estradiol
Alora, Climara, Esclim, Estrace, Estrace Vaginal Cream, Estraderm, Estring, FemPatch, Vivelle, Vivelle-Dot

estradiol cypionate
depGynogen, Depo-Estradiol Cypionate, DepoGen, Estro-Cyp, Estrofem

estradiol hemihydrate
Vagifem

estradiol valerate
Delestrogen ◆, Dioval 40, Dioval XX, Estra-L 40, Gynogen L.A. 10, Gynogen L.A. 20, Valergen 20

Available forms
Available by prescription only
estradiol
Ring: 2 mg/ring (0.0075 mg/24 hours)
Tablets: 0.5 mg, 1 mg, 2 mg
Transdermal: 0.025 mg/24 hours, 0.037 mg/24 hours, 0.05 mg/24 hours, 0.075 mg/24 hours, 0.1 mg/ 24 hours
Vaginal: 0.1 mg/g cream (in nonliquefying base)
estradiol cypionate
Injection: 5 mg/ml (in oil)
estradiol hemihydrate
Vaginal tablets: 25 mcg
estradiol valerate
Injection: 10 mg/ml, 20 mg/ml, 40 mg/ml (in oil)

Indications and dosages
 Atrophic vaginitis, atrophic dystrophy of the vulva, vasomotor menopausal symptoms, hypogonadism, female castration, primary ovarian failure. estradiol (tablets) Adults: 1 to 2 mg P.O. daily, in cycles of 21 days on and 7 days off or cycles of 5 days on and 2 days off.
estradiol (transdermal) Adults: Start with lowest possible dose (0.025 to 0.05 mg/24 hours). Place one transdermal patch (Alora, Esclim, Estraderm, Vivelle, Vivelle Dot) on trunk of body, preferably abdomen, twice weekly. Climara and FemPatch are applied once weekly. Administer on a cyclic schedule (3 weeks on and 1 week off).
estradiol cypionate Adults: 1 to 5 mg I.M. once q 3 to 4 weeks.
estradiol valerate Adults: 10 to 20 mg I.M. once a month.
 Atrophic vaginitis. estradiol (vaginal cream) Adults: 2 to 4 g daily for 1 to 2 weeks. When vaginal mucosa is restored, begin maintenance dosage of 1 g one to three times weekly.
estradiol (vaginal ring) Adults: Insert ring as deeply as possible into the upper third of the vaginal vault. The ring should remain in place for 3 months.
estradiol hemihydrate Adults: Initially, 1 tablet inserted vaginally once daily for 2 weeks. Then, 1 tablet inserted vaginally twice weekly.
 Female hypogonadism. estradiol cypionate Adults: 1.5 to 2 mg I.M. at monthly intervals.
estradiol valerate Adults: 10 to 20 mg I.M. q 4 weeks as needed.
 Inoperable breast cancer. estradiol (tablets) Adults: 10 mg P.O. t.i.d. for 3 months.
 Inoperable prostatic cancer. estradiol valerate Adults: 30 mg I.M. q 1 to 2 weeks.
estradiol (tablets) Adults: 1 to 2 mg P.O. t.i.d.
 Prevention of postmenopausal osteoporosis. estradiol (transdermal) Adults: 0.025 mg/ day system (Alora, Vivelle, Vivelle-Dot) or one Estraderm 0.05 mg/day system, on trunk of body, preferably the abdomen, twice weekly in a continuous regimen for women who have had a hysterectomy or cyclic regimen for those with an intact uterus; or 0.025 mg/ day patch (Climara) applied once weekly in a continuous regimen. Adjust dose as needed.
estradiol (tablets) Adults: 0.5 mg P.O. daily in a cyclic regimen (3 weeks on, 1 week off).

Pharmacodynamics
Estrogenic action: Estradiol mimics the action of endogenous estrogen in treating female hypogonadism, menopausal symptoms, and atrophic vaginitis. It inhibits growth of hormone-sensitive tissue in advanced, inoperable prostatic cancer and in certain carefully selected cases of breast cancer in men and postmenopausal women.

Pharmacokinetics
Absorption: After oral administration, estradiol and other natural unconjugated estrogens are well absorbed but substantially inactivated by the liver. Therefore, unconjugated estrogens are usually administered parenterally. After I.M. administration, absorption begins rapidly and continues for days. The cypionate and valerate esters administered in oil have prolonged durations of action because of their slow absorption characteristics. Topically applied estradiol is absorbed readily into the systemic circulation.
Distribution: Estradiol and other natural estrogens are about 50% to 80% plasma protein-bound, particularly the estradiol-binding globulin. Distribution occurs throughout the body, with highest levels appearing in fat.
Metabolism: Steroidal estrogens, including estradiol, are metabolized primarily in the liver, where they are conjugated with sulfate and glucuronide. Because of the rapid metabolism, nonesterified forms of estrogen, including estradiol, must usually be administered daily.
Excretion: Most estrogen elimination occurs through the kidneys in the form of sulfate or glucuronide conjugates.

Contraindications and precautions
Contraindicated in pregnant patients and patients with active thrombophlebitis or thromboembolic disorders, estrogen-dependent neoplasia, breast or reproductive organ cancer (except for palliative treatment), or undiagnosed abnormal genital bleeding. Also contraindicated in patients with history of thrombophlebitis or thromboembolic disorders from previous estrogen use (except for palliative treatment of breast and prostate cancer).
 Use cautiously in patients with cerebrovascular or coronary artery disease, hypertension, asthma, bone diseases, gallbladder disease, migraine, seizures, or cardiac, hepatic, or renal dysfunction. Also use cautiously in women with a strong family history of breast cancer or who have breast nodules, fibrocystic disease, or abnormal mammographic findings.

Interactions
Drug-drug. Corticosteroids: May enhance corticosteroid effects. Monitor patient closely.
Cyclosporine: May increase risk of toxicity. Monitor patient and cyclosporine levels frequently.
Dantrolene, other hepatotoxic drugs: May increase risk of hepatotoxicity. Monitor patient closely.
Drugs that induce hepatic metabolism, such as carbamazepine, barbiturates, phenytoin, primidone, rifampin: Decreases estrogenic effects and increases metabolism of certain other drugs. Monitor patient closely.
Insulin, oral antidiabetics: Alters blood glucose levels. Adjust dosage if needed.
Tamoxifen: Decreases tamoxifen effects. Monitor patient closely.
Warfarin-type anticoagulants: Decreases anticoagulant effect. Adjust dosage if needed.
Drug-food. Caffeine: May increase serum caffeine levels. Discourage caffeine use.
Grapefruit juice: Elevates estrogen levels. Advise patient to take drug with liquid other than grapefruit juice.
Drug-lifestyle. Smoking: Increases risk of adverse CV effects. Discourage smoking.

Adverse reactions
CNS: headache, dizziness, chorea, depression, CVA, seizures.
CV: thrombophlebitis; thromboembolism; hypertension; edema; pulmonary embolism, MI.
EENT: worsening of myopia or astigmatism, intolerance of contact lenses.
GI: nausea, vomiting, abdominal cramps, bloating, anorexia, increased appetite, weight changes, pancreatitis, gallbladder disease.
GU: breakthrough bleeding, altered menstrual flow, dysmenorrhea, amenorrhea, endometrial cancer, cervical erosion, altered cervical secretions, enlargement of uterine fibromas, vaginal candidiasis, testicular atrophy, impotence.
Hematologic: increased norepinephrine-induced platelet aggregability.
Hepatic: cholestatic jaundice, hepatic adenoma.
Metabolic: hypercalcemia.
Skin: melasma, rash, hirsutism or hair loss, erythema nodosum, dermatitis.
Other: breast cancer, breast changes (tenderness, enlargement, secretion), gynecomastia in men.

Effects on lab test results
• May increase levels of calcium; triglyceride; glucose; phospholipid; clotting factors VII, VIII, IX, and X; total T₄; thyroid-binding globulin; and triglycerides. May decrease serum folate, pyridoxine, and antithrombin III levels.
• May increase PT, INR, and norepinephrine-induced platelet aggregation.

Overdose and treatment
Serious toxicity hasn’t been reported after overdose. Nausea may occur.
 Provide appropriate supportive care.

Special considerations
• Make sure patient has physical examination before therapy. Patient receiving long-term therapy should be examined yearly.
• Ask patient about allergies, especially to foods and plants. Estradiol is available as an aqueous solution or as a solution in peanut oil; estradiol cypionate, as a solution in cottonseed oil; estradiol valerate, and as a solution in castor oil or sesame oil.
• To administer I.M. injection, make sure drug is well dispersed in solution by rolling vial between palms. Inject deeply into large muscle. Rotate injection sites to prevent muscle atrophy. Never give drug I.V.
• Apply transdermal patch to clean, dry, hairless, intact skin on abdomen or buttocks. Don’t apply it to breasts, waistline, or other areas where clothing can loosen patch. When applying, ensure thorough contact between patch and skin, especially around edges, and hold in place for about 10 seconds. Rotate application sites.
• In women also taking oral estrogen, treatment with the Estraderm transdermal patch can begin 1 week after withdrawal of oral therapy, sooner if menopausal symptoms appear before the end of the week.
• Transdermal systems are sometimes used on a continuous basis (not cyclic). Other alternatives are 1 to 5 mg (cypionate) I.M. q 3 to 4 weeks; or 10 to 20 mg (valerate) I.M. q 4 weeks, p.r.n.
• Because of risk of thromboembolism, therapy should be discontinued at least 1 month before procedures that cause prolonged immobilization or raise the risk of thromboembolism, such as knee or hip surgery.
• Notify pathologist about estrogen therapy when sending specimens to laboratory for evaluation.
Pregnant patients
• Drug is contraindicated in pregnant women.
Breast-feeding patients
• Drug is contraindicated in breast-feeding women.
Geriatric patients
• Frequent physical examinations are recommended in postmenopausal women taking estrogen.

Patient education
• Tell patient not to apply patch to breast area.
• Remind patient not to use the same skin site for at least 1 week after removal of the transdermal system.
• Tell patient to insert Vagifem applicator as far into the vagina as it can comfortably go, without using force. Patients with severely atrophic vaginal mucosa should use extra care during insertion.
• Tell patient to read package insert describing estrogen’s adverse effects; however, also give patient verbal explanation.
• Emphasize importance of regular physical examinations. Postmenopausal women who use estrogen replacement for longer than 5 years to treat menopausal symptoms may be at increased risk for endometrial cancer. This risk is reduced by using cyclic rather than continuous therapy and the lowest possible estrogen dosage. Adding progestins to the regimen decreases risk of endometrial hyperplasia; however, it isn’t known whether progestins affect risk of endometrial cancer. No increased risk of breast cancer has been reported.
 ALERT Warn patient to immediately report abdominal pain; pain, numbness, or stiffness in legs or buttocks; pressure or pain in chest or shortness of breath; severe headaches; visual disturbances, such as blind spots, flashing lights, or blurriness; vaginal bleeding or discharge; breast lumps; swelling of hands or feet; yellow skin or sclera; dark urine; and light-colored stools.
• Tell diabetic patient to report elevated blood glucose level so that antidiabetic dosage can be adjusted.
• Teach woman to perform routine breast self-examination.
• Advise woman of childbearing age to call immediately if she becomes pregnant.
• Teach patient methods to decrease risk of thromboembolism.

Reactions may be common, uncommon, life-threatening, or COMMON AND LIFE THREATENING.
◆ Canada only
◇ Unlabeled clinical use