estradiol/norethindrone acetate (Rx)

Brand and Other Names:Activella, CombiPatch, more...Lopreeza, Mimvey
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Dosing & Uses


Dosage Forms & Strengths

estradiol/norethindrone acetate


  • 1mg/0.5mg
  • 0.5mg//0.1mg

patch, extended release

  • 0.05mg/0.25mg per 24 hr
  • 0.05mg/0.14mg per 24 hr

Menopause & Vasomotor Symptoms

Oral tablets: 1 tablet PO qDay

Patch: Apply 1 patch to lower abdomen continuously, changed 2 times a week

Alternative patch regimen: 1 estradiol patch (0.05 mg/d) days 1-14, changed 2 times a week; then 1 patch on days 15-28, changed 2 times a week


  • Activella, Lopreeza, Mimvey (1 mg/0.5 mg or 0.5 mg/0.1 mg): Treatment of moderate-to-severe vasomotor symptoms due to menopause in patients with an intact uterus, and for prevention of osteoporosis in postmenopausal women with an intact uterus
  • Activella, Lopreeza. Mimvey (1 mg/0.5 mg): Treatment of moderate-to-severe symptoms of valvar/vaginal atrophy due to menopause
  • CombiPatch: Treatment of moderate to severe vasomotor symptoms in menopause, vulvar/vaginal atrophy; treatment of hypoestrogenisms due to hypogonadism, castration, or primary ovarian failure

Not indicated



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            Adverse Effects



            Breakthrough bleeding

            Change in menstrual flow





            Frequency Not Defined

            Change in weight






            Breast tenderness


            Abdominal pain


            Cholestatic jaundice

            Deep vein thrombosis


            Postmarketing reports

            Endometrial hyperplasia

            Endocervical polyp

            Uterine leiomyomata

            Fallopian tube cyst

            Uterine spasms

            Breast cancer


            Varicose veins

            Jaundice cholestatic


            Gall bladder disorder

            Transaminases increased

            Skin discoloration

            Lability affected

            Libido disorder






            Weight increased



            Black Box Warnings

            Cardiovascular risks

            • Estrogens with and without progestins should not be used to prevent cardiovascular disease
            • Estrogens plus progestins: Women’s Health Initiative (WHI) Estrogen Plus Progestin substudy reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, 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
            • Estrogens alone: 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 w/ oral conjugated estrogens (0.625 mg/day) alone compared with placebo

            Dementia risks

            • Estrogens with and without progestins should not be used to prevent dementia
            • Women's Health Initiative Memory Study (WHIMS), a substudy of the WHI study, reported increased risk of developing probable dementia in postmenopausal women aged 65 yr or older during 4 yr of treatment with daily CE 0.625 mg combined with MPA 2.5 mg, compared with placebo
            • Estrogens alone: A substudy of the WHIMS 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
            • Unknown whether these findings apply to younger postmenopausal women

            Breast Cancer

            • The WHI estrogen plus progestin substudy also demonstrated an 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
            • Because of these risks, estrogens with or without progestins should be prescribed at lowest effective dose and for shortest duration consistent with treatment goals and individual risks

            Endometrial cancer

            • Estrogens alone: There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens
            • Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer


            Hypersensitivity, including anaphylaxis or angioedema to estrogen/progestins Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders


            Estrogen-dependent neoplasia

            Current/history of: DVT/PE, arterial thromboembolic disease, breast cancer, liver disease/tumours

            Undiagnosed abnormal vaginal bleeding

            Jaundice with previous oral contraceptive use


            History of pruritus gravidarum, pemphigoid gestationis, deterioration of otosclerosis or idiopathic jaundice during pregnancy

            Untreated endometrial hyperplasia


            Caution in patients with bone mineral density changes, current/history of depression, DM, HTN, hyperlipidemia, hypertriglyceridemia, obesity, endometriosis, family history of breast cancer & DVT/PE, smoking, epilepsy, migraine, renal/cardiac impairment

            Discontinue if the following develop: jaundice, visual problems, 4-6 wk before major surgery, any symptoms of VTE, massive BP increase, unusually severe migraines or first-time migraines, depression

            Increased risk of post-op thromboembolic complications

            Conditions exacerbated by fluid retention (eg, asthma, migraine, cardiac/renal dysfunction, epilepsy)

            History of migraine with aura

            In some epidemiologic studies, use of estrogen plus progestin and estrogen-only products, in particular for 5 or more years, has been associated with increased risk of ovarian cancer; however, duration of exposure associated with increased risk is not consistent across all epidemiologic studies and some report no association

            Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases; if hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce serum calcium levels

            Angioedema involving eye/eyelid, face, larynx, pharynx, tongue and extremity (hands, legs, ankles, and fingers) with or without urticaria requiring medical intervention has occurred in postmarketing; women who develop angioedema anytime during course of treatment should not receive it again; exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema

            Cases of anaphylactic/ anaphylactoid reactions, which developed anytime during course of treatment and required emergency medical management, reported in postmarketing setting

            Studies of addition of progestin for 10 or more days of cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone

            In women with preexisting hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis; consider discontinuation of treatment if pancreatitis occurs

            Although transdermally administered estrogen therapy avoids first-pass hepatic metabolism, estrogens may be poorly metabolized in women with impaired liver function; for women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised and in the case of recurrence, medication should be discontinued

            Estrogen administration leads to increased thyroid-binding globulin (TBG) levels; women dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of thyroid replacement therapy; these women should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range

            Estrogens plus progestins may cause some degree of fluid retention; women with conditions which might be influenced by this factor, such as cardiac or renal impairment warrant careful observation when estrogens plus progestins are prescribed

            Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur

            For women known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered

            Estrogen therapy may cause exacerbation of asthma, diabetes mellitus, epilepsy, migraine or porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions

            Do not use with conditions that predispose to hyperkalemia

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

            Retinal vascular thrombosis reported in patients receiving estrogens; discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine; if examination reveals papilledema or retinal vascular lesions, estrogens should be discontinued

            There are, possible risks that may be associated with use of progestins with estrogens compared to estrogen-alone regimens, including a possible increased risk of breast cancer, adverse effects on lipoprotein metabolism (e.g., lowering HDL, raising LDL), and impairment of glucose tolerance

            Use caution in individuals with severe hypocalcemia


            Pregnancy & Lactation

            Pregnancy Category: X

            Lactation: enters breast milk; use with caution

            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

            Estradiol: Endogenous estrogen; reduces the release of gonadotropin-releasing hormone from hypothalamus, reduces release of LH and FSH from pituitary gland; increases synthesis of DNA, RNA, and various proteins in target tissues. Estrogen replacement reduces elevated levels of estrogen and progesterone LH and FSH in postmenopausal women.

            Norethindrone acetate: Progestin; inhibits secretion of gonadotropins from pituitary gland; prevents follicular maturation and ovulation, stimulates growth of mamary tissues


            Peak Plasma Time: Estradiol: 5-8 hr (PO); norethindrone: 1-2 hr (PO)

            Protein Bound: Estradiol: 98%, norethindrone: 90-97%

            Bioavailability: Estradiol (50%); norethindrone (100%)


            • Estradiol: liver, undergoes extensive first-pass metabolism
            • Norethindrone: Liver


            • Estradiol: 12-14 hr (PO), 2-3 hr (patch)
            • Norethindrone: 8-11 hr (PO), 6-8 hr (patch)


            • Estradiol: estriol, estrone
            • Norethindrone: sulfate, glucuronide (inactive)


            • Estradiol: urine as conjugates, most estrogens are also excreted in the bile and undergo enterohepatic recycling
            • Norethindrone: Urine 33-81%; Feces 35-43%




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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.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.