by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.nilotinibMonitor Closely (2)nilotinib will increase the level or effect of conjugated estrogens, vaginal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. nilotinib will increase the level or effect of conjugated estrogens, vaginal by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.nilutamideMonitor Closely (1)nilutamide will increase the level or effect of conjugated estrogens, vaginal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.nortriptylineMinor (1)conjugated estrogens, vaginal, nortriptyline. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Estrogens and progestins may decr tricyclic antidepressant effects, while increasing TCA plasma concentration and adverse effects.ospemifeneMonitor Closely (1)ospemifene, conjugated estrogens, vaginal. Either increases effects of the other by pharmacodynamic synergism. Modify Therapy/Monitor Closely.oxcarbazepineMonitor Closely (1)oxcarbazepine will decrease the level or effect of conjugated estrogens, vaginal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.pentobarbitalMonitor Closely (1)pentobarbital will decrease the level or effect of conjugated estrogens, vaginal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.phenindioneMonitor Closely (1)conjugated estrogens, vaginal decreases effects of phenindione by pharmacodynamic antagonism. Modify Therapy/Monitor Closely. Risk of thromboembolic disorders.phenobarbitalMonitor Closely (2)phenobarbital will decrease the level or effect of conjugated estrogens, vaginal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. phenobarbital will decrease the level or effect of conjugated estrogens, vaginal by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.phenytoinMonitor Closely (2)phenytoin will decrease the level or effect of conjugated estrogens, vaginal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. phenytoin will decrease the level or effect of conjugated estrogens, vaginal by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. If the estrogen is being used for contraception then loss of contraception may occur. phytoestrogensMinor (1)phytoestrogens decreases effects of conjugated estrogens, vaginal by pharmacodynamic antagonism. Minor/Significance Unknown.pleurisy rootMinor (1)pleurisy root decreases effects of conjugated estrogens, vaginal by unspecified interaction mechanism. Minor/Significance Unknown. Theoretical interaction.posaconazoleMonitor Closely (1)posaconazole will increase the level or effect of conjugated estrogens, vaginal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.prednisoneMonitor Closely (1)prednisone will decrease the level or effect of conjugated estrogens, vaginal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.primidoneMonitor Closely (1)primidone will decrease the level or effect of conjugated estrogens, vaginal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.progesterone, naturalMinor (1)progesterone, natural, conjugated estrogens, vaginal. Mechanism: pharmacodynamic synergism. Minor/Significance Unknown. Combination may produce breast tenderness.protamineMonitor Closely (1)conjugated estrogens, vaginal decreases effects of protamine by pharmacodynamic antagonism. Modify Therapy/Monitor Closely. Risk of thromboembolic disorders.protriptylineMinor (1)conjugated estrogens, vaginal, protriptyline. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Estrogens and progestins may decr tricyclic antidepressant effects, while increasing TCA plasma concentration and adverse effects.pyridoxineMinor (1)conjugated estrogens, vaginal decreases levels of pyridoxine by altering metabolism. Minor/Significance Unknown.pyridoxine (Antidote)Minor (1)conjugated estrogens, vaginal decreases levels of pyridoxine (Antidote) by altering metabolism. Minor/Significance Unknown.quercetinMonitor Closely (1)quercetin will decrease the level or effect of conjugated estrogens, vaginal by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.quinidineSerious - Use Alternative (1)quinidine will increase the level or effect of conjugated estrogens, vaginal by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug.quinupristin/dalfopristinMonitor Closely (1)quinupristin/dalfopristin will increase the level or effect of conjugated estrogens, vaginal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.ranolazineMonitor Closely (1)ranolazine will increase the level or effect of conjugated estrogens, vaginal by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.rifabutinSerious - Use Alternative (1)rifabutin will decrease the level or effect of conjugated estrogens, vaginal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.rifampinMonitor Closely (1)rifampin will decrease the level or effect of conjugated estrogens, vaginal by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.Serious - Use Alternative (1)rifampin will decrease the level or effect of conjugated estrogens, vaginal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.rifapentineMonitor Closely (1)rifapentine will decrease the level or effect of conjugated estrogens, vaginal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.ritonavirMonitor Closely (2)ritonavir will increase the level or effect of conjugated estrogens, vaginal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. ritonavir will increase the level or effect of conjugated estrogens, vaginal by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.ropiniroleMinor (1)conjugated estrogens, vaginal increases levels of ropinirole by unspecified interaction mechanism. Minor/Significance Unknown.rose hipsMinor (1)conjugated estrogens, vaginal decreases levels of rose hips by increasing elimination. Minor/Significance Unknown.rufinamideMonitor Closely (1)rufinamide will decrease the level or effect of conjugated estrogens, vaginal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.secobarbitalMonitor Closely (1)secobarbital will decrease the level or effect of conjugated estrogens, vaginal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.simvastatinMonitor Closely (1)simvastatin will increase the level or effect of conjugated estrogens, vaginal by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.sirolimusMonitor Closely (1)sirolimus will increase the level or effect of conjugated estrogens, vaginal by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.somapacitanMonitor Closely (1)conjugated estrogens, vaginal decreases effects of somapacitan by Other (see comment). Modify Therapy/Monitor Closely. Comment: Oral estrogens may reduce the serum IGF-1 response to somapacitan. Patients may require higher somapacitan dosages. See drug monograph for starting dose recommendations.St John's WortMonitor Closely (1)St John's Wort will decrease the level or effect of conjugated estrogens, vaginal by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.Serious - Use Alternative (1)St John's Wort will decrease the level or effect of conjugated estrogens, vaginal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.tacrolimusMonitor Closely (1)tacrolimus will increase the level or effect of conjugated estrogens, vaginal by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.teniposideMonitor Closely (1)teniposide will increase the level or effect of conjugated estrogens, vaginal by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.tesamorelinMonitor Closely (1)tesamorelin will decrease the level or effect of conjugated estrogens, vaginal by altering metabolism. Use Caution/Monitor. May decrease efficacy; monitortolvaptanMonitor Closely (1)tolvaptan will increase the level or effect of conjugated estrogens, vaginal by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.topiramateMonitor Closely (1)topiramate will decrease the level or effect of conjugated estrogens, vaginal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.trazodoneMonitor Closely (1)trazodone will decrease the level or effect of conjugated estrogens, vaginal by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.Minor (1)conjugated estrogens, vaginal, trazodone. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Estrogens and progestins may decr tricyclic antidepressant effects, while increasing TCA plasma concentration and adverse effects.trimipramineMinor (1)conjugated estrogens, vaginal, trimipramine. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Estrogens and progestins may decr tricyclic antidepressant effects, while increasing TCA plasma concentration and adverse effects.verapamilMonitor Closely (2)verapamil will increase the level or effect of conjugated estrogens, vaginal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. verapamil will increase the level or effect of conjugated estrogens, vaginal by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.voriconazoleMonitor Closely (1)voriconazole will increase the level or effect of conjugated estrogens, vaginal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.zafirlukastMonitor Closely (1)zafirlukast will increase the level or effect of conjugated estrogens, vaginal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. 1-10% Breast pain (4.9%) Headache (3.5%) Pelvic pain (2.8%) Vulvovaginal disorder (2.8%) Vasodilation (2.1%) Leukorrhea (2.1%) Moniliasis (1.4%) Pain (1.4%) Muscle cramps (1.4%) Pruritus (1.4%) Dysuria (1.4%) Vaginal hemorrhage (1.4%) Vaginitis (1.4%) <1% Abdominal pain Dizziness Breast enlargement Urinary urgency Postmarketing Reports Genitourinary system: Abnormal uterine bleeding or spotting, dysmenorrhea or pelvic pain, increase in size of uterine leiomyomata, vaginitis (including vaginal candidiasis), change in cervical secretion, cystitis-like syndrome, application site reactions of vulvovaginal discomfort, (including burning, irritation, and genital pruritus), endometrial hyperplasia, endometrial cancer, precocious puberty, leukorrhea Breasts: Tenderness, enlargement, pain, discharge, fibrocystic breast changes, breast cancer, gynecomastia in males Cardiovascular: DVT, PE, MI, stroke, increased BP Gastrointestinal: Nausea, vomiting, abdominal cramps, bloating, increased incidence of gallbladder disease Skin: Chloasma that may persist when drug is discontinued, loss of scalp hair, hirsutism, rash Eyes: Retinal vascular thrombosis, intolerance to contact lenses Central nervous system: Headache, migraine, dizziness, mental depression, nervousness, mood disturbances, irritability, dementia Miscellaneous: Increase or decrease in weight, glucose intolerance, edema, arthralgias, leg cramps, changes in libido, urticaria, exacerbation of asthma, increased triglycerides, hypersensitivity Black Box Warnings Endometrial cancer Estrogens increase risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens 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 the use of synthetic estrogens at equivalent estrogen doses Breast cancer Using conjugated estrogens in combination with medroxyprogesterone increases risk of invasive breast cancer Cardiovascular risks Estrogens with 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 (MI), stroke, invasive breast cancer, pulmonary embolism (PE), and deep vein thrombosis (DVT) in postmenopausal women (aged 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: A substudy of the WHI study reported increased risk for stroke and DVT in postmenopausal women (aged 50-79 years) during 6.8 years of treatment with daily PO conjugated estrogens (0.625 mg) alone in comparison with placebo Dementia risks Estrogens with or 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 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: A substudy of the WHIMS reported increased risk of developing probable dementia in postmenopausal women aged ≥65 years during 5.2 years of treatment with daily PO conjugated estrogens (0.625 mg) alone in comparison with placebo Unknown whether these findings apply to younger postmenopausal women Dose and 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 the lowest effective dosage and for the 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 a history of these conditions Active arterial thromboembolic disease (eg, stroke, MI), or a history of these conditions Known anaphylactic reaction or angioedema to conjugated estrogen preparations Known liver dysfunction or disease Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders Known or suspected pregnancy Cautions Systemic absorption occurs with use of vaginal cream Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, may lower incidence of endometrial hyperplasia compared to estrogen treatment alone; endometrial hyperplasia may be a precursor to endometrial cancer There are possible risks that may be associated with use of progestins with estrogens compared to estrogen-alone regimens, including increased risk of breast cancer If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization Most studies show no significant increased risk of endometrial cancer associated with use of estrogens for <1 year; the greatest risk appears to be associated with prolonged use, with increased risks of 15-to 24-fold for 5 to 10 years or more; this risk has been shown to persist for at least 8-15 years after estrogen therapy discontinued All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations; in addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results Risk of cardiovascular, endometrial cancer, breast cancer, and dementia; see Black Box Warnings Estrogens increase the risk of gallbladder disease Discontinue estrogen if severe hypercalcemia, severe hypertriglyceridemia occurs Monitor thyroid function in women on thyroid replacement therapy Estrogens may be poorly metabolized in women with impaired liver function; for women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised, and in the case of recurrence, medication should be discontinued Hormonal therapy for menopausal symptoms associated with increased risk for ovarian cancer; the exact duration of hormone therapy use associated with increased risk of ovarian cancer, is unknown Retinal vascular thrombosis has been 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,