estradiol/progesterone

General

Genetic Implications:

Pronunciation:
es-tra-dye-ole/proe-jess-te-rone

Trade Name(s)

Bijuva

Ther. Class.

hormones

Pharm. Class.

estrogens

progestins

Indications

Moderate to severe vasomotor symptoms due to menopause.

Action

Estradiol: Represents the primary estrogen secreted prior to menopause. Modulates the pituitary secretion of the gonadotropins, luteinizing hormone, and follicle-stimulating hormone through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women. Progesterone: Opposes the action of estrogen by ↓ estrogen receptor levels, ↑ the metabolism of estrogen to less active metabolites, or blunting the response to estrogen at the cellular level.

Therapeutic Effect(s):

Reduction in frequency and severity of moderate to severe vasomotor symptoms.

Pharmacokinetics

Estradiol

Absorption: Absorption subject to first-pass metabolism.

Distribution: Widely distributed to tissues.

Metabolism and Excretion: Mostly metabolized by the liver; also undergo enterohepatic recirculation via conjugation in the liver; primarily excreted in urine.

Half-life: 26 hr.

Progesterone

Absorption: Absorption subject to first-pass metabolism.

Distribution: Unknown.

Protein Binding: 96–99%.

Metabolism and Excretion: Primarily metabolized by the liver; excreted in urine and bile.

Half-life: 10 hr.

TIME/ACTION PROFILE (plasma concentrations)

ROUTE	ONSET	PEAK	DURATION
Estradiol PO	unknown	5 hr	unknown
Progesterone PO	unknown	3 hr	unknown

Contraindication/Precautions

Contraindicated in:

History of anaphylaxis or angioedema to estradiol or progesterone;
Black Box: Undiagnosed abnormal vaginal bleeding;
Black Box: History of breast cancer;
Black Box: History of estrogen-dependent cancer;
Black Box: Thromboembolic disease (e.g., deep vein thrombosis [DVT], pulmonary embolism [PE], MI, stroke);
Black Box: Protein C, protein S, or antithrombin deficiency or other thrombophilic disorder;
Hepatic impairment;
OB: Pregnancy;
Lactation: Lactation.

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;
Hypothyroidism;
Renal impairment;
History of hereditary angioedema;
Asthma, diabetes, seizure disorders, migraine, porphyria, or systemic lupus erythematosus (↑ risk of exacerbation);
Hypoparathyroidism (↑ risk of hypocalcemia).

Adverse Reactions/Side Effects

CV: DVT, hypertension, MI, peripheral edema

EENT: retinal thrombosis

Endo: hypothyroidism

F and E: hypercalcemia, hypocalcemia

GI: cholelithiasis

GU: pelvic pain, vaginal bleeding, vaginal discharge

Metabolic: hypertriglyceridemia

Neuro: dementia, headache, STROKE

Resp: PE

Misc: breast tenderness, MALIGNANCY (BREAST, ENDOMETRIAL, OVARIAN)

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

Interactions

Drug-Drug

Strong CYP3A4 inhibitors, including clarithromycin, erythromycin, itraconazole, ketoconazole, or ritonavir, may ↑ levels and risk of toxicity.
Strong CYP3A4 inducers, including carbamazepine, phenobarbital, and rifampin, may ↓ levels and effectiveness.

Drug-Natural Products:

St. John's wort may ↓ levels and effectiveness.

Drug-Food:

Grapefruit juice may ↑ levels and risk of toxicity.

Route/Dosage

PO (Adults): One capsule (estradiol 1 mg/progesterone 100 mg) each evening with food.

Availability (generic available)

Capsules: estradiol 1 mg/progesterone 100 mg

Assessment

Assess frequency and severity of vasomotor symptoms periodically during therapy.
Assess BP and weight before and periodically during therapy.
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 are suspected.
Monitor for breast tenderness, lumps, or discharge. Perform baseline mammogram before starting treatment.

Lab Test Considerations:

May ↑ HDL and triglycerides and ↓ serum LDL and total cholesterol concentrations.

May ↑ serum glucose; sodium; cortisol; prolactin; prothrombin; and factor VII, VIII, IX, and X levels. May ↓ serum folate, pyridoxine, antithrombin III, and urine pregnanediol concentrations.
Monitor hepatic function before and periodically during therapy.
May cause false interpretations of thyroid function tests.

Implementation

Limit to lowest effective dose and for shortest duration. Reevaluate postmenopausal women periodically to determine if therapy is still necessary.
If feasible, discontinue estradiol/progesterone ≥4–6 wk before surgeries with an ↑ risk of thromboembolism or during periods of prolonged immobilization.
PO Administer each evening with food.

Patient/Family Teaching

Instruct patient to take medication as directed. Advise patient to avoid drinking grapefruit juice during therapy. Take missed doses as soon as remembered but not within 2 hr of next dose. Do not double doses. Advise patient to read Patient Information before starting therapy and with each Rx refill in case of changes.
Black Box: Inform patient that estrogens should not be used to ↓ risk of cardiovascular disease or dementia. Estrogens may ↑ risk of cardiovascular disease (MI, stroke), PE, DVT, dementia, and breast cancer.
Advise patient to report signs and symptoms of fluid retention (swelling of ankles and feet, weight gain), depression, hepatic dysfunction (yellowed skin or eyes, pruritus, dark urine, light-colored stools), new breast lumps, or abnormal vaginal bleeding to health care provider.
Advise patient to report signs and symptoms of thromboembolic disorders (pain, swelling, tenderness in extremities, headache, chest pain, blurred vision).
Caution patient that cigarette smoking during estrogen therapy may ↑ risk of serious side effects, especially for women over age 35.
Black Box: Emphasize the importance of routine follow-up physical exams, including BP check; 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. If on continuous (not cyclical) therapy or without concurrent progestins, endometrial biopsy may be recommended, if uterus is intact.
Instruct patient to notify health care provider of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care provider before taking other medications, especially St. John's wort.
Rep: May cause fetal harm. Instruct patient to stop taking medication and notify health care provider if pregnancy is planned or suspected or if breastfeeding.