estradiol/progesterone (Rx)

>10%

Breast tenderness (10.4%)

1-10%

Headache (3.4%)

Vaginal bleeding (3.4%)

Vaginal discharge (3.4%)

Pelvic pain (3.1%)

Postmarketing Reports

Gastrointestinal disorders: Abdominal pain and discomfort, abdominal distention, diarrhea, nausea, vomiting.

General disorders and administration site conditions: Fatigue, feeling abnormal, malaise

Metabolism and nutrition disorders: Fluid retention, weight increased

Musculoskeletal and connective tissue disorders: Muscle spasms, pain in extremity; nervous system disorders dizziness, headache, somnolence, psychiatric disorders

Sleep disorder: Insomnia

Reproductive system and breast disorders: Breast pain, breast tenderness, uterine bleeding. Skin and subcutaneous tissue disorders Night sweats, pruritus

Vascular disorders: Hot flush

Contraindications

Undiagnosed abnormal genital bleeding

Known, suspected, or 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 a history of these conditions

Known anaphylactic reaction, angioedema, or hypersensitivity to estradiol, progesterone, or any excipients

Known liver impairment or disease

Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders

Cautions

Increased risk of PE, DVT, stroke, and MI with estrogen plus progestin hormone replacement therapy (HRT)

Nonsignificant increased risk for ovarian cancer reported in the WHI estrogen plus progestin substudy

Risk of probable dementia increased in women aged 65-79 yr taking estrogen plus progestin or estrogen alone

A 2- to 4-fold increase for risk of gallbladder disease requiring surgery reported in postmenopausal women receiving estrogens

Estrogen may lead to severe hypercalcemia in women with breast cancer and bone metastases; discontinue therapy if hypercalcemia occurs, and take appropriate measures to reduce serum calcium level

Retinal vascular thrombosis reported in women receiving estrogens; discontinue therapy pending examination if there is a sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine; permanently discontinue therapy if examination reveals papilledema or retinal vascular lesions

Adding progestin for ≥10 days of estrogen administration cycle, or daily with an estrogen continuous regimen, a lowered incidence of endometrial hyperplasia was reported than would be induced by estrogen treatment alone

In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens; in a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogens on blood pressure was not seen

In women with preexisting hypertriglyceridemia, estrogen therapy may be associated with elevated plasma triglycerides leading to pancreatitis

Estrogens may be poorly metabolized with impaired liver function; caution with history of cholestatic jaundice associated with past estrogen use or with pregnancy

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

Estrogens and progestins cause some degree of fluid retention; caution with conditions that may be affected (eg, cardiac or renal dysfunction); monitor any woman with a condition(s) that might predispose her to fluid retention, such as cardiac or renal impairment; discontinue estrogen plus progestogen therapy, with evidence of medically concerning fluid retention

Estrogen-induced hypocalcemia may occur in women with hypoparathyroidism; consider whether benefits of therapy outweigh risks in such women

Residual endometrial implants reported in women treated post-hysterectomy with estrogen-alone therapy; consider addition of progesterone for these women

Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema; consider whether benefits outweigh risks in such women

Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas; consider whether benefits of estrogen therapy outweigh risks in women with such conditions

Serum follicle-stimulating hormone (FSH) and estradiol levels have not been shown to be useful in the management of moderate-to-severe vasomotor symptoms

Manage appropriately any risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE; for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus)

Increase in risk of stroke demonstrated after first year and persisted; immediately discontinue estrogen with or without progestogen therapy if a stroke occurs or suspected

Venous thromboembolism reported with therapy; increase in VTE risk demonstrated during first year and persisted; immediately discontinue estrogen plus progestogen therapy if a VTE occurs or suspected; if feasible, discontinue estrogens at least 4-6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization

Breast cancer reported with therapy; all women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations; in addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results

Studies of addition of a progestogen for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone; endometrial hyperplasia may be a precursor to endometrial cancer; there are, however, possible risks that may be associated with use of progestogens with estrogens compared to estrogen-alone regimens; these include an increased risk of breast cancer

Estrogens may be poorly metabolized in women with hepatic impairment; exercise caution in any woman with a history of cholestatic jaundice associated with past estrogen use or with pregnancy; in the case of recurrence of cholestatic jaundice, discontinue

Exacerbation of hypothyroidism

• Estrogen administration leads to increased thyroid-binding globulin (TBG) levels; women with normal thyroid function can compensate for increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range
• Women dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy; monitor thyroid function in these women during therapy to maintain free thyroid hormone levels in an acceptable range

Endometrial cancer

• Increased risk of endometrial cancer reported with unopposed estrogen therapy in women with a uterus; endometrial cancer risk among unopposed estrogen users is about 2- to 12-fold greater than in nonusers and appears dependent on treatment duration and estrogen dose
• Clinical surveillance of all women using estrogen-alone or estrogen plus progestogen therapy is important; perform adequate diagnostic measures, including directed or random endometrial sampling when indicated, to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding with unknown etiology
• There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose; adding a progestogen to estrogen therapy in postmenopausal women has been shown to reduce risk of endometrial hyperplasia, which may be a precursor to endometrial cancer

Drug interaction overview

• Estrogens and progestins are metabolized partially by CYP3A4
• CYP3A4 inducers may reduce plasma estrogen/progestin concentration, possibly resulting in decreased therapeutic effect
• CYP3A4 inhibitors may increase plasma concentrations of estrogen/progestin, possibly resulting increased adverse effects

Not indicated for women who are premenopausal, pregnant, or lactating

Pregnancy

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

Lactation

Estrogens plus progestogens 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; the developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy and any potential adverse effects on breastfed child from therapy or from underlying maternal condition

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.

Mechanism of Action

Replaces 17 beta-estradiol and progesterone hormones

Estradiol: Estrogen replacement therapy; reduces the release of gonadotropin-releasing hormone from hypothalamus and luteinizing hormone and FSH from pituitary gland

Progesterone: Progestin replacement therapy; inhibits secretion of gonadotropins from pituitary gland; enhances cellular differentiation and generally opposes the actions of estrogens by decreasing estrogen receptor levels

Absorption

Estradiol and progesterone subject to first-pass metabolism

Peak plasma time: 5 hr (estradiol); 3 hr (progesterone)

Peak plasma concentration: 42.27 pg/mL (estradiol); 11.31 ng/mL (progesterone)

AUC: 772.4 pg·hr/mL (estradiol); 18.5 ng·hr/mL (progesterone)

Steady-state achieved: 7 days

Food effect: Food increased progesterone AUC and Cmax compared with fasting; food did not affect estradiol AUC, but decreased Cmax and delayed peak plasma time to 12 hr

Distribution

Estradiol

• Exogenous estrogen distribution similar to that of endogenous estrogens; widely distributed in the body and are generally found in higher concentrations in sex hormone target organs

Progesterone

• Protein bound: 96-99%; primarily to albumin (50-54%) and transcortin (43-48%)

Metabolism

Estradiol

• Metabolized in the same manner as endogenous estrogens; circulating estrogens exist in a dynamic equilibrium of metabolic interconversions that take place mainly in the liver
• Estradiol is converted reversibly to estrone, and both can be converted to estriol, the major urinary metabolite
• Also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption

Progesterone

• Metabolized primarily by the liver largely to pregnanediol and pregnenolone
• Pregnanediol and pregnenolone are conjugated in the liver to glucuronide and sulfate metabolites
• Excreted in the bile; may be deconjugated and further metabolized in the intestine via reduction, dehydroxylation, and epimerization

Elimination

Half-life: ~26 hr (estradiol); ~10 hr (progesterone)

Excretion

• Estradiol

  • Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates

• Progesterone

  • Conjugates excreted in the bile; may be deconjugated and further metabolized in the intestine via reduction, dehydroxylation, and epimerization
  • Progesterone metabolites are mainly eliminated by the kidneys

Oral Administration

Take each evening with food

Missed dose: Take missed dose as soon as possible with food, unless it is within 2 hr of the next evening dose

Storage

Store at 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F)