Intramuscular Moderate to severe vasomotor symptoms associated with menopause, Vaginal atrophy associated with menopause, Vulvar atrophy associated with menopause
Adult: As estradiol cypionate: 1-5 mg every 3-4 weeks.
Oral Castration-associated estrogen deficiency, Hypogonadism-associated estrogen deficiency, Menopausal hormone replacement therapy, Moderate to severe vasomotor symptoms associated with menopause, Primary ovarian failure-associated estrogen deficiency, Vaginal atrophy associated with menopause, Vulvar atrophy associated with menopause
Adult: 1-2 mg daily continuously or cyclically. Use the lowest effective dose for the shortest duration consistent with treatment goals and risks for the individual woman. Treatment and dosing recommendations may vary among individual products and between countries (refer to specific product guidelines).
Oral Prophylaxis of osteoporosis in postmenopausal women
Adult: For women at significant risk of osteoporosis and for whom non-estrogen medications are not considered to be appropriate: 1-2 mg daily. Dose is individualised based on patient’s menopausal symptoms. Treatment and dosing recommendations may vary among individual products and between countries (refer to specific product guidelines).
Oral Palliative treatment of advanced prostate cancer
Adult: 1-2 mg tid.
Oral Metastatic breast cancer
Adult: As palliative treatment: 10 mg tid for at least 3 months.
Adult: Each patch delivers 0.025-0.1 mg estradiol per 24 hours: Apply once or twice weekly on a clean, dry area of skin of the lower abdomen or upper buttock. As gel containing 0.5 or 1 mg estradiol per single-dose container: Apply 0.5-1.5 mg daily on the right or left lower trunk of thigh. May be used continuously or cyclically. As spray releasing 1.53 mg estradiol per actuation: Initially, 1 spray once daily to dry and healthy skin of the forearm; may increase up to 3 sprays daily based on the degree of menopausal symptoms after at least 4 weeks of continuous treatment. Dosing recommendations may vary among individual products and between countries (refer to specific product guidelines).
Transdermal Moderate to severe vasomotor symptoms associated with menopause
Adult: As spray releasing 1.53 mg estradiol per actuation: Initially, 1 spray once daily, then adjust based on clinical response to 1-3 sprays once daily (in the morning) on adjacent, non-overlapping areas on the inner surface of the forearm. As gel containing 0.25-1.25 mg estradiol per single-dose container: Apply 0.25-1.25 mg once daily to the right or left upper thigh. Use the lowest effective dose for the shortest duration consistent with treatment goals and risks for the individual woman. Dosing recommendations may vary among individual products and between countries (refer to specific product guidelines).
Transdermal Prophylaxis of osteoporosis in postmenopausal women
Adult: Each patch delivers 0.04-0.1 mg estradiol per 24 hours: Apply once or twice weekly on a clean, dry area of skin of the lower abdomen or upper buttock. Dosing recommendations may vary among individual products and between countries (refer to specific product guidelines).
Transdermal Castration-associated estrogen deficiency, Hypogonadism-associated estrogen deficiency, Moderate to severe vasomotor symptoms associated with menopause, Primary ovarian failure-associated estrogen deficiency, Vaginal atrophy associated with menopause, Vulvar atrophy associated with menopause
Adult: Each patch delivers 0.025-0.1 mg estradiol per 24 hours: Apply once or twice weekly on a clean, dry area of skin of the lower abdomen or upper buttock. Dosing recommendations may vary among individual products and between countries (refer to specific product guidelines).
Vaginal Moderate to severe vasomotor symptoms associated with menopause
Adult: As vaginal ring releasing 0.05 or 0.1 mg estradiol per 24 hours: Place 1 ring into the upper third of the vagina every 90 days. Start at the lowest effective dose for the shortest duration consistent with treatment goals.
Vaginal Vaginal atrophy associated with menopause, Vulvar atrophy associated with menopause
Adult: As vaginal ring releasing 0.0075 mg, 0.05 mg, or 0.1 mg estradiol per 24 hours: Place 1 ring into the upper third of the vagina every 90 days. Start at the lowest effective dose for the shortest duration consistent with treatment goals. As vaginal tab containing 0.01 mg estradiol: Place 1 tab daily for 2 weeks then, 1 tab twice weekly. As 0.01% vaginal cream: 2-4 g daily for 1 or 2 weeks, reduce to 1-2 g daily for 1 or 2 weeks, then 1 g 1-3 times weekly as maintenance. Dosing recommendations may vary among individual products and between countries (refer to specific product guidelines).
Hepatic Impairment
Contraindicated.
Administration
May be taken with or without food.
Contraindications
Hypersensitivity. History or current breast cancer (except for certain metastatic breast cancer cases), previous or current venous thromboembolism (e.g. pulmonary embolism, DVT), active or recent arterial thromboembolic disease (e.g. MI, angina, stroke); estrogen-dependent tumours (e.g. endometrial cancer); undiagnosed genital bleeding; untreated endometrial hyperplasia; thrombophilic disorders (e.g. protein C, protein S, antithrombin deficiency), porphyria. Active or history of liver disease. Pregnancy and lactation.
Special Precautions
Patient with history of endometrial hyperplasia, cholestatic jaundice associated with past estrogen use or pregnancy, chloasma gravidarum, risk factors for arterial vascular disorders or venous thromboembolism (e.g. personal or family history, obesity, diabetes mellitus with or without vascular involvement, hypertension, hypercholesterolaemia, SLE, major trauma or surgery, prolonged immobilisation); risk factors for estrogen dependent tumours (e.g. 1st degree heredity for breast cancer), leiomyoma (uterine fibroids) or endometriosis, migraine or severe headache, epilepsy, asthma, cholelithiasis, hypertriglyceridaemia, hypoparathyroidism, severe hypocalcaemia, otosclerosis, cardiac impairment, hereditary angioedema; short, narrow vagina; uterovaginal prolapse, vaginal infection (vaginal). Smokers. Patient undergoing surgery. Non-hysterectomised women. Not intended for prevention of dementia and CV disease. Renal impairment.
Adverse Reactions
Significant: Increased risk of breast, endometrial, or ovarian cancers; endometrial hyperplasia, exacerbation of endometriosis, asthma, diabetes mellitus, epilepsy, migraine, porphyria, SLE, and hepatic hemangiomas; breakthrough bleeding and spotting, CV disorders (e.g. MI, stroke, pulmonary embolism, DVT), fluid retention, angioedema, retinal vascular thrombosis, increased risk of probable dementia (over the age of 65), increased risk of gallbladder disease requiring surgery, hypertension, hypertriglyceridaemia, increased HDL-cholesterol and decreased LDL-cholesterol, increased thyroid binding globulin levels, chloasma; impotence and feminising effects in males (when used as palliative treatment for advanced prostate cancer), severe hypercalcaemia in patients with breast cancer and bone metastases; UTI, vaginal irritation or infection (vaginal); breast budding or masses in prepubertal females, gynaecomastia and breast masses in prepubertal males (due to secondary exposure to transdermal spray). Cardiac disorders: Palpitations. Ear and labyrinth disorders: Otitis media, vertigo. Eye disorders: Visual disturbances. Gastrointestinal disorders: Nausea, vomiting, diarrhoea, constipation, dyspepsia, flatulence, abdominal pain, gastroenteritis; anorectal discomfort (vaginal). General disorders and administration site conditions: Weakness, lethargy, oedema, pain, flu-like symptoms. Infections and infestations: Fungal infections. Injury, poisoning and procedural complications: Application site reactions (transdermal). Investigations: Increased or decreased weight. Musculoskeletal and connective tissue disorders: Leg cramps, arthralgia, myalgia. Nervous system disorders: Headache, dizziness. Psychiatric disorders: Nervousness, anxiety, depression, insomnia, libido disorder. Renal and urinary disorders: Bladder discomfort (vaginal). Reproductive system and breast disorders: Pelvic pain, dysmenorrhoea, metrorrhagia, vaginal discharge, breast tenderness, pain, discharge or enlargement; vulvovaginal discomfort, vaginal haemorrhage, pruritus genitalis (vaginal). Respiratory, thoracic and mediastinal disorders: Cough, sinus congestion, sinusitis, nasopharyngitis, pharyngitis, upper respiratory tract infection, bronchitis, rhinitis. Skin and subcutaneous tissue disorders: Rash, erythema, pruritus, hyperhidrosis, acne, alopecia. Vascular disorders: Hot flushes. Potentially Fatal: Anaphylaxis.
Assess personal and family medical history before and periodically during therapy. Obtain blood pressure, serum triglycerides, TSH, glucose levels (in diabetic patients). Perform annual gynaecological exam. Monitor bone density (when used as prophylaxis of osteoporosis); signs and symptoms of thromboembolism, hypertension, oedema, CNS changes. Periodically evaluate the need to continue treatment.
Overdosage
Symptoms: Nausea, vomiting, dizziness, sleepiness, fatigue, bloating, abdominal pain, breast pain or tenderness, withdrawal bleeding. Management: Symptomatic treatment.
Drug Interactions
May increase plasma concentrations with CYP3A4 inhibitors (e.g. fluconazole, clarithromycin, verapamil, diltiazem). May decrease plasma concentrations with CYP3A4 inducers (e.g. phenobarbital, carbamazepine, phenytoin, griseofulvin, rifampicin, efavirenz). May increase or decrease plasma concentrations with protease inhibitors (e.g. ritonavir, nelfinavir). Decreases absorption of folic acid. May increase serum concentration of tacrolimus, ciclosporin, fentanyl, and theophylline.
Food Interaction
May increase serum levels with alcohol. May cause increased exposure with grapefruit juice. Concomitant use with St. John's wort may induce the metabolism of estrogen.
Lab Interference
May interfere with results of tests for coagulation factors, lipids, glucose tolerance and binding proteins. Decreases response to metyrapone test.
Action
Description: Mechanism of Action: Estradiol is a synthetic sex hormone similar to endogenous estrogen. In post-menopausal women, estradiol substitutes for the loss of estrogen production and alleviates menopausal symptoms. It also reduces bone resorption and prevents postmenopausal bone loss. Pharmacokinetics: Absorption: Well absorbed from the gastrointestinal tract, skin, and mucous membranes. Time to peak plasma concentration: 1.5-2 hours (oral). Distribution: Widely distributed in the body, with high concentrations in the sex hormone target organs. Enters breast milk. Plasma protein binding: Approx 30-52% to albumin and approx 46-69% to sex hormone binding globulin (SHBG). Metabolism: Metabolised in the liver partially by CYP3A4 enzymes to estrone and estriol. Undergoes enterohepatic recirculation (oral). Excretion: Mainly via urine as estradiol, estrone, estriol and its glucuronide and sulfate conjugates.
Chemical Structure
Estradiol Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 5757, Estradiol. https://pubchem.ncbi.nlm.nih.gov/compound/Estradiol. Accessed Oct. 27, 2022.
Storage
Store between 20-25°C. Do not freeze transdermal spray. Storage recommendations may vary among countries or individual products (refer to specific product guidelines).
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