Version May 2024
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. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be taken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal genital bleeding.
Estrogen-alone therapy should not be used 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.
Estrogen plus progestin therapy should not be used 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 WHI estrogen-plus-progestin substudy demonstrated an increased risk of invasive breast cancer.
Estrogen-alone therapy should not be used 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 of age or 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.
Estrogen plus progestin therapy should not be used 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 of age 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.
In the absence of comparable data, these risks should be assumed to be similar for other doses of conjugated estrogens (with or without medroxyprogesterone acetate) and other dosage forms of estrogens (with or without progestins). Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.
Abnormal uterine bleeding, acute:
Note: For use in patients without high risk of thrombosis. High dose estrogen therapy typically requires a concurrent antiemetic (Ref).
Hemodynamically unstable patients: Note: Surgical management is preferred; however, IV estrogen may be used in select patients (ie, those in whom delayed therapeutic onset is unlikely to cause adverse outcomes) (Ref). IM, IV: 25 mg every 4 to 6 hours for 24 hours, then transition to oral therapy (eg, a combined oral contraceptive taper) (Ref).
Hemodynamically stable patients: Note: Oral estrogen may be used as an alternative to combined oral contraceptives (Ref). Oral (off-label route) (alternative agent): 2.5 mg every 6 hours. When bleeding subsides or is minimal, may decrease dose to 2.5 mg twice daily for a total duration of 21 to 25 days. Follow with progestin therapy for 10 days (Ref).
Breast cancer, metastatic: Oral: 10 mg 3 times/day for at least 3 months.
Osteoporosis, postmenopausal, prevention (alternative agent):
Note: For use as an alternative to first-line therapies to prevent bone loss in patients with moderate to severe vasomotor symptoms of menopause (Ref). In patients without menopausal vasomotor symptoms who require fracture risk reduction, other first-line therapies are preferred. Avoid initiating in patients >60 years of age or who are >10 years beyond menopause (Ref). Ensure adequate calcium and vitamin D intake during therapy.
Oral: Initial: 0.3 mg/day administered once daily or cyclically (3 weeks on, 1 week off, or 25 days on, 5 days off), depending on medical assessment of patient. Dosage adjustments are individualized based on menopausal symptoms; use the lowest effective dose. Doses ≥0.3 mg/day have been associated with bone mineral density (BMD) benefits; separate therapy to reduce the risk of osteoporotic fractures is not required for patients who attain BMD targets (Ref).
Duration of therapy: The optimal duration of therapy has not been established. Estrogens should be used for the shortest duration possible consistent with treatment goals (Ref). Extended use may be considered in patients in whom alternative therapies are not appropriate and when benefits of therapy are expected to outweigh risks (Ref).
Discontinuation of therapy: If continued osteoporosis therapy is necessary, switch to antiresorptive therapy (eg, with a bisphosphonate) following discontinuation (Ref).
Prostate cancer, advanced: Oral: 1.25 to 2.5 mg 3 times/day.
Secondary amenorrhea, hypoestrogenism (alternative agent):
Manufacturer’s labeling: Oral: 1.25 mg/day given cyclically; adjust according to severity of symptoms and patient response. For maintenance, adjust to the lowest effective dose. In a patient with a uterus, give estrogen with a progestogen (ie, a natural progesterone or synthetic progestin).
Uremic bleeding (off-label use): IV: 0.6 mg/kg/day for 5 days (Ref).
Vasomotor symptoms associated with menopause (alternative agent): 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). Initiate at the lowest dose and increase approximately every 4 weeks as needed to relieve symptoms (Ref). Evaluate routinely to minimize drug exposure and optimize administration route. Younger patients (eg, bilateral oophorectomy) may require higher doses. In patients with a uterus, give estrogen with a progestogen (ie, a natural progesterone or synthetic progestin), dosed either cyclically (preferred in late menopausal transition or early postmenopause) or continuously (preferred if >2 to 3 years postmenopause) (Ref).
Oral: Initial: 0.3 mg per day. Dosage range: 0.3 to 1.25 mg per day.
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: Initial: 0.3 mg/day. The lowest dose that will control symptoms should be used. May be given cyclically or daily, depending on medical assessment of patient. Adjust dose based on patient's response.
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 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, nonoral routes of administration (preferred in patients ≥60 years of age), choice of progestogen, and discontinuation of therapy (Ref).
Refer to adult dosing.
(For additional information see "Conjugated equine estrogens (systemic): Pediatric drug information")
Constitutional delay of growth and puberty (CDGP) (females): Limited data available: Note: Begin with the lowest available dose and gradually increase. Obtain bone age every 6 months to avoid premature epiphyseal closure. If treatment continues beyond 1 year or breast growth is significant and has plateaued or breakthrough bleeding occurs, add cyclic progesterone. Continue until menstruation has been established, or longer if clinically indicated (Ref).
Adolescents: Oral: Initial: 0.3 mg once daily; continue for 6 to 12 months then evaluate serum parameters and adjust accordingly; if a lower dose needed, consider a different estrogen preparation; requirements may change over the course of puberty; duration of therapy variable; once bone age advanced, may consider discontinuation of therapy (patient may continue pubertal advancement on own) (Ref). Note: Use of other estrogens (eg, estradiol) is preferred; if conjugated estrogens deemed necessary, the transdermal route may be preferred due to observed cardiovascular risks in post-menopausal females with the systemic route (Ref).
Hypogonadism, hypoestrogenism (females): Limited data available: Note: Begin with the lowest available dose and gradually increase dose over 2 to 3 years. Obtain bone age every 6 months to avoid premature epiphyseal closure. As puberty progresses, cyclic progesterone will need added (Ref).
Children ≥12 years and Adolescents: Oral: Initial: 0.3 mg once daily, titrate at 6 to 12 months intervals to 0.45 mg once daily and then 0.625 mg once daily. After the first 4 to 6 months of therapy or once breakthrough bleeding occurs, estrogen should be switched from continuous to cyclic therapy and administered for the first 21 days of the month in combination with periodic progesterone (Ref). Overall estrogen replacement will be of extended duration and in some cases lifelong; experts suggest transitioning to transdermal estradiol therapy when able. Some experts suggest an initial dose of 0.1625 mg once daily and then titrating upwards every 6 to 12 months (0.3, 0.45, 0.625 mg once daily, respectively); however, an appropriate commercially available dosage form is not available in the US (Ref). Note: Use of other estrogens (eg, estradiol) is preferred; if conjugated estrogens deemed necessary, the transdermal route may be preferred due to observed cardiovascular risks in post-menopausal females with the systemic route (Ref).
Turner syndrome: Limited data available: Note: Estradiol is preferable to initiate hormone replacement therapy in females with Turner syndrome (particularly transdermal route); therapy is initiated around 12 years of age, and slowly increased over 2 to 4 years to adult estrogen levels; once achieved may consider transition to conjugated estrogens although transdermal preferred (Ref). Adolescents ≥14 years: Usual dose: 1.25 to 2.5 mg once daily; reported range: 0.625 to 2.5 mg; adjust dose based on response and serum parameters (Ref).
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; estrogens may cause water retention, monitor fluid status in patients with renal disorders.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied). Use is contraindicated with hepatic dysfunction or disease.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
Percentages reported in postmenopausal women following oral use.
>10%:
Central nervous system: Headache (26% to 32%), pain (17% to 20%)
Gastrointestinal: Abdominal pain (15% to 17%)
Genitourinary: Vaginal hemorrhage (2% to 14%), mastalgia (7% to 12%)
Neuromuscular & skeletal: Back pain (13% to 14%), arthralgia (7% to 14%)
Respiratory: Pharyngitis (10% to 12%), sinusitis (6% to 11%)
1% to 10%:
Central nervous system: Depression (5% to 8%), dizziness (4% to 6%), nervousness (2% to 5%)
Dermatologic: Pruritus (4% to 5%)
Gastrointestinal: Diarrhea (6% to 7%), flatulence (6% to 7%)
Genitourinary: Vaginitis (5% to 7%), leukorrhea (4% to 7%), vulvovaginal candidiasis (5% to 6%)
Neuromuscular & skeletal: Weakness (7% to 8%), leg cramps (3% to 7%)
Respiratory: Increased cough (4% to 7%)
Frequency not defined (injection): Local: Injection site phlebitis, pain at injection site, swelling at injection site
<1%, postmarketing, and/or case reports: Abnormal uterine bleeding, alopecia, anaphylaxis, angioedema, bloating, breast hypertrophy, breast tenderness, cerebrovascular accident, change in cervical secretions, change in libido, chloasma, cholestatic jaundice, contact lens intolerance, decreased glucose tolerance, deep vein thrombosis, dementia, dysmenorrhea, edema, endometrial carcinoma, endometrial hyperplasia, erythema multiforme, erythema nodosum, exacerbation of asthma, exacerbation of epilepsy, exacerbation of hepatic hemangioma, exacerbation of porphyria, fibrocystic breast changes, galactorrhea, gallbladder disease, growth potentiation of benign meningioma, gynecomastia, hirsutism, hypersensitivity reaction, hypertension, increased serum triglycerides, irritability, ischemic colitis, malignant neoplasm of breast, migraine, mood changes, myocardial infarction, nausea, nipple discharge, ovarian carcinoma, pancreatitis, pelvic pain, pulmonary embolism, retinal thrombosis, skin rash, superficial venous thrombosis, thrombophlebitis, urticaria, uterine fibroids (increased size), vomiting, vulvovaginal candidiasis, weight changes
Angioedema or anaphylactic reaction to estrogens or any component of the formulation; undiagnosed abnormal genital bleeding; DVT or PE (current or history of); active or history of arterial thromboembolic disease (eg, stroke, MI); breast cancer (except in appropriately selected patients being treated for metastatic disease); estrogen-dependent tumor (known or suspected); hepatic impairment or disease; known protein C, protein S, antithrombin deficiency or other known thrombophilic disorders; pregnancy
Canadian labeling: Additional contraindications (not in US labeling): Endometrial hyperplasia; partial or complete vision loss due to ophthalmic vascular disease; migraine with or without aura
Concerns related to adverse effects:
• Anaphylaxis: Anaphylaxis requiring emergency medical management has been reported within minutes to hours of taking conjugated estrogen (CE) tablets. Angioedema involving the face, feet, hands, larynx, and tongue has also been reported.
• Breast cancer: Based on data from the Women’s Health Initiative (WHI) studies, an increased risk of invasive breast cancer was observed in patients who are postmenopausal using CEs in combination with medroxyprogesterone acetate (MPA). Observational studies noted this risk declines once therapy is discontinued. The WHI study did not observe an increased risk of invasive breast cancer in patients with a hysterectomy using CE alone. 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 considered for patients who have entered menopause following an oophorectomy if the patient does not have a personal history of breast cancer; treatment for menopausal symptoms should be individualized (SGO/ASRM [Chen 2019]). 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 progestin to prevent dementia. In the Women’s Health Initiative Memory Study, an increased incidence of probable dementia was observed in patients ≥65 years of age taking CE alone or in combination with MPA. Because the WHI memory studies were conducted in patients ≥65 years of age, 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 progestin 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 postmenopausal patients 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 (NAMS 2022).
• 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 high-density lipoprotein cholesterol and decreased low-density lipoprotein cholesterol. Triglycerides may also be increased in patients with preexisting hypertriglyceridemia; discontinue if pancreatitis occurs. Use with caution in patients with familial defects of lipoprotein metabolism.
• 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 use 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.
• 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]).
• Cardiovascular disease: Do not use estrogens with or without progestin to prevent cardiovascular disease. The WHI studies reported an increased risk of deep vein thrombosis (DVT) and stroke with CE and an increased risk of DVT, stroke, pulmonary emboli, and myocardial infarction using CE with MPA in postmenopausal patients 50 to 79 years of age. Additional risk factors include diabetes mellitus, hypercholesterolemia, hypertension, systemic lupus erythematosus (SLE), obesity, tobacco use, and/or history of venous thromboembolism. 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 2013b; ES [Stuenkel 2015]).
• Diseases exacerbated by fluid retention: Use with caution in patients with diseases that may be exacerbated by fluid retention, including cardiac or renal dysfunction.
• Epilepsy: Use caution 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 may be 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 with migraine; may exacerbate disease.
• Porphyria: Use with caution in patients with porphyria; may exacerbate disease.
• Systemic lupus erythematosus: Use with caution in patients with SLE; may exacerbate disease.
Special populations:
• Pediatric: Prior to puberty, estrogens may cause premature closure of the epiphyses. Premature breast development, vaginal bleeding and vaginal cornification may be induced in girls. Modification of the normal puberty process may occur in boys.
• 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 form specific issues:
• Injection: Although the injection is indicated for short-term use only, consider all warnings and precautions associated with oral administration.
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 in the absence of vasomotor symptoms due to increased efficacy and decreased systemic effects (eg, cardiovascular effects, cancer risk) (NAMS 2022; NAMS 2020).
• 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. Use may be considered for patients at high risk of fractures who are not candidates for other osteoporosis therapies (ES [Eastell 2019]; NAMS 2022; NAMS 2021).
• 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 postmenopausal patients. Other combinations and dosage forms of estrogens and progestins were not studied. 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 progestins until comparable data become available.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Injection:
Premarin: 25 mg (1 ea)
Tablet, Oral:
Premarin: 0.3 mg [contains fd&c blue #2 (indigotine,indigo carmine), quinoline yellow (d&c yellow #10)]
Premarin: 0.45 mg [contains fd&c blue #2 (indigotine,indigo carmine)]
Premarin: 0.625 mg [contains fd&c blue #2 (indigotine,indigo carmine), fd&c red #40 (allura red ac dye)]
Premarin: 0.9 mg
Premarin: 1.25 mg [contains fd&c yellow #6 (sunset yellow), quinoline yellow (d&c yellow #10)]
No
Solution (reconstituted) (Premarin Injection)
25 mg (per each): $441.66
Tablets (Premarin Oral)
0.3 mg (per each): $8.29
0.45 mg (per each): $8.29
0.625 mg (per each): $8.29
0.9 mg (per each): $8.29
1.25 mg (per each): $8.29
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. [DSC] = Discontinued product
Solution Reconstituted, Injection:
Premarin: 25 mg (1 ea)
Tablet, Oral:
C.E.S.: 0.625 mg [DSC] [contains fd&c blue #2 (indigotine,indigo carmine), fd&c red #40 (allura red ac dye), methylparaben, sodium benzoate]
Tablet Extended Release, Oral:
Premarin: 0.3 mg [contains fd&c blue #2 (indigo carm) aluminum lake, quinoline (d&c yellow #10) aluminum lake]
Premarin: 0.625 mg [contains fd&c blue #2 (indigo carm) aluminum lake, fd&c red #40(allura red ac)aluminum lake]
Premarin: 1.25 mg [contains fd&c yellow #6(sunset yellow)alumin lake, quinoline (d&c yellow #10) aluminum lake]
Injection: May be administered IV or IM; when administered IV, administer slowly to avoid the occurrence of a flushing reaction.
Oral tablet: Administer at the same time each day. May be administered without regard to meals. If a dose is missed, administer as soon as possible unless it is almost time for the next dose, then skip the missed dose and go back to the normal schedule. Do not administer 2 doses at the same time.
Vasomotor symptoms associated with menopause: Recently menopausal patients (<2 years) with a uterus may benefit from a cyclic regimen (continuous regimens may be associated with unscheduled bleeding) (Ref).
Oral: Administer without regard to meals; administration of dose at bedtime may decrease adverse effects
Parenteral: May be administered IV or IM; administer slow IV to avoid vascular flushing
Hazardous agent (NIOSH 2016 [group 2]).
Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage.
NIOSH recommends single gloving for administration of intact tablets or capsules. For injectable products, NIOSH recommends double gloving, a protective gown, ventilated engineering controls (a class II biological safety cabinet or a compounding aseptic containment isolator), and closed system transfer devices (CSTDs) for preparation. Double gloving, a gown, and (if dosage form allows) CSTDs are required during administration (NIOSH 2016). Assess risk to determine appropriate containment strategy (USP-NF 2017).
Abnormal uterine bleeding, acute: Treatment of acute abnormal uterine bleeding due to hormonal imbalance in the absence of organic pathology.
Limitations of use: For short term use only to provide a rapid and temporary increase in estrogen levels in patients with acute abnormal uterine bleeding (ie, heavy menstrual bleeding) without contraindications to estrogen and no known or suspected bleeding disorders (ACOG 2013a; ACOG 2019).
Breast cancer, metastatic: Treatment of metastatic breast cancer (palliation only) in appropriately selected males and postmenopausal females.
Osteoporosis, postmenopausal, prevention: Prevention of postmenopausal osteoporosis.
Limitations of use: For use only in patients who are postmenopausal at significant risk of osteoporosis; consider use of nonestrogen medications.
Prostate cancer, advanced: Treatment of androgen-dependent prostatic cancer (palliation).
Secondary amenorrhea, hypoestrogenism: Treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure.
Vasomotor symptoms associated with menopause: Treatment of moderate to severe vasomotor symptoms associated with menopause.
Vulvar and vaginal atrophy associated with menopause: Treatment of moderate to severe vulvar and vaginal atrophy due to 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 (Portman 2014).
Uremic bleeding
Premarin may be confused with Primaxin, Provera, Remeron
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs that have a heightened risk of causing significant patient harm when used in error.
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 CYP1A2 (minor), CYP2A6 (minor), CYP2B6 (minor), CYP2C19 (minor), CYP2C9 (minor), CYP2D6 (minor), CYP2E1 (minor), 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 Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Ajmaline: Estrogen Derivatives may enhance the adverse/toxic effect of Ajmaline. Specifically, the risk for cholestasis may be increased. Risk C: Monitor therapy
Anastrozole: Estrogen Derivatives may diminish the therapeutic effect of Anastrozole. Risk X: Avoid combination
Anthrax Immune Globulin (Human): Estrogen Derivatives may enhance the thrombogenic effect of Anthrax Immune Globulin (Human). Risk C: Monitor therapy
Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
C1 inhibitors: Estrogen Derivatives may enhance the thrombogenic effect of C1 inhibitors. Risk C: Monitor therapy
Chenodiol: Estrogen Derivatives may diminish the therapeutic effect of Chenodiol. Risk C: Monitor therapy
Chlorprothixene: Estrogen Derivatives may enhance the adverse/toxic effect of Chlorprothixene. Estrogen Derivatives may enhance the therapeutic effect of Chlorprothixene. Risk C: Monitor therapy
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
CloZAPine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of CloZAPine. Risk C: Monitor therapy
Corticosteroids (Systemic): Estrogen Derivatives may increase the serum concentration of Corticosteroids (Systemic). Risk C: Monitor therapy
Cosyntropin: Estrogen Derivatives may diminish the diagnostic effect of Cosyntropin. Management: Discontinue estrogen containing drugs 4 to 6 weeks prior to cosyntropin (ACTH) testing. Risk D: Consider therapy modification
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Estrogen Derivatives. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Estrogen Derivatives. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Estrogen Derivatives. Risk C: Monitor therapy
Dantrolene: Estrogen Derivatives may enhance the hepatotoxic effect of Dantrolene. Risk C: Monitor therapy
Dehydroepiandrosterone: May enhance the adverse/toxic effect of Estrogen Derivatives. Risk X: Avoid combination
Exemestane: Estrogen Derivatives may diminish the therapeutic effect of Exemestane. Risk X: Avoid combination
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Fezolinetant: CYP1A2 Inhibitors (Weak) may increase the serum concentration of Fezolinetant. Risk X: Avoid combination
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Growth Hormone Analogs: Estrogen Derivatives may diminish the therapeutic effect 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 diminish the therapeutic effect of Hemin. Risk X: Avoid combination
Hyaluronidase: Estrogen Derivatives may diminish the therapeutic effect of Hyaluronidase. Risk C: Monitor therapy
Hydrocortisone (Systemic): Estrogen Derivatives may increase the serum concentration of Hydrocortisone (Systemic). Estrogen Derivatives may decrease the serum concentration of Hydrocortisone (Systemic). Risk C: Monitor therapy
Immune Globulin: Estrogen Derivatives may enhance the thrombogenic effect of Immune Globulin. Risk C: Monitor therapy
Indium 111 Capromab Pendetide: Estrogen Derivatives may diminish the diagnostic effect of Indium 111 Capromab Pendetide. Risk X: Avoid combination
LamoTRIgine: Estrogen Derivatives may decrease the serum concentration of LamoTRIgine. Risk C: Monitor therapy
Lenalidomide: Estrogen Derivatives may enhance the thrombogenic effect of Lenalidomide. Risk C: Monitor therapy
Melatonin: Estrogen Derivatives may increase the serum concentration of Melatonin. Risk C: Monitor therapy
MetyraPONE: Estrogen Derivatives may diminish the diagnostic effect of MetyraPONE. Management: Consider alternatives to the use of the metyrapone test in patients taking estrogen derivatives. Risk D: Consider therapy modification
Mivacurium: Estrogen Derivatives may increase the serum concentration of Mivacurium. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective): May enhance the thrombogenic effect of Estrogen Derivatives. Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective) may increase the serum concentration of Estrogen Derivatives. Risk C: Monitor therapy
Ospemifene: Estrogen Derivatives may enhance the adverse/toxic effect of Ospemifene. Risk X: Avoid combination
Pomalidomide: Estrogen Derivatives may enhance the thrombogenic effect of Pomalidomide. Risk C: Monitor therapy
Protease Inhibitors: May decrease the serum concentration of Estrogen Derivatives. Protease Inhibitors may increase the serum concentration of Estrogen Derivatives. Risk C: Monitor therapy
Raloxifene: Estrogen Derivatives may enhance the adverse/toxic effect of Raloxifene. Risk X: Avoid combination
ROPINIRole: Estrogen Derivatives may increase the serum concentration of ROPINIRole. Risk C: Monitor therapy
Succinylcholine: Estrogen Derivatives may increase the serum concentration of Succinylcholine. Risk C: Monitor therapy
Tacrolimus (Systemic): Estrogen Derivatives may increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Thalidomide: Estrogen Derivatives may enhance the thrombogenic effect of Thalidomide. Risk C: Monitor therapy
Theophylline Derivatives: CYP1A2 Inhibitors (Weak) may increase the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy
Thyroid Products: Estrogen Derivatives may diminish the therapeutic effect of Thyroid Products. Risk C: Monitor therapy
TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use is necessary, initiate tizanidine at an adult dose of 2 mg and increase in 2 to 4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Risk D: Consider therapy modification
Tranexamic Acid: Estrogen Derivatives may enhance the thrombogenic effect of Tranexamic Acid. Risk X: Avoid combination
Ursodiol: Estrogen Derivatives may diminish the therapeutic effect of Ursodiol. Risk C: Monitor therapy
Folic acid absorption may be decreased.
Use is contraindicated during pregnancy.
In general, the use of estrogen and progestogen as in combination hormonal contraceptives have not been associated with teratogenic effects when inadvertently taken early in pregnancy.
Estrogens can be detected in breast milk.
Estrogen has been shown to decrease the quantity and quality of human milk. The manufacturer recommends that caution be used if administered to a breastfeeding patient.
Ensure adequate calcium and vitamin D intake when used for the prevention of osteoporosis. Powder for reconstitution for injection (25 mg) contains lactose 200 mg.
Prior to therapy, baseline risk for breast cancer and CVD. During therapy, age-appropriate breast and pelvic exams; blood pressure; 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.
Abnormal uterine bleeding, acute: Response to treatment that may be dependent upon etiology of bleed (ACOG 2013a; Haamid 2017).
Prevention of osteoporosis: Bone density measurement
Uremic bleeding: Bleeding time
Conjugated estrogens contain a mixture of estrone sulfate, equilin sulfate, 17 alpha-dihydroequilin, 17 alpha-estradiol and 17 beta-dihydroequilin. Estrogens are responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Estradiol is the principle intracellular human estrogen and is more potent than estrone and estriol at the receptor level; it is the primary estrogen secreted prior to menopause. Following menopause, estrone and estrone sulfate are more highly produced. Estrogens modulate the pituitary secretion of gonadotropins, luteinizing hormone, and follicle-stimulating hormone through a negative feedback system; estrogen replacement reduces elevated levels of these hormones in patients who are postmenopausal.
Absorption: Well absorbed.
Distribution: Widely distributes throughout the body; sex hormone target organs contain higher concentrations.
Protein binding: Binds to sex-hormone-binding globulin and albumin.
Metabolism: Hepatic via CYP3A4; estradiol is converted to estrone and estriol; estrone is also converted to estriol and is converted to estradiol (Note: A dynamic equilibrium of metabolic interconversions between estrogens exists in the circulation); also undergoes enterohepatic recirculation (avoided with vaginal administration); estrone sulfate is the main metabolite in patients who are postmenopausal.
Half-life elimination: Total estrone: 27 hours.
Time to peak, plasma: Total estrone: 7 hours.
Excretion: Urine (primarily estriol, also as estradiol, estrone, and conjugates.
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