Introduction

Tissue-selective, estrogen agonist-antagonist.

Uses for Bazedoxifene

Osteoporosis

Bazedoxifene/conjugated estrogens in fixed combination: Prevention of osteoporosis in postmenopausal women with an intact uterus.

Not FDA-labeled for treatment^{† [off-label]} of osteoporosis in postmenopausal women in the US. Bazedoxifene commercially available in other countries for this use.

Not recommended for prevention of osteoporosis in premenopausal women^{† [off-label]}; safety and efficacy not established.

Vasomotor Symptoms

Bazedoxifene/conjugated estrogens in fixed combination: Management of moderate to severe vasomotor symptoms associated with menopause in women with an intact uterus.

Bazedoxifene Dosage and Administration

General

• Use for shortest duration consistent with treatment goals and risks for the individual woman. Reevaluate patients periodically to determine if continued treatment is necessary.

• When used for prevention of osteoporosis, use supplemental calcium and/or vitamin D concomitantly if daily dietary intake is considered inadequate.

Administration

Oral Administration

Administer orally without regard to meals.

Swallow tablets whole.

Dosage

Available as bazedoxifene acetate; dosage expressed in terms of bazedoxifene.

Each tablet of bazedoxifene/conjugated estrogens in fixed combination contains bazedoxifene 20 mg and conjugated estrogens 0.45 mg.

Adults

Osteoporosis

Prevention in Postmenopausal Women

Bazedoxifene 20 mg in fixed combination with conjugated estrogens 0.45 mg once daily.

Vasomotor Symptoms

Oral

Bazedoxifene 20 mg in fixed combination with conjugated estrogens 0.45 mg once daily.

Special Populations

When bazedoxifene is used in fixed combination with conjugated estrogens, dosage requirements for conjugated estrogens should be considered.

Hepatic Impairment

Bazedoxifene/conjugated estrogens in fixed combination: Contraindicated. (See Contraindications and Hepatic Effects under Cautions.)

Renal Impairment

Bazedoxifene/conjugated estrogens in fixed combination: Not recommended.

Contraindications

• Undiagnosed abnormal uterine bleeding.

• Known or suspected estrogen-dependent neoplasia.

• Known or suspected breast cancer or history of breast cancer.

• Active DVT, PE, or arterial thromboembolic disease (e.g., stroke, MI), or history of these conditions.

• Hepatic impairment or disease.

• Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders.

• Women who are or may become pregnant and women who are breast-feeding. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

• Hypersensitivity (e.g., anaphylaxis, angioedema) to any ingredient in the formulation.

Warnings/Precautions

Warnings

Use of Fixed Combinations

When used in fixed combination with conjugated estrogens, consider the cautions, precautions, contraindications, and interactions associated with conjugated estrogens.

Cardiovascular Effects

Manage risk factors for cardiovascular disorders, arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, obesity), and/or venous thromboembolism (VTE) (e.g., personal or family history of VTE, obesity, systemic lupus erythematosus). Do not use estrogens for prevention of cardiovascular disease.

Increased risk of stroke and VTE observed in postmenopausal women receiving daily dosages of oral conjugated estrogens alone; increased risk of VTE observed with individual use of estrogen agonists-antagonists (e.g., bazedoxifene). Not known if risk of VTE with bazedoxifene/conjugated estrogens in fixed combination is different from other estrogen preparations.

Discontinue therapy immediately if VTE or stroke occurs or is suspected.

Discontinue therapy at least 4–6 weeks prior to surgery associated with increased risk of thromboembolism or during periods of prolonged immobilization, if possible. Do not resume therapy until patient is fully ambulatory. Advise women receiving the drug to ambulate periodically during travel involving prolonged immobilization.

Increased BP reported in women receiving estrogens; attributed to idiosyncratic reactions associated with estrogens. Generalized effect of estrogens on BP not observed in large, randomized, placebo-controlled study.

May increase plasma HDL-cholesterol and HDL2-cholesterol subfraction concentrations, decrease LDL-cholesterol concentrations, and increase triglyceride concentrations.

Estrogens may cause some degree of fluid retention. Carefully observe women with conditions that might be aggravated by fluid retention (e.g., cardiac dysfunction, renal impairment) when receiving estrogens.

Dementia

Increased risk of probable dementia in women 65–79 years of age receiving daily dosages of conjugated estrogens alone in WHI Memory Study. Not known whether this finding applies to younger postmenopausal women.

Do notuse estrogen therapy for prevention of dementia.

GU Effects

Increased risk of endometrial cancer reported in postmenopausal women with an intact uterus who use estrogen alone. Use of bazedoxifene/conjugated estrogens in fixed combination reduces risk of endometrial hyperplasia (possible precursor to endometrial cancer).

Clinical surveillance important for all women receiving bazedoxifene/conjugated estrogens in fixed combination. Rule out malignancy in postmenopausal women with undiagnosed persistent or recurrent abnormal genital bleeding. Do not use additional estrogens concurrently with such therapy as this may increase risk of endometrial hyperplasia.

Other Warnings/Precautions

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm. If used during pregnancy or if woman becomes pregnant, apprise of potential fetal hazard.

Body Mass Index

Systemic exposure of bazedoxifene predicted to be reduced by 17% in women with body mass index (BMI) >27 kg/m². Reduced bazedoxifene exposure may be associated with increased risk of endometrial hyperplasia.

Regardless of BMI, clinical surveillance important for all women receiving bazedoxifene/conjugated estrogens in fixed combination. Rule out malignancy in postmenopausal women with undiagnosed persistent or recurrent abnormal genital bleeding.

Carcinogenicity

No increased risk of invasive breast cancer observed in postmenopausal women receiving daily dosages of conjugated estrogens alone. Increased incidence of abnormal mammograms requiring further evaluation reported with estrogen alone.

Effect of bazedoxifene/conjugated estrogens in fixed combination on breast cancer risk unknown. Annual breast examinations by clinician and monthly breast self-examinations recommended in all women receiving such therapy. Schedule mammography based on patient age, risk factors, and prior mammogram results.

Epidemiologic studies suggest use of estrogen-only products for ≥5 years associated with increased risk of ovarian cancer. Data inconsistent regarding duration of exposure associated with this risk. Effect of bazedoxifene/conjugated estrogens in fixed combination on ovarian cancer risk unknown.

Endocrine and Metabolic Effects

Estrogen therapy increases thyroxine-binding globulin (TBG) concentrations. Bazedoxifene/conjugated estrogens in fixed combination also may increase TBG concentrations leading to increased circulating total thyroid hormone. Increased thyroid hormone dosage may be required in women receiving thyroid hormone therapy. Monitor thyroid function in such patients to maintain free thyroid hormone concentrations in acceptable range.

Use of estrogens may be associated with increased plasma triglyceride concentrations leading to pancreatitis in women with preexisting hypertriglyceridemia. Consider discontinuance of therapy if pancreatitis occurs.

Bazedoxifene/conjugated estrogens in fixed combination may cause impaired glucose tolerance.

May decrease free hormone concentrations (e.g., testosterone, estradiol). 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.

May increase concentrations of certain plasma proteins (e.g., angiotensinogen/renin substrate, α₁-antitrypsin, ceruloplasmin).

Exacerbation of Other Conditions

Estrogen therapy may exacerbate asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas; use with caution in women with these conditions.

GI Effects

Twofold or fourfold increased risk of gallbladder disease requiring surgery reported in postmenopausal women receiving estrogens.

Hematologic Effects

Bazedoxifene/conjugated estrogens in fixed combination may cause accelerated PT, PTT, or platelet aggregation time. 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.

Hepatic Effects

Bazedoxifene/conjugated estrogens in fixed combination not studied in women with hepatic impairment or history of cholestatic jaundice.

Contraindicated in patients with hepatic impairment. (See Contraindications under Cautions.) Use with caution in women with history of cholestatic jaundice associated with previous estrogen use or pregnancy. If such conditions recur, discontinue therapy.

Hereditary Angioedema

Estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema.

Hypocalcemia

Use estrogens with caution in women with hypoparathyroidism; may induce hypocalcemia in such patients.

Laboratory Monitoring

Monitoring serum follicle-stimulating hormone (FSH) and estradiol concentrations not shown to be useful in management of moderate to severe vasomotor symptoms.

Ocular Effects

Retinal vascular thrombosis reported in patients receiving estrogens. Discontinue bazedoxifene/conjugated estrogens in fixed combination pending diagnostic evaluation for sudden partial or complete loss of vision or sudden onset of proptosis, diplopia, or migraine. Permanently discontinue therapy if ophthalmologic examination reveals papilledema or retinal vascular lesions.

Use in Premenopausal Women

Not recommended. Efficacy and safety not established.

Use with Progestins, Estrogens, or Estrogen Agonists-Antagonists

Do not use progestins, additional estrogens, or additional estrogen agonists-antagonists concomitantly with bazedoxifene/conjugated estrogens in fixed combination.

Specific Populations

Pregnancy

Category X. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether distributed into milk. Estrogen use in nursing women shown to decrease quantity and quality of milk. Do not use in nursing women.

Pediatric Use

Not indicated for use in pediatric patients.

Geriatric Use

Bazedoxifene/conjugated estrogens in fixed combination not recommended in women >75 years of age.

No overall differences in safety or efficacy observed in women 65–74 years of age compared with younger women. Greater sensitivity in some older women cannot be ruled out.

Hepatic Impairment

Bazedoxifene/conjugated estrogens in fixed combination contraindicated in patients with hepatic impairment. (See Contraindications under Cautions.)

Renal Impairment

Bazedoxifene/conjugated estrogens in fixed combination not recommended in women with renal impairment. Pharmacokinetics, safety, and efficacy of the drug not studied in such patients.

Study results with bazedoxifene 20 mg once daily alone in postmenopausal women with mild, moderate, or severe renal impairment showed no increase in incidence or severity of adverse effects compared with placebo.

Common Adverse Effects

Nausea, diarrhea, dyspepsia, upper abdominal pain, muscle spasms, neck pain, dizziness, nasopharyngitis, oropharyngeal pain.

General

• Use for shortest duration consistent with treatment goals and risks for the individual woman. Reevaluate patients periodically to determine if continued treatment is necessary.

• When used for prevention of osteoporosis, use supplemental calcium and/or vitamin D concomitantly if daily dietary intake is considered inadequate.

Administration

Oral Administration

Administer orally without regard to meals.

Swallow tablets whole.

Dosage

Available as bazedoxifene acetate; dosage expressed in terms of bazedoxifene.

Each tablet of bazedoxifene/conjugated estrogens in fixed combination contains bazedoxifene 20 mg and conjugated estrogens 0.45 mg.

Adults

Osteoporosis

Prevention in Postmenopausal Women

Bazedoxifene 20 mg in fixed combination with conjugated estrogens 0.45 mg once daily.

Vasomotor Symptoms

Oral

Bazedoxifene 20 mg in fixed combination with conjugated estrogens 0.45 mg once daily.

Special Populations

When bazedoxifene is used in fixed combination with conjugated estrogens, dosage requirements for conjugated estrogens should be considered.

Hepatic Impairment

Bazedoxifene/conjugated estrogens in fixed combination: Contraindicated. (See Contraindications and Hepatic Effects under Cautions.)

Renal Impairment

Bazedoxifene/conjugated estrogens in fixed combination: Not recommended.

Formal drug interaction studies not performed to date with bazedoxifene/conjugated estrogens in fixed combination.

Bazedoxifene metabolized by UGT enzymes in the intestinal tract and liver.

Bazedoxifene undergoes little or no metabolism by CYP isoenzymes. Does not induce or inhibit the activity of CYP isoenzymes.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Drugs metabolized by CYP isoenzymes: Clinically important interactions with bazedoxifene unlikely.

Inducers of CYP3A4: May decrease estrogen plasma concentrations and result in decreased therapeutic effect and/or changes in uterine bleeding.

Inhibitors of CYP3A4: May increase conjugated estrogen exposures resulting in increased risk of endometrial hyperplasia. If a CYP3A4 inhibitor is used concomitantly with bazedoxifene/conjugated estrogens in fixed combination for >30 days, rule out malignancy in postmenopausal women with undiagnosed persistent or recurrent abnormal genital bleeding.

Drugs Affecting or Metabolized by UGT

Inducers of UGT: Metabolism of bazedoxifene may be increased; decreased bazedoxifene exposures may be associated with increased risk of endometrial hyperplasia. Rule out malignancy in postmenopausal women with undiagnosed persistent or recurrent abnormal genital bleeding.

Specific Drugs