Vulvar and vaginal atrophy: Intravaginal: Insert 0.5 to 4 g daily; adjust to lowest effective dose which controls symptoms. Administration should be cyclic (3 weeks on, 1 week off). Intended for short term therapy. Use of a progestin is recommended in postmenopausal patients with a uterus.
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 in active hepatic dysfunction or disease.
Refer to adult dosing.
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.
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Cream, Vaginal:
Estragyn: 1 mg/g (10 g, 20 g, 45 g) [contains methylparaben, peg 40 stearate, propylparaben]
Not available in the US
Intravaginal: Administer intravaginally with the provided calibrated applicator at the same time each day at a time convenient to patient's schedule. Patient should be lying on their back, applicator should be inserted deeply into the vagina as far as it can go comfortably, pointing slightly downward. Following use, applicator may be cleaned with mild detergent and warm water. Do not use hot water (may soften the plastic).
The use of a progestin is recommended when administering estrogens to postmenopausal patients with a uterus.
In case of a missed dose, restart at the time of the next dose.
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 double gloving and a protective gown for administration of a topical product (NIOSH 2016).
Note: Not approved in the United States.
Vulvar and vaginal atrophy: For the short-term symptomatic treatment of vulvar and vaginal atrophy due to estrogen deficiency.
Limitations of use: To be prescribed with an appropriate progestin in patients with a uterus.
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).
Estragyn: Brand name for estrone vaginal [Canada] and estrogens esterified oral [Canada]
ALERT: Canadian Boxed Warning: Health Canada-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Frequency not defined:
Cardiovascular: Chest pain, cerebrovascular accident, edema, increased blood pressure, syncope, thromboembolic disease, thrombophlebitis, venous thromboembolism
Central nervous system: Aphasia, depression, dizziness, exacerbation of epilepsy, exacerbation of migraine headache, headache, loss of consciousness, migraine, numbness of extremities, paralysis
Endocrine & metabolic: Decreased glucose tolerance, exacerbation of porphyria, fluid retention, hypothyroidism, increased serum glucose, lipid metabolism disorder
Gastrointestinal: Abdominal pain, gallbladder disease, nausea, vomiting
Genitourinary: Abnormal vaginal hemorrhage, breakthrough bleeding, breast swelling, breast tenderness, endometrial hyperplasia, exacerbation of endometriosis, spotting
Hematologic & oncologic: Endometrial carcinoma, enlargement of uterine fibroid, malignant neoplasm of ovary, uterine fibroids (increase in tenderness/pain)
Hepatic: Cholestatic jaundice, exacerbation of hepatic hemangioma
Hypersensitivity: Angioedema
Neuromuscular & skeletal: Osteosclerosis
Ophthalmic: Visual disturbance
Respiratory: Hemoptysis
Hypersensitivity to estrone 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) or active thrombophlebitis; breast cancer (known, suspected or history of); estrogen-dependent tumor (known or suspected); progestin dependent malignant tumor (eg, endometrial cancer); endometrial hyperplasia; hepatic impairment or disease; partial or complete loss of vision due to ophthalmic vascular disease; classical migraine; breastfeeding; pregnancy.
Documentation of allergenic cross-reactivity for estrogens is limited; however, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.
Concerns related to adverse effects:
• Bone disease: Prolonged estrogen use, with or without progestin, may influence calcium and phosphorus metabolism. Use caution in patients with metabolic and malignant bone disease associated with hyperglycemia.
• Breast cancer: [Canadian Boxed Warning]: The Women’s Health Initiative (WHI) trial examined the health benefits and risks of oral combined estrogen plus progestin therapy (n=16,608) and oral estrogen–alone therapy (n=10,739) in postmenopausal women 50 to 79 years of age. The estrogen plus progestin arm of the WHI trial (mean age 63.3 years) indicated an increased risk of invasive breast cancer in postmenopausal women receiving treatment with combined conjugated equine estrogens (0.625 mg/day) and medroxyprogesterone acetate (2.5 mg/day) for 5.2 years compared to those receiving placebo. 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. Due to increased risks, estrogens are contraindicated in patients with known or suspected breast cancer; however, 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]).
• Dementia: In the Women’s Health Initiative Memory Study, an increased incidence of probable dementia was observed in women ≥65 years of age taking oral conjugated estrogen alone or in combination with medroxyprogesterone acetate.
• 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.
• Hypertension: Use may be associated with an increase in BP; monitor.
• Inherited thrombophilia: Women with inherited thrombophilias (eg, protein C or S deficiency) may have increased risk of venous thromboembolism (DeSancho 2010; van Vlijmen 2011).
• 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 visual disturbances occur.
Disease-related concerns:
• Asthma: Use caution with asthma; may exacerbate disease.
• Cardiovascular disease: [Canadian Boxed Warning]: The WHI trial examined the health benefits and risks of oral combined estrogen plus progestin therapy (n=16,608) and oral estrogen–alone therapy (n=10,739) in postmenopausal women 50 to 79 years of age. The estrogen plus progestin arm of the WHI trial (mean age 63.3 years) indicated an increased risk of myocardial infarction (MI), stroke, pulmonary emboli, and deep vein thrombosis (DVT) in postmenopausal women receiving treatment with combined conjugated equine estrogen (0.625 mg/day) and medroxyprogesterone acetate (2.5 mg/day) for 5.2 years compared to those receiving placebo. The estrogen-alone arm of the WHI trial (mean age 63.6 years) indicated an increased risk of stroke and DVT in hysterectomized women treated with conjugated equine estrogen alone (0.625 mg/day) for 6.8 years compared to those receiving placebo. Estrogens with or without progestins should not be prescribed for primary or secondary prevention of cardiovascular diseases. 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).
• Cerebrovascular insufficiency: Discontinue if classical migraine, loss of consciousness, paralysis, transient aphasia, or visual disturbances occur.
• Diabetes: May impair glucose tolerance; use caution in patients with diabetes.
• Diseases exacerbated by fluid retention: Use 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.
• Fibroids: Use with caution in patients with fibroids (leiomyomata); discontinue use with sudden enlargement, pain, or tenderness of fibroids.
• Gallbladder disease: Use of postmenopausal estrogen may be associated with an increased risk of gallbladder disease requiring surgery.
• Hepatic hemangiomas: Use caution in patients with hepatic hemangiomas; may exacerbate disease.
• Hepatic dysfunction: Use caution with a history of hepatic or biliary disorders. Discontinue if jaundice develops.
• Hereditary angioedema: Exogenous estrogens may exacerbate angioedema symptoms in patients with hereditary angioedema.
• Otosclerosis: Use caution in patients with otosclerosis.
• Porphyria: Use caution in patients with porphyria.
• Systemic lupus erythematosus: Use caution in patients with SLE; may exacerbate disease.
Special populations:
• Surgical patients: Whenever possible, estrogens should be discontinued 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 cream: Contains mineral oil that may not be compatible with latex rubber in condoms
Other warnings/precautions:
• Risks versus 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]). 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). 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. In addition, consider risk factors for cardiovascular disease when evaluating therapy and route of administration (AACE/ACE [Cobin 2017]; NAMS 2017). [Canadian Boxed Warning]: Estrogens with or without progestins should be prescribed at the lowest effective dose for the approved indication. Estrogens with or without progestins should be prescribed for the shortest period possible for the approved indication. 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 conjugated estrogen 0.625 mg with or without medroxyprogesterone acetate 2.5 mg relative to placebo in postmenopausal women. Other combinations and dosage forms of estrogens and progestins were not studied but should be considered similar until comparable data are available.
Substrate of CYP1A2 (minor), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
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. Management: Monitor clinical response to chenodiol closely when used together with any estrogen derivative. Risk C: Monitor therapy
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). 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
Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy
Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
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
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
Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy
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
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. Estrogen Derivatives may diminish the therapeutic 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
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
Thyroid Products: Estrogen Derivatives may diminish the therapeutic effect of Thyroid Products. Risk C: Monitor therapy
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
Use is not compatible with latex condoms.
Use is contraindicated in patients known or suspected to be pregnant.
Use is contraindicated in breastfeeding patients.
Prior to therapy, baseline risk for breast cancer and cardiovascular disease. 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 (in patients with baseline level >200 mg/dL); thyroid-stimulating hormone (in patients taking thyroid replacement); efficacy beginning 1 to 3 months after starting therapy, then every 6 to 12 months as appropriate. Duration of treatment should be evaluated at least annually (ES [Stuenkel 2015]).
Note: Monitoring of follicle-stimulating hormone and serum estradiol is not useful when managing genitourinary syndrome of menopause.
Estradiol is the principle intracellular human estrogen and the primary estrogen secreted prior to menopause. Following menopause, estrone is more highly produced. Application of vaginal estrone replaces decreased endogenous estrone and relieves symptoms of vulvovaginal atrophy.
Absorption: Readily absorbed through skin and mucous membranes.
Distribution: Widely distributed; high concentrations in the sex hormone target organs.
Protein binding: Bound to sex hormone-binding globulin and albumin.
Metabolism: Hepatic; no first-pass metabolism via vaginal administration, but undergoes enterohepatic uptake and recycling.
Excretion: Urine.