(1)estradiol, trimipramine. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Estrogens and progestins may decr tricyclic antidepressant effects, while increasing TCA plasma concentration and adverse effects.tucatinibSerious - Use Alternative (1)tucatinib will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid concomitant use of tucatinib with CYP3A substrates, where minimal concentration changes may lead to serious or life-threatening toxicities. If unavoidable, reduce CYP3A substrate dose according to product labeling.valproic acidMonitor Closely (1)estradiol will decrease the level or effect of valproic acid by increasing elimination. Modify Therapy/Monitor Closely. May lead to increased seizure frequencyvancomycinMonitor Closely (1)vancomycin will decrease the level or effect of estradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Use Caution/Monitor.verapamilMonitor Closely (2)verapamil will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. verapamil will increase the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.voriconazoleMonitor Closely (1)voriconazole will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.voxelotorSerious - Use Alternative (1)voxelotor will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Voxelotor increases systemic exposure of sensitive CYP3A4 substrates. Avoid coadministration with sensitive CYP3A4 substrates with a narrow therapeutic index. Consider dose reduction of the sensitive CYP3A4 substrate(s) if unable to avoid.warfarinMonitor Closely (1)estradiol increases effects of warfarin by unspecified interaction mechanism. Use Caution/Monitor.zafirlukastMonitor Closely (1)zafirlukast will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. 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 Postmarketing Reports Nasopharyngitis Upper respiratory tract infection Vaginal mycosis Metrorrhagia Dysmenorrhea Ovarian cyst Vaginal discharge Gynecomastia Palpitations Ventricular extrasystoles Flatulence Rash pruritic, urticaria Retinal vein occlusion Tremor Arthralgia Application site rash Asthenia Chest discomfort Fatigue Feeling abnormal Heart rate increased Insomnia Malaise Muscle spasms Pain in extremity 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 Relevance of WHI findings regarding effects of lower conjugated estrogen doses, other routes of administration, or other estrogen-alone products on adverse cardiovascular events not known; without such data, not possible to definitively exclude risks or determine extent of risks for other products; discuss with patient benefits and risks of estrogen-alone therapy, taking into account individual risk profile 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 Relevance of WHI findings regarding effects of lower conjugated estrogen doses, other routes of administration, or other estrogen-alone products on dementia not known; without such data, not possible to definitively exclude risks or determine extent of risks for other products; discuss with patient benefits and risks of estrogen-alone therapy, taking into account individual risk profile 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 Increased risks of stroke and DVT reported with estrogen-alone and estrogen plus progestin therapy; immediately discontinue estrogen with or without progestogen if any of these occur or are suspected Use caution in patients with 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 ovarian cancer reported in women who used hormonal therapy for menopausal symptoms 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; discontinue therapy if hypercalcemia occurs, and take appropriate measures to reduce serum calcium level Exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema; consider whether benefits of estrogen therapy outweigh the risks in such women 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) Clinical surveillance of all women using estrogen-alone or estrogen plus progestogen therapy important; perform adequate diagnostic measures, including directed or random endometrial sampling when indicated to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding with unknown etiology 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 Cases of ring adherence to vaginal or bladder wall, making ring removal difficult, reported in women using vaginal rings and may require surgical removal of device; women should be carefully evaluated for vaginal or bladder wall ulceration or erosion; cases of vaginal erosion and vaginal ulceration reported with other estradiol vaginal rings Manage appropriately risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (e.g., personal history or family history of VTE, obesity, and systemic lupus erythematosus) A 2 to 4-fold increase in risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens reported Retinal vascular thrombosis reported in patients receiving estrogens; discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine; permanently discontinue therapy if examination reveals papilledema or retinal vascular lesions 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 In patients with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications Estrogens may be poorly metabolized in patients with impaired liver function; exercise caution in patients with a history of cholestatic jaundice associated with past estrogen use or with pregnancy; in the case of recurrence, discontinue medication Patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of thyroid replacement therapy; these patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range Estrogen-induced hypocalcemia may occur in women with hypoparathyroidism; consider whether benefits of estrogen therapy, outweigh risks Estradiol absorption increased when sunscreen applied 10 minutes before Elestrin application; do not apply sunscreen to application site until at least 25 minutes after application Pregnancy Therapy 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 (estrogen and progestins) before conception or during early pregnancy Lactation Therapy not indicated for use in females of reproductive potential; estrogens present in human milk and can reduce milk production in breast-feeding females; reduction can occur at any time but is less likely to occur once breast-feeding is well- established Consider developmental and health benefits of breast-feeding along with mother’s clinical need for therapy and any potential adverse effects on breast-fed child from therapy or from 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 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