bazedoxifene/conjugated estrogens (Duavee)

Dosing and uses of Bazedoxifene/conjugated estrogens (Duavee)

• Adult
• Pediatric

 

Adult dosage forms and strengths

bazedoxifene/conjugated estrogens

tablet

• 20mg/0.45mg

 

Menopausal Vasomotor Symptoms

Indicated for vasomotor symptoms associated with menopause

20 mg/0.45 mg (1 tablet) PO qDay

 

Osteoporosis

Indicated for prevention of postmenopausal osteoporosis in nonhysterectomized women; when prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk and nonestrogen medication should be carefully considered

20 mg/0.45 mg (1 tablet) PO qDay

Take supplemental calcium and/or vitamin D if daily intake is inadequate

 

Dosage modifications

Renal impairment: Not evaluated, and therefore not recommended

Hepatic impairment: Contraindicated

 

Dosing Considerations

Should be used for the shortest duration consistent with treatment goals and risks for the individual woman

 

Administration

May take with or without food

Swallow tablet whole, do not chew, crush, or split

If a dose is missed, instruct patients to take it as soon as remembered unless it is almost time for the next scheduled dose; do not take 2 doses at the same time

 

Pediatric dosage forms and strengths

Not indicated

 

Bazedoxifene/conjugated estrogens (Duavee) adverse (side) effects

1-10%

Muscle spasms (9%)

Nausea (8%)

Diarrhea (8%)

Dyspepsia (7%)

Upper abdominal pain (7%)

Oropharyngeal pain (7%)

Neck pain (5%)

Dizziness (5%)

 

Warnings

Black box warnings

Do not take additional estrogens

Estrogen therapy should not be used for the prevention of cardiovascular disease or dementia

The Women’s Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and DVT in postmenopausal women (aged 50-79 years) during 7.1 years of treatment with daily oral conjugated estrogens (0.625 mg)-alone, relative to placebo

The WHI Memory Study (WHIMS) estrogen-alone ancillary study of WHI reported an increased risk of probable dementia in postmenopausal women >65 years during 5.2 years of treatment with daily conjugated estrogens (0.625 mg)-alone, relative to placebo; unknown whether this finding applies to younger postmenopausal women

Estrogens should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman

Endometrial hyperplasia

• Increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens; bazedoxifene/conjugated estrogens has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer
• Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding

 

Contraindications

Undiagnosed abnormal uterine bleeding

Known, suspected, or past history of breast cancer

Known or suspected estrogen-dependent neoplasia

Active DVT, PE, or history of these conditions

Active arterial thromboembolic disease (eg, stroke, MI) or history of these conditions

Hypersensitivity (eg, 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; may cause fetal harm when administered to a pregnant woman

 

Cautions

Should not take progestins, additional estrogens, or additional estrogen agonist/antagonists

Estrogens and estrogen agonist/antagonists are known to increase risk of thromboembolism, including DVT, PE, and stroke

Discontinue 4-6 weeks before surgery that is associated with increased risk of thromboembolism, or during periods of prolonged immobilization

Absolute risk of dementia with estrogen-alone use vs placebo from the Women’s Health Initiative was 37 versus 25 cases per 10,000 women-years; relative risk was 1.49 A 2- to 4-fold risk of gallbladder disease requiring surgery is reported in postmenopausal women receiving estrogens

Retinal vascular thrombosis reported

Substantial increases in blood pressure described in a small number of case reports in women receiving estrogens; this effect was not observed in a large, randomized, placebo-controlled clinical study

Estrogens may exacerbate pre-existing hypertriglyceridemia and lead to pancreatitis

Caution with history of cholestatic jaundice associated with past estrogen use or with pregnancy

Estrogen administration leads to increased thyroid-binding globulin (TBG) levels; women dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased thyroid hormone doses

May cause fluid retention

May exacerbate asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas

Estrogens are metabolized partially by CYP3A4 and therefore coadministration with inhibitors and inducers of this isoenzyme may increase risk of toxicity or alter therapeutic effect

Bazedoxifene undergoes metabolism by UGT enzymes in the intestinal tract and liver; coadministration with UGT inducers may reduce bazedoxifene exposure/efficacy and therefore increase risk of endometrial hyperplasia

Malignant neoplasms

• Endometrial cancer: Increase risk reported with use of unopposed estrogen therapy in women with a uterus; risk is 2-12 times greater than non-users and is dependent on estrogen dose and duration; bazedoxidfene’s agonist/antagonist effect reduces risk of endometrial hyperplasia
• Breast cancer: No increased risk was shown in the Women’s Health Initiative randomized clinical study about breast cancer in women using estrogen-alone (conjugated estrogens 0.625 mg/day); average follow-up 7.1 yr, relative risk [RR] 0.80
• Ovarian cancer: Unknown, some epidemiological showed an increased risk with use of estrogen-only products, in particular for 5 or more years; however, the duration of exposure associated with increased risk is not consistent across all epidemiologic studies, and some report no association

 

Pregnancy and lactation

Pregnancy category: X

Lactation: Contraindicated; 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

 

Pregnancy categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

 

Pharmacology of Bazedoxifene/conjugated estrogens (Duavee)

Mechanism of action

Bazedoxifene: Selective estrogen receptor modulator (SERM); estrogen-like effects on bone (increase bone density) and lipids (decrease LDL); antiestrogenic in uterus and breast (reduces risk of endometrial hyperplasia that can occur with conjugated estrogens)

Conjugated estrogens: Replaces endogenous estrogen

 

Absorption

Bioavailability: Readily absorbed

Food effect: High fat/high calorie meal increases absolute bioavailability of bazedoxifene by 25%

Following multiple doses of bazedoxifene/conjugated estrogens (CE) at Day 10

• Peak plasma time: 6.5 hr (CE); 2.5 hr (bazedoxifene)
• Peak plasma concentration: 2.6 ng/mL; 6.9 ng/mL (bazedoxifene)
• AUC at steady state: 35 ng•hr/mL (CE): 71 ng•hr/mL (bazedoxifene)

 

Distribution

Distribution of conjugated estrogens/bazedoxifene has not been studied; following results are from monotherapy studies

Conjugated estrogens

• Wide distribution with higher concentrations in sex hormone target organs
• Highly bound to sex hormone binding globulin (SHBG) and albumin

Bazedoxifene (3 mg IV dose)

• VD: 14.7 L/kg
• Highly bound to plasma proteins (98-99%); does not bind to SHBG

 

Metabolism

Metabolism of conjugated estrogens/bazedoxifene has not been studied; following results are from monotherapy studies

Conjugated estrogens

• Metabolized in the liver to glucuronide and sulfate conjugates
• Major metabolites: estradiol, estrone, and estriol

Bazedoxifene (20 mg PO dose)

• Extensive glucuronidation

 

Elimination

Half-life

• After administration of single dose of conjugated estrogens/bazedoxifene at steady state concentration by 2nd week of once daily dosing CE, baseline-adjusted total estrone: 17 hr
• Bazedoxifene: 30 hr

Excretion

• Results of monotherapy studies
• Conjugated estrogens: Urine excretion of metabolites
• Bazedoxifene (20 mg PO dose): Biliary excretion is major route; 85% feces, <1% urine