg of radiolabeled bazedoxifene is via biliary excretion, followed by elimination in the feces (~85%), with < 1% of the radioactive dose eliminated in the urine. Based on these results, it is expected that bazedoxifene undergoes entero-hepatic recycling from the gut back to the systemic circulation, therefore, some drugs may potentially interfere with bazedoxifene recycling process in the gut by various mechanisms resulting in a decrease in its systemic exposure.

  Use in Specific Populations

  Pediatric

  The pharmacokinetics of conjugated estrogens/bazedoxifene tablets have not been evaluated in a pediatric population

  [see Use in Specific Populations (8.4)].

  Geriatric

  The effect of age on the pharmacokinetics of conjugated estrogens/bazedoxifene tablets have not been evaluated

  [see Use in Specific Populations (8.5)]

  .

  No pharmacokinetic studies with conjugated estrogens were conducted in specific populations, including women over 75 years of age.

  The pharmacokinetics of a 20 mg single-dose of bazedoxifene, were evaluated in postmenopausal women. On average, compared to women 51 to 64 years of age (n=8), women 65 to 74 years of age (n=8) showed a 1.5-fold increase in AUC, and women ≥ 75 years of age (n=8) showed a 2.6-fold increase in AUC.

  Renal Impairment

  The pharmacokinetics of conjugated estrogens/bazedoxifene tablets have not been evaluated in women with renal impairment

  [see Dosage and Administration (2.6)and Use in Specific Populations (8.6)]

  .

  Hepatic Impairment

  The pharmacokinetics of conjugated estrogens/bazedoxifene tablets have not been evaluated in women with hepatic impairment

  [see Contraindications (4), Warnings and Precautions (5.5), and Use in Specific Populations (8.7)].

  No pharmacokinetic studies with conjugated estrogens were conducted in specific populations, including women with hepatic impairment.

  A single dose of bazedoxifene 20 mg was given to fasted, healthy (N=18) and hepatically impaired postmenopausal women. In six mild hepatic impairment patients (Child Pugh Class A), C_maxand AUC of bazedoxifene increased 67% and 143%, respectively, compared to healthy subjects. In six moderate hepatic impairment patients (Child Pugh Class B), C_maxand AUC of bazedoxifene increased 32% and 109%, respectively, compared to healthy subjects. In six severe hepatic impairment patients (Child Pugh Class C), C_maxand AUC of bazedoxifene increased 20% and 268%, respectively, compared to healthy subjects. Half-life was prolonged from 32 to 50 hrs in patients with severe hepatic impairment, compared to healthy subjects.

  Body Mass Index

  In a clinical study, a single dose of DUAVEE (conjugated estrogens 0.45 mg/bazedoxifene 20 mg) was administered to 12 obese [mean (SD) BMI = 32.7 (2.7) kg/m²] and 12 non-obese [mean (SD) BMI = 25.3 (2.6) kg/m²] postmenopausal women. In obese subjects, systemic exposure (AUC_0–72) of total estrone was 2% lower and systemic exposures (AUC_0–inf) of total equilin and bazedoxifene were 32% and 13% lower, respectively, compared to non-obese subjects.

  Drug Interactions

  Effect of Co-Administered Drugs on the Pharmacokinetics of Conjugated Estrogens/Bazedoxifene

  In a drug-drug interaction study, itraconazole 200 mg, a strong CYP3A4 inhibitor, was administered with breakfast to 24 postmenopausal women for 4 days, followed by a fifth dose of itraconazole 200 mg with breakfast and DUAVEE on Day 5 (3 hours after itraconazole). Itraconazole 200 mg was continued for 2 additional days after the co-administration of itraconazole 200 mg and DUAVEE. Following co-administration of DUAVEE and itraconazole, baseline-adjusted total estrone C_maxand AUC_0–72increased 9% and 9%, respectively, total equilin C_maxand AUC_0–72increased 11% and 5%, respectively, and bazedoxifene C_maxand AUC_0–infincreased 11% and 40%, respectively, compared to subjects treated with DUAVEE alone.

  Effect of Co-Administered Drugs on the Pharmacokinetics of Bazedoxifene

  Conjugated Estrogens

  Conjugated estrogens 0.625 mg were administered alone for 6 consecutive days prior to the co-administration of a single dose of 20 mg bazedoxifene and conjugated estrogens 0.625 mg in thirty postmenopausal women. Conjugated estrogens 0.625 mg were continued for 2 additional days after the co-administration of bazedoxifene and conjugated estrogens. The C_maxof bazedoxifene increased by 3% and AUC of bazedoxifene decreased by 6%.

  Ibuprofen

  A single dose of ibuprofen 600 mg was given with a bazedoxifene 20 mg capsule in twelve postmenopausal women after an overnight fast. Co-administration of ibuprofen and bazedoxifene increased C_maxand AUC of bazedoxifene by 18% and 7%, respectively.

  Atorvastatin

  Atorvastatin 20 mg was given once with bazedoxifene 40 mg in thirty postmenopausal women. Co-administration of atorvastatin and bazedoxifene decreased C_maxof bazedoxifene by 3% and increased AUC of bazedoxifene by 6%.

  Azithromycin

  Azithromycin 500 mg was given once daily for 8 consecutive days in thirty postmenopausal women. Azithromycin 500 mg and a bazedoxifene 40 mg tablet were co-administered on Day 9. Azithromycin 250 mg administration once daily continued on Days 10 to 13. Co-administration of azithromycin and bazedoxifene increased C_maxof bazedoxifene by 6% and decreased AUC of bazedoxifene by 15%.

  Aluminum and Magnesium Hydroxide

  A single dose of 460 mg aluminum hydroxide and 400 mg magnesium hydroxide was given with a bazedoxifene 40 mg tablet in thirty postmenopausal women after an overnight fast. Co-administration of aluminum/magnesium hydroxide and bazedoxifene decreased C_maxof bazedoxifene by 8% and increased AUC of bazedoxifene by 7%.

  Effect of Bazedoxifene on the Pharmacokinetics of Co-Administered Drugs

  Conjugated Estrogens

  Bazedoxifene 20 mg was administered alone for 8 consecutive days prior to co-administration of a single dose of conjugated estrogens 0.625 mg and bazedoxifene 20 mg in twenty-six postmenopausal women. Bazedoxifene 20 mg was continued for 2 additional days after co-administration of bazedoxifene and conjugated estrogens. The C_maxand AUC of unconjugated estrone increased by 11% and 3%, respectively. The C_maxand AUC of unconjugated equilin increased by 17% and 14%, respectively.

  Ibuprofen

  A single dose of bazedoxifene 20 mg capsule was given with a single dose of ibuprofen 600 mg in twelve fasted, postmenopausal women. Co-administration of bazedoxifene and ibuprofen increased the C_maxof ibuprofen by 6%. The AUC of ibuprofen was unchanged.

  Atorvastatin

  Bazedoxifene 40 mg was given for 8 consecutive days prior to co-administration of bazedoxifene 40 mg and atorvastatin 20 mg. Co-administration of bazedoxifene and atorvastatin decreased C_maxof atorvastatin by 14%. The AUC of atorvastatin was unchanged. The C_maxand AUC of 2-OH atorvastatin were decreased by 18% and 8%, respectively.
  )