Pronunciation:

(es tra DYE ole & nor eth IN drone)

U.S. Brand Names:

Synonyms:

Generic Available:

Canadian Brand Names:

Use:

Tablet: Treatment of moderate-to-severe vasomotor symptoms associated with menopause; treatment of vulvar and vaginal atrophy; prophylaxis for postmenopausal osteoporosis

Transdermal patch: Treatment of moderate-to-severe vasomotor symptoms associated with menopause; treatment of vulvar and vaginal atrophy; treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure

Pregnancy Risk Factor:

Pregnancy Implications:

Estrogens: Increased risk of fetal reproductive tract disorders and other birth defects; do not use during pregnancy.

Progestins: Associated with fetal genital abnormalities when used during the 1st trimester; not recommended for use during pregnancy.

Lactation:

Contraindications:

Warnings/Precautions:

Cardiovascular-related considerations: Estrogens with or without progestin should not be used to prevent coronary heart disease. Use caution with cardiovascular disease or dysfunction. May increase the risks of hypertension, myocardial infarction (MI), stroke, pulmonary emboli (PE), and deep vein thrombosis; incidence of these effects was shown to be significantly increased in postmenopausal women using conjugated equine estrogens (CEE) in combination with medroxyprogesterone acetate (MPA). Nonfatal MI, PE, and thrombophlebitis have also been reported in males taking high doses of CEE (eg, for prostate cancer). Estrogen compounds are generally associated with lipid effects such as increased HDL-cholesterol and decreased LDL-cholesterol. Triglycerides may also be increased; use with caution in patients with familial defects of lipoprotein metabolism. Whenever possible, estrogens should be discontinued at least 4-6 weeks prior to surgeries associated with an increased risk of thromboembolism or during periods of prolonged immobilization.

Neurological considerations: The risk of dementia may be increased in postmenopausal women; increased incidence was observed in women 65 years of age taking CEE in combination with MPA.

Cancer-related considerations: Unopposed estrogens may increase the risk of endometrial carcinoma in postmenopausal women. Estrogens may increase the risk of breast cancer. An increased risk of invasive breast cancer was observed in postmenopausal women using CEE in combination with MPA; a smaller increase in risk was seen with estrogen therapy alone in observational studies. An increase in abnormal mammograms has also been reported with estrogen and progestin therapy. Estrogen use may lead to severe hypercalcemia in patients with breast cancer and bone metastases; discontinue estrogen if hypercalcemia occurs.

Estrogens may cause retinal vascular thrombosis; discontinue permanently if papilledema or retinal vascular lesions are observed on examination. Use with caution in patients with diseases which may be exacerbated by fluid retention, including asthma, epilepsy, migraine, diabetes or renal dysfunction. Use with caution in patients with a history of severe hypocalcemia, SLE, hepatic hemangiomas, porphyria, endometriosis, and gallbladder disease. Use caution with history of cholestatic jaundice associated with past estrogen use or pregnancy. Safety and efficacy in pediatric patients have not been established.

Before prescribing estrogen therapy to postmenopausal women, the risks and benefits must be weighed for each patient. Women should be informed of these risks and benefits, as well as possible effects of progestin when added to estrogen therapy. Estrogens with or without progestin should be used for shortest duration possible consistent with treatment goals. Conduct periodic risk:benefit assessments.

When used solely for prevention of osteoporosis in women at significant risk, nonestrogen treatment options should be considered. When used solely for the treatment of vulvar and vaginal atrophy, topical vaginal products should be considered.

Transdermal patch may contain conducting metal (eg, aluminum); remove patch prior to MRI.

Adverse Reactions:

Cardiovascular: Altered blood pressure, cardiovascular accident, edema, venous thromboembolism

Central nervous system: Dizziness, fatigue, headache, insomnia, mental depression, migraine, nervousness

Dermatologic: Chloasma, erythema multiforme, erythema nodosum, hemorrhagic eruption, hirsutism, itching, loss of scalp hair, melasma, pruritus, skin rash

Endocrine & metabolic: Breast enlargement, breast tenderness, breast pain, libido (changes in)

Gastrointestinal: Abdominal pain, bloating, changes in appetite, flatulence, gallbladder disease, nausea, pancreatitis, vomiting, weight gain/loss

Genitourinary: Alterations in frequency and flow of menses, changes in cervical secretions, cystitis-like syndrome, increased size of uterine leiomyomata, premenstrual-like syndrome, vaginal candidiasis, vaginitis

Hematologic: Aggravation of porphyria

Hepatic: Cholestatic jaundice

Local: Application site reaction (transdermal patch)

Neuromuscular & skeletal: Arthralgia, back pain, chorea, myalgia, weakness

Ocular: Intolerance to contact lenses, steeping of corneal curvature

Respiratory: Pharyngitis, pulmonary thromboembolism, rhinitis

Miscellaneous: Allergic reactions, carbohydrate intolerance, flu-like syndrome

Drug Interactions:

Estradiol: Substrate of CYP1A2 (major), 2A6 (minor), 2B6 (minor), 2C8/9 (minor), 2C19 (minor), 2D6 (minor), 2E1 (minor), 3A4 (major); Inhibits CYP1A2 (weak); Induces CYP3A4 (weak)

Norethindrone: Substrate of CYP3A4 (major); Induces CYP2C19 (weak)

Also see individual agents.

Ethanol/Nutrition/Herb Interactions:

Ethanol: Avoid ethanol (routine use increases estrogen level and risk of breast cancer). Ethanol may also increase the risk of osteoporosis.

Food: Folic acid absorption may be decreased

Herb/Nutraceutical: St John's wort may decrease estradiol levels. Avoid black cohosh, dong quai (has estrogenic activity). Avoid red clover, saw palmetto, ginseng.

Pharmacodynamics/Kinetics:

Activella™:

Bioavailability: Estradiol: 50%; Norethindrone: 100%

Half-life elimination: Estradiol: 12-14 hours; Norethindrone: 8-11 hours

Time to peak: Estradiol: 5-8 hours

See individual agents.

Dosage:

Oral (Activella™): 1 tablet daily

Transdermal patch (CombiPatch®):

Continuous combined regimen: Apply one patch twice weekly

Continuous sequential regimen: Apply estradiol-only patch for first 14 days of cycle, followed by one CombiPatch™ applied twice weekly for the remaining 14 days of a 28-day cycle

Transdermal patch, combination pack (product-specific dosing for Canadian formulation):

Estalis®: Continuous combined regimen: Apply a new patch twice weekly during a 28-day cycle

Estalis-Sequi®: Continuous sequential regimen: Apply estradiol-only patch (Vivelle®) for first 14 days, followed by one Estalis® patch applied twice weekly during the last 14 days of a 28-day cycle

Note: In women previously receiving oral estrogens, initiate upon reappearance of menopausal symptoms following discontinuation of oral therapy.

Administration:

Monitoring Parameters:

Menopausal symptoms: Assess need for therapy at 3- to 6-month intervals

Prevention of osteoporosis: Bone density measurement

Patient Education:

Dental Health: Effects on Dental Treatment:

Dental Health: Vasoconstrictor/Local Anesthetic Precautions:

Mental Health: Effects on Mental Status:

Mental Health: Effects on Psychiatric Treatment:

Dosage Forms:

Combination pack (Estalis-Sequi® [CAN; not available in U.S.]):

140/50:

Transdermal system (Vivelle®): Estradiol 50 mcg per day (4s) [14.5 sq cm; total estradiol 4.33 mg]

Transdermal system (Estalis®): Norethindrone acetate 140 mcg and estradiol 50 mcg per day (4s) [9 sq cm; total norethindrone acetate 2.7 mg, total estradiol 0.62 mg; not available in U.S.]

250/50:

Transdermal system (Vivelle®): Estradiol 50 mcg per day (4s) [14.5 sq cm; total estradiol 4.33 mg]

Transdermal system (Estalis®): Norethindrone acetate 250 mcg and estradiol 50 mcg per day (4s) [16 sq cm; total norethindrone acetate 4.8 mg, total estradiol 0.51 mg; not available in U.S.]

Tablet (Activella®): Estradiol 1 mg and norethindrone acetate 0.5 mg (28s)

Transdermal system:

CombiPatch®:

0.05/0.14: Estradiol 0.05 mg and norethindrone acetate 0.14 mg per day (8s) [9 sq cm]

0.05/0.25: Estradiol 0.05 mg and norethindrone acetate 0.25 mg per day (8s) [16 sq cm]

Estalis® [CAN]:

140/50: Norethindrone acetate 140 mcg and estradiol 50 mcg per day (8s) [9 sq cm; total norethindrone acetate 2.7 mg, total estradiol 0.62 mg; not available in U.S.]

250/50 Norethindrone acetate 250 mcg and estradiol 50 mcg per day (8s) [16 sq cm; total norethindrone acetate 4.8 mg, total estradiol 0.51 mg; not available in U.S.]

International Brand Names: