Drug information of bazedoxifene/conjugated estrogens

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

Conjugated estrogens: Well-absorbed from the gastrointestinal tract

Distribution

Bazedoxifene: V_d: ~15 L/kg

Metabolism

Bazedoxifene: Metabolized via glucuronidation; forms metabolites; little or no CYP mediated metabolism; undergoes hepatic recirculation

Conjugated estrogens: Hepatic via CYP3A4; estradiol is converted to estrone and estriol; also undergoes enterohepatic recirculation; estrone sulfate is the main metabolite in postmenopausal females

Excretion

Conjugated estrogens: Urine (primarily estriol, also as estradiol, estrone, and conjugates)

Bazedoxifene: Biliary; feces (~85%); urine (<1%)

Onset of Action

Relief of vasomotor symptoms: A significant reduction in the number and severity of moderate/severe hot flashes was observed after 4 weeks of therapy .

Osteoporosis: A significant increase in BMD measured at the lumbar spine and hip was observed at 12 months of therapy (Lindsay, 2009).

Time to Peak

Bazedoxifene: ~2.5 hours

Total estrone: ~6.5 hours

Half-Life Elimination

Bazedoxifene: ~30 hours

Total estrone: ~17 hours

Protein Binding

Bazedoxifene: 98% to 99%; does not bind to sex-hormone binding globulin

Conjugated estrogens: Binds to sex-hormone-binding globulin and albumin

-Osteoporosis, prevention

-Vasomotor symptoms

20 mg/0.45 mg (1 tablet) PO qDay

-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

Muscle spasms

Nausea

Diarrhea

Dyspepsia

Upper abdominal pain

Oropharyngeal pain

Neck pain

Dizziness

-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 and of gallbladder disease

-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

-Do not use with conditions that predispose to hyperkalemia

-Retinal vascular thrombosis 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;

-There are, possible risks that may be associated with use of progestins with estrogens compared to estrogen-alone regimens, including a possible increased risk of breast cancer, adverse effects on lipoprotein metabolism (e.g., lowering HDL, raising LDL), and impairment of glucose tolerance

-Use caution in individuals with severe hypocalcemia

-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

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

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

-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

-You should not use bazedoxifene and conjugated estrogens if you are allergic to bazedoxifene or conjugated estrogens, or if you have:

• unusual vaginal bleeding that has not been checked by a doctor;
• liver disease;
• a history of heart attack, stroke, or blood clot;
• an increased risk of having blood clots due to a heart problem or a hereditary blood disorder; or
• a history of hormone-related cancer, or cancer of the breast, uterus/cervix, or vagina.

Contraindicated for use in pregnant women; not indicated for use in females of reproductive potential