estradiol/progesterone (Rx)

Brand and Other Names:Bijuva
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Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

estradiol/progesterone

capsule

  • 0.5mg/100mg
  • 1mg/100mg

Vasomotor Symptoms

Indicated for women with a uterus for moderate-to-severe vasomotor symptoms related to menopause

1 capsule (1 mg/100 mg) PO each evening with food

Dosage Modifications

Hepatic impairment: Estrogens may be poorly metabolized with impaired liver function; caution advised

Dosing Considerations

Limit estrogen use, alone or in combination with progestogen, to the lowest effective dose available and for the shortest duration consistent with treatment goals and risks for the individual woman

Postmenopausal women should be reevaluated periodically as clinically appropriate to determine if treatment is still necessary

Not indicated

In the women’s health initiative (WHI) studies, estrogen plus progestin (conjugated estrogen 0.625 mg/day plus medroxyprogesterone 2.5 mg/day) showed higher relative risk of nonfatal stroke and invasive breast cancer in women aged >65 yr

WHI estrogen-alone substudy showed higher relative risk of stroke in women aged >65 yr

WHI memory study found an increased risk of developing probable dementia in women receiving estrogen plus progestin or estrogen alone compared with placebo

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Interactions

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                    Adverse Effects

                    >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

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                    Warnings

                    Black Box Warnings

                    Estrogen plus progestin therapy

                    • Cardiovascular disorders and probable dementia
                      • Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia
                      • Women’s Health Initiative (WHI) Estrogen Plus Progestin substudy reported increased risks of myocardial infarction (MI), stroke, pulmonary embolism (PE), and deep vein thrombosis (DVT) in postmenopausal women (aged 50-79 yr) during 5.6 yr of treatment with daily PO conjugated estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg) compared with placebo
                      • WHI Memory Study, a substudy of the WHI study, reported increased risk of developing probable dementia in postmenopausal women aged ≥65 yr during 4 yr of treatment with daily CE 0.625 mg combined with MPA 2.5 mg, compared with placebo
                    • Breast cancer
                      • WHI demonstrated increased risk of invasive breast cancer
                      • In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA, and other combinations and dosage forms of estrogens and progestins
                      • Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman

                    Estrogen-alone therapy

                    • Endometrial cancer
                      • There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens
                      • Adding a progestin to estrogen therapy reduces endometrial hyperplasia risk, which may be a precursor to endometrial cancer
                    • Cardiovascular disorders and probable dementia
                      • Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia
                      • The estrogen alone substudy of the WHI Study reported increased risks of stroke and DVT in postmenopausal women (aged 50-79 yr) during 6.8 yr of treatment with oral conjugated estrogens (0.625 mg/day) alone compared with placebo
                      • A substudy of the WHI Memory Study reported an increased risk of developing probable dementia in postmenopausal women aged 65 yr or older during 5.2 yr of treatment with conjugated estrogens 0.625 mg alone compared with placebo

                    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)

                    Increased risk of breast cancer with estrogen plus progestin HRT

                    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

                    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

                    Retinal vascular thrombosis reported in women receiving estrogens

                    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

                    Several case reports describe substantial increased blood pressure attributed to idiosyncratic reactions to estrogens

                    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)

                    Caution with hypoparathyroidism as estrogen-induced hypocalcemia may occur

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

                    Exogenous estrogens may exacerbate symptoms of angioedema

                    Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas

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

                    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
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                    Pregnancy & Lactation

                    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.

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                    Pharmacology

                    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
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                    Administration

                    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)

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                    Images

                    BRAND FORM. UNIT PRICE PILL IMAGE
                    Bijuva oral
                    -
                    1-100 mg capsule

                    Copyright © 2010 First DataBank, Inc.

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                    Patient Handout

                    A Patient Handout is not currently available for this monograph.
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                    Formulary

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                    Tier Description
                    1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
                    2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
                    3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
                    4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
                    5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
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                    NC NOT COVERED – Drugs that are not covered by the plan.
                    Code Definition
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