Bazedoxifene acetate is a tissue-selective, estrogen agonist-antagonist.1, 25
Prevention in Postmenopausal Women
Bazedoxifene acetate in fixed combination with conjugated estrogens is used for the prevention of osteoporosis in postmenopausal women with an intact uterus.1 Safety and efficacy of bazedoxifene/conjugated estrogens in fixed combination for prevention of osteoporosis in premenopausal women† have not been established;1 use in such patients is not recommended.1
Safety and efficacy of bazedoxifene in fixed combination with conjugated estrogens have been evaluated for the prevention of osteoporosis in postmenopausal women in 2 double-blind, randomized, placebo- and active-controlled studies (SMART-1 and SMART-5).1, 3, 4 In the SMART-1 study, postmenopausal women with an intact uterus were randomized to 1 of 8 treatment groups; 6 treatment groups received various dosage combinations of bazedoxifene/conjugated estrogens fixed-combination therapy once daily, while the other 2 groups received raloxifene 60 mg once daily or placebo.1, 3 Women also received supplemental calcium (600-1200 mg) and vitamin D (200-400 units) daily.1, 3 The SMART-1 study consisted of 2 substudies.1, 3 In Substudy I, women were more than 5 years postmenopausal, had a lumbar spine or total hip bone mineral density (BMD) T-score of -1 to -2.5, and had at least 1 additional risk factor for osteoporosis.1 Of the 1454 women in this substudy (mean age 58 years), 182 received bazedoxifene 20 mg in fixed combination with conjugated estrogens 0.45 mg once daily (mean baseline BMD T-score of -1.43) and 184 women received placebo (mean baseline BMD T-score of -1.52).1, 3 Women in Substudy II were 1-5 years postmenopausal and had at least 1 additional risk factor for osteoporosis.1, 3 Of the 861 women in this substudy (mean age 52 years), 111 received bazedoxifene 20 mg in fixed combination with conjugated estrogens 0.45 mg once daily (mean baseline BMD T-score of -0.81) and 108 women received placebo (mean baseline BMD T-score of -0.94).1, 3 The primary end point of both substudies was change in BMD at the lumbar spine;3 change in BMD of the hip was evaluated as a secondary end point.3 At 24 months, women receiving bazedoxifene 20 mg in fixed combination with conjugated estrogens 0.45 mg experienced substantially increased lumbar spine BMD compared with women receiving placebo in Substudy I (treatment difference 3.11%) and Substudy II (treatment difference 3.62%).1, 3 These women also had substantially increased total hip BMD compared with those receiving placebo in Substudy I (treatment difference 1.73%) and Substudy II (treatment difference 1.96%).1, 2, 3
In the SMART-5 study, bazedoxifene in fixed combination with conjugated estrogens was evaluated for the prevention of osteoporosis in a substudy of 590 women less than 5 years postmenopausal with an intact uterus.1, 4 Women were randomized to receive once daily therapy with bazedoxifene 20 mg in fixed combination with conjugated estrogens 0.45 mg, bazedoxifene 20 mg in fixed combination with conjugated estrogens 0.625 mg, bazedoxifene 20 mg alone, medroxyprogesterone acetate 1.5 mg in fixed combination with conjugated estrogens 0.45 mg, or placebo.4 All women also received supplemental calcium 600 mg daily and vitamin D 400 units daily.4 The primary end point of the osteoporosis substudy was percent change from baseline in lumber spine BMD;4 change in BMD of the hip was evaluated as a secondary end point.4 At 12 months, all active treatment groups showed an increased lumbar spine BMD and total hip BMD while women in the placebo group experienced decreased BMD.4 Women receiving bazedoxifene 20 mg in fixed combination with conjugated estrogens 0.45 mg experienced substantially increased mean lumbar spine and total hip BMD (treatment difference of 1.51 and 1.21%, respectively, compared with placebo).1
Treatment in Postmenopausal Women
Bazedoxifene 20 mg is commercially available in other countries for the treatment† of postmenopausal osteoporosis.7 However, the drug currently is not FDA-labeled for the treatment of osteoporosis in the US.1 Efficacy and safety of bazedoxifene were evaluated in a randomized, double-blind, placebo- and active-controlled, phase 3 clinical study in postmenopausal women with osteoporosis.14, 15 Patients receiving bazedoxifene 20 or 40 mg once daily for up to 5 years experienced a substantially decreased incidence of new vertebral fractures, increased lumbar spine BMD, and decreased bone turnover markers (e.g., serum osteocalcin and C-telopeptide) compared with those receiving placebo.14, 15
Bazedoxifene/conjugated estrogens fixed-combination therapy is used for the management of moderate to severe vasomotor symptoms associated with menopause in women with an intact uterus.1
Safety and efficacy of bazedoxifene/conjugated estrogens fixed-combination therapy have been evaluated for the treatment of moderate to severe vasomotor symptoms associated with menopause in a randomized, double-blind, placebo-controlled study (SMART-2).1, 5, 8 Over 300 women (mean age 53 years, mean time since menopause 4.5 years) with a baseline of at least 7 moderate to severe hot flushes per day or at least 50 per week were randomized to receive once daily therapy with bazedoxifene 20 mg in fixed combination with conjugated estrogens 0.45 mg, bazedoxifene 20 mg in fixed combination with conjugated estrogens 0.625 mg, or placebo.1, 5, 8 The primary efficacy outcomes were change from baseline in the average daily number of hot flushes (moderate and severe) and severity rating of hot flushes.5 At 12 weeks, women receiving bazedoxifene 20 mg in fixed combination with conjugated estrogens 0.45 mg experienced a 74% reduction in number of hot flushes from baseline compared with a 47% reduction in women receiving placebo.1 The severity rating of hot flushes also was substantially decreased in women receiving bazedoxifene/conjugated estrogens fixed-combination therapy when compared with placebo.1, 5 Reduction in severity of hot flushes was observed as early as 3 weeks following initiation of therapy with bazedoxifene 20 mg in fixed combination with conjugated estrogens 0.45 mg.5 In a secondary analysis of data from the SMART-2 study, women receiving bazedoxifene 20 mg in fixed combination with conjugated estrogens 0.45 mg showed a mean increase from baseline of 2.8 days per week without moderate to severe hot flushes compared with an increase of 1 day per week in women receiving placebo.8
In a double-blind, randomized, placebo- and active-controlled study (SMART-1), the number and severity of hot flushes were evaluated in a subset of 216 women reporting at least 7 hot flushes per day or more than 50 per week at baseline.6 At 12 weeks, women receiving bazedoxifene 20 mg in fixed combination with conjugated estrogens 0.45 mg experienced a greater mean reduction from baseline in the average daily number of hot flushes and also experienced a decreased severity of hot flushes compared with those receiving placebo.6, 7 These effects were sustained through 2 years of treatment with the fixed-combination therapy.6
Bazedoxifene acetate in fixed combination with conjugated estrogens should be prescribed at the lowest effective dosage for the shortest duration consistent with treatment goals and risks for the individual woman.1 Postmenopausal women receiving the fixed-combination therapy should be reevaluated periodically as clinically appropriate to determine if continued treatment is necessary.1
Patients receiving bazedoxifene/conjugated estrogens fixed-combination therapy for prevention of osteoporosis should receive supplemental calcium and/or vitamin D if daily dietary intake is inadequate.1
Bazedoxifene/conjugated estrogens fixed-combination tablets are administered orally without regard to meals.1 Tablets should be swallowed whole.1
Dosage of bazedoxifene acetate is expressed in terms of bazedoxifene.1
Each tablet of bazedoxifene acetate in fixed combination with conjugated estrogens contains bazedoxifene 20 mg and conjugated estrogens 0.45 mg.1
For the prevention of osteoporosis in postmenopausal women, the recommended dosage of bazedoxifene/conjugated estrogens fixed-combination therapy is bazedoxifene 20 mg with conjugated estrogens 0.45 mg once daily.1
For the management of moderate to severe vasomotor symptoms associated with menopause, the recommended dosage of bazedoxifene/conjugated estrogens fixed-combination therapy is bazedoxifene 20 mg with conjugated estrogens 0.45 mg once daily.1
When bazedoxifene acetate is used in fixed combination with conjugated estrogens, dosage requirements for conjugated estrogens should be considered.1
Bazedoxifene/conjugated estrogens fixed-combination therapy is contraindicated in patients with hepatic impairment.1 (See Cautions: Contraindications.)
Use of bazedoxifene/conjugated estrogens fixed-combination therapy is not recommended in patients with renal impairment.1
Bazedoxifene acetate in fixed combination with conjugated estrogens is contraindicated in women with undiagnosed abnormal uterine bleeding, women with known or suspected estrogen-dependent neoplasia, and women with known or suspected breast cancer or a history of breast cancer.1 (See Genitourinary Effects under Warnings/Precautions: Warnings, in Cautions and also see Carcinogenicity under Warnings/Precautions: Other Warnings/Precautions, in Cautions.)
The fixed-combination therapy is contraindicated in women with active deep-vein thrombosis (DVT), pulmonary embolism (PE), active arterial thromboembolic disease (e.g., stroke, myocardial infarction [MI]), or history of these conditions.1 (See Cardiovascular Effects under Warnings/Precautions: Warnings, in Cautions.)
The fixed-combination therapy also is contraindicated in women with known hepatic impairment or disease; known protein C, protein S, or antithrombin deficiency; other known thrombophilic disorders; or hypersensitivity (e.g., anaphylaxis, angioedema) to any ingredient in the formulation.1
Bazedoxifene/conjugated estrogens fixed-combination therapy is contraindicated in women who are or may become pregnant.1 (See Fetal/Neonatal Morbidity and Mortality under Warnings/ Precautions: Other Warnings/Precautions, in Cautions and also see Pregnancy under Warnings/Precautions: Specific Populations, in Cautions.) The drug also is contraindicated in women who are breast-feeding.1 (See Lactation under Warnings/Precautions: Specific Populations, in Cautions.)
When bazedoxifene acetate is used in fixed combination with conjugated estrogens, the usual cautions, precautions, contraindications, and interactions associated with conjugated estrogens must be considered.1 Cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, or geriatric patients) should be considered for each drug in the fixed combination.1
Risk factors for cardiovascular disorders, arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, obesity), and/or venous thromboembolism (VTE) including personal or family history of VTE, obesity, or systemic lupus erythematosus should be managed appropriately during bazedoxifene/conjugated estrogens fixed-combination therapy.1 Estrogen therapy should not be used for the prevention of cardiovascular disease.1
When used individually, estrogen agonists-antagonists, including bazedoxifene, and conjugated estrogens are known to increase the risk of VTE.1 In the Women's Health Initiative (WHI) study of estrogen alone, an increased risk of stroke and VTE (including DVT and PE) was reported in postmenopausal women (50-79 years of age) receiving oral conjugated estrogens alone at a dosage of 0.625 mg daily over 7.1 years compared with women receiving placebo.1 Increased risk of stroke was demonstrated during the first year of the study and persisted; for VTE, increased risk was evident during the first 2 years of the study.1 In the WHI study, no overall effect on coronary heart disease (CHD) events (i.e., nonfatal or silent MI, CHD death) was reported in women receiving estrogen therapy alone versus placebo.1 In clinical studies of bazedoxifene/conjugated estrogens fixed-combination therapy, VTE was reported in 0% of women receiving the fixed combination and 0.1% of women receiving placebo.1 As a result of the low rate of VTE in both groups, it is not possible to conclude that the risk of VTE with bazedoxifene/conjugated estrogens fixed-combination therapy is different from that observed with other estrogen preparations.1
Bazedoxifene/conjugated estrogens fixed-combination therapy should be discontinued immediately if VTE (including PE or DVT) or stroke occurs or is suspected.1 If possible, the drug should be discontinued at least 4-6 weeks prior to surgery associated with an increased risk of thromboembolism or during periods of prolonged immobilization and should not be resumed until the patient is fully ambulatory.1 Women receiving bazedoxifene/conjugated estrogens fixed-combination therapy should be advised to ambulate periodically during travel involving prolonged immobilization.1
There have been reports of substantial increases in blood pressure attributed to idiosyncratic reactions to estrogens.1 A generalized effect of estrogens on blood pressure was not observed in a large, randomized, placebo-controlled study.1
Bazedoxifene/conjugated estrogens fixed-combination therapy may cause increased plasma high-density lipoprotein [HDL]-cholesterol and HDL2-cholesterol subfraction concentrations, decreased low-density lipoprotein [LDL]-cholesterol concentrations, and increased triglyceride concentrations.1
Estrogens may cause some degree of fluid retention.1 Therefore, women with conditions that might be aggravated by fluid retention (e.g., cardiac dysfunction, renal impairment) should be carefully observed when receiving estrogens.1
Results from the WHI Memory Study (WHIMS; an ancillary study of the WHI study in women 65-79 years of age without an intact uterus) indicate that use of conjugated estrogens 0.625 mg daily increases the risk of probable dementia in women receiving conjugated estrogens compared with women receiving placebo (absolute risk: 37 versus 25 cases per 10,000 women-years; relative risk: 1.49 [0.83-2.66]) after an average follow-up of 5.2 years.1 It is unknown whether this finding is applicable to younger postmenopausal women.1
Estrogen therapy should not be used for the prevention of dementia.1
Bazedoxifene is an estrogen agonist-antagonist, which reduces the risk of endometrial hyperplasia that can occur when conjugated estrogens are used alone.1, 2, 4, 9 Postmenopausal women with an intact uterus receiving estrogen therapy alone are at increased risk of endometrial cancer.1 Such risk is dependent on duration of therapy and estrogen dosage and has been shown to persist for at least 8-15 years after estrogen therapy is discontinued.1 The use of bazedoxifene with conjugated estrogens reduces the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.1 In clinical studies of bazedoxifene/conjugated estrogens fixed-combination therapy, the incidence of endometrial hyperplasia or malignancy was less than 1% in women receiving the fixed combination for up to 24 months.1, 4, 9
Clinical surveillance is important for all women receiving bazedoxifene/conjugated estrogens fixed-combination therapy.1 Adequate diagnostic measures, including directed and random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurrent abnormal genital bleeding.1 In addition, women receiving the fixed-combination therapy should not use additional estrogens as this may increase the risk of endometrial hyperplasia.1
Fetal/Neonatal Morbidity and Mortality
Bazedoxifene may cause fetal harm.1 No animal studies were performed to evaluate the effect of bazedoxifene in fixed combination with conjugated estrogens.1 Reduced numbers of live fetuses and/or reduction in fetal body weight have been observed in rats at bazedoxifene exposures of 0.3 or more times the human exposure with the 20-mg dose; abortions and an increased incidence of heart and skeletal system anomalies also occurred in rabbits at 2 times the human exposure associated with the 20-mg dose.1
If the fixed combination of bazedoxifene and conjugated estrogens is used during pregnancy or if a woman becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus.1
Results from a population pharmacokinetic model of bazedoxifene/conjugated estrogens fixed-combination therapy show that systemic exposure of bazedoxifene is predicted to be reduced by 17% in women with a body mass index (BMI) greater than 27 kg/m2 compared with women having a BMI of 27 kg/m2 or less.1 Reduced bazedoxifene exposure may be associated with an increased risk of endometrial hyperplasia.1
Regardless of BMI, adequate diagnostic measures, including directed and random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurrent abnormal genital bleeding.1
In the WHI estrogen-alone study, postmenopausal women who received conjugated estrogens 0.625 mg once daily did not have an increased risk of invasive breast cancer when compared with those receiving placebo (average follow-up of 7.1 years).1 However, an increased incidence of abnormal mammograms requiring further evaluation has been reported with use of estrogen therapy alone.1 The effect of bazedoxifene/conjugated estrogens fixed-combination therapy on the risk of breast cancer is unknown.1 In a clinical study of women receiving bazedoxifene 20 mg in fixed combination with conjugated estrogens 0.45 mg, there was no observed increase in breast density after 12 months when compared with placebo.19 In a clinical study of up to 2 years' duration, there was no observed increased risk of breast cancer in women receiving the fixed-combination therapy.7 All women receiving bazedoxifene/conjugated estrogens fixed-combination therapy should receive annual breast examinations by a clinician and perform monthly breast self-examinations.1 In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.1
Some epidemiologic studies suggest that use of estrogen-only preparations for 5 or more years is associated with an increased risk of ovarian cancer.1 However, data regarding the duration of exposure associated with this risk have been inconsistent.1 The effect of bazedoxifene/conjugated estrogens fixed-combination therapy on the risk of ovarian cancer is unknown.1
Endocrine and Metabolic Effects
Estrogen administration leads to increased thyroxine-binding globulin (TBG) concentrations.1 Bazedoxifene/conjugated estrogens fixed-combination therapy also may increase TBG concentrations leading to increased circulating total thyroid hormone (as measured by protein-bound iodine [PBI]), thyroxine (T4) concentrations (by column or radioimmunoassay [RIA]), or triiodothyronine (T3) concentrations (by RIA).1 Women with normal thyroid function are able to compensate for increased TBG concentrations by synthesizing more thyroid hormone and, thereby, maintaining T4 and T3 concentrations in the normal range.1 Women receiving thyroid hormone replacement therapy and estrogens concomitantly may require an increased dosage of thyroid hormone.1 Thyroid function should be monitored in such patients to maintain free thyroid hormone concentrations in an acceptable range.1
In women with preexisting hypertriglyceridemia, use of estrogens may be associated with increased plasma triglyceride concentrations leading to pancreatitis.1 Discontinuance of bazedoxifene/conjugated estrogens fixed-combination therapy should be considered if pancreatitis occurs.1
Bazedoxifene/conjugated estrogens fixed-combination therapy may cause impaired glucose tolerance.1
Bazedoxifene/conjugated estrogens fixed-combination therapy may decrease free hormone concentrations (e.g., testosterone, estradiol).1 Concentrations of certain binding proteins may be elevated (e.g., corticosteroid-binding globulin [CBG], sex hormone binding globulin [SHBG]) leading to increased total circulating corticosteroids and sex steroids, respectively.1 The fixed-combination therapy also may increase concentrations of certain plasma proteins (e.g., angiotensinogen/renin substrate, α1-antitrypsin, ceruloplasmin).1
Exacerbation of Other Conditions
Estrogens may exacerbate asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.1
A twofold to fourfold increased risk of gallbladder disease requiring surgery has been reported in postmenopausal women receiving estrogens.1
Bazedoxifene/conjugated estrogens fixed-combination therapy may cause accelerated prothrombin time (PT), partial thromboplastin time (PTT), or platelet aggregation time.1 The fixed-combination therapy also may increase platelet count and increase factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and β-thromboglobulin.1
Bazedoxifene/conjugated estrogens fixed-combination therapy has not been studied in women with hepatic impairment or in those with a history of cholestatic jaundice.1 Women with hepatic impairment receiving bazedoxifene alone had a 4.3-fold increased overall exposure when compared with controls; estrogens also may be poorly metabolized in women with hepatic impairment.1
Bazedoxifene/conjugated estrogens fixed-combination therapy is contraindicated in patients with hepatic impairment.1 (See Cautions: Contraindications.) The fixed-combination therapy should be used with caution in women with a history of cholestatic jaundice associated with previous estrogen use or with pregnancy.1 If such conditions recur, bazedoxifene/conjugated estrogens fixed-combination therapy should be discontinued.1
Use of estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema.1
Estrogens should be used with caution in women with hypoparathyroidism; estrogen therapy may induce hypocalcemia in such patients.1
Monitoring of serum follicle-stimulating hormone (FSH) and estradiol concentrations has not been shown to be useful in the management of moderate to severe vasomotor symptoms.1
Retinal vascular thrombosis has been reported in patients receiving estrogens.1 Bazedoxifene/conjugated estrogens fixed-combination therapy should be discontinued pending diagnostic evaluation if there is a sudden partial or complete loss of vision or a sudden onset of proptosis, diplopia, or migraine.1 The fixed combination should be permanently discontinued if ophthalmologic examination reveals papilledema or retinal vascular lesions.1
Safety and efficacy of bazedoxifene in fixed combination with conjugated estrogens in premenopausal women† have not been established;1 use in such patients is not recommended.1
Use with Progestins, Estrogens, or Estrogen Agonists-Antagonists
Postmenopausal women receiving bazedoxifene/conjugated estrogens fixed-combination therapy should not receive concomitant therapy with progestins, additional estrogens, or additional estrogen agonists-antagonists.1
Category X.1 (See Cautions: Contraindications and also see Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Other Warnings/Precautions, in Cautions.)
It is not known whether the fixed combination of bazedoxifene and conjugated estrogens is distributed into human milk.1 Estrogen administration to nursing women has been shown to decrease the quantity and quality of milk.1 The fixed-combination therapy should not be used in nursing women.1
Bazedoxifene/conjugated estrogens fixed-combination therapy is not indicated for use in pediatric patients.1
Bazedoxifene/conjugated estrogens fixed-combination therapy is not recommended in women older than 75 years of age.1 Women older than 75 years of age were not included in clinical studies of the fixed-combination therapy.1 Following a single 20-mg dose of bazedoxifene alone, area under the concentration-time curve (AUC) was 1.5-fold higher in women 65-74 years of age and 2.6-fold higher in women 75 years of age or older compared with women 51-64 years of age.1
No overall differences in safety or efficacy were observed in women 65-74 years of age compared with younger women.1 However, greater sensitivity in some older women cannot be ruled out.1
Bazedoxifene/conjugated estrogens fixed-combination therapy is contraindicated in patients with hepatic impairment.1 (See Cautions: Contraindications.)
Women with mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, or C) receiving a single 20-mg dose of bazedoxifene had increased peak plasma concentrations (67, 32, or 20%, respectively) and increased AUC (143, 109, or 268%, respectively) compared with healthy women.1 The half-life of the drug was prolonged to 50 hours in women with severe hepatic impairment compared with 32 hours in healthy women.1 The pharmacokinetics, safety, and efficacy of bazedoxifene/conjugated estrogens fixed-combination therapy have not been studied in women with hepatic impairment.1
Bazedoxifene/conjugated estrogens fixed-combination therapy is not recommended in women with renal impairment.1 Pharmacokinetics, safety, and efficacy of the fixed-combination therapy have not been studied in such patients.1
When bazedoxifene 20 mg once daily was studied alone in postmenopausal women with mild, moderate, or severe renal impairment, results showed no increase in the incidence or severity of adverse effects compared with placebo.10
Adverse effects occurring in at least 5% of patients receiving bazedoxifene/conjugated estrogens fixed-combination therapy and more frequently than that with placebo include nausea,1, 6 diarrhea,1, 6 dyspepsia,1 upper abdominal pain,1, 6 muscle spasms,1, 6 neck pain,1 dizziness,1 nasopharyngitis,4, 6 and oropharyngeal pain.1, 6
Formal drug interaction studies have not been performed to date with bazedoxifene acetate in fixed combination with conjugated estrogens.1
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Bazedoxifene undergoes little or no metabolism by cytochrome P-450 (CYP) isoenzymes.1 The drug does not induce or inhibit the activity of CYP isoenzymes; in vitro data suggest that bazedoxifene is unlikely to interact with drugs metabolized by these isoenzymes.1
Estrogens are metabolized partially by CYP3A4.1 Inducers of CYP3A4 (e.g., carbamazepine, phenobarbital, rifampin, St. John's wort [ Hypericum perforatum ]) may decrease estrogen plasma concentrations and result in decreased therapeutic effect and/or changes in uterine bleeding.1 Inhibitors of CYP3A4 (e.g., clarithromycin, erythromycin, grapefruit juice, itraconazole, ketoconazole, ritonavir) may increase conjugated estrogen exposures resulting in increased risk of endometrial hyperplasia.1 If a patient receives a CYP3A4 inhibitor concomitantly with bazedoxifene/conjugated estrogens fixed-combination therapy for more than 30 days, adequate diagnostic measures, including directed and random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurrent abnormal genital bleeding.1
Drugs Affecting or Metabolized by Uridine Diphosphate-glucuronosyltransferase
Bazedoxifene is metabolized by uridine diphosphate-glucuronosyltransferase (UGT) enzymes in the intestinal tract and liver.1 The metabolism of bazedoxifene may be increased if used concomitantly with drugs known to induce UGT enzymes (e.g., rifampin, phenobarbital, carbamazepine, phenytoin).1 Decreased bazedoxifene exposures may be associated with an increased risk of endometrial hyperplasia.1 Adequate diagnostic measures, including directed and random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurrent abnormal genital bleeding.1
Concomitant use of a single 40-mg dose of bazedoxifene with a single dose of antacid containing aluminum hydroxide 460 mg and magnesium hydroxide 400 mg increased bazedoxifene area under the concentration-time curve (AUC) by 7% and decreased peak plasma concentrations by 8%.1
Estrogens and Estrogen Agonists-Antagonists
There are no clinically important pharmacokinetic interactions between conjugated estrogens and bazedoxifene.2
Concomitant use of conjugated estrogens 0.625 mg daily for 8 days and a single dose of bazedoxifene 20 mg in fixed combination with conjugated estrogens 0.625 mg decreased bazedoxifene AUC by 6% and increased peak plasma concentrations by 3%.1 Concomitant use of bazedoxifene 20 mg daily for 10 days and a single dose of bazedoxifene 20 mg in fixed combination with conjugated estrogens 0.625 mg increased AUC and peak concentrations of unconjugated estrone by 3 and 11%, respectively; the AUC and peak plasma concentrations of equilin increased by 14 and 17%, respectively.1
Bazedoxifene/conjugated estrogens fixed-combination therapy should not be used concomitantly with additional estrogens as this may increase the risk of endometrial hyperplasia.1
Bazedoxifene/conjugated estrogens fixed-combination therapy should not be used concomitantly with additional estrogen agonists-antagonists.1
Concomitant use of bazedoxifene 40 mg and atorvastatin 20 mg in healthy postmenopausal women did not substantially affect the pharmacokinetics of either drug.1, 2
Concomitant use of azithromycin 500 mg daily for 9 days followed by azithromycin 250 mg daily for 4 days and a single 40-mg dose of bazedoxifene did not substantially affect the pharmacokinetics of bazedoxifene.1, 2
Nonsteroidal Anti-inflammatory Agents
Concomitant use of bazedoxifene 20 mg and ibuprofen 600 mg did not substantially affect the pharmacokinetics of either drug.1, 2
Bazedoxifene/conjugated estrogens fixed-combination therapy should not be used concomitantly with progestins.1
Bazedoxifene acetate is a tissue-selective, estrogen agonist-antagonist;1, 25 the drug also is referred to as a selective estrogen receptor modulator (SERM).3, 5, 6, 9 Bazedoxifene has mixed estrogen agonist and antagonist activities resulting in activation of estrogenic pathways in some tissues and blockade of estrogenic pathways in other tissues.1 The drug binds to estrogen receptor (ER) α and ERβ, with slightly stronger binding occurring at the ERα receptor.1, 11, 20, 24, 25
In animal studies, bazedoxifene exhibits estrogen antagonistic effects on the endometrium when given alone and when given concomitantly with conjugated estrogens; these effects also were demonstrated in clinical trials (e.g., no difference from placebo in the effect on endometrial thickness or endometrial hyperplasia).9, 11, 12, 13, 16, 17, 21, 25, 26 In vitro, bazedoxifene has been shown to have limited estrogen agonistic effects on human breast cancer cells and blocks stimulatory actions of estradiol and conjugated estrogens on breast cells, which reverses negative effects of estrogen in breast cancer cells.11, 18, 20, 25, 26 Bazedoxifene also has been shown to increase bone mass in animal models and in clinical studies.11, 14, 15, 24
The combination of a SERM (e.g., bazedoxifene) and estrogens is also referred to as a tissue-selective estrogen complex (TSEC).3, 4, 5, 6, 26 Bazedoxifene in fixed combination with conjugated estrogens produces a composite effect specific to each target tissue.1, 26 The bazedoxifene component of the fixed-combination therapy reduces the risk of endometrial hyperplasia associated with use of conjugated estrogens alone.1
Following oral administration of multiple doses of bazedoxifene 20 mg in fixed combination with conjugated estrogens 0.45 mg to healthy, postmenopausal women, peak bazedoxifene plasma concentrations are attained at approximately 2.5 hours after the dose.1 The absolute bioavailability of bazedoxifene is approximately 6%.1 Area under the concentration-time curve (AUC) of bazedoxifene is increased by 25% when the fixed combination is taken with a high-fat, high-calorie meal;1 peak plasma concentrations of bazedoxifene are not affected by food.1 In vitro, bazedoxifene is highly bound to plasma proteins (98-99%);1 the drug does not bind to sex hormone binding globulin (SHBG).1 Following oral administration of bazedoxifene 20 mg alone, the drug undergoes extensive metabolism principally by glucuronidation; little or no metabolism is mediated by cytochrome P-450 (CYP) isoenzymes.1 The major metabolite is bazedoxifene-5-glucuronide;1 plasma concentrations of the metabolite are approximately tenfold higher than those of unchanged drug.1 The drug is expected to undergo enterohepatic recycling from the gut to systemic circulation.1 Bazedoxifene undergoes biliary excretion followed by elimination in feces (85%);1 less than 1% of a dose is eliminated in urine.1 After oral administration of bazedoxifene/conjugated estrogens in fixed combination, the half-life of bazedoxifene is approximately 30 hours.1
Importance of instructing patients to read the manufacturer's patient information prior to initiation of therapy and each time the prescription is refilled.1
Importance of instructing patients to open only 1 foil pouch containing bazedoxifene/conjugated estrogens fixed-combination tablets at a time (if more than 1 blister package is dispensed) and to record the date the blister package is opened on the package label.1 The tablets should not be used if the package is opened for more than 60 days.1 Only 1 tablet should be removed from the blister package at the time of use.1 The tablets should be kept in the original package and should not be placed in pill boxes or pill organizers.1
If a dose is missed, importance of advising patients to take it as soon as they remember.1 Patients should not take the missed dose if it is almost time for the next scheduled dose.1 Patients should be informed not to take 2 doses at the same time to make up for a missed dose.1
Importance of advising patients to add supplemental calcium and/or vitamin D to the diet if daily intake is inadequate.1
Importance of patients immediately reporting any signs or symptoms related to venous thrombosis and thromboembolic events to a clinician.1
Importance of women reporting any unusual vaginal bleeding to a clinician as soon as possible.1
Importance of informing women of possible serious adverse effects of estrogen therapy (e.g., cardiovascular disorders, malignant neoplasms, probable dementia).1
Importance of informing women of possible less serious, but common adverse effects of bazedoxifene in fixed combination with conjugated estrogens (e.g., muscle spasms, nausea, diarrhea, dyspepsia, upper abdominal pain, throat pain, dizziness, neck pain).1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 (See Cautions: Contraindications.)
Importance of informing patients of other important precautionary information.1 (See Cautions.)
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
1. Pfizer Inc. Duavee® (conjugated estrogens/bazedoxifene) tablets prescribing information. Philadelphia, PA; 2013 Oct.
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