Conjugated estrogens/bazedoxifene

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# Black Box Warning

# Overview
Conjugated estrogens/bazedoxifene is a combination of conjugated estrogens with an estrogen agonist/antagonist that is FDA approved for the treatment of moderate to severe vasomotor symptoms associated with menopause and prevention of postmenopausal osteoporosis. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include muscle spasms, nausea, diarrhea, dyspepsia, abdominal pain upper, oropharyngeal pain, dizziness, and neck pain.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- The recommended dosage is one DUAVEE tablet daily.
- The recommended dosage is one DUAVEE tablet daily.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Conjugated estrogens/bazedoxifene in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Conjugated estrogens/bazedoxifene in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Conjugated estrogens/bazedoxifene in pediatric patients.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Conjugated estrogens/bazedoxifene in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Conjugated estrogens/bazedoxifene in pediatric patients.

# 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, women who may become pregnant, and nursing mothers. DUAVEE may cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus

# Warnings

### Precautions
- Drugs Containing Progestins, Estrogens or Estrogen Agonist/Antagonists
- DUAVEE contains conjugated estrogens and bazedoxifene, an estrogen agonist/antagonist. Women taking DUAVEE should not take progestins, additional estrogens or additional estrogen agonist/antagonists.
- Cardiovascular Disorders
- Estrogen agonist/antagonists (including bazedoxifene, a component of DUAVEE) and estrogens individually are known to increase the risk of VTE.
- An increased risk of stroke and DVT has been reported with estrogen-alone therapy. Should any of these occur or be suspected, DUAVEE should be discontinued immediately.
- Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or VTE (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately.
- Stroke
- In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily conjugated estrogens (CE) (0.625 mg)-alone compared to women in the same age group receiving placebo (45 versus 33 per 10,000 women-years). The increase in risk was demonstrated in year 1 and persisted .
- Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving conjugated estrogens (0.625 mg)-alone versus those receiving placebo (18 versus 21 per 10,000 women-years).
- Should a stroke occur or be suspected, DUAVEE should be discontinued immediately.
- Coronary Heart Disease
- In the WHI estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as nonfatal myocardial infarction, silent myocardial infarction, or CHD death) was reported in women receiving estrogen-alone compared to placebo.
- Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant reduction in CHD events (CE -alone compared to placebo) in women with less than 10 years since menopause (8 versus 16 per 10,000 women-years).
- Venous Thromboembolism (VTE)
- In the WHI estrogen-alone substudy, the risk of VTE ] and pulmonary embolism (PE)] was increased for women receiving daily conjugated estrogens (0.625 mg)-alone compared to placebo (30 versus 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 versus 15 per 10,000 women-years). The increase in VTE risk was demonstrated during the first 2 years .
- If feasible, DUAVEE should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. Because immobilization increases the risk for venous thromboembolic events independent of therapy, DUAVEE should be discontinued prior to and during prolonged immobilization (e.g., post-surgical recovery, prolonged bed rest) and DUAVEE therapy should be resumed only after the patient is fully ambulatory. In addition, women taking DUAVEE should be advised to move about periodically during travel involving prolonged immobilization.
- Malignant Neoplasms
- Endometrial Cancer
- An increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in women with a uterus. The reported endometrial cancer risk among unopposed estrogen users is about 2 to 12 times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than 1 year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more of treatment. This risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.
- DUAVEE contains an estrogen agonist/antagonist. This component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component. Endometrial hyperplasia may be a precursor to endometrial cancer. Women taking DUAVEE should not take additional estrogens as this may increase the risk of endometrial hyperplasia.
- Clinical surveillance of all women taking DUAVEE is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding.
- Breast Cancer
- The most important randomized clinical study providing information about breast cancer in estrogen-alone users is the WHI substudy of daily conjugated estrogens (0.625 mg)-alone. In the WHI estrogen-alone substudy, after an average follow-up of 7.1 years, daily conjugated estrogen (0.625 mg)-alone was not associated with an increased risk of invasive breast cancer (relative risk  0.80).
- The use of estrogen-alone has been reported to result in an increase in abnormal mammograms requiring further evaluation. The effect of treatment with DUAVEE on the risk of breast cancer is unknown.
- All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.
- Ovarian Cancer
- In some epidemiological studies, the use of estrogen-only products, in particular for 5 or more years, has been associated with an increased risk of ovarian cancer. However, the duration of exposure associated with increased risk is not consistent across all epidemiologic studies, and some report no association. The effect of treatment with DUAVEE on the risk of ovarian cancer is unknown.
- Probable Dementia
- In the WHIMS estrogen-alone ancillary study of WHI, a population of 2,947 hysterectomized women 65 to 79 years of age was randomized to daily CE (0.625 mg)-alone or placebo.
- After an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.832.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years.
- Gallbladder Disease
- A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.
- Visual Abnormalities
- Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, DUAVEE should be permanently discontinued.
- Elevated Blood Pressure
- In a small number of case reports in women receiving estrogens, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical study, a generalized effect of estrogens on blood pressure was not seen.
- Hypertriglyceridemia
- In women with pre-existing hypertriglyceridemia, treatment with estrogens may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of DUAVEE if pancreatitis occurs.
- Hepatic Impairment and Past History of Cholestatic Jaundice
- DUAVEE has not been studied in women with impaired liver function or past history of cholestatic jaundice.
- Estrogens may be poorly metabolized in women with impaired liver function.
- On average, women with hepatic impairment treated with bazedoxifene alone showed a 4.3-fold increase in overall exposures compared with controls.
- For women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised; and in the case of recurrence, DUAVEE should be discontinued. Use of DUAVEE in patients with hepatic impairment is contraindicated.
- Hypothyroidism
- Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Women with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Women dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These women should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.
- Fluid Retention
- Estrogens may cause some degree of fluid retention. Because of this, patients who have conditions that might be influenced by this factor, such as cardiac dysfunction or renal impairment, warrant careful observation when estrogens are prescribed. Use of DUAVEE in patients with renal impairment is not recommended.
- Hypocalcemia
- Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur.
- Hereditary Angioedema
- Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema.
- Exacerbation of Other Conditions
- Estrogens may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine or porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.
- Premenopausal Women
- There is no indication for premenopausal use of DUAVEE. The efficacy and safety of DUAVEE in premenopausal women have not been established, and its use is not recommended.
- Laboratory Tests
- Serum follicle stimulating hormone (FSH) and estradiol levels have not been shown to be useful in the management of moderate to severe vasomotor symptoms.
- Drug-Laboratory Test Interactions
- Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of antifactor Xa and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.
- Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay), or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Women on thyroid replacement therapy may require higher doses of thyroid hormone.
- Other binding proteins may be elevated in serum, for example, corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG), leading to increased total circulating corticosteroids and sex steroids, respectively. Free hormone concentrations, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).
- Increased plasma high-density lipoprotein (HDL) and HDL2 cholesterol subfraction concentrations, reduced low-density lipoprotein (LDL) cholesterol concentrations, increased triglyceride levels.
- Impaired glucose tolerance.

# Adverse Reactions

## 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 (6001200 mg) and vitamin D (200400 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.
- 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.

## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Conjugated estrogens/bazedoxifene in the drug label.

# Drug Interactions
- Cytochrome P450 (CYP)
- In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Inducers of CYP3A4, such as St. John's Wort (Hypericum perforatum) preparations, phenobarbital, carbamazepine, and rifampin, may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile.
- Inhibitors of CYP3A4, such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice, may increase the exposure of conjugated estrogens resulting in an increased risk of endometrial hyperplasia. Therefore, for chronically administered CYP3A4 inhibitors (>30 days) concurrently administered with DUAVEE, adequate diagnostic measures, including directed or random endometrial sampling when indicated by signs and symptoms of endometrial hyperplasia, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding.
- Bazedoxifene undergoes little or no cytochrome P450 (CYP)-mediated metabolism. 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.
- 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.
- 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.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category X
- DUAVEE must not be used in women who are or may become pregnant.
- No studies were performed on animals to evaluate the effects on reproduction with conjugated estrogens/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).
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Conjugated estrogens/bazedoxifene in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Conjugated estrogens/bazedoxifene during labor and delivery.

### Nursing Mothers
- DUAVEE should not be used by lactating women. It is not known whether this drug is excreted in human milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving conjugated estrogens. Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of the milk.

### Pediatric Use
- DUAVEE is not indicated for use in children.

### Geriatic Use
- DUAVEE is not recommended for use in women greater than 75 years of age\.
- 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 6574 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)\.

### Gender
There is no FDA guidance on the use of Conjugated estrogens/bazedoxifene with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Conjugated estrogens/bazedoxifene with respect to specific racial populations.

### Renal Impairment
- DUAVEE is not recommended for use in patients with renal impairment.
- The pharmacokinetics, safety, and efficacy of DUAVEE have not been evaluated in women with renal impairment.

### Hepatic Impairment
- DUAVEE is contraindicated in patients with hepatic impairment.
- The pharmacokinetics, safety, and efficacy of DUAVEE have not been evaluated in women with hepatic impairment. In a pharmacokinetics study of bazedoxifene 20 mg alone, the Cmax and AUC of bazedoxifene increased 67% and 143%, respectively, in women with mild hepatic impairment (Child Pugh Class A), compared to healthy women. The Cmax and AUC of bazedoxifene increased 32% and 109%, respectively, in women with moderate hepatic impairment (Child Pugh Class B). The Cmax and AUC of bazedoxifene increased 20% and 268%, respectively, in women with severe hepatic impairment (Child Pugh Class C).
No pharmacokinetic studies with conjugated estrogens were conducted in women with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Conjugated estrogens/bazedoxifene in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Conjugated estrogens/bazedoxifene in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Oral

### Monitoring
There is limited information regarding Monitoring of Conjugated estrogens/bazedoxifene in the drug label.

# IV Compatibility
There is limited information regarding IV Compatibility of Conjugated estrogens/bazedoxifene in the drug label.

# Overdosage

## Acute Overdose

### Signs and Symptoms
- 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.

### Management
- In case of overdosage, there is no specific antidote, and the treatment should be symptomatic.

## Chronic Overdose
There is limited information regarding Chronic Overdose of Conjugated estrogens/bazedoxifene in the drug label.

# Pharmacology
There is limited information regarding Conjugated estrogens/bazedoxifene Pharmacology in the drug label.

## Mechanism of Action
- DUAVEE pairs conjugated estrogens with bazedoxifene. Conjugated estrogens and bazedoxifene function by binding to and activating estrogen receptors (ER)  and , which vary in proportion from tissue to tissue. Conjugated estrogens are composed of multiple estrogens and are agonists of ER-  and . 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.

## Structure
- 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, 17-dihydroequilin, 17-estradiol, and 17-dihydroequilin.
- Bazedoxifene is supplied as the acetate salt (bazedoxifene acetate) and has the chemical name 1H-Indol-5-ol, 1-phenyl]methyl]-2-(4-hydroxyphenyl)-3-methyl-, monoacetate. The empirical formula is C30H34N2O3  C2H4O2, 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 gA/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.

## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Conjugated estrogens/bazedoxifene in the drug label.

## 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.
- 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 AUC0inf of bazedoxifene by 25%. The Cmax 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- 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, 17-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.
- Geriatric
- The effect of age on the pharmacokinetics of conjugated estrogens/bazedoxifene tablets have not been evaluated.
- 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.
- Hepatic Impairment
- The pharmacokinetics of conjugated estrogens/bazedoxifene tablets have not been evaluated in women with hepatic impairment.
- 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.
- Drug Interactions
- No drug-drug interaction studies were conducted with conjugated estrogens/bazedoxifene tablets.
- 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 Cmax 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 Cmax 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 Cmax 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 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. Co-administration 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
- 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 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.
- 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 Cmax 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 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.

## Nonclinical Toxicology
- 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.
- 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.

# Clinical Studies
- 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 4264 (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.
- 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 15 years postmenopausal with at least one additional risk factor for osteoporosis. A total of 3,397 women age 4075 (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 (6001200 mg) and vitamin D (200400 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).
- 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 4660 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 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).
- 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.
- 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.
- 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  and overall mortality .
- 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, 0.832.66). 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.

# How Supplied
- 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:
- 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 20C to 25C (68F to 77F); excursions permitted to 15C to 30C (59F to 86F). 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.

## Storage
There is limited information regarding Conjugated estrogens/bazedoxifene Storage in the drug label.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
- 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.
- Venous Thromboembolic Events
- Advise patients to immediately report to their physician any signs or symptoms related to venous thrombosis and thromboembolic events.
- Abnormal Vaginal Bleeding
- Inform postmenopausal women of the importance of reporting abnormal vaginal bleeding to their healthcare provider as soon as possible.
- 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.
- 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.
- Calcium and Vitamin D Intake
- Advise patients to add supplemental calcium and/or vitamin D to the diet if daily intake is inadequate.

# Precautions with Alcohol
- Alcohol-Conjugated estrogens/bazedoxifene interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- DUAVEE

# Look-Alike Drug Names
There is limited information regarding Conjugated estrogens/bazedoxifene Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price