Conjugated Estrogens Bazedoxifene Tablets (Nasavee)

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; patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of thyroid replacement therapy; these patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range

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; if examination reveals papilledema or retinal vascular lesions, estrogens should be discontinued

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

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 & Lactation

  Pregnancy

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

  There are no data with the use of conjugated estrogens in pregnant women; however, epidemiologic studies and meta-analyses have not found an increased risk of genital and non-genital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to combined hormonal contraceptives before conception or during early pregnancy

  There are no available data on bazedoxifene use in pregnant women to inform a drug associated risk of adverse developmental outcomes

  Based on animal data, bazedoxifene administration may adversely affect female fertility; ;owever, clinical fertility studies with bazedoxifene not conducted

  Animal data

  • Animal studies have shown that oral bazedoxifene administered during period of organogenesis to pregnant rats or rabbits at 0.3 and 2 times, respectively, exposure at maximum recommended dose, can cause fetal harm; based on mechanism of action, bazedoxifene may block important functions that estrogen has during all stages of pregnancy

  Lactation

  Not indicated for use in females of reproductive potential

  Estrogens are present in human milk and can reduce milk production in breast-feeding females; this reduction can occur at any time but is less likely to occur once breast-feeding is well-established

  There are no data on presence of bazedoxifene in either human or animal breast milk, effect on breastfed infant, or on milk production; based on mechanism of action, bazedoxifene may block important functions that estrogen has in mammary tissue during lactation

  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

  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