endometrial cancer in women with a uterus 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; prescribe estrogens with or without progestins 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 Contraindications Undiagnosed abnormal genital bleeding Known, suspected, or history of breast cancer Known or suspected estrogen-dependent neoplasia Active DVT, PE, or history of these conditions Active arterial thromboembolic disease (eg, stroke, MI), or a history of these conditions Known anaphylactic reaction or angioedema to estrogen Known liver impairment or disease Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders Known or suspected pregnancy Cautions System absorption occurs with intravaginal administration; consider warnings, precautions, and adverse effects associated with systemic estrogen-alone therapy Increased risk of stroke and DVT reported with estrogen-alone therapy; increased risk of PE, DVT, stroke, and MI reported with estrogen plus progestin therapy; discontinue drug immediately if these conditions occur or are suspected (see Black Box Warnings) The WHI estrogen plus progestin substudy reported a statistically nonsignificant increased risk of ovarian cancer (4 vs 3 cases per 10,000 women-years) Estrogen with or without progesterone may increase risk of dementia (see Black Box Warnings) Increased risk of gallbladder disease (2- to 4-fold) requiring surgery in postmenopausal women receiving estrogen has been reported Severe hypercalcemia in women with breast cancer and bone metastases reported with estrogen use; if hypercalcemia occurs, discontinue estrogen and initiate appropriate treatment to reduce serum calcium level Retinal vascular thrombosis reported; discontinue estrogen pending examination if there is a sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine; if papilledema or retinal vascular lesions diagnosed, permanently discontinue estrogens Rare occurrences reported of substantial blood pressure increases that were attributed to idiosyncratic reactions to estrogens May cause elevated triglycerides that lead to pancreatitis in women with preexisting hypertriglyceridemia; discontinue estrogens if pancreatitis occurs Estrogens may be poorly metabolized with hepatic impairment; if cholestatic jaundice occurs, discontinued estrogens; exercise caution in any woman with a history of cholestatic jaundice associated with past estrogen use or with pregnancy Estrogen administration leads to increased thyroid-binding globulin (TBG) levels; women with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range, however, women dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy; monitor thyroid function in these women during treatment to maintain their free thyroid hormone levels in an acceptable range Estrogens may cause some degree of fluid retention; women with conditions that might be influenced by this factor (eg, cardiac or renal impairment) warrant careful observation; monitor any woman with a condition(s) that might predispose her to fluid retention, such as cardiac or renal impairment; discontinue estrogen-alone therapy with evidence of medically concerning fluid retention Malignant transformation of residual endometrial implants have been reported in women treated posthysterectomy with estrogen-alone therapy; if residual endometriosis posthysterectomy exists, the addition of progestin should be considered Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema; consider whether benefits of estrogen therapy outweigh risks in such women Estrogen therapy may exacerbate asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas; consider whether benefits of estrogen therapy outweigh risks in women with these conditions Local abrasion induced by vaginal tablet applicator reported Serum follicle stimulating hormone (FSH) and estradiol levels not shown for the management of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex, and beta-thromboglobulin; decreased levels of antifactor and antithrombin III, decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity Estrogen-induced hypocalcemia may occur in women with hypoparathyroidism; consider whether benefits of estrogen therapy outweigh risks in such women Endometrial cancer Increased risk of endometrial cancer reported with use of unopposed estrogen therapy in a woman with a uterus (see Black Box Warnings); clinical surveillance of all women using estrogen-alone or estrogen plus progestogen therapy is important There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose Adding a progestogen to estrogen therapy in postmenopausal women has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer Breast cancer The most important randomized clinical trial providing information about breast cancer in estrogen-alone users is the Women’s Health Initiative (WHI) substudy of daily PO conjugated estrogens (CE) (0.625 mg)-alone In the WHI estrogen-alone substudy, after an average follow-up of 7.1 years, daily CE-alone was not associated with an increased risk of invasive breast cancer (see Black Box Warnings) Drug interactions overview CYP3A4 inducers or inhibitors may affect estrogen drug metabolism CYP3A4 inducers (eg, St. John's wort [Hypericum perforatum] preparations, phenobarbital, carbamazepine, and rifampin) may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile CYP3A4 inhibitors (eg, erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir, grapefruit juice) may increase plasma concentrations of estrogens and may result in side effects Pregnancy Not indicated for use in pregnancy; there are no data with use in pregnant women; however, epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to combined hormonal contraceptives (estrogens and progestins) before conception or during early pregnancy Lactation Estrogens are present in human milk and can reduce milk production in breast-feeding females; this reduction can occur at any time but is less likely to occur once breastfeeding is well-established; the clinical need for therapy and any potential adverse effects on breastfed child or from underlying maternal condition. developmental and health benefits of breastfeeding should be considered along with the mother’sPregnancy 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. Mechanism of Action Estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics Absorption Estrogen drug products are well absorbed through the skin, mucous membranes, and the GI tract Vaginal delivery of estrogens circumvents first-pass metabolism Peak plasma concentration (Imvexxy): 4.8-7.3 pg/mL Distribution Distribution of exogenous estrogens is similar to that of endogenous estrogens Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs Estrogens circulate in the blood largely bound to sex hormone-binding globulin (SHBG) and albumin Metabolism Exogenous estrogens are metabolized in the same manner as endogenous estrogens Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions that take place mainly in the liver Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption In postmenopausal women, a significant portion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens Elimination Excretion: Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate conjugates Intravaginal Administration Intravaginal ring Insert in upper third of vaginal vault; the ring is to remain in place continuously for 3 months, after which it is to be removed and, if appropriate, replaced by a new ring Should the ring be removed or fall out at any time during the 90-day treatment period, rinse the ring in lukewarm water and reinsert (by the patient, or, if necessary, by a physician or nurse) Vaginal tablet or cream Use applicator provided with drug to insert vaginal tablet or measure dose of vaginal cream Lay on back with pelvis slightly tilted upward, or stand with one knee bent (ie, foot on seat of chair or toilet), insert the prescribed dose with applicator The applicator should be inserted (without forcing) as far as comfortably possible, or until half of the applicator is inside vagina Note: The vaginal tablet dissolves gradually over several hours, so bedtime application may be desired Vaginal insert Administer intravaginally Insert with the smaller end up for a depth of about 2 inches into the vaginal canal Storage Estrace Vaginal: Room temperature; protect from temperatures exceeding 40°C (104°F) Estring: Controlled room temperature 15-25°C (59-77°F) Vagifem: Controlled room temperature 25°C (77°F), excursions permitted to 15-30°C (59-86°F); do not refrigerate Femring: Controlled room temperature 25°C (77°F), excursions permitted to 15-30°C (59-86°F); do not store out of the protective pouch; insert immediately upon remove from the protective pouch Imvexxy: Store at 20-25°C (68-77°F), excursions permitted to 15-30°C (59-86°F) BRAND FORM. UNIT PRICE PILL IMAGE Femring vaginal- 0.1 mg/24 hr ringFemring vaginal- 0.05 mg/24 hr ringCopyright © 2010 First DataBank, Inc.Print Patient Educationestradiol acetate vaginal ESTRADIOL ACETATE RING - VAGINAL (ES-tra-DYE-ol AS-e-tate) COMMON BRAND NAME(S): Femring WARNING: Estrogens, either used alone or with another hormone (progestin), have rarely caused very serious side effects. Discuss the risks and benefits of hormone treatment with your doctor. Estrogens should not be used to prevent heart disease or dementia.Estrogens can increase the risk of cancer of the uterus (endometrial cancer). Taking a progestin as directed by your doctor can help decrease this risk. Tell your doctor right away if you have any unusual vaginal bleeding.In postmenopausal women, estrogens, taken with or without a progestin, increase the risk of cancer of the breast/ovaries, stroke, dementia, and serious blood clots. When used along with a progestin, estrogens also increase the risk of heart disease (such as heart attacks).The risk for serious side effects may depend on