Version June 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. 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.
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 (CE) (0.625 mg) alone, relative to placebo. Do not use estrogen-alone therapy for the prevention of cardiovascular disease.
The WHI estrogen plus progestin substudy reported increased risks of DVT, pulmonary embolism, stroke, and myocardial infarction in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral CE (0.625 mg) combined with medroxyprogesterone acetate (MPA) (2.5 mg), relative to placebo. Do not use estrogen plus progestin therapy for the prevention of cardiovascular disease.
The WHI estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer.
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 during 5.2 years of treatment with daily CE (0.625 mg) alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. Do not use estrogen-alone 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 of age during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. Do not use estrogen plus progestin therapy for the prevention of dementia.
Only daily oral CEs (0.625 mg) and daily oral CE (0.625 mg) and MPA (2.5 mg) were studied in the estrogen-alone and estrogen plus progestin substudies of the WHI, respectively. Therefore, the relevance of the WHI findings regarding the adverse cardiovascular events and dementia to lower CE doses, other routes of administration, or other estrogen-alone products is not known. Likewise, the relevance of the WHI findings regarding the adverse cardiovascular events, dementia, and breast cancer to lower CE plus other MPA doses, other routes of administration, or other estrogen plus progestin products is not known. Without such data, it is not possible to definitively exclude these risks or determine the extent of the risks for other products. Discuss with your patient the benefits and risks of estrogen-alone or estrogen plus progestin therapy, taking into account her individual risk profile. Prescribe estrogens with or without progestins at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.
General dosing guidelines: When treating symptoms of menopause, evaluate hormone therapy routinely for appropriate dose, duration, and route of administration for each individual patient based on treatment goals, risk factors, and overall health (Ref). Combined estrogen/progestin therapy is indicated for postmenopausal persons with a uterus to decrease the risk of endometrial cancer. Individuals who have had a hysterectomy generally do not need a progestin; however, one may be needed if there is a history of endometriosis. Adjust dose based on patient response.
Cystitis, uncomplicated, prophylaxis for recurrent infection (for patients who are peri- and postmenopausal) (off-label use):
Vaginal cream (Estrace): Insert 2 g daily intravaginally for 2 weeks, followed by a maintenance dose of 1 g two to three times per week (Ref).
Vaginal ring (Estring): 2 mg intravaginally; following insertion, ring should remain in place for 90 days (Ref).
Vaginal tablet (Vagifem): Initial: Insert 1 tablet (10 mcg) intravaginally once daily for 2 weeks; Maintenance: Insert 1 tablet 2 to 3 times weekly (Ref).
Vulvar and vaginal atrophy associated with menopause:
Vaginal cream (Estrace): Initial: 500 mg to 1 g/day intravaginally for 2 weeks, then 500 mg to 1 g one to three times per week (Ref) or 2 to 4 g daily intravaginally for 1 to 2 weeks, then gradually reduce to 1/2 the initial dose for 1 to 2 weeks, followed by a maintenance dose of 1 g one to three times per week (Ref) (may not reflect current practice).
Vaginal insert (Imvexxy): Initial: Insert 4 mcg once daily intravaginally for 2 weeks, then gradually reduce to 1 insert twice weekly, every 3 to 4 days (eg, Monday and Thursday).
Vaginal ring (Estring): 2 mg intravaginally; following insertion, ring should remain in place for 90 days.
Vaginal tablet (Vagifem, Yuvafem): Initial: Insert 1 tablet (10 mcg) intravaginally once daily for 2 weeks; Maintenance: Insert 1 tablet twice weekly.
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).
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); use is contraindicated with hepatic impairment or disease.
Cardiovascular events: Discontinue therapy immediately if adverse cardiovascular events (eg, deep vein thrombosis, myocardial infarction, pulmonary embolism, stroke) occur or are suspected.
Hepatotoxicity: Discontinue if jaundice develops or if acute or chronic hepatic disturbances occur.
Hypercalcemia: Estrogen use may lead to severe hypercalcemia in patients with breast cancer and bone metastases; discontinue therapy if hypercalcemia occurs.
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%: Nervous system: Headache (4% to 13%)
1% to 10%:
Dermatologic: Urticaria
Endocrine & metabolic: Hot flash (2%)
Gastrointestinal: Diarrhea (5%), abdominal pain (4%), nausea (3%)
Genitourinary: Vulvovaginal pruritus (8%), genital candidiasis (6% to 8%), leukorrhea (7%), vaginitis (5%), vaginal discomfort (≤5%), vaginal pain (≤5%), bacterial vaginosis (4%; asymptomatic), vaginal hemorrhage (4%), urinary tract infection (2%), mastalgia (1%)
Hypersensitivity: Hypersensitivity reaction (1%)
Nervous system: Insomnia (4%), stress (2%), migraine
Neuromuscular & skeletal: Back pain (6% to 7%), arthritis (4%), arthralgia (3%), skeletal pain (2%)
Respiratory: Upper respiratory tract infection (5%), sinusitis (4%), flu-like symptoms (3%), pharyngitis (1%)
Frequency not defined:
Cardiovascular: Acute myocardial infarction, cerebrovascular accident, pulmonary embolism
Dermatologic: Allergic skin rash
Nervous system: Dementia
<1%, postmarketing and/or case reports: Abdominal distention, arthropathy, breast engorgement, breast hypertrophy, decreased libido, deep vein thrombosis, depression, dizziness, endometrial carcinoma, endometrial hyperplasia, erythematous rash, exacerbation of migraine headache, excoriation of skin (vaginal), fluid retention, genital edema, genital pruritus, increased plasma estrogen concentration, intermenstrual bleeding, intestinal obstruction (ring), malignant neoplasm of breast, mechanical complication of genitourinary device (ring adherence to vaginal wall), nervousness, pruritic rash, pruritus, pruritus ani, skin rash, thrombophlebitis, urethral disease, urinary frequency, vaginal discharge, vaginal disease (erosion), vaginal ulcer, vaginismus, visual disturbance, vomiting, vulvar disease, vulvar swelling, vulvovaginal burning, weight changes, weight gain
Angioedema, anaphylactic reaction, or hypersensitivity to estradiol 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 (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; pregnancy.
Canadian labeling: Additional contraindications (not in US labeling): Endometrial hyperplasia; partial or complete loss of vision due to ophthalmic vascular disease; breastfeeding; porphyria.
Concerns related to adverse effects:
• Anaphylaxis: Anaphylaxis requiring emergency medical management has been reported following oral estrogen administration and may develop at any time during therapy. 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 postmenopausal patients using oral conjugated estrogens (CE) 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 postmenopausal patients on hormone therapy may depend upon type of estrogen and/or progestin, dose, timing of therapy initiation, duration of therapy, route of administration, and individual patient characteristics (AACE/ACE [Cobin 2017]; NAMS 2017). Hormone therapy may be associated with increased breast density (NAMS 2017); an increase in abnormal mammogram findings requiring further evaluation has been reported with estrogen alone or in combination with progestin therapy. Estrogen use may lead to severe hypercalcemia in patients with breast cancer and bone metastases; discontinue estrogen if hypercalcemia occurs. Patients with genitourinary syndrome of menopause (GSM) in whom nonhormone therapy has failed may be treated with local estrogen based on specific breast cancer diagnosis, evaluation of symptoms, and risk for recurrence. Products with the lowest systemic absorption are recommended (NAMS [Faubion 2018]).
• Endometrial cancer: The use of unopposed estrogen in patients with a uterus is associated with an increased risk of endometrial cancer. The risk of endometrial cancer appears to be dose and duration dependent, greatest with use ≥5 years, and may persist following discontinuation of therapy. Based on available data, the risk of endometrial cancer following low-dose vaginal estrogen is similar to rates observed in the general population. The use of a progestin is not generally required when low doses of estrogen are used locally for vaginal atrophy, although long-term data (>1 year) supporting this recommendation are lacking (NAMS 2017; NAMS 2020). When nonhormonal treatments are not effective for GSM, low-dose vaginal therapy that has limited systemic absorption may be considered in appropriately selected patients with endometrial cancer (ES [Stuenkel 2015]; NAMS 2017). Patients with endometrial cancer should be closely monitored (NAMS 2020).
• Endometriosis: Estrogens may exacerbate endometriosis. Malignant transformation of residual endometrial implants has been reported posthysterectomy with unopposed estrogen therapy. Consider adding a progestin 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 use if pancreatitis occurs.
• Ovarian cancer: Available information related to the use of menopausal estrogen or estrogen/progestin 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 2017).
• Retinal thrombosis: Estrogens may cause retinal thrombosis; discontinue 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: Using data from the WHI studies, an increased risk of deep vein thrombosis (DVT) and stroke has been reported with oral CE and an increased risk of DVT, stroke, pulmonary emboli (PE), and myocardial infarction (MI) has been reported with oral 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. The increased risks of cardiovascular outcomes associated with systemic estrogen or estrogen/progestin therapy may not be the same and are unlikely with low dose vaginal estrogen (Crandall 2018; NAMS 2020).
• 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 which may be exacerbated by fluid retention, including cardiac or renal dysfunction; consider discontinuation of therapy if medically concerning fluid retention occurs.
• 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 impairment: 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 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:
• Surgical patients: 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:
• Vaginal ring: Use may not be appropriate in patients with narrow or short vagina, vaginal stenosis, vaginal infections, prolapse, or other conditions that may increase the risk of vaginal irritation, or ulceration. Remove ring in case of infection, ulceration, erosion, or adherence to vaginal wall; do not reinsert until healing is complete.
• Vaginal tablet: Local applicator-induced abrasion may occur in patients with severely atrophic vaginal mucosa.
Other warnings/precautions:
• Duration of use: Extended use of menopausal hormone therapy may be considered for persistent vasomotor symptoms or issues related to quality of life. Menopausal hormonal therapy does not need to be routinely discontinued in patients >60 years of age and may continue in patients >65 years of age after clinical evaluation and discussion of benefits and risks of treatment. Perform annual exams with a review of comorbidities; discuss possible adjustments to safer lower-dose and/or route of administration (ACOG 2013; NAMS 2017).
• Genitourinary syndrome of menopause (GSM): Low-dose vaginal estrogen is preferred over systemic therapy for GSM in the absence of vasomotor symptoms due to increased efficacy and decreased systemic effects (eg, cardiovascular effects, cancer risk) (Crandall 2018; NAMS 2017; NAMS 2020).
• Risks vs benefits: Systemic absorption occurs following vaginal use; however, the risk of adverse events associated with low-dose vaginal estrogens (defined as ≤0.5 g/day) may be lower than with systemic estrogens. Consider warnings, precautions, and adverse events observed with oral therapy and weigh risk versus benefit before and during therapy (NAMS [Pinkerton 2020]). When used for the relief of menopausal symptoms, 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. Risk factors for cardiovascular disease should also be considered when evaluating therapy and route of administration (AACE/ACE [Cobin 2017]; NAMS 2017). Use should be for the shortest duration possible at the lowest effective dose consistent with treatment goals and risks for the individual patient. Patients should be reevaluated 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. Outcomes reported from clinical trials using CE with or without MPA should be assumed 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. [DSC] = Discontinued product
Cream, Vaginal:
Estrace: 0.1 mg/g (42.5 g) [contains edetate (edta) disodium, methylparaben, propylene glycol]
Generic: 0.1 mg/g (42.5 g)
Insert, Vaginal:
Imvexxy Maintenance Pack: 4 mcg (8 ea); 10 mcg (8 ea) [contains alcohol, usp, fd&c red #40 (allura red ac dye)]
Imvexxy Starter Pack: 4 mcg (18 ea); 10 mcg (18 ea) [contains alcohol, usp, fd&c red #40 (allura red ac dye)]
Ring, Vaginal, as base:
Estring: 7.5 mcg/24 hr (1 ea); 2 mg (1 ea [DSC])
Tablet, Vaginal, as base:
Vagifem: 10 mcg [contains corn starch]
Yuvafem: 10 mcg [contains corn starch]
Generic: 10 mcg
May be product dependent
Cream (Estrace Vaginal)
0.1 mg/g (per gram): $9.74
Cream (Estradiol Vaginal)
0.1 mg/g (per gram): $2.82 - $8.45
INST (Imvexxy Maintenance Pack Vaginal)
4 mcg (per each): $32.35
10 mcg (per each): $32.35
INST (Imvexxy Starter Pack Vaginal)
4 mcg (per each): $32.35
10 mcg (per each): $32.35
Ring (Estring Vaginal)
7.5 mcg/24 hrs (per each): $654.77
Tablets (Estradiol Vaginal)
10 mcg (per each): $24.25
Tablets (Vagifem Vaginal)
10 mcg (per each): $25.52
Tablets (Yuvafem Vaginal)
10 mcg (per each): $24.25
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.
Insert, Vaginal:
Imvexxy: 4 mcg (2 ea, 18 ea); 10 mcg (2 ea, 18 ea) [contains fd&c red #40 (allura red ac dye)]
Ring, Vaginal, as base:
Estring: 2 mg (1 ea)
Tablet, Vaginal, as base:
Vagifem: 10 mcg
Vaginal cream: Gently insert applicator filled with vaginal cream deeply into vagina. Cleanse applicator after use with warm water and mild soap (do not boil or use hot water).
Vaginal insert: Insert with smaller end up approximately 2 inches into the vaginal canal at the same time each day.
Vaginal ring: Insert as deeply as possible into the upper one-third of the vagina; exact positioning is not critical for efficacy; however, patient should not feel anything once inserted. In case of discomfort, push ring further into vagina. Straining at defecation may make the ring move down in the lower part of the vagina; if this occurs, push up ring with finger. If ring is expelled prior to 90 days, it may be rinsed in lukewarm water and reinserted. If vaginal infection, ulceration, erosion, or adherence to vaginal wall develops, remove ring and reinsert only after healing is complete.
Vaginal tablet: Insert tablet with supplied applicator at the same time each day. Once inserted, press plunger until fully depressed, then remove applicator and discard. If tablet comes out of applicator prior to insertion, do not replace; use a new tablet filled applicator instead (if the tablet has fallen out of applicator but still remains in the package, it can be reinserted in the applicator for use). Local abrasion caused by the vaginal applicator has been reported in patients with severely atrophic vaginal mucosa.
Hazardous agent (NIOSH 2016 [group 2]).
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 2016; 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.
Vulvar and vaginal atrophy associated with menopause: Treatment of moderate to severe vulvar and vaginal atrophy associated with menopause
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).
Cystitis, uncomplicated, prophylaxis for recurrent infection (for patients who are peri- and postmenopausal)
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.
Estring [US, Canada, and multiple international markets] may be confused with Estrena [Finland]
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
Patients on gender affirming testosterone therapy may experience vaginal atrophy and require use of vaginal estrogen for 2 weeks prior to pelvic exam or placement of an intrauterine device (Bonnington 2020).
Use is contraindicated during pregnancy.
In general, the use of estrogen and progestin as in combination hormonal contraceptives has not been associated with teratogenic effects when inadvertently taken early in pregnancy.
Estrogens are present in breast milk and have been shown to decrease the quantity and quality of human milk. The manufacturer recommends caution be used in patients who are breastfeeding.
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. 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 symptoms associated with GSM.
In studies for vulvar and vaginal atrophy in postmenopausal patients, local estrogens have been shown to reduce vaginal pH levels and mature the vaginal and urethral mucosa after 12 weeks of therapy, thereby improving vaginal dryness and mucosal atrophy.
Absorption: Average serum estradiol concentrations (Cavg) vary by product
Vaginal: Vaginal absorption is typically low; any contribution to circulating estradiol concentrations via systemic absorption does not exceed normal postmenopausal ranges (Ulrich 2010; Weisberg 2005).
Estring: Average steady state serum concentrations decrease from 11.2 pg/mL at 48 hours to 8 pg/mL at 12 weeks
Imvexxy: Cavg: 3.6 pg/mL (4 mcg dose); 4.6 pg/mL (10 mcg dose) following once daily dose for 14 days
Vagifem: Cavg: 10.9 pg/mL on day 1, 5.5 pg/mL on day 83
Distribution: Widely distributed; high concentrations in the sex hormone target organs
Protein binding: Bound to sex hormone-binding globulin and albumin
Metabolism: Hepatic; partial metabolism via CYP3A4 enzymes; estradiol is reversibly converted to estrone and estriol. Sulfate conjugates are the primary form found in postmenopausal patients.
Time to peak, serum: Estring: 0.5 to 1 hour
Excretion: Primarily urine (as estradiol, estrone, estriol and their glucuronide and sulfate conjugates)
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