bazedoxifene/conjugated estrogens

General

bazedoxifene/conjugated estrogens

Pronunciation:
ba-ze-dox-i-feen / kon-joo-gay-ted es-troe-jenz


Trade Name(s)

  • Duavee
  • Duavive Canadian Trade name

Ther. Class.

bone resorption inhibitors

hormones

Pharm. Class.

selective estrogen receptor modulators

estrogens

Indications

  • Treatment of moderate/severe vasomotor symptoms of menopause in female patients with an intact uterus.
  • Prevention of postmenopausal osteoporosis in female patients with an intact uterus (supplemental calcium and vitamin D recommended if dietary intake is not adequate).

Action

Both bazedoxifene and conjugated estrogens bind to α and β estrogen receptors. Conjugated estrogen acts as an agonist at these receptors. Bazedoxifene acts as an agonist in some tissues and an antagonist in other tissues, including the uterus. The combined effect is estrogen replacement while minimizing the risk of endometrial hyperplasia and prevention of postmenopausal osteoporosis.

Therapeutic Effect(s):

Reduced vasomotor symptoms of menopause with reduced risk of endometrial hyperplasia and prevention of postmenopausal osteoporosis.

Pharmacokinetics

Bazedoxifene

Absorption: 6% absorbed following oral administration.

Distribution: Unknown.

Protein Binding: 98–99%.

Metabolism and Excretion: Undergoes extensive metabolism by UGT enzymes in the intestinal tract and liver; undergoes biliary excretion with enterohepatic recycling and elimination in feces (85%).

Half-life: 30 hr.

Conjugated Estrogens

Absorption: Well absorbed following oral administration.

Distribution: Widely distributed; higher concentrations found in sex hormone target organs.

Metabolism and Excretion: Primarily metabolized by the liver via the CYP3A4 isoenzyme; some metabolites are hormonally active. Metabolites are renally excreted.

Half-life: 17 hr (estrone).

TIME/ACTION PROFILE (effect on vasomotor symptoms†)

ROUTEONSETPEAKDURATION
POwithin 4 wk12 wkduration of treatment
†Effects on osteoporosis were noted at 12–24 mo and lasted throughout treatment (5 yr).

Contraindication/Precautions

Contraindicated in:

  • Undiagnosed/abnormal vaginal bleeding;
  • Hepatic or renal impairment or BMI > 27 kg/m2  (↑ risk of endometrial hyperplasia;
  • Black Box:  Thromboembolic disease (e.g., deep vein thrombosis [DVT], pulmonary embolism [PE], MI, stroke);
  • Black Box:  Undiagnosed vaginal bleeding;
  • Black Box:  History of breast cancer;
  • Black Box:  History of estrogen-dependent cancer;
  • Black Box:  Protein C, protein S, or antithrombin deficiency or other thrombophilic disorder;
  • OB:  Pregnancy;
  • Lactation: Lactation;
  • Rep:   Women of reproductive potential;
  • Geri:  Black Box:  Not recommended for use in patients ≥75 yr; has been associated with dementia in patients ≥65 yr.

Use Cautiously in:

  • Black Box:  Long-term use (more than 4–5 yr); may ↑ risk of MI, stroke, invasive breast cancer, PE, DVT, and dementia in postmenopausal women;
  • Black Box:  Underlying cardiovascular disease;
  • Black Box:  Risk factors for thromboembolic phenomenon, including diabetes, family history, obesity, or systemic lupus erythematosus;
  • History of cholestatic jaundice associated with estrogen use;
  • Hypothyroidism (may need ↑ dose of thyroid replacement);
  • History of hereditary angioedema (estrogen may provoke);
  • History of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, or hepatic hemangiomas (estrogen may exacerbate these conditions).

Adverse Reactions/Side Effects

CV: ↑ BP, edema, DVT, MI

Derm: hot flash

EENT: retinal vascular thrombosis

F and E: hypocalemia

GI: cholestatic jaundice, diarrhea, dyspepsia, gall bladder disease, nausea, oropharyngeal pain, upper abdominal pain

MS: muscle spasms, neck pain

Neuro: dementia, STROKE

Resp: PE

Misc: MALIGNANCY (BREAST, ENDOMETRIAL, OVARIAN)

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

  •  UGT inducers, including  carbamazepine,  phenobarbital,  phenytoin, and  rifampin, may ↓ bazedoxifene levels and result in ↑ risk of endometrial hyperplasia.
  •  CYP3A4 inhibitors, including  clarithromycin,  erythromycin,  itraconazole, ,  ketoconazole, and  ritonavir, may ↑ levels of conjugated estrogens and risk of endometrial hyperplasia.
  •  CYP3A4 inducers, including  carbamazepine,  phenobarbital, and  rifampin, may ↓ levels and effectiveness of conjugated estrogens and alter uterine bleeding patterns.
  •  Progestins, other  estrogens, or  estrogen agonist/antagonists  may alter the effectiveness or treatment and/or ↑ risk of adverse reactions; avoid concurrent use.

Drug-Natural Products:

 St. John's wort  may ↓ levels and effectiveness of conjugated estrogens and alter uterine bleeding patterns.

Drug-Food:

Grapefruit juice may ↑ levels of conjugated estrogens and risk of endometrial hyperplasia.

Route/Dosage

Black Box:  Estrogens should be used in the lowest doses for the shortest period of time consistent with desired therapeutic outcome.

PO (Adults): One tablet (bazedoxifene 20 mg/conjugated estrogen 0.45 mg) once daily.

Availability

Tablets: bazedoxifene 20 mg/conjugated estrogens 0.45 mg

Assessment

  • Assess for frequency and intensity of postmenopausal vasomotor symptoms (hot flashes).
  • Assess BP before and periodically during therapy.
  • Monitor intake and output and weekly weight. Report significant discrepancies or steady weight gain.
  • Monitor for signs and symptoms of venous thromboembolism, such as PE (chest pain, dyspnea, tachycardia) or DVT (calf pain or tenderness, lower extremity edema, localized warmth or erythema), or emerging cardiovascular disease, such as MI (chest pain, dyspnea, diaphoresis, dizziness, nausea) or stroke (weakness, slurred speech, confusion, dizziness); discontinue therapy in all patients if PE, DVT, stroke, or MI is suspected.
  • If persistent or recurring abnormal genital bleeding occur in postmenopausal women, directed or random endometrial sampling may need to be performed to rule out malignancy.
  • Monitor for breast tenderness, lumps, or discharge. Perform baseline mammogram before starting treatment.

Lab Test Considerations:

May cause hypocalcemia.

  • May ↑ HDL and triglycerides and ↓ LDL.
  • May ↑ prothrombin time, partial thromboplastin time, and platelet aggregation time. May ↑ factors II, VII, VIII, IX, X, and XII levels. May ↓ antithrombin III and ↑ levels of fibrinogen and fibrinogen activity and plasminogen antigen and activity.
  • May ↑ thyroid-binding globulin, causing ↑ circulating total thyroid hormone; may require higher doses of thyroid replacement therapy.
  • May cause impaired glucose tolerance.

Implementation

  • Supplement calcium and/or vitamin D if diet is inadequate.
  • PO Administer once daily without regard to meals.  DNC: Swallow tablets whole; do not crush, break, or chew. 

Patient/Family Teaching

  • Instruct patient to take medication as directed. Take missed doses as soon as remembered unless almost time for next dose; do not double doses. Advise patient to keep  Duavee  in original container to protect from moisture; avoid placing in pill boxes or organizers. Open only one blister pouch and one tablet at a time; record date opened and discard after 60 days. Advise patient to read  Medication Guide  before starting therapy and with each Rx refill in case of changes.
  • Advise patient to avoid grapefruit juice during therapy.
  • Instruct patient to notify health care provider of all Rx or OTC medications, vitamins, or herbal products being taken and to avoid concurrent use of Rx, OTC, and herbal products, especially progestins, additional estrogens, or additional estrogen agonist/antagonists, without consulting health care provider; may ↑ risk of uterine cancer.
  • Inform postmenopausal women that long-term use may ↑ risk of MI, stroke, invasive breast cancer, PE, DVT, and dementia.
  • Advise patient to report signs and symptoms of thromboembolic disorders (pain, swelling, tenderness in extremities, headache, chest pain, blurred vision).
  • Advise patient to report signs and symptoms of fluid retention (swelling of ankles and feet, weight gain), new breast lumps, changes in vision or speech, sudden new severe headaches, severe pains in chest or legs with or without shortness or breath, weakness, fatigue, or abnormal vaginal bleeding to health care provider.
  • Caution patient that cigarette smoking during estrogen therapy may increase risk of serious side effects, especially for women over age 35.
  • Advise patient treated for osteoporosis that exercise has been found to arrest and reverse bone loss. Discuss any exercise limitations with health care provider before beginning program.
  • Emphasize the importance of routine follow-up physical exams, including BP; breast, abdomen, and pelvic examinations; Papanicolaou smears every 6–12 mo; and mammogram every 12 mo or as directed. Health care provider will evaluate possibility of discontinuing medication every 3–6 mo.
  • Advise patient to notify health care provider promptly if unusual vaginal bleeding occurs during therapy. Vaginal bleeding after menopause may be a sign of uterine cancer.
  • Rep:  May cause fetal harm. Advise women of reproductive potential to notify health care provider if pregnancy is planned or suspected and to avoid breastfeeding.

Evaluation/Desired Outcomes

  • Reduction in frequency and intensity of moderate to severe hot flashes.

  • Decreased risk of development of osteoporosis.

    • Therapy should be used for the shortest time possible and need for therapy evaluated regularly.