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  • Duavee BAZEDOXIFENE ACETATE 20 mg/1 U.S. Pharmaceuticals
FDA Drug information

Duavee

Read time: 1 mins
Marketing start date: 18 Jun 2024

Summary of product characteristics


Adverse Reactions

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Cardiovascular Disorders [see Warnings and Precautions (5.2) ] • Malignant Neoplasms [see Warnings and Precautions (5.3) ] • Gallbladder Disease [see Warnings and Precautions (5.5) ] • Hypertriglyceridemia [see Warnings and Precautions (5.8) ] In four prospective, randomized, placebo-controlled trials the common adverse reactions (incidence ≥ 5%) were muscle spasms, nausea, diarrhea, dyspepsia, abdominal pain upper, oropharyngeal pain, dizziness, and neck pain ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of conjugated estrogens/bazedoxifene was evaluated in four Phase 3 clinical trials ranging from 12 weeks to 24 months in duration and enrolling 6,210 postmenopausal women age 40 to 75 years (mean age 55 years). A total of 1,224 patients were treated with DUAVEE and 1,069 patients received placebo. Women enrolled in Studies 1 and 2 received calcium (600–1200 mg) and vitamin D (200–400 IU) daily, while women in Studies 3 and 4 received no calcium and vitamin D supplementation as part of the protocol. The incidence of all-cause mortality was 0.0% in the DUAVEE group and 0.2% in the placebo group. The incidence of serious adverse reactions was 3.5% in the DUAVEE group and 4.8% in the placebo group. The percentage of patients who withdrew from treatment due to adverse reactions was 7.5% in the DUAVEE group and 10.0% in the placebo group. The most common adverse reactions leading to discontinuation were hot flush, abdominal pain upper, and nausea. The most commonly observed adverse reactions (incidence ≥ 5%) more frequently reported in women treated with DUAVEE than placebo are presented in Table 1. Table 1: Adverse Reactions (Incidence ≥ 5%) More Common in the DUAVEE Treatment Group in Placebo-controlled Trials DUAVEE (N=1224) n (%) Placebo (N=1069) n (%) Gastrointestinal disorders Nausea 100 (8) 58 (5) Diarrhea 96 (8) 57 (5) Dyspepsia 84 (7) 59 (6) Abdominal pain upper 81 (7) 58 (5) Musculoskeletal and connective tissue disorders Muscle spasms 110 (9) 63 (6) Neck pain 62 (5) 46 (4) Nervous system disorders Dizziness 65 (5) 37 (3) Respiratory, thoracic, and mediastinal disorders Oropharyngeal pain 80 (7) 61 (6) Venous thromboembolism : In the clinical studies with DUAVEE, the reporting rates for venous thromboembolism (deep venous thrombosis, pulmonary embolism, and retinal vein thrombosis) were low in all treatment groups. Adverse reactions of venous thromboembolism were reported in 0.0% of patients treated with DUAVEE and 0.1% of patients treated with placebo. Due to the low rate of events in both groups, it is not possible to conclude that the risk of venous thromboembolism with DUAVEE is different from that seen with other estrogen therapies [see Warnings and Precautions (5.2) ] .

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 )

Description

11 DESCRIPTION DUAVEE (conjugated estrogens/bazedoxifene), contains conjugated estrogens with bazedoxifene, an estrogen agonist/antagonist. Conjugated estrogens are purified from pregnant mares' urine and consist of the sodium salts of water-soluble estrogen sulfates blended to represent the average composition of material derived from pregnant mares' urine. Conjugated estrogens are a mixture of sodium estrone sulfate and sodium equilin sulfate, and also contain as concomitant components, sodium sulfate conjugates, 17α-dihydroequilin, 17α-estradiol, and 17β-dihydroequilin. Bazedoxifene is supplied as the acetate salt (bazedoxifene acetate) and has the chemical name 1 H -Indol-5-ol, 1-[[4-[2-(hexahydro-1 H -azepin-1-yl) ethoxy]phenyl]methyl]-2-(4-hydroxyphenyl)-3-methyl-, monoacetate. The empirical formula is C 30 H 34 N 2 O 3 ∙ C 2 H 4 O 2, and the molecular weight is 530.65. Bazedoxifene acetate is a white to tan powder. The aqueous solubility of bazedoxifene is pH-dependent. Solubility is higher at lower pH. The solubility of bazedoxifene acetate in unbuffered sterile water was measured to be 923 microgramsA/mL at pH 5.4. The following represents the chemical structure of bazedoxifene acetate: DUAVEE is available for oral administration as tablets containing 0.45 mg of conjugated estrogens with 20 mg of bazedoxifene (equivalent to 22.6 mg of bazedoxifene acetate). Each tablet of DUAVEE contains the following inactive ingredients: calcium phosphate tribasic, hydroxypropyl cellulose, microcrystalline cellulose, powdered cellulose, hypromellose, lactose monohydrate, magnesium stearate, polyethylene glycol, sucrose, ascorbic acid, sucrose palmitic acid ester, hydroxyethylcellulose, titanium dioxide, red iron oxide, yellow iron oxide, black iron oxide, povidone, polydextrose, maltitol, poloxamer 188, propylene glycol, and isopropyl alcohol. chemical Structure

Dosage And Administration

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

Indications And Usage

1 INDICATIONS AND USAGE DUAVEE is indicated in women with a uterus for: DUAVEE is a combination of conjugated estrogens with an estrogen agonist/antagonist indicated for treatment of the following conditions in women with a uterus: • Treatment of moderate to severe vasomotor symptoms associated with menopause ( 1.1 ) • Prevention of postmenopausal osteoporosis ( 1.2 ) Limitation of Use : DUAVEE should be used for the shortest duration consistent with treatment goals and risks for the individual woman ( 1.3 ) 1.1 Treatment of Moderate to Severe Vasomotor Symptoms Associated with Menopause 1.2 Prevention of Postmenopausal Osteoporosis 1.3 Important Limitations of Use • Use DUAVEE for the shortest duration consistent with treatment goals and risks for the individual woman. Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary. • When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered.

Overdosage

10 OVERDOSAGE In case of overdosage, there is no specific antidote, and the treatment should be symptomatic. Symptoms of overdosage of estrogen-containing products in adults and children may include nausea, vomiting, breast tenderness, dizziness, abdominal pain, drowsiness/fatigue; withdrawal bleeding may occur.

Adverse Reactions Table

Table 1: Adverse Reactions (Incidence ≥ 5%) More Common in the DUAVEE Treatment Group in Placebo-controlled Trials
DUAVEE (N=1224) n (%)Placebo (N=1069) n (%)

Gastrointestinal disorders

Nausea

100 (8)

58 (5)

Diarrhea

96 (8)

57 (5)

Dyspepsia

84 (7)

59 (6)

Abdominal pain upper

81 (7)

58 (5)

Musculoskeletal and connective tissue disorders

Muscle spasms

110 (9)

63 (6)

Neck pain

62 (5)

46 (4)

Nervous system disorders

Dizziness

65 (5)

37 (3)

Respiratory, thoracic, and mediastinal disorders

Oropharyngeal pain

80 (7)

61 (6)

Drug Interactions

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.

Clinical Pharmacology

12 CLINICAL PHARMACOLOGY 12.1 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. 12.2 Pharmacodynamics Generally, a serum estrogen concentration does not predict an individual woman’s therapeutic response to DUAVEE nor her risk for adverse outcomes. Likewise, exposure comparisons across different estrogen products to infer efficacy or safety for the individual woman may not be valid. 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) C max (ng/mL) T max (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–inf of bazedoxifene by 25%. The C max of 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 max and AUC of bazedoxifene increased 67% and 143%, respectively, compared to healthy subjects. In six moderate hepatic impairment patients (Child Pugh Class B), C max and AUC of bazedoxifene increased 32% and 109%, respectively, compared to healthy subjects. In six severe hepatic impairment patients (Child Pugh Class C), C max 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/m 2 ] and 12 non-obese [mean (SD) BMI = 25.3 (2.6) kg/m 2 ] 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 max and AUC 0–72 increased 9% and 9%, respectively, total equilin C max and AUC 0–72 increased 11% and 5%, respectively, and bazedoxifene C max and AUC 0–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 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 max of 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 max and 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 max of 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 max 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. Co-administration of aluminum/magnesium hydroxide and bazedoxifene decreased C max of 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 max and AUC of unconjugated estrone increased by 11% and 3%, respectively. The C max and 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 max of 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 max of atorvastatin by 14%. The AUC of atorvastatin was unchanged. The C max and AUC of 2-OH atorvastatin were decreased by 18% and 8%, respectively.

Clinical Pharmacology Table

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

Mechanism Of Action

12.1 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.

Pharmacodynamics

12.2 Pharmacodynamics Generally, a serum estrogen concentration does not predict an individual woman’s therapeutic response to DUAVEE nor her risk for adverse outcomes. Likewise, exposure comparisons across different estrogen products to infer efficacy or safety for the individual woman may not be valid.

Pharmacokinetics

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) C max (ng/mL) T max (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–inf of bazedoxifene by 25%. The C max of 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 max and AUC of bazedoxifene increased 67% and 143%, respectively, compared to healthy subjects. In six moderate hepatic impairment patients (Child Pugh Class B), C max and AUC of bazedoxifene increased 32% and 109%, respectively, compared to healthy subjects. In six severe hepatic impairment patients (Child Pugh Class C), C max 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/m 2 ] and 12 non-obese [mean (SD) BMI = 25.3 (2.6) kg/m 2 ] 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 max and AUC 0–72 increased 9% and 9%, respectively, total equilin C max and AUC 0–72 increased 11% and 5%, respectively, and bazedoxifene C max and AUC 0–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 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 max of 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 max and 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 max of 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 max 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. Co-administration of aluminum/magnesium hydroxide and bazedoxifene decreased C max of 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 max and AUC of unconjugated estrone increased by 11% and 3%, respectively. The C max and 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 max of 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 max of atorvastatin by 14%. The AUC of atorvastatin was unchanged. The C max and AUC of 2-OH atorvastatin were decreased by 18% and 8%, respectively.

Pharmacokinetics Table

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

Effective Time

20231101

Version

8

Dosage Forms And Strengths

3 DOSAGE FORMS AND STRENGTHS 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. Tablet containing conjugated estrogens 0.45 mg and bazedoxifene 20 mg ( 3 )

Spl Product Data Elements

Duavee conjugated estrogens/bazedoxifene ESTROGENS, CONJUGATED ESTROGENS, CONJUGATED BAZEDOXIFENE ACETATE BAZEDOXIFENE TRIBASIC CALCIUM PHOSPHATE HYDROXYPROPYL CELLULOSE (1600000 WAMW) MICROCRYSTALLINE CELLULOSE POWDERED CELLULOSE HYPROMELLOSE 2208 (100000 MPA.S) LACTOSE MONOHYDRATE MAGNESIUM STEARATE POLYETHYLENE GLYCOL 400 SUCROSE ASCORBIC ACID SUCROSE PALMITATE HYDROXYETHYL CELLULOSE (100 MPA.S AT 2%) TITANIUM DIOXIDE FERRIC OXIDE RED FERRIC OXIDE YELLOW FERROSOFERRIC OXIDE POVIDONE, UNSPECIFIED POLYDEXTROSE MALTITOL POLOXAMER 188 PROPYLENE GLYCOL ISOPROPYL ALCOHOL pink oval 045;20

Animal Pharmacology And Or Toxicology

13.2 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.

Carcinogenesis And Mutagenesis And Impairment Of Fertility

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Carcinogenicity studies with conjugated estrogens/bazedoxifene have not been conducted. Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver. In 6-month oral gavage carcinogenicity studies of bazedoxifene in transgenic Tg.RasH2 mice, there was a drug-related increased incidence of benign, ovarian granulosa-cell tumors in female mice given 150 or 500 mg/kg/day. In a two-year dietary carcinogenicity study of bazedoxifene in rats (administered at 0.003%, 0.01%, 0.03%, or 0.1%) a drug-related marked increased incidence of benign, ovarian granulosa-cell tumors was observed in female rats at concentrations of 0.03% and 0.1%. Systemic exposure (AUC) of bazedoxifene in these groups was 3 and 8 times that observed in postmenopausal women administered 20 mg/day. In male rats, drug-related renal tumors (adenomas and carcinomas), in the presence of renal toxicity, were observed at all doses tested, which corresponded to exposure ratios of 0.06 to 5 times the clinical AUC at a dose of 20 mg. Mutagenesis Mutagenicity studies with conjugated estrogens/bazedoxifene have not been conducted. Bazedoxifene was not genotoxic or mutagenic in a battery of tests, including in vitro bacterial reverse mutation assay, in vitro mammalian cell forward mutation assay at the thymidine kinase (TK+/-) locus in L5178Y mouse lymphoma cells, in vitro chromosome aberration assay in Chinese hamster ovary (CHO) cells, and in vivo mouse micronucleus assay. Impairment of Fertility Impairment of fertility studies with conjugated estrogens/bazedoxifene have not been conducted. Female rats were administered daily dosages of 0.3 to 30 mg/kg bazedoxifene (0.03 to 10 times human AUC at the 20 mg dose) prior to and during mating with untreated males. Estrous cycles and fertility were adversely affected in all bazedoxifene-treated female groups.

Nonclinical Toxicology

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Carcinogenicity studies with conjugated estrogens/bazedoxifene have not been conducted. Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver. In 6-month oral gavage carcinogenicity studies of bazedoxifene in transgenic Tg.RasH2 mice, there was a drug-related increased incidence of benign, ovarian granulosa-cell tumors in female mice given 150 or 500 mg/kg/day. In a two-year dietary carcinogenicity study of bazedoxifene in rats (administered at 0.003%, 0.01%, 0.03%, or 0.1%) a drug-related marked increased incidence of benign, ovarian granulosa-cell tumors was observed in female rats at concentrations of 0.03% and 0.1%. Systemic exposure (AUC) of bazedoxifene in these groups was 3 and 8 times that observed in postmenopausal women administered 20 mg/day. In male rats, drug-related renal tumors (adenomas and carcinomas), in the presence of renal toxicity, were observed at all doses tested, which corresponded to exposure ratios of 0.06 to 5 times the clinical AUC at a dose of 20 mg. Mutagenesis Mutagenicity studies with conjugated estrogens/bazedoxifene have not been conducted. Bazedoxifene was not genotoxic or mutagenic in a battery of tests, including in vitro bacterial reverse mutation assay, in vitro mammalian cell forward mutation assay at the thymidine kinase (TK+/-) locus in L5178Y mouse lymphoma cells, in vitro chromosome aberration assay in Chinese hamster ovary (CHO) cells, and in vivo mouse micronucleus assay. Impairment of Fertility Impairment of fertility studies with conjugated estrogens/bazedoxifene have not been conducted. Female rats were administered daily dosages of 0.3 to 30 mg/kg bazedoxifene (0.03 to 10 times human AUC at the 20 mg dose) prior to and during mating with untreated males. Estrous cycles and fertility were adversely affected in all bazedoxifene-treated female groups. 13.2 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.

Application Number

NDA022247

Brand Name

Duavee

Generic Name

conjugated estrogens/bazedoxifene

Product Ndc

63539-122

Product Type

HUMAN PRESCRIPTION DRUG

Route

ORAL

Package Label Principal Display Panel

PRINCIPAL DISPLAY PANEL - 7 Tablet Blister Card PROFESSIONAL SAMPLE - NOT FOR SALE NDC 63539-122-07 Pfizer Duavee™ (conjugated estrogens/ bazedoxifene) tablets per tablet 0.45 mg/20 mg* *Each tablet contains bazedoxifene equivalent to 22.6 mg of bazedoxifene acetate 7 tablets After opening foil pouch, product must be used within 60 days. Date foil pouch opened: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. DOSAGE AND USE: See accompanying prescribing information. Store product in original package to keep from moisture. Tablets should not be removed from blisters until immediately before administration. Do not place medication in pill boxes. Distributed by U.S. Pharmaceuticals Pfizer Inc, NY, NY 10017 MADE IN IRELAND Rx only PAA042983 LOT: EXP: PRINCIPAL DISPLAY PANEL - 15 Tablet Blister Card

Recent Major Changes

Boxed Warning 12/2022

Recent Major Changes Table

Boxed Warning

12/2022

Spl Unclassified Section

This product's labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com. LAB-0582-8.0 Logo

Information For Patients

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information) . 17.1 Instructions for Patients • Keep DUAVEE in the original container to protect from moisture. Do not place DUAVEE in pill boxes or pill organizers. • If more than one blister package is dispensed to the patient, instruct them to open one foil pouch at a time. • Instruct patient to record the date the blister package is opened in the space provided on the blister package label. Do not use if the blister package has been open more than 60 days. • Instruct patient to remove only one tablet from the blister package at the time of use. 17.2 Venous Thromboembolic Events Advise patients to immediately report to their physician any signs or symptoms related to venous thrombosis and thromboembolic events [see Warnings and Precautions (5.2) ] . 17.3 Abnormal Vaginal Bleeding Inform postmenopausal women of the importance of reporting abnormal vaginal bleeding to their healthcare provider as soon as possible [see Warnings and Precautions (5.3) ]. 17.4 Possible Serious Adverse Reactions with Estrogen Therapy Inform postmenopausal women of possible serious adverse reactions of estrogen therapy including Cardiovascular Disorders, Malignant Neoplasms, and Probable Dementia [see Warnings and Precautions (5.2 , 5.3 , 5.4) ] . 17.5 Possible Less Serious Adverse Reactions with DUAVEE Inform postmenopausal women of possible less serious but common adverse reactions of DUAVEE therapy such as muscle spasms, nausea, diarrhea, dyspepsia, upper abdominal pain, throat pain, dizziness and neck pain. 17.6 Calcium and Vitamin D Intake Advise patients to add supplemental calcium and/or vitamin D to the diet if daily intake is inadequate.

Spl Patient Package Insert Table

What is the most important information I should know about DUAVEE?

  • Do not take additional estrogen products while you are taking DUAVEE.
  • Using estrogen-alone may increase your chance of getting cancer of the uterus (womb).
  • Report any unusual vaginal bleeding right away while you are taking DUAVEE. Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause.
  • Do not use estrogens to prevent heart disease, heart attacks, strokes or dementia (decline in brain function).
  • Using estrogen-alone may increase your chances of getting strokes or blood clots.
  • Using estrogen-alone may increase your chance of getting dementia, based on a study of women 65 years of age or older.
  • The risks listed above are based on a study of an estrogen-alone oral product. Since other products and doses have not been studied in the same way, it is not known how the use of DUAVEE will affect your chances of getting these conditions. You and your healthcare provider should talk regularly about whether you still need treatment with DUAVEE.
  • Clinical Studies

    14 CLINICAL STUDIES 14.1 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, placebo-controlled 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) Frequency Severity DUAVEE Placebo DUAVEE Placebo N 122 63 122 63 Baseline 10.3 10.5 2.3 2.3 Week 4 Mean Change Change from baseline using ANCOVA model -5.9 -2.8 -0.6 -0.1 Treatment Difference Based on raw data analysis using ANCOVA model: Difference= Treatment + Baseline + Site -3.1 (-4.4, -1.7) p<0.001 -- -0.5 (-0.7, -0.3) -- Week 12 Mean Change -7.6 -4.9 -0.9 -0.3 Treatment Difference -2.7 (-3.8, -1.6) -- -0.6 (-0.9, -0.4) -- 14.2 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) DUAVEE Placebo ** 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. Between 1 and 5 Years Postmenopausal N 95 95 % Mean Change 1.72 -1.90 Difference from Placebo (95% C.I.) 3.62 (2.64, 4.60) p-value < 0.001 More Than 5 Years Postmenopausal N 155 151 % Mean Change 1.64 -1.47 Difference from Placebo (95% C.I.) 3.11 (2.29, 3.93) – 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%. 14.3 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 STUDY 1 = Efficacy Evaluable population STUDY 2 Treatment Group Month % (n/N) 1 – Sided 95% UL % (n/N) 1 – Sided 95% UL UL = Upper limit DUAVEE 12 0.00% (0/336) 0.89 0.30% (1/335) 1.41 24 0.68% (2/294) 2.13 -- -- 14.4 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. 14.5 Women'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 "global index" 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 WHI Adapted from numerous WHI publications. WHI publications can be viewed at www.nhlbi.nih.gov/whi. Event Relative Risk CE vs. Placebo (95% nCI Nominal confidence intervals unadjusted for multiple looks and multiple comparisons. ) CE n = 5,310 Placebo N = 5,429 Absolute Risk per 10,000 Women-Years CHD events Results are based on centrally adjudicated data for an average follow-up of 7.1 years. 0.95 (0.78–1.16) 54 57 Non-fatal MI 0.91 (0.73–1.14) 40 43 CHD death 1.01 (0.71–1.43) 16 16 All strokes 1.33 (1.15–1.68) 45 33 Ischemic stroke 1.55 (1.19–2.01) 38 25 Deep vein thrombosis , Not included in "global index". 1.47 (1.06–2.06) 23 15 Pulmonary embolism 1.37 (0.90–2.07) 14 10 Invasive breast cancer 0.80 (0.62–1.04) 28 34 Colorectal cancer Results are based on an average follow-up of 6.8 years. 1.08 (0.75–1.55) 17 16 Hip fracture 0.65 (0.45–0.94) 12 19 Vertebral fractures , 0.64 (0.44–0.93) 11 18 Lower arm/wrist fractures , 0.58 (0.47–0.72) 35 59 Total fractures , 0.71 (0.64–0.80) 144 197 Death due to other causes , All deaths, except from breast or colorectal cancer, definite or probable CHD, PE, or cerebrovascular disease. 1.08 (0.88–1.32) 53 50 Overall mortality , 1.04 (0.88–1.22) 79 75 Global Index A subset of the events was combined in a "global index", 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. 1.02 (0.92–1.13) 206 201 For those outcomes included in the WHI "global index" 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 "global index" 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)]. 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) ] .

    Clinical Studies Table

    Table 3: Adjusted Mean Change from Baseline in the Average Daily Frequency and Severity of Hot Flushes (Study 3)
    FrequencySeverity
    DUAVEEPlaceboDUAVEEPlacebo

    N

    122

    63

    122

    63

    Baseline

    10.3

    10.5

    2.3

    2.3

    Week 4

    Mean ChangeChange from baseline using ANCOVA model

    -5.9

    -2.8

    -0.6

    -0.1

    Treatment DifferenceBased on raw data analysis using ANCOVA model: Difference= Treatment + Baseline + Site

    -3.1 (-4.4, -1.7)p<0.001

    --

    -0.5 (-0.7, -0.3)

    --

    Week 12

    Mean Change

    -7.6

    -4.9

    -0.9

    -0.3

    Treatment Difference

    -2.7 (-3.8, -1.6)

    --

    -0.6 (-0.9, -0.4)

    --

    Geriatric Use

    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) ].

    Pediatric Use

    8.4 Pediatric Use DUAVEE is not indicated for use in children [see Indications and Usage (1) ] .

    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).

    Use In Specific Populations

    8 USE IN SPECIFIC POPULATIONS • Geriatric Use: DUAVEE was not studied in women aged 75 or older ( 8.5 , 12.3 ); use in this population is not recommended ( 2.7 , 8.5 ) • 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 , 8.5 , 14.6 ) • Renal Impairment: DUAVEE was not studied in women with renal impairment; use in this population is not recommended ( 2.6 , 8.6 , 12.3 ) 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). 8.2 Lactation 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) ]. 8.3 Females and Males of Reproductive Potential 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) ] . 8.4 Pediatric Use DUAVEE is not indicated for use in children [see Indications and Usage (1) ] . 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) ]. 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 . 8.7 Hepatic 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 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. 8.8 Body Mass Index (BMI) 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/m 2 ] and 12 non-obese BMI < 30 [mean (SD) 25.3 (2.6) kg/m 2 ] 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) ] .

    How Supplied

    16 HOW SUPPLIED/STORAGE AND HANDLING DUAVEE tablets contain 0.45 mg conjugated estrogens and 20 mg bazedoxifene. The tablets are oval, biconvex, and pink, branded with "0.45/20" in black ink on one side. DUAVEE ® tablets are supplied as follows: Package NDC number Conjugated estrogens 0.45 mg/bazedoxifene 20 mg 2 blisters of 15 tablets each NDC 0008-1123-12 Storage Blisters DUAVEE tablets should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). See USP Controlled Room Temperature. Dispense product in the original package. Tablets should not be removed from blisters until immediately before use. Protect from moisture. After opening foil pouch, product must be used within 60 days.

    How Supplied Table

    PackageNDC number

    Conjugated estrogens 0.45 mg/bazedoxifene 20 mg

    2 blisters of 15 tablets each

    NDC 0008-1123-12

    Storage And Handling

    Storage Blisters DUAVEE tablets should be stored at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). See USP Controlled Room Temperature. Dispense product in the original package. Tablets should not be removed from blisters until immediately before use. Protect from moisture. After opening foil pouch, product must be used within 60 days.

    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 disease or dementia ( 5.2 , 5.4 ) • The Women's Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) ( 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 ( 5.4 )

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