Brand and Other Names:Estrace, Vivelle-Dot, more...Vagifem, Delestrogen, DepoEstradiol, Divigel, Elestrin, Alora, Estrace Cream, Estrace Vaginal, Estraderm Transdermal, Estring, estradiol intravaginal, estradiol topical, Estradot, Estrasorb, Estrogel, Evamist, Femtrace, Femring, Menostar, Minivelle, Vivelle, Climara
- Classes: Estrogen Derivatives
Dosing & Uses
Dosage Forms & Strengths
- 0.45mg (as acetate)
- 0.9mg (as acetate)
- 4.35mg/1.74g (0.25%)
Vulvar and Vaginal Atrophy in Menopause
Estrace: 1-2 mg PO once daily for 3 weeks, followed by 1 week off
Valerate: 10-20 mg IM q4weeks
Femring: 0.05 mg intravaginally; ring should remain in place for 3 months; increase dose to 0.1 mg if necessary
EstroGel: 1.25 g/day 3 weeks on, 1 week off
Alora, Climara Vivelle-Dot, Estraderm: Use transdermally and follow product-specific directions
Prevention of osteoporosis: 0.5 mg PO once daily for 3 weeks, followed by 1 week off
Metastatic breast cancer: 10 mg PO q8hr for 3 months
Prostate cancer: 1-2 mg PO q8hr for ≥3 months
Hypoestrogenism from Castration, Hypogonadonism, or Ovarian Failure
PO (Estrace): 1-2 mg PO qDay; titrate to use minimal effective dose
Transdermal (Alora, Estraderm, Climara, Vivelle-Dot, Minivelle): Use transdermally and follow product-specific directions
Valerate: 10-20 mg IM q4week
Metastatic Breast Cancer
Estrace: 10 mg PO 3 times daily
Cypionate: 1.5-2 mg IM every 4 weeks
PO (Estrace): 0.5 mg/day for 23 days of 28 day cycle used in clinical studies
Transdermal (Alora, Menostar, Estraderm, Vivell-Dot, Minivelle): Follow product specific directions
Vasomotor Symptoms Associated with Menopause
Estrace: 1-2 mg/day 3 weeks on, 1 week off
Valerate: 10-20 mg IM q3-4weeks
Cypionate: 1-5 mg IM q3-4weeks
Estrasorb: 3.48 g of emulsion applied qDay in the morning
Elestrin: 0.87 g/day gel applied at the same time each day; use patient's response to adjust dose
Divigel: 0.25 g/day gel; adjust dose based on patient response
EstroGel: 1.25 g/day gel applied at the same time each day
Estrace: 1-2 mg PO three times daily
Valerate: 30 mg IM or more q1-2weeks
Estrogen Replacement in Turner Syndrome (Orphan)
Orphan indication sponsor
- Ascend Therapeutics, Inc, 607 Herndon Parkway, Suite 110, Herndon, VA 21070
Safety and efficacy not established
Serious - Use Alternative
Significant - Monitor Closely
Frequency Not Defined
Skin irritation and redness at application site (transdermal)
Vaginal discomfort, vaginal erosion, vaginal ulceration, adherence of the vaginal ring to the vaginal wall (Estring)
Black Box Warnings
Increased risk of endometrial cancer
- Close clinical surveillance of all women taking estrogens is important
- Risk of endometrial cancer increases with use of unopposed estrogens; adding progestin to estrogen therapy may reduce risk of endometrial hyperplasia, a precursor to endometrial cancer;
- Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding
- Estrogens with and without progestins should not be used to prevent cardiovascular disease
- Estrogens plus progestins: Women’s Health Initiative (WHI) Estrogen Plus Progestin substudy reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary embolism (PE), and deep vein thrombosis (DVT) in postmenopausal women (50-79 years) during 5.6 years of treatment with daily PO conjugated estrogens (0.625 mg) combined with medroxyprogesterone acetate (2.5 mg) in comparison with placebo
- Estrogens alone: Substudy of WHI study reported increased risk of stroke and DVT in postmenopausal women (50-79 years) during 6.8 years of treatment with PO conjugated estrogens (0.625 mg/day) alone in comparison with placebo
- Estrogens with and without progestins should not be used to prevent dementia
- Women's Health Initiative Memory Study (WHIMS), substudy of WHI study, reported increased risk of developing probable dementia in postmenopausal women ≥65 years during 4 years of treatment with daily PO conjugated estrogens (0.625 mg) combined with medroxyprogesterone acetate (2.5 mg) in comparison with placebo
- Estrogens alone: Substudy of WHIMS reported increased risk of developing probable dementia in postmenopausal women ≥65 years during 5.2 years of treatment with conjugated estrogens (0.625 mg/day) alone in comparison with placebo
- Unknown whether these findings apply to younger postmenopausal women
- The WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer; estrogens with or without progestins should be prescribed at the lowest doses and for the shortest duration
Dose & duration
- In the absence of comparable data, these risks should be assumed to be similar for other doses of conjugated estrogens and medroxyprogesterone acetate, as well as for other combinations and dosage forms of estrogens and progestins
- Because of these risks, estrogens with or without progestins should be prescribed at lowest effective dose and for shortest duration consistent with treatment goals and individual risks
Unintentional secondary exposure to transdermal products
- Breast budding, breast masses in prepubertal females, and gynecomastia in prepubertal males have been reported after unintentional secondary exposure
Known anaphylactic reaction or angioedema with topical emulsion
Known protein C, protein S, or antithrombin deficiency or other known thrombophilic disorder
Active or previous breast cancer
Arterial thromboembolic disease (stroke, myocardial infarction [MI]), thrombophlebitis, DVT/PE, thrombogenic valvular disease
Uncontrolled hypertension, diabetes mellitus with vascular involvement, jaundice with previous oral contraceptive (OC) use
Undiagnosed abnormal vaginal bleeding
Liver disease, liver tumors
Severe anaphylactic reactions including hives , pruritus, swollen lips-tong-face, respiratory compromise, abdominal pain, vomiting during transdermal treatment reported
Family history of breast cancer or DVT/PE; current or previous depression, endometriosis, diabetes mellitus, hypertension, bone mineral density changes, renal or hepatic impairment, bone metabolic disease, systemic lupus erythematosus; conditions exacerbated by fluid retention (eg, migraine, asthma, epilepsy)
Discontinue if the following develop: Jaundice, visual problems (may cause contact lens intolerance), any signs of venous thromboembolism, migraine with unusual severity, significang blood pressure increase, severe depression, increased risk of thromboembolic complications after surgery
Discontinue 4 weeks before major surgery or prolonged immobilization
Patients on warfarin or other oral anticoagulants (increase in anticoagulant dose may be warranted)
Some studies link OC use with increased risk of breast cancer, whereas other studies have not shown any change in risk; risk depends on conditions where naturally high hormone levels persist for long periods, including early-onset menstruation (<12 years), late-onset menopause (>55 years), first child after age 30 years, nulliparity
Increased risk of cervical cancer with OC use; however human papillomavirus (HPV) remains main risk factor for this cancer; evidence suggests long-term (≥5 years) use of OCs may be associated with increased risk
Increased risk of liver cancer with OC use; risk increases with longer duration of use
Hypercalcemia may occur in patients with breast cancer or bone metastases
Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema
Angioedema involving eye/eyelid, face, larynx, pharynx, tongue and extremity (hands, legs, ankles, and fingers) with or without urticaria reported; discontinue therapy permanently if angioedema occurs
Femring is more potent than Estring and should be used with progesterone therapy to prevent endometrial hyperplasia
Caution regarding unintentional exposure in children (see Black Box Warnings)
Risk of endometrial cancer increases with use of unopposed estrogens (see Black Box Warnings)
An increased risk of invasive breast cancer reported with estrogen plus progestin in WHI substury; estrogens with or without progestins should be prescribed at lowest doses and for shortest duration
There is no evidence that the use of "natural" estrogens results in different endometrial risk profile from use of synthetic estrogens at equivalent estrogen doses
Pregnancy & Lactation
Pregnancy category: X
Lactation: Drug enters breast milk; use with caution
A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA:Information not available.
Mechanism of Action
Endogenous estrogen; reduces release of gonadotropin-releasing hormone and luteinizing hormone-releasing hormone from hypothalamus; reduces gonadotropin release from pituitary; increases synthesis of DNA, RNA, and various proteins in target tissues
Readily absorbed through GI tract, skin, mucous membrane
Onset: PO, 2-4 weeks; transdermal, 4 hr
Duration: Estradiol valerate, 7-8 days; estradiol cypionate, 11 days
Protein bound: To globulin and albumin
Half-life: 1.5-5 hr (IM); 4 hr (transdermal)
Excretion: Mainly in urine (as conjugates with small amount of unchanged drug); most estrogens are also excreted in bile and undergo enterohepatic recycling
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