Mechanism Of Action
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.
Pharmacodynamic studies have not been conducted with DUAVEE.
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)
|C max (ng/mL)||Tmax (hr)||AUCss (nghr/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%.
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 AUC0-inf of bazedoxifene by 25%. The Cmax of bazedoxifene was unchanged.
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.
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.
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 enterohepatic 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
The pharmacokinetics of conjugated estrogens/bazedoxifene tablets have not been evaluated in a pediatric population [see Use In Specific Populations].
The effect of age on the pharmacokinetics of conjugated estrogens/bazedoxifene tablets have not been evaluated [see Use In Specific Populations].
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.
The pharmacokinetics of conjugated estrogens/bazedoxifene tablets have not been evaluated in women with renal impairment [see DOSAGE AND ADMINISTRATION and Use In Specific Populations].
The pharmacokinetics of conjugated estrogens/bazedoxifene tablets have not been evaluated in women with hepatic impairment [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and Use In Specific Populations].
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), Cmax and AUC of bazedoxifene increased 67% and 143%, respectively, compared to healthy subjects. In six moderate hepatic impairment patients (Child Pugh Class B), Cmax and AUC of bazedoxifene increased 32% and 109%, respectively, compared to healthy subjects. In six severe hepatic impairment patients (Child Pugh Class C), Cmax and 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 (AUC0-72) of total estrone was 2% lower and systemic exposures (AUC0-inf) of total equilin and bazedoxifene were 32% and 13% lower, respectively, compared to non-obese subjects.
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 coadministration of itraconazole 200 mg and DUAVEE. Following co-administration of DUAVEE and itraconazole, baseline-adjusted total estrone Cmax and AUC0-72 increased 9% and 9%, respectively, total equilin Cmax and AUC0-72 increased 11% and 5%, respectively, and bazedoxifene Cmax and AUC0-inf increased 11% and 40%, respectively, compared to subjects treated with DUAVEE alone.
Effect Of Co-Administered Drugs On The Pharmacokinetics Of Bazedoxifene
Conjugated estrogens 0.625 mg were administered alone for 6 consecutive days prior to the coadministration 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 Cmax of bazedoxifene increased by 3% and AUC of bazedoxifene decreased by 6%.
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 Cmax and AUC of bazedoxifene by 18% and 7%, respectively.
Atorvastatin 20 mg was given once with bazedoxifene 40 mg in thirty postmenopausal women. Co-administration of atorvastatin and bazedoxifene decreased Cmax of bazedoxifene by 3% and increased AUC of bazedoxifene by 6%.
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.Â Azithromycin 250 mg administration once daily continued on Days 10 to 13. Co-administration of azithromycin and bazedoxifene increased Cmax of 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. Coadministration of aluminum/magnesium hydroxide and bazedoxifene decreased Cmax of bazedoxifene by 8% and increased AUC of bazedoxifene by 7%.
Effect Of Bazedoxifene On The Pharmacokinetics Of Co-Administered Drugs
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 Cmax and AUC of unconjugated estrone increased by 11% and 3%, respectively. The Cmax and AUC of unconjugated equilin increased by 17% and 14%, respectively.
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 Cmax of ibuprofen by 6%. The AUC of ibuprofen was unchanged.
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 Cmax of atorvastatin by 14%. The AUC of atorvastatin was unchanged. The Cmax and AUC of 2-OH atorvastatin were decreased by 18% and 8%, respectively.
Animal Toxicology And/Or Pharmacology
In a 12-month study in ovariectomized rats, co-administration of conjugated estrogens (2.5 mg/kg/day) and bazedoxifene (0.1, 0.3, or 1 mg/kg/day) prevented the loss of bone mass at the spine, femur, and tibia with concomitant maintenance of biomechanical strength parameters.
Treatment Of Moderate To Severe Vasomotor Symptoms Associated With Menopause In Women With A Uterus
The safety and efficacy of DUAVEE as a treatment for moderate to severe vasomotor symptoms associated with menopause was established in a 12-week randomized, double-blind, placebocontrolled study (Study 3). Study 3 enrolled a total of 318 women, age 42-64 (mean age of 53 years), who had at least 7 moderate to severe hot flushes per day or at least 50 per week at baseline. The mean number of years since menopause was 4.5 years with all women undergoing natural menopause. A total of 127 women were assigned to DUAVEE and 63 women were assigned to placebo.
In Study 3, DUAVEE significantly reduced the number and severity of moderate to severe hot flushes, as measured by the daily severity score, compared with placebo at Weeks 4 and 12. The change from baseline in the number and severity of moderate to severe hot flushes observed and the difference from placebo in Study 3 are shown in Table 3.
Table 3: Adjusted Mean Change from Baseline in the Average Daily Frequency and Severity of Hot Flushes (Study 3)
1 Change from baseline using ANCOVA model
2 Based on raw data analysis using ANCOVA model: Difference= Treatment + Baseline + Site
Prevention Of Postmenopausal Osteoporosis In Women With A Uterus
The safety and efficacy of DUAVEE for the prevention of postmenopausal osteoporosis was demonstrated in Study 1 and Study 2.
Study 1 was a 24-month, double-blind, randomized, placebo- and active-controlled study evaluating the safety and efficacy of multiple combinations of conjugated estrogen/bazedoxifene (including conjugated estrogens 0.45 mg/bazedoxifene 20 mg) compared to placebo. The primary endpoint of the study was the incidence of endometrial hyperplasia at Year 1. Bone mineral density change at the lumbar spine at Year 2 was the key secondary endpoint, assessed in two subsets of patients (Substudy I and Substudy II). Patients enrolled into Substudy I had to be more than 5 years postmenopausal, have a lumbar spine or total hip T-score of -1 to -2.5, and have at least one additional risk factor for osteoporosis (e.g., Caucasian race, family history of osteoporosis, early menopause, thin/small frame, inactive lifestyle, tobacco abuse). Those enrolled into Substudy II had to be 1-5 years postmenopausal with at least one additional risk factor for osteoporosis. A total of 3,397 women age 40-75 (mean age of 56 years) were enrolled in the overall study. Substudy I enrolled a total of 1,454 women (182 women receiving DUAVEE) with mean baseline T-scores of -1.43 and -1.52 in the DUAVEE and placebo groups, respectively. Substudy II enrolled a total of 861 women (with 111 women receiving DUAVEE) with mean baseline T-scores of -0.81 and -0.94 in the DUAVEE and placebo groups, respectively. Women also took calcium (600-1200 mg) and vitamin D (200-400 IU) daily.
In these substudies, treatment with DUAVEE significantly increased lumbar spine bone mineral density (BMD) at 24 months compared to placebo in both groups of postmenopausal women (Table 4).
Table 4: Lumbar Spine Bone Mineral Density Results at 24 Months (Study 1)
|Between 1 and 5 Years Postmenopausal|
|% Mean Change||1.72||-1.90|
|Difference from Placebo (95% C.I.)||3.62|
|More Than 5 Years Postmenopausal|
|% Mean Change||1.64||-1.47|
|Difference from Placebo (95% C.I.)||3.11|
|* p-value < 0.001|
** Adjusted mean changes, confidence intervals, and p-values based on an ANCOVA model with treatment and region (U.S. or non-U.S.) as factors and baseline BMD value and years since menopause as covariates using the Modified Intention to Treat population with Last Observation Carried Forward. Study 1 excludes those subjects with missing source documentation.
In Study 1, treatment with DUAVEE also significantly increased total hip BMD. The treatment difference (or difference from placebo) in total hip BMD at 24 months was 1.96% (DUAVEE minus placebo) in women who had been postmenopausal between 1 and 5 years and 1.73% (DUAVEE minus placebo) in women who had been postmenopausal for more than 5 years.
Study 2 was a 12-month, double-blind, randomized, placebo- and active-controlled study. The primary endpoint was the incidence of endometrial hyperplasia at 12 months. The prevention of osteoporosis was assessed in a substudy that enrolled women (n=590) who were less than 5 years postmenopausal (mean 2.5 years). The mean baseline T-score in the substudy was -0.91 in the DUAVEE group and -0.95 in the placebo group. The mean age of women (n=135) taking DUAVEE was 53 years (range 46-60 years). Women also took calcium (600 mg) and vitamin D (400 IU) daily.
In Study 2, treatment with DUAVEE significantly increased mean lumbar spine BMD (treatment difference, 1.51%), at 12 months compared to placebo in women who had been postmenopausal between 1 and 5 years. Treatment with DUAVEE also increased total hip BMD. The treatment difference in total hip BMD at 12 months was 1.21%.
Effects On The Endometrium
Effects of DUAVEE on endometrial hyperplasia and endometrial malignancy were assessed in Study 1 and Study 2. The Efficacy Evaluable population included patients who had taken at least one dose of DUAVEE, had baseline and post baseline endometrial biopsies, or had been diagnosed with hyperplasia. By endometrial biopsy, the incidence of endometrial hyperplasia or malignancy for DUAVEE was below 1% in both studies (see Table 5).
Table 5: Incidence of Endometrial Hyperplasia or Malignancy at Month 12 and Month 24
|Treatment Group||Month||STUDY 1*||STUDY 2*|
|% (n/N)||1 - Sided 95% UL||% (n/N)||1 - Sided 95% UL|
|DUAVEE||12||0.00% (0/336)||0.89||0.30% (1/335)||1.41|
|UL = Upper limit|
* = Efficacy Evaluable population
Effects On Uterine Bleeding And Spotting
Uterine bleeding or spotting were evaluated in two clinical studies (Studies 1 and 2) by daily diary. In Study 1, cumulative amenorrhea at Year 1 was 83% in women treated with DUAVEE and 85% in women who received placebo. In Study 2, cumulative amenorrhea at Year 1 was 88% in women treated with DUAVEE and 84% in women who received placebo.
Womenâ€™s Health Initiative Studies
The WHI enrolled approximately 11,000 predominantly healthy postmenopausal women to assess the risks and benefits of daily oral conjugated estrogens 0.625 mg compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of CHD (defined as nonfatal MI, silent MI and CHD death), with invasive breast cancer as the primary adverse outcome. A â€œglobal indexâ€Â included the earliest occurrence of CHD, invasive breast cancer, stroke, PE, colorectal cancer, hip fracture, or death due to other cause. These substudies did not evaluate the effects of conjugated estrogens on menopausal symptoms.
The WHI estrogen-alone substudy was stopped early because an increased risk of stroke was observed, and it was deemed that no further information would be obtained regarding the risks and benefits of estrogen-alone in predetermined primary endpoints.
Results of the estrogen-alone substudy, which included 10,739 women (average 63 years of age, range 50 to 79; 75.3 percent White, 15.1 percent Black, 6.1 percent Hispanic, 3.6 percent Other), after an average follow- up of 7.1 years are presented in Table 6.
Table 6: Relative and Absolute Risk Seen in the Estrogen Alone Substudy of WHIa
|Event||Relative Risk CE vs. Placebo (95% nCIb)||CE|
n = 5,310
N = 5,429
|Absolute Risk per 10,000 Women-Years|
|CHD eventsc||0.95 (0.78-1.16)||54||57|
|Non-fatal MIc||0.91 (0.73-1.14)||40||43|
|CHD deathc||1.01 (0.71-1.43)||16||16|
|All strokesc||1.33 (1.15-1.68)||45||33|
|Ischemic strokec||1.55 (1.19-2.01)||38||25|
|Deep vein thrombosisc,d||1.47 (1.06-2.06)||23||15|
|Pulmonary embolismc||1.37 (0.90-2.07)||14||10|
|Invasive breast cancerc||0.80 (0.62-1.04)||28||34|
|Colorectal cancere||1.08 (0.75-1.55)||17||16|
|Hip fracturec||0.65 (0.45-0.94)||12||19|
|Vertebral fracturesc,d||0.64 (0.44-0.93)||11||18|
|Lower arm/wrist fracturesc,d||0.58 (0.47-0.72)||35||59|
|Total fracturesc,d||0.71 (0.64-0.80)||144||197|
|Death due to other causese,f||1.08 (0.88-1.32)||53||50|
|Overall mortalityc,d||1.04 (0.88-1.22)||79||75|
|Global Indexg||1.02 (0.92-1.13)||206||201|
|a Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi.|
b Nominal confidence intervals unadjusted for multiple looks and multiple comparisons.
c Results are based on centrally adjudicated data for an average follow-up of 7.1 years.
d Not included in â€œglobal indexâ€Â.
e Results are based on an average follow-up of 6.8 years.
f All deaths, except from breast or colorectal cancer, definite or probable CHD, PE, or cerebrovascular disease.
g A subset of the events was combined in a â€œglobal indexâ€Â, defined as the earliest occurrence of CHD events, invasive breast cancer, stroke, PE, endometrial cancer, colorectal cancer, hip fracture, or death due to other causes.
those outcomes included in the WHI â€œglobal indexâ€Â that reached statistical significance, the absolute excess risk per 10,000 women-years in the group treated with CE-alone was 12 more strokes, while the absolute risk reduction per 10,000 women-years was 7 fewer hip fractures. The absolute excess risk of events included in the â€œglobal indexâ€Â was a non-significant 5 events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality.
No overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) and invasive breast cancer incidence in women receiving conjugated estrogens-alone compared to placebo was reported in final centrally adjudicated results from the estrogen-alone substudy, after an average follow-up of 7.1 years.
Centrally adjudicated results for stroke events from the estrogen-alone substudy, after an average follow-up of 7.1 years, reported no significant differences in distribution of stroke subtype or severity, including fatal strokes, in women receiving conjugated estrogens-alone compared to placebo. Estrogen-alone increased the risk for ischemic stroke, and this excess risk was present in all subgroups of women examined.
Timing of the initiation of estrogen-alone therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen-alone substudy, stratified by age, showed in women 50 to 59 years of age a non-significant trend toward reduced risk for CHD [hazard ratio (HR) 0.63 (95 percent CI, 0.36-1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46-1.11)].
Womenâ€™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 Alzheimerâ€™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 and Use In Specific Populations].