estradiol/norethindrone acetate (Rx)

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

AdultPediatric

Dosage Forms & Strengths

estradiol/norethindrone acetate

tablet

  • 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

Indications

  • 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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Interactions

Interaction Checker

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              Serious - Use Alternative (21)

              • abametapir

                abametapir will increase the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. For 2 weeks after abametapir application, avoid taking drugs that are CYP3A4 substrates. If not feasible, avoid use of abametapir.

              • acitretin

                acitretin decreases effects of norethindrone acetate by unknown mechanism. Contraindicated. Contraceptive failure may result.

              • apalutamide

                apalutamide will decrease the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration of apalutamide, a strong CYP3A4 inducer, with drugs that are CYP3A4 substrates can result in lower exposure to these medications. Avoid or substitute another drug for these medications when possible. Evaluate for loss of therapeutic effect if medication must be coadministered. Adjust dose according to prescribing information if needed.

              • belzutifan

                belzutifan will decrease the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration of belzutifan with hormonal contraceptives may lead to contraceptive failure or increased breakthrough bleeding. Advise females of reproductive potential to use effective nonhormonal contraception. Based on animal studies, belzutifan can cause fetal harm.

              • carbamazepine

                carbamazepine will decrease the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration unless benefit outweighs risk. When coadministered, hormonal contraceptives are not a reliable method of effective birth control. Concomitant use may increase incidence of menstruation associated adverse effects (amenorrhea, dysmenorrhea, menorrhagia).

              • enzalutamide

                enzalutamide will decrease the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration unless benefit outweighs risk. When coadministered, hormonal contraceptives are not a reliable method of effective birth control. Concomitant use may increase incidence of menstruation associated adverse effects (amenorrhea, dysmenorrhea, menorrhagia).

              • fexinidazole

                fexinidazole will increase the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Fexinidazole inhibits CYP3A4. Coadministration may increase risk for adverse effects of CYP3A4 substrates.

              • fosphenytoin

                fosphenytoin will decrease the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration unless benefit outweighs risk. When coadministered, hormonal contraceptives are not a reliable method of effective birth control. Concomitant use may increase incidence of menstruation associated adverse effects (amenorrhea, dysmenorrhea, menorrhagia).

              • idelalisib

                idelalisib will increase the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Idelalisib is a strong CYP3A inhibitor; avoid coadministration with sensitive CYP3A substrates

              • ivosidenib

                ivosidenib will decrease the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of sensitive CYP3A4 substrates with ivosidenib or replace with alternative therapies. If coadministration is unavoidable, monitor patients for loss of therapeutic effect of these drugs.

              • lumacaftor/ivacaftor

                lumacaftor/ivacaftor will decrease the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration unless benefit outweighs risk. When coadministered, hormonal contraceptives are not a reliable method of effective birth control. Concomitant use may increase incidence of menstruation associated adverse effects (amenorrhea, dysmenorrhea, menorrhagia).

              • mitotane

                mitotane will decrease the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration unless benefit outweighs risk. When coadministered, hormonal contraceptives are not a reliable method of effective birth control. Concomitant use may increase incidence of menstruation associated adverse effects (amenorrhea, dysmenorrhea, menorrhagia).

              • phenobarbital

                phenobarbital will decrease the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration unless benefit outweighs risk. When coadministered, hormonal contraceptives are not a reliable method of effective birth control. Concomitant use may increase incidence of menstruation associated adverse effects (amenorrhea, dysmenorrhea, menorrhagia).

              • phenytoin

                phenytoin will decrease the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration unless benefit outweighs risk. When coadministered, hormonal contraceptives are not a reliable method of effective birth control. Concomitant use may increase incidence of menstruation associated adverse effects (amenorrhea, dysmenorrhea, menorrhagia).

              • primidone

                primidone will decrease the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration unless benefit outweighs risk. When coadministered, hormonal contraceptives are not a reliable method of effective birth control. Concomitant use may increase incidence of menstruation associated adverse effects (amenorrhea, dysmenorrhea, menorrhagia).

              • rifabutin

                rifabutin will decrease the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration unless benefit outweighs risk. When coadministered, hormonal contraceptives are not a reliable method of effective birth control. Concomitant use may increase incidence of menstruation associated adverse effects (amenorrhea, dysmenorrhea, menorrhagia).

              • rifampin

                rifampin decreases levels of norethindrone acetate by increasing metabolism. Avoid or Use Alternate Drug. Avoid coadministration unless benefit outweighs risk. When coadministered, hormonal contraceptives are not a reliable method of effective birth control. Concomitant use may increase incidence of menstruation associated adverse effects (amenorrhea, dysmenorrhea, menorrhagia).

              • rifapentine

                rifapentine will decrease the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration unless benefit outweighs risk. When coadministered, hormonal contraceptives are not a reliable method of effective birth control. Concomitant use may increase incidence of menstruation associated adverse effects (amenorrhea, dysmenorrhea, menorrhagia).

              • topiramate

                topiramate will decrease the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration unless benefit outweighs risk. When coadministered, hormonal contraceptives are not a reliable method of effective birth control. Concomitant use may increase incidence of menstruation associated adverse effects (amenorrhea, dysmenorrhea, menorrhagia).

              • tucatinib

                tucatinib will increase the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid concomitant use of tucatinib with CYP3A substrates, where minimal concentration changes may lead to serious or life-threatening toxicities. If unavoidable, reduce CYP3A substrate dose according to product labeling.

              • voxelotor

                voxelotor will increase the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Voxelotor increases systemic exposure of sensitive CYP3A4 substrates. Avoid coadministration with sensitive CYP3A4 substrates with a narrow therapeutic index. Consider dose reduction of the sensitive CYP3A4 substrate(s) if unable to avoid.

              Monitor Closely (23)

              • albiglutide

                norethindrone acetate decreases effects of albiglutide by pharmacodynamic antagonism. Use Caution/Monitor. Oral contraceptives may decrease hypoglycemic effects of antidiabetics by impairing glucose tolerance. Monitor for glycemic control in diabetic patients.

              • atazanavir

                atazanavir, norethindrone acetate. Either decreases effects of the other by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Use alternatives if available.

              • cenobamate

                cenobamate will decrease the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Increase dose of CYP3A4 substrate, as needed, when coadministered with cenobamate.

              • clobazam

                clobazam will decrease the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Clobazam is a weak CYP3A4 inducer; effectiveness of hormonal contraceptives may be diminished when given concurrently with clobazam. Additional non-hormonal forms of contraception are recommended.

              • dabrafenib

                dabrafenib will decrease the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely.

              • elagolix

                elagolix decreases levels of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Elagolix is a weak-to-moderate CYP3A4 inducer. Monitor CYP3A substrates if coadministered. Consider increasing CYP3A substrate dose if needed.

              • exenatide injectable solution

                norethindrone acetate, exenatide injectable solution. Other (see comment). Use Caution/Monitor. Comment: Oral contraceptives may decrease hypoglycemic effects of antidiabetics by impairing glucose tolerance. The effect of exenatide to slow gastric emptying may reduce the extent and rate of oral medications that require rapid GI absorption. Advise patients to take oral contraceptives at least 1 hr before exenatide. .

              • exenatide injectable suspension

                norethindrone acetate, exenatide injectable suspension. Other (see comment). Use Caution/Monitor. Comment: Oral contraceptives may decrease hypoglycemic effects of antidiabetics by impairing glucose tolerance. The effect of exenatide to slow gastric emptying may reduce the extent and rate of oral medications that require rapid GI absorption. Advise patients to take oral contraceptives at least 1 hr before exenatide.

              • fedratinib

                fedratinib will increase the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Adjust dose of drugs that are CYP3A4 substrates as necessary.

              • iloperidone

                iloperidone increases levels of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Iloperidone is a time-dependent CYP3A inhibitor and may lead to increased plasma levels of drugs predominantly eliminated by CYP3A4.

              • insulin degludec

                norethindrone acetate decreases effects of insulin degludec by pharmacodynamic antagonism. Use Caution/Monitor. Progestins may impair glucose tolerance.

              • insulin degludec/insulin aspart

                norethindrone acetate decreases effects of insulin degludec/insulin aspart by pharmacodynamic antagonism. Use Caution/Monitor. Progestins may impair glucose tolerance.

              • insulin inhaled

                norethindrone acetate decreases effects of insulin inhaled by pharmacodynamic antagonism. Use Caution/Monitor. Progestins may impair glucose tolerance.

              • istradefylline

                istradefylline will increase the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Istradefylline 40 mg/day increased peak levels and AUC of CYP3A4 substrates in clinical trials. This effect was not observed with istradefylline 20 mg/day. Consider dose reduction of sensitive CYP3A4 substrates.

              • liraglutide

                norethindrone acetate decreases effects of liraglutide by pharmacodynamic antagonism. Use Caution/Monitor. Oral contraceptives may decrease hypoglycemic effects of antidiabetics by impairing glucose tolerance. Monitor for glycemic control in diabetic patients.

              • maraviroc

                norethindrone acetate increases levels of maraviroc by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Potential for increased toxicity.

              • mifepristone

                mifepristone decreases effects of norethindrone acetate by pharmacodynamic antagonism. Use Caution/Monitor. Backup contraceptive method recommended.

              • rucaparib

                rucaparib will increase the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Adjust dosage of CYP3A4 substrates, if clinically indicated.

              • rufinamide

                rufinamide decreases effects of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Rufinamide is a weak inducer of the CYP 3A4 enzyme and can decrease exposure of drugs that are substrates of CYP3A4. .

              • siltuximab

                siltuximab, norethindrone acetate. Other (see comment). Use Caution/Monitor. Comment: CYP450 activity in the liver is down regulated by infection and inflammation stimuli including cytokines (eg, IL-6); inhibition of IL-6 by siltuximab may restore CYP450 enzymatic activity; caution if coadministered with CYP substrates that have a narrow therapeutic index.

              • stiripentol

                stiripentol, norethindrone acetate. affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Stiripentol is a CYP3A4 inhibitor and inducer. Monitor CYP3A4 substrates coadministered with stiripentol for increased or decreased effects. CYP3A4 substrates may require dosage adjustment.

              • tazemetostat

                tazemetostat will decrease the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              • tecovirimat

                tecovirimat will decrease the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Tecovirimat is a weak CYP3A4 inducer. Monitor sensitive CYP3A4 substrates for effectiveness if coadministered.

              Minor (0)

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                Adverse Effects

                >10%

                Amenorrhea

                Breakthrough bleeding

                Change in menstrual flow

                Spotting

                Edema

                Anorexia

                Weakness

                Frequency Not Defined

                Change in weight

                Depression

                Dizziness

                Headache

                Nervousness

                Somnolence

                Breast tenderness

                Galactorrhea

                Abdominal pain

                Nausea/vomiting

                Cholestatic jaundice

                Deep vein thrombosis

                Thrombophlebitis

                Postmarketing reports

                Endometrial hyperplasia

                Endocervical polyp

                Uterine leiomyomata

                Fallopian tube cyst

                Uterine spasms

                Breast cancer

                Hypertension

                Varicose veins

                Jaundice cholestatic

                Cholelithiasis

                Gall bladder disorder

                Transaminases increased

                Skin discoloration

                Lability affected

                Libido disorder

                Migraine

                Vertigo

                Paresthesia

                Angioedema

                Hypersensitivity

                Weight increased

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                Warnings

                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

                Contraindications

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

                Pregnancy

                Estrogen-dependent neoplasia

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

                Undiagnosed abnormal vaginal bleeding

                Cautions

                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 estrogen with or without progestogen, if DVT/PE, stroke or MI occur or suspected

                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; consider whether benefits of estrogen therapy outweigh risks in such women

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

                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 that might be influenced by this factor, such as cardiac or renal impairment warrant careful observation when estrogens plus progestins are prescribed; discontinue estrogen plus progestogen therapy, with evidence of medically concerning fluid retention

                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; consider whether benefits of estrogen therapy outweigh risks in such women

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

                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

                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

                Use caution in individuals with severe hypocalcemia; consider whether benefits of estrogen therapy outweigh risks in such women

                Endometrial Cancer

                • 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
                • Increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in a woman with a uterus; the reported endometrial cancer risk among unopposed estrogen users is about 2- to 12- fold greater than in nonusers, and appears dependent on duration of treatment and on estrogen dose
                • Most studies show no significant increased risk associated with use of estrogens for less than 1 year; the greatest risk appears to be associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more
                • This risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued
                • 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 the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer

                Drug interaction overview

                • In-vitro and in-vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4); therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism
                • Inducers of CYP3A4 such as St. John’s wort (Hypericum perforatum) preparations, phenobarbital, carbamazepine, and rifampin may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile
                • Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase plasma concentrations of estrogens and result in adverse reactions
                • Drugs or herbal products that induce or inhibit cytochrome P-450 enzymes, including CYP3A4, may decrease or increase the serum concentrations of norethindrone
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                Pregnancy & Lactation

                Pregnancy

                Not indicated for use in pregnancy; there are no data with use of in pregnant women; however, epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac abnormalities 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 breastfeeding women; this reduction can occur at any time but is less likely to occur once breastfeeding is well established; the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for therapy and any potential adverse effects on the 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

                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

                Pharmacokinetics

                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%)

                Metabolism

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

                Half-Life

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

                Metabolites

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

                Excretion

                • 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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                Patient Handout

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

                FormularyPatient Discounts

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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.
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                NC NOT COVERED – Drugs that are not covered by the plan.
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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.