Version July 2025
There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestogen to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding.
Do not use estrogen-alone therapy for the prevention of cardiovascular disease. The Women's Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral conjugated estrogens (0.625 mg) alone, relative to placebo.
Do not use estrogen plus progestogen therapy for the prevention of cardiovascular disease. The WHI estrogen plus progestin substudy reported increased risks of DVT, pulmonary embolism (PE), stroke, and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogens (0.625 mg) combined with medroxyprogesterone acetate (2.5 mg), relative to placebo.
The Women's Health Initiative (WHI) estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer.
Do not use estrogen-alone therapy for the prevention of dementia. The WHI Memory Study (WHIMS) estrogen-alone ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years and older during 5.2 years of treatment with daily conjugated estrogens (0.625 mg) alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women.
Do not use estrogen plus progestogen therapy for the prevention of dementia. The WHIMS estrogen plus progestin ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years or older during 4 years of treatment with daily conjugated estrogens (0.625 mg) combined with medroxyprogesterone acetate (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women.
Only daily oral conjugated estrogen (CE) 0.625 mg was studied in the estrogen-alone substudy of the WHI. Therefore, the relevance of the WHI findings regarding adverse cardiovascular events and dementia to lower CE doses, other routes of administration, or other estrogen-alone products is not known. Without such data, it is not possible to definitively exclude these risks or determine the extent of these risks for other products. Discuss with your patient the benefits and risks of estrogen-alone therapy, taking into account her individual risk profile. Prescribe estrogens with or without progestogens at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.
Osteoporosis, prevention: Oral: Estradiol 0.5 mg/norethindrone 0.1 mg or estradiol 1 mg/norethindrone 0.5 mg: one tablet daily.
Secondary amenorrhea, hypoestrogenism: Note: Combination products are only indicated for patients with a uterus; the progestogen (ie, a natural progesterone or synthetic progestin) component prevents estrogen therapy-associated endometrial hyperplasia. For functional hypothalamic amenorrhea (FHA), initiate only if menses have not returned after 6 to 12 months of nonpharmacologic (eg, behavioral, lifestyle) therapy. For hypoestrogenism due to other causes (eg, primary ovarian insufficiency), may initiate after diagnosis confirmed if no contraindications (eg, breast cancer) (Ref).
Transdermal (CombiPatch): Estradiol 0.05 mg/norethindrone acetate 0.14 mg per day or estradiol 0.05 mg/norethindrone acetate 0.25 mg per day: Apply 1 patch twice weekly. Initiate with lower dose; may increase after 6 months if higher dose of progestin is needed (eg, for irregular menstrual bleeding). Note: For twice-weekly dosing, replace patch every 3 to 4 days.
Duration of therapy: If amenorrhea is expected to be transient (eg, FHA), discontinue after ~18 months to assess for recovery (Ref). If amenorrhea is expected to be permanent (eg, primary ovarian insufficiency), continue at least until the average age of natural menopause (age ~50 years) (Ref).
Vasomotor symptoms associated with menopause: Note:For use in symptomatic patients who are <60 years of age or within 10 years of menopause who do not have contraindications to hormone therapy (eg, breast cancer) (Ref). Nonoral estrogen preparations are preferred in patients with hypertriglyceridemia, risk factors for venous thromboembolic disease, active gallbladder disease, and/or migraine headache with aura (Ref). Combination products are only indicated for patients with a uterus; the progestogen (ie, a natural progesterone or synthetic progestin) component prevents estrogen therapy-associated endometrial hyperplasia. Use of a combination product offers less dosing flexibility for initiating and tapering estrogen compared to separate estrogen and progestogen products.
Oral: Estradiol 0.5 mg/norethindrone 0.1 mg or estradiol 1 mg/norethindrone 0.5 mg: 1 tablet daily. Note: Initiate at the lowest dose and increase after ~4 weeks as needed to relieve symptoms (Ref).
Transdermal (CombiPatch, Estalis [Canadian product]):
Continuous combined regimen: Estradiol 0.05 mg/norethindrone acetate 0.14 mg per day or estradiol 0.05 mg/norethindrone acetate 0.25 mg per day: Apply 1 patch twice weekly. Note: For twice-weekly dosing, replace the patch every 3 to 4 days. Initiate with lower dose; may increase after 3 to 6 months if higher dose of progestin is needed (eg, for irregular menstrual bleeding).
Duration of therapy: Not clearly established; continued use may be appropriate in patients ≥60 years of age or >10 years after menopause with a low risk of cardiovascular disease and breast cancer and with persistent vasomotor symptoms after attempted taper/discontinuation of estrogen and trial of alternative therapies. Evaluate routinely for comorbidities and appropriateness of lower doses, nonoral routes of administration (preferred in patients ≥60 years of age), choice of progestogen, and discontinuation of therapy (Ref).
Vulvar and vaginal atrophy associated with menopause:
Oral: Estradiol 1 mg/norethindrone 0.5 mg: One tablet daily
Transdermal: Estradiol 0.05 mg/norethindrone acetate 0.14 mg per day or estradiol 0.05 mg/norethindrone acetate 0.25 mg per day
CombiPatch:
Continuous combined regimen: Apply 1 patch twice weekly
Continuous sequential regimen: Apply estradiol-only patch for first 14 days of cycle, followed by 1 CombiPatch applied twice weekly for the remaining 14 days of a 28-day cycle.
Estalis [Canadian product]: Continuous combined regimen: Apply a new patch twice weekly during a 28-day cycle
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); use with caution.
Use is contraindicated with hepatic dysfunction or disease.
Note: The Beers Criteria recommends avoiding systemic estrogen therapy in postmenopausal patients ≥65 years of age (independent of diagnosis or condition). In older postmenopausal patients already taking systemic estrogens, consider deprescribing (Ref). Duration of use is not clearly established; continued use may be appropriate in patients ≥60 years of age or >10 years after menopause with a low risk of cardiovascular disease and breast cancer with persistent vasomotor symptoms after attempted taper/discontinuation of estrogen and trial of alternative therapies. Evaluate routinely for comorbidities and appropriateness of lower doses, non-oral routes of administration (preferred in patients ≥60 years of age), choice of progestogen, and discontinuation of therapy (Ref).
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions are for the oral and transdermal products unless otherwise indicated.
>10%:
Endocrine & metabolic: Menstrual disease (transdermal: 6% to 19%), postmenopausal bleeding (oral: 10% to 11%)
Gastrointestinal: Abdominal pain (transdermal: 6% to 14%), diarrhea (transdermal: 9% to 14%), nausea (3% to 12%)
Genitourinary: Dysmenorrhea (transdermal: 20% to 31%), mastalgia (oral: 17% to 21%; transdermal: 25% to 48%), vaginal hemorrhage (oral: 26%; transdermal: 3% to 6%), vaginitis (transdermal: 6% to 13%)
Local: Application-site reaction (transdermal: 6% to 23%; including application-site burning, application-site dryness, application-site edema, application-site erythema, application-site irritation, application-site pain, application-site pruritus, application-site rash, application-site vesicles, bleeding, bruise, eczema, local discomfort, local skin discoloration, local skin hyperpigmentation, local swelling, papule of skin, paresthesia, urticaria)
Nervous system: Asthenia (transdermal: 8% to 13%), headache (11% to 25%), pain (transdermal: 15% to 19%)
Neuromuscular & skeletal: Back pain (6% to 15%)
Respiratory: Flu-like symptoms (transdermal: 9% to 14%), nasopharyngitis (oral: 21%), respiratory system disorder (transdermal: 9% to 13%), rhinitis (transdermal: 13% to 22%), sinusitis (7% to 15%)
1% to 10%:
Cardiovascular: Peripheral edema (transdermal: 6%)
Dermatologic: Acne vulgaris (transdermal: 4% to 5%), skin rash (transdermal: 5% to 6%)
Endocrine & metabolic: Heavy menstrual bleeding (transdermal: 2% to 5%), weight gain (oral: 9%)
Gastrointestinal: Constipation (transdermal: 2% to 5%), dyspepsia (transdermal: 6% to 8%), flatulence (transdermal: 5% to 7%), gastroenteritis (oral: 6%)
Genitourinary: Abnormal cervical or vaginal Papanicolaou smear (transdermal: 8%), breast hypertrophy (transdermal: 2% to 7%), endometrial hyperplasia (oral: ≤10%), leukorrhea (transdermal: 5% to 10%), ovarian cyst (oral: 7%), vulvovaginal candidiasis (oral: 6%)
Infection: Infection (transdermal: 3% to 5%)
Nervous system: Depression (transdermal: 8% to 9%), dizziness (transdermal: 6% to 7%), emotional lability (oral: 6%), insomnia (6% to 8%), nervousness (transdermal: 3% to 6%)
Neuromuscular & skeletal: Arthralgia (transdermal: 6%), limb pain (oral: 5%)
Respiratory: Bronchitis (transdermal: 3% to 5%), pharyngitis (transdermal: 4% to 10%), upper respiratory tract infection (oral: 10%)
Postmarketing (any formulation):
Cardiovascular: Acute myocardial infarction, edema, hypertension, thrombophlebitis, varicose veins, venous thromboembolism (including deep vein thrombosis, pulmonary embolism)
Dermatologic: Chloasma, erythema multiforme, erythema nodosum, hemorrhagic eruption of the skin, loss of scalp hair, pruritus, seborrhea, skin discoloration
Endocrine & metabolic: Change in libido, change in menstrual flow, fibrocystic breast changes, galactorrhea not associated with childbirth, hirsutism, increased serum triglycerides, irregular menses, premenstrual-like syndrome, spotting, weight loss
Gastrointestinal: Bloating, change in appetite, cholelithiasis, gallbladder disease, pancreatitis, stomach cramps, vomiting
Genitourinary: Breakthrough bleeding, breast tenderness, cervical ectropion, cervical polyp, change in cervical secretions, cystitis-like syndrome, endometrial carcinoma, fallopian tube disease (cyst), malignant neoplasm of breast, nipple discharge, ovarian carcinoma, uterine fibroids, uterine spasm, withdrawal bleeding
Hepatic: Cholestatic jaundice, increased serum transaminases
Hypersensitivity: Hypersensitivity reaction (including anaphylaxis, angioedema, nonimmune anaphylaxis)
Nervous system: Cerebrovascular accident, chorea, dementia, exacerbation of epilepsy, fatigue, irritability, migraine, mood changes, paresthesia, vertigo
Neuromuscular & skeletal: Lower limb cramp
Ophthalmic: Contact lens intolerance, retinal thrombosis
Respiratory: Exacerbation of asthma
Angioedema, anaphylactic reaction, or hypersensitivity to estradiol or any component of the formulation; undiagnosed abnormal genital bleeding; deep vein thrombosis or pulmonary embolism (current or history of); active or history of arterial thromboembolic disease (eg, stroke, myocardial infarction); breast cancer (known, suspected, or history of); estrogen-dependent tumor (known or suspected); hepatic impairment or disease; known protein C, protein S, antithrombin deficiency, or other known thrombophilic disorders.
Canadian labeling: Additional contraindications (not in US labeling): Known, suspected, or history of estrogen-dependent or progestin-dependent malignant neoplasm (eg, endometrial cancer); endometrial hyperplasia; porphyria; partial or complete loss of vision associated with ophthalmic vascular disease; active thrombophlebitis; classical migraine; pregnancy; breastfeeding.
Concerns related to adverse effects:
• Anaphylaxis: Anaphylaxis requiring emergency medical management has been reported and may develop at any time during therapy.
• Breast cancer: Estrogen with or without progestogen for the management of menopausal symptoms may be associated with an increased risk of breast cancer. The risk of breast cancer in patients who are postmenopausal on hormone therapy may depend upon type of estrogen and/or progestogen, dose, timing of therapy initiation, duration of therapy, route of administration, and individual patient characteristics (AACE/ACE [Cobin 2017]; NAMS 2022). Hormone therapy may be associated with increased breast density (NAMS 2022); an increase in abnormal mammogram findings requiring further evaluation has been reported with estrogen alone or in combination with progestogen therapy. Estrogen use may lead to severe hypercalcemia in patients with breast cancer and bone metastases; discontinue estrogen if hypercalcemia occurs.
• Dementia: Do not use estrogens with or without progestogen to prevent dementia. In the Women's Health Initiative Memory Study (WHIMS), an increased incidence of probable dementia was observed in patients ≥65 years of age taking CE alone or in combination with MPA. It is unknown if these findings apply to younger patients who are postmenopausal. However, hormone therapy is not recommended at any age to prevent or treat cognitive decline or dementia (AACE [Goodman 2011]; NAMS 2022).
• Endometrial cancer: The use of unopposed estrogen in patients with a uterus is associated with an increased risk of endometrial cancer. The addition of a progestogen to estrogen therapy may decrease the risk of endometrial hyperplasia, a precursor to endometrial cancer. Perform adequate diagnostic measures, including endometrial sampling if indicated, to rule out malignancy in patients who are postmenopausal with undiagnosed abnormal vaginal bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens at equivalent estrogen doses. The risk of endometrial cancer appears to be dose and duration dependent, greatest with use ≥5 years, and may persist following discontinuation of therapy.
• Endometriosis: Estrogens may exacerbate endometriosis. Malignant transformation of residual endometrial implants has been reported posthysterectomy with unopposed estrogen therapy. Consider adding a progestogen in patients with residual endometriosis posthysterectomy.
• Lipid effects: Estrogen compounds are generally associated with lipid effects such as increased HDL-cholesterol and decreased LDL-cholesterol. Triglycerides may also be increased in patients with preexisting hypertriglyceridemia; discontinue if pancreatitis occurs.
• Ovarian cancer: Available information related to the use of menopausal estrogen or estrogen/progestogen therapy and risk of ovarian cancer is inconsistent. If an association is present, the absolute risk is likely rare and may be influenced by duration of therapy (AACE [Goodman 2011]; ES [Stuenkel 2015]; NAMS 2022).
• Retinal thrombosis: Estrogens may cause retinal vascular thrombosis; discontinue pending examination if migraine, loss of vision, proptosis, diplopia, or other visual disturbances occur; discontinue permanently if papilledema or retinal vascular lesions are observed on examination.
Disease-related concerns:
• Asthma: Use caution in patients with asthma; may exacerbate disease.
• Cardiovascular disease: Do not use estrogens with or without progestogen to prevent cardiovascular disease. The WHI studies reported increased risk of deep vein thrombosis (DVT) and stroke with CE, and an increased risk of DVT, stroke, pulmonary emboli (PE) and myocardial infarction (MI) with CE with MPA in patients who are postmenopausal 50 to 79 years of age. Additional risk factors include diabetes mellitus, hypercholesterolemia, hypertension, SLE, obesity, tobacco use, and/or history of venous thromboembolism (VTE). Manage risk factors appropriately; discontinue use immediately if adverse cardiovascular events occur or are suspected. Due to possible lower risk of thrombotic events, transdermal administration may be preferred for treating vasomotor symptoms of menopause in patients with risk factors for cardiovascular disease (AACE/ACE [Cobin 2017]; ACOG 556 2013; ES [Stuenkel 2015]).
• Diabetes: May impair glucose tolerance; use caution in patients with diabetes. Prior to therapy, consider age, cardiovascular and metabolic risk factors in patients previously diagnosed with diabetes (AACE/ACE [Cobin 2017]).
• Diseases exacerbated by fluid retention: Use with caution in patients with diseases that may be exacerbated by fluid retention, including cardiac or renal dysfunction; consider discontinuation of therapy if medically concerning fluid retention occurs.
• Epilepsy: Use caution in patients with epilepsy; may exacerbate disease.
• Gallbladder disease: Use of postmenopausal estrogen may be associated with an increased risk of gallbladder disease requiring surgery.
• Hepatic dysfunction: Estrogens are poorly metabolized in patients with hepatic dysfunction. Use caution with a history of cholestatic jaundice associated with prior estrogen use or pregnancy. Discontinue if jaundice develops or if acute or chronic hepatic disturbances occur.
• Hepatic hemangiomas: Use with caution in patients with hepatic hemangiomas; may exacerbate disease.
• Hereditary angioedema: Exogenous estrogens may exacerbate angioedema symptoms in patients with hereditary angioedema.
• Hypoparathyroidism: Use caution in patients with hypoparathyroidism; estrogen-induced hypocalcemia may occur.
• Migraine: Use caution in patients with migraine; may exacerbate disease.
• Otosclerosis: Use caution in patients with otosclerosis.
• Porphyria: Use with caution in patients with porphyria; may exacerbate disease.
• Systemic lupus erythematosus: Use with caution in patients with systemic lupus erythematosus; may exacerbate disease.
Special populations:
• Surgery: Whenever possible, discontinue estrogens at least 4 to 6 weeks prior to elective surgery associated with an increased risk of thromboembolism or during periods of prolonged immobilization.
Dosage forms specific issues:
• Lactose: Tablets may contain lactose; use caution in patients with galactose intolerance, lactase deficiency, or glucose-galactose metabolism.
Other warnings/precautions:
• Duration of use: Not clearly established; continued use may be appropriate in patients ≥60 years of age or >10 years after menopause with a low risk of cardiovascular disease and breast cancer with persistent vasomotor symptoms after attempted taper/discontinuation of estrogen and trial of alternative therapies. Evaluate routinely for comorbidities and appropriateness of lower doses, nonoral routes of administration (preferred in patients ≥60 years of age), choice of progestogen, and discontinuation of therapy (NAMS 2022).
• Genitourinary syndrome of menopause: Low-dose vaginal estrogen is preferred over systemic therapy for genitourinary syndrome of menopause (GSM) in the absence of vasomotor symptoms due to increased efficacy and decreased systemic effects (eg, cardiovascular effects, cancer risk) (Crandall 2018; NAMS 2020; NAMS 2022).
• Osteoporosis use: In patients with premature menopause, hormone therapy to prevent bone loss may be used unless otherwise contraindicated; reassess therapy when the average age of menopause is reached. It is also an appropriate bone-active therapy for patients with vasomotor symptoms who are <60 years of age or within 10 years of menopause onset. Consider use in patients at high risk of fractures who are not candidates for other osteoporosis therapies (NAMS 2022).
• Risks vs benefits: When used for the relief of menopausal symptoms or increased risk of bone fracture/loss, the benefit-risk of hormone therapy is most favorable if started in patients who have no contraindications to therapy, are <60 years of age, within 10 years of menopause onset, have a favorable lipid profile, and do not have the factor V Leiden genotype or metabolic syndrome. Consider cardiovascular disease risk factors when evaluating therapy and route of administration (AACE/ACE [Cobin 2017]; NAMS 2022). Use for the shortest duration possible at the lowest effective dose consistent with treatment goals and risks for the individual patient. Reevaluate patients as clinically appropriate to determine if treatment is still necessary. Available data related to treatment risks are from WHI studies, which evaluated oral CE 0.625 mg with or without MPA 2.5 mg relative to placebo in women who were postmenopausal. Assume outcomes reported from clinical trials using CE with or without MPA to be similar for other doses and other dosage forms of estrogens and progestogens until comparable data become available.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Patch Twice Weekly, Transdermal:
CombiPatch: estradiol 0.05 mg and norethindrone acetate 0.14 mg per day (8 ea); 0.05/0.25: Estradiol 0.05 mg and norethindrone acetate 0.25 mg per day (8 ea)
Tablet, Oral:
Activella: estradiol 1 mg and norethindrone acetate 0.5 mg [contains corn starch]
Amabelz: estradiol 1 mg and norethindrone acetate 0.5 mg [DSC], estradiol 0.5 mg and norethindrone acetate 0.1 mg [DSC] [contains corn starch]
Mimvey: estradiol 1 mg and norethindrone acetate 0.5 mg
Generic: 1/0.5: Estradiol 1 mg and norethindrone acetate 0.5 mg, estradiol 0.5 mg and norethindrone acetate 0.1 mg, estradiol 1 mg and norethindrone acetate 0.5 mg
May be product dependent
Patch, twice-weekly (CombiPatch Transdermal)
0.05-0.14 mg/day (per each): $39.05
0.05-0.25 mg/day (per each): $39.05
Tablets (Activella Oral)
1-0.5 mg (per each): $12.04
Tablets (Estradiol-Norethindrone Acet Oral)
0.5-0.1 mg (per each): $4.44 - $6.48
1-0.5 mg (per each): $4.89 - $5.90
Tablets (Mimvey Oral)
1-0.5 mg (per each): $4.89
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Patch Twice Weekly, Transdermal:
Estalis: estradiol 0.05 mg and norethindrone acetate 0.14 mg per day (8 ea); estradiol 0.05 mg and norethindrone acetate 0.25 mg per day (8 ea)
Tablet, Oral:
Activelle: estradiol 1 mg and norethindrone acetate 0.5 mg
Activelle LD: estradiol 0.5 mg and norethindrone acetate 0.1 mg
Oral: Take at the same time each day.
Transdermal patch: Apply to smooth (fold free), clean, dry skin. Do not apply transdermal patch to breasts; apply to lower abdomen, avoiding waistline (Estalis [Canadian product] may be applied to lower abdomen or buttocks). Do not apply to oily, damaged or irritated skin. Rotate application sites; allow at least a 1-week interval before applying to the same site. Hold system firmly in place for ≥10 seconds. If system falls off, the same system may be applied to another area of the lower abdomen or a new system may be applied if necessary (continue with original treatment schedule). Wear only 1 system during the dosing interval. Do not expose the applied transdermal system to the sun for long periods of time. Following removal of the system, allow area to dry for 15 minutes, then gently rub with an oil-based cream or lotion if needed to remove any remaining adhesive. Apply the patch at any time in patients not previously using oral estrogen or estrogen/progestogen therapy. Complete the current cycle before applying the patch in patients receiving oral therapy. If bleeding occurs when the oral cycle is completed, the first day of bleeding is an appropriate time to start the patch.
Hazardous agent (NIOSH 2024 [table 1]).
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2023; NIOSH 2024; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
Osteoporosis prevention (tablet): Prevention of postmenopausal osteoporosis
Limitations of use: For use only in patients at significant risk of postmenopausal osteoporosis; consider use of nonestrogen medications.
Secondary amenorrhea, hypoestrogenism (patch): Treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure in patients with a uterus.
Vasomotor symptoms associated with menopause (patch, tablet): Treatment of moderate to severe vasomotor symptoms associated with menopause.
Vulvar and vaginal atrophy associated with menopause (patch, tablet): Treatment of moderate to severe vulvar and vaginal atrophy associated with menopause.
Limitations of use: When used solely for the treatment of vulvar and vaginal atrophy, consider topical vaginal products.
Note: The International Society for the Study of Women’s Sexual Health and The North American Menopause Society have endorsed the term genitourinary syndrome of menopause (GSM) as new terminology for vulvovaginal atrophy. The term GSM encompasses all genital and urinary signs and symptoms associated with a loss of estrogen due to menopause (Ref).
Beers Criteria: Estrogens (oral or topical patch products only), with or without progestins, are identified in the Beers Criteria as potentially inappropriate medications to be avoided in postmenopausal patients ≥65 years of age (independent of diagnosis or condition) due to their carcinogenic potential (breast and endometrium) and lack of cardioprotection or cognitive protection. Starting therapy in postmenopausal patients ≥60 years of age has greater risks (eg, heart disease, stroke, blood clots, dementia) than benefits. In postmenopausal patients already taking systemic estrogens, consider deprescribing (Beers Criteria [AGS 2023]).
Substrate of CYP3A4 (Major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP1A2 (Weak);
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Ajmaline: Estrogen Derivatives may increase adverse/toxic effects of Ajmaline. Specifically, the risk for cholestasis may be increased. Risk C: Monitor
Anastrozole: Estrogen Derivatives may decrease therapeutic effects of Anastrozole. Risk X: Avoid
Anthrax Immune Globulin (Human): Estrogen Derivatives may increase thrombogenic effects of Anthrax Immune Globulin (Human). Risk C: Monitor
Antidiabetic Agents: Hyperglycemia-Associated Agents may decrease therapeutic effects of Antidiabetic Agents. Risk C: Monitor
C1 Inhibitors: Estrogen Derivatives may increase thrombogenic effects of C1 Inhibitors. Risk C: Monitor
Chenodiol: Estrogen Derivatives may decrease therapeutic effects of Chenodiol. Risk C: Monitor
Chlorprothixene: Estrogen Derivatives may increase adverse/toxic effects of Chlorprothixene. Estrogen Derivatives may increase therapeutic effects of Chlorprothixene. Risk C: Monitor
Chlorprothixene: Progestins may increase therapeutic effects of Chlorprothixene. Progestins may increase adverse/toxic effects of Chlorprothixene. Risk C: Monitor
Clofazimine: May increase serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor
CloZAPine: CYP1A2 Inhibitors (Weak) may increase serum concentration of CloZAPine. Risk C: Monitor
Corticosteroids (Systemic): Estrogen Derivatives may increase serum concentration of Corticosteroids (Systemic). Risk C: Monitor
Cosyntropin: Coadministration of Estrogen Derivatives and Cosyntropin may alter diagnostic results. Management: Discontinue estrogen containing drugs 4 to 6 weeks prior to cosyntropin (ACTH) testing. Risk D: Consider Therapy Modification
CYP3A4 Inducers (Moderate): May decrease serum concentration of Estrogen Derivatives. Risk C: Monitor
CYP3A4 Inducers (Strong): May decrease serum concentration of Estrogen Derivatives. Risk C: Monitor
CYP3A4 Inhibitors (Strong): May increase serum concentration of Estrogen Derivatives. Risk C: Monitor
Dantrolene: Estrogen Derivatives may increase hepatotoxic effects of Dantrolene. Risk C: Monitor
Exemestane: Estrogen Derivatives may decrease therapeutic effects of Exemestane. Risk X: Avoid
Fezolinetant: CYP1A2 Inhibitors (Weak) may increase serum concentration of Fezolinetant. Risk X: Avoid
Fusidic Acid (Systemic): May increase serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Consider avoiding this combination if possible. If required, monitor patients closely for increased adverse effects of the CYP3A4 substrate. Risk D: Consider Therapy Modification
Growth Hormone Analogs: Estrogen Derivatives may decrease therapeutic effects of Growth Hormone Analogs. Management: Initiate somapacitan at 2 mg once weekly in patients receiving oral estrogens. Monitor for reduced efficacy of growth hormone analogs; increased doses may be required. Risk D: Consider Therapy Modification
Hemin: Estrogen Derivatives may decrease therapeutic effects of Hemin. Risk X: Avoid
Hyaluronidase: Estrogen Derivatives may decrease therapeutic effects of Hyaluronidase. Risk C: Monitor
Hydrocortisone (Systemic): Estrogen Derivatives may increase serum concentration of Hydrocortisone (Systemic). Estrogen Derivatives may decrease serum concentration of Hydrocortisone (Systemic). Risk C: Monitor
Immune Globulin: Estrogen Derivatives may increase thrombogenic effects of Immune Globulin. Management: Use the lowest dose of immune globulin and minimum infusion rate practicable during coadministration with estrogen derivatives. Risk D: Consider Therapy Modification
Indium 111 Capromab Pendetide: Coadministration of Estrogen Derivatives and Indium 111 Capromab Pendetide may alter diagnostic results. Risk X: Avoid
LamoTRIgine: Estrogen Derivatives may decrease serum concentration of LamoTRIgine. Risk C: Monitor
Lenalidomide: Estrogen Derivatives may increase thrombogenic effects of Lenalidomide. Risk C: Monitor
Melatonin: Estrogen Derivatives may increase serum concentration of Melatonin. Risk C: Monitor
MetyraPONE: Coadministration of Estrogen Derivatives and MetyraPONE may alter diagnostic results. Management: Consider alternatives to the use of the metyrapone test in patients taking estrogen derivatives. Risk D: Consider Therapy Modification
MetyraPONE: Coadministration of Progestins and MetyraPONE may alter diagnostic results. Management: Consider alternatives to the use of the metyrapone test in patients taking progestins. Risk D: Consider Therapy Modification
Mivacurium: Estrogen Derivatives may increase serum concentration of Mivacurium. Risk C: Monitor
Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective): May increase thrombogenic effects of Estrogen Derivatives. Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective) may increase serum concentration of Estrogen Derivatives. Risk C: Monitor
Ospemifene: Estrogen Derivatives may increase adverse/toxic effects of Ospemifene. Risk X: Avoid
Pomalidomide: Estrogen Derivatives may increase thrombogenic effects of Pomalidomide. Risk C: Monitor
Protease Inhibitors: May decrease serum concentration of Estrogen Derivatives. Protease Inhibitors may increase serum concentration of Estrogen Derivatives. Risk C: Monitor
Raloxifene: Estrogen Derivatives may increase adverse/toxic effects of Raloxifene. Risk X: Avoid
ROPINIRole: Estrogen Derivatives may increase serum concentration of ROPINIRole. Risk C: Monitor
Succinylcholine: Estrogen Derivatives may increase serum concentration of Succinylcholine. Risk C: Monitor
Tacrolimus (Systemic): Estrogen Derivatives may increase serum concentration of Tacrolimus (Systemic). Risk C: Monitor
Thalidomide: Estrogen Derivatives may increase thrombogenic effects of Thalidomide. Risk C: Monitor
Theophylline Derivatives: CYP1A2 Inhibitors (Weak) may increase serum concentration of Theophylline Derivatives. Risk C: Monitor
Thyroid Products: Estrogen Derivatives may decrease therapeutic effects of Thyroid Products. Risk C: Monitor
TiZANidine: CYP1A2 Inhibitors (Weak) may increase serum concentration of TiZANidine. Management: Avoid the use of tizanidine with weak CYP1A2 inhibitors when possible. If combined, monitor closely for increased tizanidine toxicities (eg, hypotension, bradycardia, drowsiness). Tizanidine dose reduction or discontinuation may be necessary. Risk D: Consider Therapy Modification
Tranexamic Acid: Estrogen Derivatives may increase thrombogenic effects of Tranexamic Acid. Risk X: Avoid
Ulipristal: May decrease therapeutic effects of Progestins. Progestins may decrease therapeutic effects of Ulipristal. Risk X: Avoid
Ursodiol: Estrogen Derivatives may decrease therapeutic effects of Ursodiol. Risk C: Monitor
Folic acid absorption may be decreased.
Do not use estradiol/norethindrone during pregnancy.
Refer to individual monographs for additional information.
Estrogens and progestogens are present in breast milk.
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother.
Ensure adequate calcium and vitamin D intake when used for the prevention of osteoporosis.
Prior to therapy, baseline risk for breast cancer and CVD. During therapy, age appropriate breast and pelvic exams; BP; unscheduled bleeding lasting >6 months for endometrial pathology (sooner in patients with obesity, diabetes, or a history of endometrial cancer); serum triglycerides (2 weeks after starting therapy in patients with baseline level >200 mg/dL); TSH (6 to 12 weeks after starting oral therapy in patients taking thyroid replacement) (ES [Stuenkel 2015]).
Menopausal symptoms: Efficacy beginning 1 to 3 months after starting therapy, then every 6 to 12 months as appropriate. Evaluate duration of treatment at least annually (ES [Stuenkel 2015]).
Note: Monitoring of FSH and serum estradiol is not useful when managing vasomotor symptoms or genitourinary symptoms of menopause.
Prevention of osteoporosis: Bone density measurement
See individual agents.
Absorption: Patch: Average serum estradiol concentrations (Cavg): 45 to 50 pg/mL
Time to peak: Tablet: Estradiol 5 to 8 hours; Norethindrone: 0.5 to 1.5 hours
Half-life elimination: Tablet: Estradiol 12 to 14 hours; Norethindrone: 8 to 11 hours
