estradiol (Estrace, Vivelle-Dot, Delestrogen, DepoEstradiol, Divigel, Elestrin, Alora, Estrace Cream, Estraderm Transdermal, estradiol topical, Estradot, Estrasorb, Estrogel, Evamist, Femtrace, Menostar, Minivelle, Vivelle, Climara)

Dosing and uses of Estrace, Vivelle-Dot (estradiol)

• Adult
• Pediatric

 

Adult dosage forms and strengths

geL

• 0.06%
• 0.1%

injectable solution

• 5mg/mL
• 10mg/mL
• 20mg/mL
• 40mg/mL

tablet

• 0.45mg (as acetate)
• 0.5mg
• 0.9mg (as acetate)
• 1mg
• 1.5mg
• 2mg

transdermal patch

• 0.025mg
• 0.0375mg
• 0.05mg
• 0.06mg
• 0.075mg
• 0.1mg

topical emulsion

• 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

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

 

Hypoestrogenism

Cypionate: 1.5-2 mg IM every 4 weeks

 

Osteoporosis

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

 

Prostate Cancer

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

 

Pediatric dosage forms and strengths

Safety and efficacy not established

 

Estrace, Vivelle-Dot (estradiol) adverse (side) effects

Frequency not defined

Anxiety

Abdominal cramping

Amenorrhea

Bloating

Breakthrough bleeding

Breast enlargement

Breast tenderness

Delayed ejaculation

Depression

Dry mouth

Headache

Hypertension

Impotency

Influenza

Leukorrhea

Melasma

Muscle cramps

Nausea

Nervousness

Peripheral edema

Polydipsia

Pruritus

Rash

Swelling

Skin irritation and redness at application site (transdermal)

Spotting

Syncope

Toothache

Vaginal discomfort, vaginal erosion, vaginal ulceration, adherence of the vaginal ring to the vaginal wall (Estring)

Vomiting

Weight changes

 

Warnings

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

Cardiovascular risks

• 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

Dementia risks

• 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

Breast cancer

• 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

 

Contraindications

Documented hypersensitivity

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

Estrogen-dependent neoplasia

Uncontrolled hypertension, diabetes mellitus with vascular involvement, jaundice with previous oral contraceptive (OC) use

Undiagnosed abnormal vaginal bleeding

Liver disease, liver tumors

 

Cautions

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 and lactation

Pregnancy category: X

Lactation: Drug enters breast milk; use with caution

 

Pregnancy categories

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.

 

Pharmacology of Estrace, Vivelle-Dot (estradiol)

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

 

Absorption

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

 

Distribution

Widely distributed

Protein bound: To globulin and albumin

 

Elimination

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