estradiol/norethindrone acetate (Rx)

Brand and Other Names:Activella, CombiPatch, more...Lopreeza, Mimvey
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

estradiol/norethindrone acetate

tablet

  • 1mg/0.5mg
  • 0.5mg//0.1mg

patch, extended release

  • 0.05mg/0.25mg per 24 hr
  • 0.05mg/0.14mg per 24 hr

Menopause & Vasomotor Symptoms

Oral tablets: 1 tablet PO qDay

Patch: Apply 1 patch to lower abdomen continuously, changed 2 times a week

Alternative patch regimen: 1 estradiol patch (0.05 mg/d) days 1-14, changed 2 times a week; then 1 patch on days 15-28, changed 2 times a week

Indications

  • Activella, Lopreeza, Mimvey (1 mg/0.5 mg or 0.5 mg/0.1 mg): Treatment of moderate-to-severe vasomotor symptoms due to menopause in patients with an intact uterus, and for prevention of osteoporosis in postmenopausal women with an intact uterus
  • Activella, Lopreeza. Mimvey (1 mg/0.5 mg): Treatment of moderate-to-severe symptoms of valvar/vaginal atrophy due to menopause
  • CombiPatch: Treatment of moderate to severe vasomotor symptoms in menopause, vulvar/vaginal atrophy; treatment of hypoestrogenisms due to hypogonadism, castration, or primary ovarian failure

Not indicated

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Interactions

Interaction Checker

and estradiol/norethindrone acetate

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            Contraindicated (1)

            • ospemifene

              ospemifene, estradiol. Either increases effects of the other by pharmacodynamic synergism. Contraindicated.

            Serious - Use Alternative (47)

            • abametapir

              abametapir will increase the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. For 2 weeks after abametapir application, avoid taking drugs that are CYP3A4 substrates. If not feasible, avoid use of abametapir.

              abametapir will increase the level or effect of estradiol by affecting hepatic enzyme CYP1A2 metabolism. Avoid or Use Alternate Drug. For 2 weeks after abametapir application, avoid taking drugs that are CYP1A2 substrates. If not feasible, avoid use of abametapir.

              abametapir will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. For 2 weeks after abametapir application, avoid taking drugs that are CYP3A4 substrates. If not feasible, avoid use of abametapir.

            • acitretin

              acitretin decreases effects of norethindrone acetate by unknown mechanism. Contraindicated. Contraceptive failure may result.

            • anastrozole

              estradiol decreases effects of anastrozole by pharmacodynamic antagonism. Contraindicated. Estrogen may diminish the pharmacologic action of anastrozole. Coadministration not recommended.

            • antithrombin alfa

              estradiol decreases effects of antithrombin alfa by pharmacodynamic antagonism. Contraindicated. Risk of thromboembolic disorders.

            • antithrombin III

              estradiol decreases effects of antithrombin III by pharmacodynamic antagonism. Contraindicated. Risk of thromboembolic disorders.

            • apalutamide

              apalutamide will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration of apalutamide, a strong CYP3A4 inducer, with drugs that are CYP3A4 substrates can result in lower exposure to these medications. Avoid or substitute another drug for these medications when possible. Evaluate for loss of therapeutic effect if medication must be coadministered. Adjust dose according to prescribing information if needed.

              apalutamide will decrease the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration of apalutamide, a strong CYP3A4 inducer, with drugs that are CYP3A4 substrates can result in lower exposure to these medications. Avoid or substitute another drug for these medications when possible. Evaluate for loss of therapeutic effect if medication must be coadministered. Adjust dose according to prescribing information if needed.

            • argatroban

              estradiol decreases effects of argatroban by pharmacodynamic antagonism. Contraindicated. Risk of thromboembolic disorders.

            • belzutifan

              belzutifan will decrease the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration of belzutifan with hormonal contraceptives may lead to contraceptive failure or increased breakthrough bleeding. Advise females of reproductive potential to use effective nonhormonal contraception. Based on animal studies, belzutifan can cause fetal harm.

            • bemiparin

              estradiol decreases effects of bemiparin by pharmacodynamic antagonism. Contraindicated. Risk of thromboembolic disorders.

            • bivalirudin

              estradiol decreases effects of bivalirudin by pharmacodynamic antagonism. Contraindicated. Risk of thromboembolic disorders.

            • carbamazepine

              carbamazepine will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              carbamazepine will decrease the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration unless benefit outweighs risk. When coadministered, hormonal contraceptives are not a reliable method of effective birth control. Concomitant use may increase incidence of menstruation associated adverse effects (amenorrhea, dysmenorrhea, menorrhagia).

            • cimetidine

              cimetidine will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • enzalutamide

              enzalutamide will decrease the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration unless benefit outweighs risk. When coadministered, hormonal contraceptives are not a reliable method of effective birth control. Concomitant use may increase incidence of menstruation associated adverse effects (amenorrhea, dysmenorrhea, menorrhagia).

            • clarithromycin

              clarithromycin will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • dalteparin

              estradiol decreases effects of dalteparin by pharmacodynamic antagonism. Contraindicated. Risk of thromboembolic disorders.

            • enoxaparin

              estradiol decreases effects of enoxaparin by pharmacodynamic antagonism. Contraindicated. Risk of thromboembolic disorders.

            • enzalutamide

              enzalutamide will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • erdafitinib

              erdafitinib will increase the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. If coadministration unavoidable, separate administration by at least 6 hr before or after administration of P-gp substrates with narrow therapeutic index.

            • erythromycin base

              erythromycin base will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • erythromycin ethylsuccinate

              erythromycin ethylsuccinate will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • erythromycin lactobionate

              erythromycin lactobionate will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • erythromycin stearate

              erythromycin stearate will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • fexinidazole

              fexinidazole will increase the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Fexinidazole inhibits CYP3A4. Coadministration may increase risk for adverse effects of CYP3A4 substrates.

              fexinidazole will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Fexinidazole inhibits CYP3A4. Coadministration may increase risk for adverse effects of CYP3A4 substrates.

            • fondaparinux

              estradiol decreases effects of fondaparinux by pharmacodynamic antagonism. Contraindicated. Risk of thromboembolic disorders.

            • fosphenytoin

              fosphenytoin will decrease the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration unless benefit outweighs risk. When coadministered, hormonal contraceptives are not a reliable method of effective birth control. Concomitant use may increase incidence of menstruation associated adverse effects (amenorrhea, dysmenorrhea, menorrhagia).

            • givosiran

              givosiran will increase the level or effect of estradiol by affecting hepatic enzyme CYP1A2 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of sensitive CYP1A2 substrates with givosiran. If unavoidable, decrease the CYP1A2 substrate dosage in accordance with approved product labeling.

            • heparin

              estradiol decreases effects of heparin by pharmacodynamic antagonism. Contraindicated. Risk of thromboembolic disorders.

            • idelalisib

              idelalisib will increase the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Idelalisib is a strong CYP3A inhibitor; avoid coadministration with sensitive CYP3A substrates

              idelalisib will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Idelalisib is a strong CYP3A inhibitor; avoid coadministration with sensitive CYP3A substrates

            • ivosidenib

              ivosidenib will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of sensitive CYP3A4 substrates with ivosidenib or replace with alternate therapies. If coadministration is unavoidable, monitor patients for loss of therapeutic effect of these drugs.

              ivosidenib will decrease the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of sensitive CYP3A4 substrates with ivosidenib or replace with alternative therapies. If coadministration is unavoidable, monitor patients for loss of therapeutic effect of these drugs.

            • lumacaftor/ivacaftor

              lumacaftor/ivacaftor will decrease the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration unless benefit outweighs risk. When coadministered, hormonal contraceptives are not a reliable method of effective birth control. Concomitant use may increase incidence of menstruation associated adverse effects (amenorrhea, dysmenorrhea, menorrhagia).

            • nefazodone

              nefazodone will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • mavacamten

              mavacamten will decrease the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Progestin and ethinyl estradiol are CYP3A4 substrates. Mavacamten may decrease systemic exposures of ethinyl estradiol and progestin, which may lead to contraceptive failure or an increase in breakthrough bleeding. Advise patients to use a contraceptive method that is not affected by CYP450 enzyme induction (eg, intrauterine system) or add nonhormonal contraception (eg, condoms) during coadministration and for 4 months after last mavacamten dose.

            • mitotane

              mitotane will decrease the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration unless benefit outweighs risk. When coadministered, hormonal contraceptives are not a reliable method of effective birth control. Concomitant use may increase incidence of menstruation associated adverse effects (amenorrhea, dysmenorrhea, menorrhagia).

            • pacritinib

              estradiol will decrease the level or effect of pacritinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • phenindione

              estradiol decreases effects of phenindione by pharmacodynamic antagonism. Contraindicated. Risk of thromboembolic disorders.

            • phenobarbital

              phenobarbital will decrease the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration unless benefit outweighs risk. When coadministered, hormonal contraceptives are not a reliable method of effective birth control. Concomitant use may increase incidence of menstruation associated adverse effects (amenorrhea, dysmenorrhea, menorrhagia).

            • phenytoin

              phenytoin will decrease the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration unless benefit outweighs risk. When coadministered, hormonal contraceptives are not a reliable method of effective birth control. Concomitant use may increase incidence of menstruation associated adverse effects (amenorrhea, dysmenorrhea, menorrhagia).

            • primidone

              primidone will decrease the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration unless benefit outweighs risk. When coadministered, hormonal contraceptives are not a reliable method of effective birth control. Concomitant use may increase incidence of menstruation associated adverse effects (amenorrhea, dysmenorrhea, menorrhagia).

            • protamine

              estradiol decreases effects of protamine by pharmacodynamic antagonism. Contraindicated. Risk of thromboembolic disorders.

            • quinidine

              quinidine will increase the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug.

            • rifabutin

              rifabutin will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              rifabutin will decrease the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration unless benefit outweighs risk. When coadministered, hormonal contraceptives are not a reliable method of effective birth control. Concomitant use may increase incidence of menstruation associated adverse effects (amenorrhea, dysmenorrhea, menorrhagia).

            • rifampin

              rifampin will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

              rifampin decreases levels of norethindrone acetate by increasing metabolism. Avoid or Use Alternate Drug. Avoid coadministration unless benefit outweighs risk. When coadministered, hormonal contraceptives are not a reliable method of effective birth control. Concomitant use may increase incidence of menstruation associated adverse effects (amenorrhea, dysmenorrhea, menorrhagia).

            • St John's Wort

              St John's Wort will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.

            • rifapentine

              rifapentine will decrease the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration unless benefit outweighs risk. When coadministered, hormonal contraceptives are not a reliable method of effective birth control. Concomitant use may increase incidence of menstruation associated adverse effects (amenorrhea, dysmenorrhea, menorrhagia).

            • topiramate

              topiramate will decrease the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration unless benefit outweighs risk. When coadministered, hormonal contraceptives are not a reliable method of effective birth control. Concomitant use may increase incidence of menstruation associated adverse effects (amenorrhea, dysmenorrhea, menorrhagia).

            • tucatinib

              tucatinib will increase the level or effect of norethindrone acetate 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.

              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.

            • voxelotor

              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.

              voxelotor will increase the level or effect of norethindrone acetate 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.

            Monitor Closely (187)

            • albiglutide

              norethindrone acetate decreases effects of albiglutide by pharmacodynamic antagonism. Use Caution/Monitor. Oral contraceptives may decrease hypoglycemic effects of antidiabetics by impairing glucose tolerance. Monitor for glycemic control in diabetic patients.

              estradiol decreases effects of albiglutide by pharmacodynamic antagonism. Use Caution/Monitor. Estradiol may decrease hypoglycemic effects of antidiabetics by impairing glucose tolerance. Monitor for glycemic control in diabetic patients.

            • amikacin

              amikacin 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.

            • atazanavir

              atazanavir, norethindrone acetate. Either decreases effects of the other by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Use alternatives if available.

            • amiodarone

              amiodarone will increase the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • amobarbital

              amobarbital will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • amoxicillin

              amoxicillin 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.

            • apalutamide

              apalutamide will decrease the level or effect of estradiol by increasing elimination. Use Caution/Monitor. Apalutamide induces UGT and may decrease systemic exposure of drugs that are UGT substrates.

            • aprepitant

              aprepitant will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • armodafinil

              armodafinil will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • artemether/lumefantrine

              artemether/lumefantrine will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • atazanavir

              atazanavir, estradiol. affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Atazanavir may increase or decrease levels of estradiol. Use alternatives if available.

            • atorvastatin

              atorvastatin will increase the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • azithromycin

              azithromycin will decrease the level or effect of estradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Modify Therapy/Monitor Closely.

            • aztreonam

              aztreonam 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.

            • belzutifan

              belzutifan will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. If unable to avoid coadministration of belzutifan with sensitive CYP3A4 substrates, consider increasing the sensitive CYP3A4 substrate dose in accordance with its prescribing information.

            • bosentan

              bosentan will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • bosutinib

              bosutinib increases levels of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • budesonide

              budesonide will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • butabarbital

              butabarbital will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • butalbital

              butalbital will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • cannabidiol

              cannabidiol, estradiol. affecting hepatic enzyme CYP1A2 metabolism. Modify Therapy/Monitor Closely. Owing to the potential for both CYP1A2 induction and inhibition with the coadministration of CYP1A2 substrates and cannabidiol, consider reducing dosage adjustment of CYP1A2 substrates as clinically appropriate.

            • cefaclor

              cefaclor 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.

            • cefadroxil

              cefadroxil 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.

            • cefamandole

              cefamandole 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.

            • cefazolin

              cefazolin 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.

            • cefepime

              cefepime 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.

            • cefixime

              cefixime 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.

            • cefpirome

              cefpirome 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.

            • cefprozil

              cefprozil 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.

            • ceftazidime

              ceftazidime 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.

            • ceftibuten

              ceftibuten 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.

            • cenobamate

              cenobamate will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Increase dose of CYP3A4 substrate, as needed, when coadministered with cenobamate.

              cenobamate will decrease the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Increase dose of CYP3A4 substrate, as needed, when coadministered with cenobamate.

            • cephalexin

              cephalexin 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.

            • clobazam

              clobazam will decrease the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Clobazam is a weak CYP3A4 inducer; effectiveness of hormonal contraceptives may be diminished when given concurrently with clobazam. Additional non-hormonal forms of contraception are recommended.

            • chloramphenicol

              chloramphenicol increases levels of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. May increase side effects.

            • chlorhexidine oral

              chlorhexidine oral 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.

            • ciprofloxacin

              ciprofloxacin 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.

            • clarithromycin

              clarithromycin will decrease the level or effect of estradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Modify Therapy/Monitor Closely.

              clarithromycin will increase the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • clindamycin

              clindamycin 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.

            • clotrimazole

              clotrimazole will decrease the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • conivaptan

              conivaptan will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • cortisone

              cortisone will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • crofelemer

              crofelemer increases levels of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Crofelemer has the potential to inhibit CYP3A4 at concentrations expected in the gut; unlikely to inhibit systemically because minimally absorbed.

            • cyclosporine

              cyclosporine will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              cyclosporine will increase the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • dabrafenib

              dabrafenib will decrease the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely.

              dabrafenib will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely.

            • dapsone

              dapsone 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.

            • elagolix

              elagolix decreases levels of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Elagolix is a weak-to-moderate CYP3A4 inducer. Monitor CYP3A substrates if coadministered. Consider increasing CYP3A substrate dose if needed.

            • darifenacin

              darifenacin will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • darunavir

              darunavir will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • dasatinib

              dasatinib will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • deferasirox

              deferasirox will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • demeclocycline

              demeclocycline 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.

            • dexamethasone

              dexamethasone will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • DHEA, herbal

              DHEA, herbal will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • diltiazem

              diltiazem will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • doxycycline

              doxycycline 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.

            • dronedarone

              dronedarone will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              dronedarone will increase the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • efavirenz

              efavirenz will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • elagolix

              elagolix will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Elagolix is a weak-to-moderate CYP3A4 inducer. Monitor CYP3A substrates if coadministered. Consider increasing CYP3A substrate dose if needed.

            • eliglustat

              eliglustat increases levels of estradiol by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. Monitor therapeutic drug concentrations, as indicated, or consider reducing the dosage of the P-gp substrate and titrate to clinical effect.

            • encorafenib

              encorafenib, estradiol. affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Encorafenib both inhibits and induces CYP3A4 at clinically relevant plasma concentrations. Coadministration of encorafenib with sensitive CYP3A4 substrates may result in increased toxicity or decreased efficacy of these agents.

            • ertapenem

              ertapenem 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.

            • erythromycin base

              erythromycin base will decrease the level or effect of estradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Modify Therapy/Monitor Closely.

              erythromycin base will increase the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • erythromycin ethylsuccinate

              erythromycin ethylsuccinate will decrease the level or effect of estradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Modify Therapy/Monitor Closely.

              erythromycin ethylsuccinate will increase the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • erythromycin lactobionate

              erythromycin lactobionate will decrease the level or effect of estradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Modify Therapy/Monitor Closely.

              erythromycin lactobionate will increase the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • erythromycin stearate

              erythromycin stearate will decrease the level or effect of estradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Modify Therapy/Monitor Closely.

              erythromycin stearate will increase the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • eslicarbazepine acetate

              eslicarbazepine acetate will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • etravirine

              etravirine will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • exemestane

              estradiol decreases effects of exemestane by pharmacodynamic antagonism. Use Caution/Monitor. Estrogens or estrogen-containing products, including combined oral contraceptives, should not be given concomitantly with exemestane; these drugs could interfere with the pharmacologic action and efficacy of exemestane.

            • exenatide injectable solution

              norethindrone acetate, exenatide injectable solution. Other (see comment). Use Caution/Monitor. Comment: Oral contraceptives may decrease hypoglycemic effects of antidiabetics by impairing glucose tolerance. The effect of exenatide to slow gastric emptying may reduce the extent and rate of oral medications that require rapid GI absorption. Advise patients to take oral contraceptives at least 1 hr before exenatide. .

              estradiol, exenatide injectable solution. Other (see comment). Use Caution/Monitor. Comment: Oral contraceptives may decrease hypoglycemic effects of antidiabetics by impairing glucose tolerance. The effect of exenatide to slow gastric emptying may reduce the extent and rate of oral medications that require rapid GI absorption. Advise patients to take oral contraceptives at least 1 hr before exenatide. .

            • exenatide injectable suspension

              estradiol, exenatide injectable suspension. Other (see comment). Use Caution/Monitor. Comment: Oral contraceptives may decrease hypoglycemic effects of antidiabetics by impairing glucose tolerance. The effect of exenatide to slow gastric emptying may reduce the extent and rate of oral medications that require rapid GI absorption. Advise patients to take oral contraceptives at least 1 hr before exenatide.

              norethindrone acetate, exenatide injectable suspension. Other (see comment). Use Caution/Monitor. Comment: Oral contraceptives may decrease hypoglycemic effects of antidiabetics by impairing glucose tolerance. The effect of exenatide to slow gastric emptying may reduce the extent and rate of oral medications that require rapid GI absorption. Advise patients to take oral contraceptives at least 1 hr before exenatide.

            • fedratinib

              fedratinib will increase the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Adjust dose of drugs that are CYP3A4 substrates as necessary.

              fedratinib will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Adjust dose of drugs that are CYP3A4 substrates as necessary.

            • felodipine

              felodipine will increase the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • iloperidone

              iloperidone increases levels of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Iloperidone is a time-dependent CYP3A inhibitor and may lead to increased plasma levels of drugs predominantly eliminated by CYP3A4.

            • fexinidazole

              fexinidazole will increase the level or effect of estradiol by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

            • fleroxacin

              fleroxacin 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.

            • fluconazole

              fluconazole will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • fludrocortisone

              fludrocortisone will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • fosamprenavir

              fosamprenavir will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • fosfomycin

              fosfomycin 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.

            • fosphenytoin

              fosphenytoin will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              fosphenytoin will decrease the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • fostamatinib

              fostamatinib will increase the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Concomitant use of fostamatinib may increase concentrations of P-gp substrates. Monitor for toxicities of the P-gp substrate drug that may require dosage reduction when given concurrently with fostamatinib.

            • gemifloxacin

              gemifloxacin 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.

            • gentamicin

              gentamicin 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.

            • glecaprevir/pibrentasvir

              glecaprevir/pibrentasvir will increase the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • grapefruit

              grapefruit will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • griseofulvin

              griseofulvin will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • hemin

              estradiol decreases effects of hemin by pharmacodynamic antagonism. Use Caution/Monitor. Drugs that increase delta-aminolevulinic acid synthetase may decrease hemin effect.

            • hyaluronidase

              estradiol decreases effects of hyaluronidase by Other (see comment). Use Caution/Monitor. Comment: Estrogens, when given in large systemic doses, may render tissues partially resistant to the action of hyaluronidase. Patients may require larger amounts of hyaluronidase for equivalent dispersing effect.

            • hydrocortisone

              hydrocortisone will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • iloperidone

              iloperidone increases levels of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Iloperidone is a time-dependent CYP3A inhibitor and may lead to increased plasma levels of drugs predominantly eliminated by CYP3A4.

            • indinavir

              indinavir will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              indinavir will increase the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • insulin degludec

              estradiol decreases effects of insulin degludec by pharmacodynamic antagonism. Use Caution/Monitor. Estrogens may impair glucose tolerance.

              norethindrone acetate decreases effects of insulin degludec by pharmacodynamic antagonism. Use Caution/Monitor. Progestins may impair glucose tolerance.

            • insulin degludec/insulin aspart

              norethindrone acetate decreases effects of insulin degludec/insulin aspart by pharmacodynamic antagonism. Use Caution/Monitor. Progestins may impair glucose tolerance.

              estradiol decreases effects of insulin degludec/insulin aspart by pharmacodynamic antagonism. Use Caution/Monitor. Estrogens may impair glucose tolerance.

            • insulin inhaled

              estradiol decreases effects of insulin inhaled by pharmacodynamic antagonism. Use Caution/Monitor. Estrogens may impair glucose tolerance.

              norethindrone acetate decreases effects of insulin inhaled by pharmacodynamic antagonism. Use Caution/Monitor. Progestins may impair glucose tolerance.

            • istradefylline

              istradefylline will increase the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Istradefylline 40 mg/day increased peak levels and AUC of CYP3A4 substrates in clinical trials. This effect was not observed with istradefylline 20 mg/day. Consider dose reduction of sensitive CYP3A4 substrates.

              istradefylline will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Istradefylline 40 mg/day increased peak levels and AUC of CYP3A4 substrates in clinical trials. This effect was not observed with istradefylline 20 mg/day. Consider dose reduction of sensitive CYP3A4 substrates.

            • itraconazole

              itraconazole will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              itraconazole will increase the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • liraglutide

              norethindrone acetate decreases effects of liraglutide by pharmacodynamic antagonism. Use Caution/Monitor. Oral contraceptives may decrease hypoglycemic effects of antidiabetics by impairing glucose tolerance. Monitor for glycemic control in diabetic patients.

            • ivacaftor

              ivacaftor increases levels of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. Ivacaftor and its M1 metabolite has the potential to inhibit P-gp; may significantly increase systemic exposure to sensitive P-gp substrates with a narrow therapeutic index.

            • ketoconazole

              ketoconazole will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              ketoconazole will increase the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • lamotrigine

              estradiol decreases levels of lamotrigine by increasing hepatic clearance. Use Caution/Monitor.

            • lapatinib

              lapatinib will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              lapatinib will increase the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • letermovir

              letermovir increases levels of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • levofloxacin

              levofloxacin 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.

            • levoketoconazole

              levoketoconazole will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              levoketoconazole will increase the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • linezolid

              linezolid 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.

            • liraglutide

              estradiol decreases effects of liraglutide by pharmacodynamic antagonism. Use Caution/Monitor. Estradiol may decrease hypoglycemic effects of antidiabetics by impairing glucose tolerance. Monitor for glycemic control in diabetic patients.

            • lomitapide

              lomitapide increases levels of estradiol by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. Consider reducing dose when used concomitantly with lomitapide.

            • lopinavir

              lopinavir will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • loratadine

              loratadine will increase the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • lovastatin

              lovastatin will increase the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • lumefantrine

              lumefantrine will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • maraviroc

              norethindrone acetate increases levels of maraviroc by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Potential for increased toxicity.

            • marijuana

              marijuana will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • meropenem

              meropenem 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.

            • meropenem/vaborbactam

              meropenem/vaborbactam 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.

            • metformin

              estradiol decreases effects of metformin by pharmacodynamic antagonism. Use Caution/Monitor.

            • methylprednisolone

              methylprednisolone will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • metronidazole

              metronidazole 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.

              metronidazole will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • miconazole vaginal

              miconazole vaginal will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • mifepristone

              mifepristone will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              mifepristone decreases effects of norethindrone acetate by pharmacodynamic antagonism. Use Caution/Monitor. Backup contraceptive method recommended.

            • minocycline

              minocycline 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.

            • rucaparib

              rucaparib will increase the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Adjust dosage of CYP3A4 substrates, if clinically indicated.

            • mitotane

              mitotane decreases levels of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Mitotane is a strong inducer of cytochrome P-4503A4; monitor when coadministered with CYP3A4 substrates for possible dosage adjustments.

            • moxifloxacin

              moxifloxacin 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.

            • nafcillin

              nafcillin 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.

              nafcillin will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • nefazodone

              nefazodone will increase the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • nelfinavir

              nelfinavir will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • neomycin PO

              neomycin PO 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.

            • nevirapine

              nevirapine will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • nicardipine

              nicardipine will increase the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • nifedipine

              nifedipine will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              nifedipine will decrease the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • nilotinib

              nilotinib will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              nilotinib will increase the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • nitrofurantoin

              nitrofurantoin 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.

            • ofloxacin

              ofloxacin 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.

            • oxcarbazepine

              oxcarbazepine will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • oxytetracycline

              oxytetracycline 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.

            • paromomycin

              paromomycin 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.

            • pentobarbital

              pentobarbital will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • phenobarbital

              phenobarbital will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              phenobarbital will decrease the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • phenytoin

              phenytoin will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              phenytoin will decrease the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • pivmecillinam

              pivmecillinam 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.

            • ponatinib

              ponatinib increases levels of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • posaconazole

              posaconazole will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • prednisone

              prednisone will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • primidone

              primidone will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • quercetin

              quercetin will decrease the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • quinupristin/dalfopristin

              quinupristin/dalfopristin 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.

              quinupristin/dalfopristin will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • ranolazine

              ranolazine will increase the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • ribociclib

              ribociclib will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • rifampin

              rifampin will decrease the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • rifapentine

              rifapentine will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • ritonavir

              ritonavir will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

              ritonavir will increase the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • roxithromycin

              roxithromycin will decrease the level or effect of estradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Modify Therapy/Monitor Closely.

            • rufinamide

              rufinamide decreases effects of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Rufinamide is a weak inducer of the CYP 3A4 enzyme and can decrease exposure of drugs that are substrates of CYP3A4. .

              rufinamide will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • secobarbital

              secobarbital will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • siltuximab

              siltuximab, norethindrone acetate. Other (see comment). Use Caution/Monitor. Comment: CYP450 activity in the liver is down regulated by infection and inflammation stimuli including cytokines (eg, IL-6); inhibition of IL-6 by siltuximab may restore CYP450 enzymatic activity; caution if coadministered with CYP substrates that have a narrow therapeutic index.

            • simvastatin

              simvastatin will increase the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • sirolimus

              sirolimus will increase the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • somapacitan

              estradiol 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 Wort

              St John's Wort will decrease the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • stiripentol

              stiripentol, estradiol. affecting hepatic enzyme CYP1A2 metabolism. Modify Therapy/Monitor Closely. Stiripentol is a CYP1A2 inhibitor and inducer. Monitor CYP1A2 substrates coadministered with stiripentol for increased or decreased effects. CYP1A2 substrates may require dosage adjustment.

              stiripentol, norethindrone acetate. affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Stiripentol is a CYP3A4 inhibitor and inducer. Monitor CYP3A4 substrates coadministered with stiripentol for increased or decreased effects. CYP3A4 substrates may require dosage adjustment.

            • streptomycin

              streptomycin 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.

            • tazemetostat

              tazemetostat will decrease the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • sulfadiazine

              sulfadiazine 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.

            • sulfamethoxazole

              sulfamethoxazole 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.

            • sulfisoxazole

              sulfisoxazole 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.

            • tacrolimus

              tacrolimus will increase the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • tazemetostat

              tazemetostat will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • tecovirimat

              tecovirimat will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Tecovirimat is a weak CYP3A4 inducer. Monitor sensitive CYP3A4 substrates for effectiveness if coadministered.

              tecovirimat will decrease the level or effect of norethindrone acetate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Tecovirimat is a weak CYP3A4 inducer. Monitor sensitive CYP3A4 substrates for effectiveness if coadministered.

            • teicoplanin

              teicoplanin 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.

            • temocillin

              temocillin 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.

            • teriflunomide

              teriflunomide decreases levels of estradiol by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.

            • tetracycline

              tetracycline 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.

            • ticarcillin

              ticarcillin 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.

            • tigecycline

              tigecycline 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.

            • tobramycin

              tobramycin 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.

            • tolvaptan

              tolvaptan will increase the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • topiramate

              topiramate will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • trazodone

              trazodone will decrease the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.

            • trimethoprim

              trimethoprim 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.

            • valproic acid

              estradiol will decrease the level or effect of valproic acid by increasing elimination. Modify Therapy/Monitor Closely. May lead to increased seizure frequency

            • vancomycin

              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.

            • verapamil

              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.

            • voriconazole

              voriconazole will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • warfarin

              estradiol increases effects of warfarin by unspecified interaction mechanism. Use Caution/Monitor.

            • zafirlukast

              zafirlukast will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            Minor (32)

            • amitriptyline

              estradiol, amitriptyline. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Estrogens and progestins may decr tricyclic antidepressant effects, while increasing TCA plasma concentration and adverse effects.

            • amoxapine

              estradiol, amoxapine. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Estrogens and progestins may decr tricyclic antidepressant effects, while increasing TCA plasma concentration and adverse effects.

            • androstenedione

              androstenedione increases effects of estradiol by pharmacodynamic synergism. Minor/Significance Unknown.

            • boron

              boron increases levels of estradiol by altering metabolism. Minor/Significance Unknown.

            • clomipramine

              estradiol, clomipramine. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Estrogens and progestins may decr tricyclic antidepressant effects, while increasing TCA plasma concentration and adverse effects.

            • cyanocobalamin

              estradiol decreases levels of cyanocobalamin by altering metabolism. Minor/Significance Unknown.

            • desipramine

              estradiol, desipramine. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Estrogens and progestins may decr tricyclic antidepressant effects, while increasing TCA plasma concentration and adverse effects.

            • dosulepin

              estradiol, dosulepin. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Estrogens and progestins may decr tricyclic antidepressant effects, while increasing TCA plasma concentration and adverse effects.

            • doxepin

              estradiol, doxepin. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Estrogens and progestins may decr tricyclic antidepressant effects, while increasing TCA plasma concentration and adverse effects.

            • folic acid

              estradiol decreases levels of folic acid by altering metabolism. Minor/Significance Unknown.

            • imipramine

              estradiol, imipramine. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Estrogens and progestins may decr tricyclic antidepressant effects, while increasing TCA plasma concentration and adverse effects.

            • isoniazid

              isoniazid will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • L-methylfolate

              estradiol decreases levels of L-methylfolate by altering metabolism. Minor/Significance Unknown.

            • lofepramine

              estradiol, lofepramine. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Estrogens and progestins may decr tricyclic antidepressant effects, while increasing TCA plasma concentration and adverse effects.

            • magnesium chloride

              estradiol decreases levels of magnesium chloride by Other (see comment). Minor/Significance Unknown. Comment: Magnesium shifted from blood to tissue storage.

            • magnesium citrate

              estradiol decreases levels of magnesium citrate by Other (see comment). Minor/Significance Unknown. Comment: Magnesium shifted from blood to tissue storage.

            • magnesium hydroxide

              estradiol decreases levels of magnesium hydroxide by Other (see comment). Minor/Significance Unknown. Comment: Magnesium shifted from blood to tissue storage.

            • magnesium oxide

              estradiol decreases levels of magnesium oxide by Other (see comment). Minor/Significance Unknown. Comment: Magnesium shifted from blood to tissue storage.

            • magnesium sulfate

              estradiol decreases levels of magnesium sulfate by Other (see comment). Minor/Significance Unknown. Comment: Magnesium shifted from blood to tissue storage.

            • maprotiline

              estradiol, maprotiline. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Estrogens and progestins may decr tricyclic antidepressant effects, while increasing TCA plasma concentration and adverse effects.

            • metyrapone

              estradiol decreases effects of metyrapone by unspecified interaction mechanism. Minor/Significance Unknown.

            • mycophenolate

              mycophenolate decreases effects of estradiol by unknown mechanism. Minor/Significance Unknown. Clinical significance unclear.

            • nortriptyline

              estradiol, nortriptyline. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Estrogens and progestins may decr tricyclic antidepressant effects, while increasing TCA plasma concentration and adverse effects.

            • phytoestrogens

              phytoestrogens decreases effects of estradiol by pharmacodynamic antagonism. Minor/Significance Unknown.

            • pleurisy root

              pleurisy root decreases effects of estradiol by unspecified interaction mechanism. Minor/Significance Unknown. Theoretical interaction.

            • protriptyline

              estradiol, protriptyline. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Estrogens and progestins may decr tricyclic antidepressant effects, while increasing TCA plasma concentration and adverse effects.

            • pyridoxine

              estradiol decreases levels of pyridoxine by altering metabolism. Minor/Significance Unknown.

            • pyridoxine (Antidote)

              estradiol decreases levels of pyridoxine (Antidote) by altering metabolism. Minor/Significance Unknown.

            • ropinirole

              estradiol increases levels of ropinirole by unspecified interaction mechanism. Minor/Significance Unknown.

            • rose hips

              estradiol decreases levels of rose hips by increasing elimination. Minor/Significance Unknown.

            • trazodone

              estradiol, trazodone. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Estrogens and progestins may decr tricyclic antidepressant effects, while increasing TCA plasma concentration and adverse effects.

            • trimipramine

              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.

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            Adverse Effects

            >10%

            Amenorrhea

            Breakthrough bleeding

            Change in menstrual flow

            Spotting

            Edema

            Anorexia

            Weakness

            Frequency Not Defined

            Change in weight

            Depression

            Dizziness

            Headache

            Nervousness

            Somnolence

            Breast tenderness

            Galactorrhea

            Abdominal pain

            Nausea/vomiting

            Cholestatic jaundice

            Deep vein thrombosis

            Thrombophlebitis

            Postmarketing reports

            Endometrial hyperplasia

            Endocervical polyp

            Uterine leiomyomata

            Fallopian tube cyst

            Uterine spasms

            Breast cancer

            Hypertension

            Varicose veins

            Jaundice cholestatic

            Cholelithiasis

            Gall bladder disorder

            Transaminases increased

            Skin discoloration

            Lability affected

            Libido disorder

            Migraine

            Vertigo

            Paresthesia

            Angioedema

            Hypersensitivity

            Weight increased

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            Warnings

            Black Box Warnings

            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, and deep vein thrombosis (DVT) in postmenopausal women (aged 50-79 yr) during 5.6 yr of treatment with daily PO conjugated estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg) compared with placebo
            • Estrogens alone: The estrogen alone substudy of the WHI Study reported increased risks of stroke and DVT in postmenopausal women (aged 50-79 yr) during 6.8 yr of treatment w/ 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 yr or older during 4 yr 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 yr or older during 5.2 yr of treatment with conjugated estrogens 0.625 mg alone compared 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
            • 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

            Endometrial cancer

            • Estrogens alone: There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens
            • Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer

            Contraindications

            Hypersensitivity, including anaphylaxis or angioedema to estrogen/progestins Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders

            Pregnancy

            Estrogen-dependent neoplasia

            Current/history of DVT/PE, arterial thromboembolic disease, breast cancer, liver disease/tumors

            Undiagnosed abnormal vaginal bleeding

            Cautions

            Caution in patients with bone mineral density changes, current/history of depression, DM, HTN, hyperlipidemia, hypertriglyceridemia, obesity, endometriosis, family history of breast cancer & DVT/PE, smoking, epilepsy, migraine, renal/cardiac impairment; discontinue estrogen with or without progestogen, if DVT/PE, stroke or MI occur or suspected

            Discontinue if the following develop: jaundice, visual problems, 4-6 wk before major surgery, any symptoms of VTE, massive BP increase, unusually severe migraines or first-time migraines, depression

            The WHI estrogen plus progestin substudy reported increased risk (not statistically significant) of coronary heart disease (CHD) events (defined as nonfatal MI, silent MI, or CHD death) in women receiving daily CE plus MPA compared to women receiving placebo; an increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5; the WHI estrogen-alone substudy reported no overall effect on CHD events in women receiving estrogen-alone compared to placebo

            Increased risk of post-op thromboembolic complications; if feasible, discontinue 4-6 wk before major surgery or the type associated with increased risk of thromboembolism, or during periods of prolonged immobilization

            History of migraine with aura reported with therapy

            In some epidemiologic studies, use of estrogen plus progestin and estrogen-only products, in particular for 5 or more years, has been associated with increased risk of ovarian cancer; however, duration of exposure associated with increased risk is not consistent across all epidemiologic studies and some report no association

            Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases; if hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce serum calcium levels

            Angioedema involving eye/eyelid, face, larynx, pharynx, tongue and extremity (hands, legs, ankles, and fingers) with or without urticaria requiring medical intervention has occurred in postmarketing; women who develop angioedema anytime during course of treatment should not receive it again; exogenous estrogens may exacerbate symptoms of angioedema in women with hereditary angioedema; consider whether benefits of estrogen therapy outweigh risks in such women

            Cases of anaphylactic/ anaphylactoid reactions, which developed anytime during course of treatment and required emergency medical management, reported in postmarketing setting

            In women with preexisting hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis; consider discontinuation of treatment if pancreatitis occurs

            Although transdermally administered estrogen therapy avoids first-pass hepatic metabolism, 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

            Estrogen administration leads to increased thyroid-binding globulin (TBG) levels; women dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of thyroid replacement therapy; these women should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range

            Estrogens plus progestins may cause some degree of fluid retention; women with conditions that might be influenced by this factor, such as cardiac or renal impairment warrant careful observation when estrogens plus progestins are prescribed; discontinue estrogen plus progestogen therapy, with evidence of medically concerning fluid retention; certain conditions may become exacerbated by fluid retention (eg, asthma, migraine, cardiac/renal dysfunction, epilepsy)

            Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur

            For women known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered; malignant transformation of residual endometrial implants reported in women treated post-hysterectomy with estrogen-alone therapy

            Estrogen therapy may cause exacerbation of asthma, diabetes mellitus, epilepsy, migraine or porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions; consider whether benefits of estrogen therapy outweigh risks in such women

            Manage appropriately any risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE), including personal history or family history of VTE, obesity, and systemic lupus erythematosus

            Do not use with conditions that predispose to hyperkalemia

            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; if examination reveals papilledema or retinal vascular lesions, estrogens should be discontinued

            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

            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; the use of estrogen-alone and estrogen plus progestin therapy reported to result in increase in abnormal mammograms requiring further evaluation

            Use caution in individuals with severe hypocalcemia; consider whether benefits of estrogen therapy outweigh risks in such women

            Endometrial Cancer

            • Studies of addition of progestin for 10 or more days of cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone
            • Increased risk of endometrial cancer has been reported with the use of unopposed estrogen therapy in a woman with a uterus; the reported endometrial cancer risk among unopposed estrogen users is about 2- to 12- fold greater than in nonusers, and appears dependent on duration of treatment and on estrogen dose
            • Most studies show no significant increased risk associated with use of estrogens for less than 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 to 15 years after estrogen therapy is discontinued
            • 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
            • 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

            Drug interaction overview

            • In-vitro and in-vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4); therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism
            • Inducers of CYP3A4 such as 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
            • Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may increase plasma concentrations of estrogens and result in adverse reactions
            • Drugs or herbal products that induce or inhibit cytochrome P-450 enzymes, including CYP3A4, may decrease or increase the serum concentrations of norethindrone
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            Pregnancy & Lactation

            Pregnancy

            Not indicated for use in pregnancy; there are no data with use of in pregnant women; however, epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac abnormalities and limb-reduction defects) following exposure to combined hormonal contraceptives (estrogen and progestins) before conception or during early pregnancy

            Lactation

            Estrogens plus progestogens are present in human milk and can reduce milk production in breastfeeding women; this reduction can occur at any time but is less likely to occur once breastfeeding is well established; the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for therapy and any potential adverse effects on the breastfed child from therapy or from underlying maternal condition

            Pregnancy 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.

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            Pharmacology

            Mechanism of Action

            Estradiol: Endogenous estrogen; reduces the release of gonadotropin-releasing hormone from hypothalamus, reduces release of LH and FSH from pituitary gland; increases synthesis of DNA, RNA, and various proteins in target tissues. Estrogen replacement reduces elevated levels of estrogen and progesterone LH and FSH in postmenopausal women.

            Norethindrone acetate: Progestin; inhibits secretion of gonadotropins from pituitary gland; prevents follicular maturation and ovulation, stimulates growth of mamary tissues

            Pharmacokinetics

            Peak Plasma Time: Estradiol: 5-8 hr (PO); norethindrone: 1-2 hr (PO)

            Protein Bound: Estradiol: 98%, norethindrone: 90-97%

            Bioavailability: Estradiol (50%); norethindrone (100%)

            Metabolism

            • Estradiol: liver, undergoes extensive first-pass metabolism
            • Norethindrone: Liver

            Half-Life

            • Estradiol: 12-14 hr (PO), 2-3 hr (patch)
            • Norethindrone: 8-11 hr (PO), 6-8 hr (patch)

            Metabolites

            • Estradiol: estriol, estrone
            • Norethindrone: sulfate, glucuronide (inactive)

            Excretion

            • Estradiol: urine as conjugates, most estrogens are also excreted in the bile and undergo enterohepatic recycling
            • Norethindrone: Urine 33-81%; Feces 35-43%
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            Patient Handout

            A Patient Handout is not currently available for this monograph.
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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.