by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.voriconazoleMonitor Closely (1)voriconazole will increase the level or effect of estrogens conjugated synthetic by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.zafirlukastMonitor Closely (1)zafirlukast will increase the level or effect of estrogens conjugated synthetic by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. >10% Abdominal pain Back pain Bloating Breast enlargement Breast tenderness Headache Nausea Peripheral edema Vomiting Frequency Not Defined Amenorrhea Breakthrough bleeding Corneal curvation change Depression Diarrhea Melasma Spotting Weight changes Postmarketing reports Abdominal discomfort, abdominal distension Muscle spasms Dizziness Insomnia Breast pain Alopecia Rash Urticaria Deep vein thrombosis, thrombosis Black Box Warnings Estrogens increase risk of endometrial cancer There is an increased risk of endometrial cancer in a woman with uterus who uses unopposed estrogens; adding a progestin to estrogen therapy has been shown to reduce risk of endometrial hyperplasia, which may be a precursor to endometrial cancer; perform adequate diagnostic measures, including directed or random endometrial sampling when indicated Close clinical surveillance of all women taking estrogens is important 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 There is no evidence that the use of "natural" estrogens results in a different endometrial risk profile than synthetic estrogens at equivalent estrogen doses 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 emboli, & deep vein thrombosis (DVT) in postmenopausal women (aged 50-79 yr) during 5.6 yr of treatment w/ daily PO conjugated estrogens (CE 0.625 mg) combined w/ medroxyprogesterone acetate (MPA 2.5 mg) compared with placebo Estrogens alone: A substudy of the WHI Study reported increased risk for stroke and DVT in postmenopausal women (aged 50-79 yr) during 6.8 year of treatment with oral conjugated estrogens (0.625 mg/day) alone compared with placebo Dementia risks Estrogens with and without progestins should not be used to prevent dementia Women's Health Initiative Memory Study (WHIMS), a substudy of the WHI study, reported increased risk of developing probable dementia in postmenopausal women aged 65 years or older during 4 year of treatment with daily CE 0.625 mg combined with MPA 2.5 mg, compared with placebo Estrogens alone: A substudy of the WHIMS reported an increased risk of developing probable dementia in postmenopausal women aged 65 years or older during 5.2 years of treatment with conjugated estrogens 0.625 mg alone compared w/ placebo Unknown whether these findings apply to younger postmenopausal women Dose & duration In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA and 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 Documented hypersensitivity; active or history of breast cancer, arterial thromboembolic disease (stroke, MI), thrombophlebitis, DVT/PE, thrombogenic valvular disease, protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders Known anaphylactic reaction or angioedema to drug or components Uncontrolled hypertension, diabetes mellitus with vascular involvement Jaundice with prior oral contraceptive use History of migraine with aura Estrogen-dependent neoplasia Undiagnosed abnormal vaginal bleeding Liver disease, liver tumors Known or suspected pregnancy Cautions Caution in history of hyperlipidemias, HTN, hepatic/renal impairment, uterine leiomyomata, porphyria, patients with defects of lipoprotein metabolism, hypertriglyceridemia, ovarian cancer, SLE, and the elderly Discontinue if the following develop jaundice, any signs of VTE, migraine with unusual severity, significant blood pressure increase, severe depression, increased risk of thromboembolic complications after surgery Discontinue 4 weeks before major surgery or prolonged immobilization Do not use with conditions that predispose to hyperkalemia There are, possible risks that may be associated with use of progestins with estrogens compared to estrogen-alone regimens, including a possible increased risk of breast cancer, adverse effects on lipoprotein metabolism (e.g., lowering HDL, raising LDL), and impairment of glucose tolerance Use caution in patients with asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic hemangiomas; exacerbations may occur Increased risk of ovarian and endometrial cancer Long-term postmenopausal estrogen treatment has been associated with increased risk of MI, stroke, DVT/PE, and dementia Patients on warfarin/oral anticoagulants: Estrogens increase thromboembolic risk; increase in anticoagulant dose may be warranted Not approved for osteoporosis prevention Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema Estrogens increase the risk of gallbladder disease Estrogen administration reported to lead to severe hypercalcemia in women with breast cancer and bone metastases; if hypercalcemia occurs, discontinue use and take appropriate measures to reduce serum calcium level Estrogens may cause some degree of fluid retention; 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 Retinal vascular thrombosis may occur; discontinue therapy, if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine, pending visual examination; permanently discontinue if examination reveals papilledema or renal vascular lesions Consider discontinuation of therapy if pancreatitis occurs; in women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis Monitor thyroid function in order to maintain free thyroid hormone levels in an acceptable range; 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 women during treatment to maintain their free thyroid hormone levels in an acceptable range Use with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur; consider whether benefits of estrogen therapy, outweigh risks A few cases of malignant transformation of residual endometrial implants reported in women treated post-hysterectomy with estrogen-alone therapy; consider addition of progestin in women known to have residual endometriosis post-hysterectomy Pregnancy Drug is 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 and nongenital birth defects (including cardiac anomalies or limb- reduction defects) following exposure to combined hormonal contraceptives (estrogen and progestins) before conception or during early pregnancy Lactation Estrogens are present in human milk and can reduce milk production in breastfeeding women; reduction is less likely to occur once breastfeeding is well- established; developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy and any potential adverse effects on breastfed child or underlying maternal conditionPregnancy 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 Replaces natural estrogen. Important for development and maintenance of the female reproductive system and secondary sexual characteristics. Derived from plant sources; B but not A contains delta 8,9-dehydroestrone sulfate Pharmacokinetics Onset: 2-4 wk (menopause; PO) Peak plasma time: 8 hr (PO) Bioavailability: Readily absorbed from GI tract Protein Bound: 80% Metabolism: In liver to inactive sulfates and glucuronides which are then excreted in urine and bile Metabolites: Estradiol, estrone, estriol Excretion: Mainly in urine as conjugates with small amount of unchanged drug, most estrogens are also excreted in bile and undergo enterohepatic recycling No images available for this drug. No images available for this drug.A Patient Handout is not currently available for this monograph.Print FormularyPatient DiscountsAdding plans allows you to compare formulary status to other drugs in the same class.To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.Create Your List of PlansAdding plans allows you to:View the formulary and any restrictions for each plan.Manage and view all your plans together – even plans in different states.Compare formulary status to other drugs in the same class.Access your plan list on any device – mobile or desktop. The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information. View explanations for tiers and restrictions Tier Description 1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs. 2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs. 3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs. 4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products. 5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products. 6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products. NC NOT COVERED – Drugs that are not covered by the plan. Code Definition PA Prior Authorization Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription. QL Quantity Limits Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered. ST Step Therapy Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription. 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