ethinyl estradiol/levonorgestrel transdermal (Rx)

Brand and Other Names:Twirla

Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

ethinyl estradiol/levonorgestrel

transdermal patch

  • (30mcg/120mcg)/day

Contraception

Indicated for contraception in females of reproductive potential with a BMI <30 kg/m2 for whom a combined hormonal contraceptive is appropriate

28-day (4-week) cycle

  • 1 new transdermal system (TDS) is applied and worn for 7 days for 3 consecutive weeks (Weeks 1, 2, and 3); no TDS is worn during Week 4 when withdrawal bleeding is expected
  • Every new TDS should be applied on the same day of the week
  • On the day after Week 4 ends, a new 28-day cycle is started by applying a new TDS
  • Under no circumstances should there be >7-day TDS-free interval between dosing cycles
  • If there are >7 TDS-free days, women may not be protected from pregnancy and nonhormonal back-up contraception (eg, condoms and spermicide, diaphragm and spermicide) must be used for 7 days
  • See Administration for how to initiate dosing if no contraception is currently used or if switching from another form of contraception

Dosing Considerations

Before prescribing, consider the drug’s reduced effectiveness in women with a BMI ≥25 to <30 kg/m2

Dosage Forms & Strengths

ethinyl estradiol/levonorgestrel

transdermal patch

  • (30mcg/120mcg)/day

Contraception

Indicated for contraception in females of reproductive potential with a BMI <30 kg/m2 for whom a combined hormonal contraceptive is appropriate

28-day (4-week) cycle

  • 1 new transdermal system (TDS) is applied and worn for 7 days for 3 consecutive weeks (Weeks 1, 2, and 3); no TDS is worn during Week 4 when withdrawal bleeding is expected
  • Every new TDS should be applied on the same day of the week
  • On the day after Week 4 ends, a new 28-day cycle is started by applying a new TDS
  • Under no circumstances should there be >7-day TDS-free interval between dosing cycles
  • If there are >7 TDS-free days, females may not be protected from pregnancy and nonhormonal back-up contraception (eg, condoms and spermicide, diaphragm and spermicide) must be used for 7 days
  • See Administration for how to initiate dosing if no contraception is currently used or if switching from another form of contraception

Dosing Considerations

Efficacy is expected to be the same in postmenarcheal females regardless of age

Before prescribing, consider the drug’s reduced effectiveness in women with a BMI ≥25 to <30 kg/m2

Next:

Interactions

Interaction Checker

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            Contraindicated (3)

            • fezolinetant

              ethinylestradiol will increase the level or effect of fezolinetant by affecting hepatic enzyme CYP1A2 metabolism. Contraindicated. Fezolinetant AUC and peak plasma concentration are increased if coadministered with drugs that are weak, moderate, or strong CYP1A2 inhibitors

            • ombitasvir/paritaprevir/ritonavir & dasabuvir (DSC)

              ombitasvir/paritaprevir/ritonavir & dasabuvir (DSC), ethinylestradiol. unspecified interaction mechanism. Contraindicated. Potential for increased ALT; contraceptive failure may occur when coadministered with protease inhibitors (ritonavir).

              ethinylestradiol, ombitasvir/paritaprevir/ritonavir & dasabuvir (DSC). Either increases toxicity of the other by unspecified interaction mechanism. Contraindicated. ALT elevations >5 x ULN (including some >20 x ULN) observed in clinical trials when ethinyl estradiol was coadministered with ombitasvir/paritaprevir/ritonavir, with or without dasabuvir. Discontinue ethinyl estradiol-containing medications before initiating ombitasvir/paritaprevir/ritonavir, and/or dasabuvir. Restart ethinyl estradiol containing medication ~2 weeks after hepatitis C combination drug regimen completed.

            • tranexamic acid oral

              tranexamic acid oral, ethinylestradiol. Either increases toxicity of the other by pharmacodynamic synergism. Contraindicated. Coadministration of tranexamic acid oral and combination hormonal contraceptives increases thrombotic risk.

            Serious - Use Alternative (64)

            • amobarbital

              amobarbital will decrease the level or effect of ethinylestradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. The efficacy of hormonal contraceptives may be reduced. Use of a nonhormonal contraceptive is recommended.

            • anastrozole

              ethinylestradiol decreases effects of anastrozole by pharmacodynamic antagonism. Avoid or Use Alternate Drug. Anastrozole should not be given concurrently with any estrogens or estrogen-containing products.

            • apalutamide

              apalutamide will decrease the level or effect of ethinylestradiol 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.

            • armodafinil

              armodafinil will decrease the level or effect of ethinylestradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. The efficacy of hormonal contraceptives may be reduced. Use of a nonhormonal contraceptive is recommended.

            • atazanavir

              atazanavir, ethinylestradiol. Other (see comment). Avoid or Use Alternate Drug. Comment: Significant changes (increase or decrease) can occur in estrogen plasma levels. Efficacy of hormonal contraceptives may be reduced. Use of a nonhormonal contraceptive is recommended. .

            • belzutifan

              belzutifan will decrease the level or effect of ethinylestradiol 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.

            • bosentan

              bosentan will decrease the level or effect of ethinylestradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. The efficacy of hormonal contraceptives may be reduced. Use of a nonhormonal contraceptive is recommended.

            • brigatinib

              brigatinib will decrease the level or effect of ethinylestradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Brigatinib induces CYP3A4 in vitro. Coadministration of hormonal contraceptives with brigatinib can result in decreased concentrations and loss of efficacy. Brigatinib can cause fetal harm. Women should use an effective nonhormonal method of contraception during treatment and for at least 4 months after the last brigatinib dose.

            • butabarbital

              butabarbital will decrease the level or effect of ethinylestradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. The efficacy of hormonal contraceptives may be reduced. Use of a nonhormonal contraceptive is recommended.

            • calaspargase pegol

              calaspargase pegol, ethinylestradiol. unknown mechanism. Avoid or Use Alternate Drug. Due to the potential for an indirect interaction between calaspargase pegol and oral contraceptives, concomitant use of these drugs is not recommended. Use another non-oral contraceptive method for females of childbearing potential.

            • carbamazepine

              ethinylestradiol will increase the level or effect of carbamazepine by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. The efficacy of hormonal contraceptives may be reduced. Use of a nonhormonal contraceptive is recommended.

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

            • conivaptan

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

            • dexamethasone

              dexamethasone will decrease the level or effect of ethinylestradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. The efficacy of hormonal contraceptives may be reduced. Use of a nonhormonal contraceptive is recommended.

            • efavirenz

              efavirenz will decrease the level or effect of ethinylestradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. The efficacy of hormonal contraceptives may be reduced. Use of a nonhormonal contraceptive is recommended.

            • elagolix

              levonorgestrel transdermal decreases effects of elagolix by pharmacodynamic antagonism. Avoid or Use Alternate Drug. Based on the mechanism of action of elagolix, estrogen-containing contraceptives are expected to reduce elagolix efficacy. Effects of progestin-only contraceptives on the efficacy of elagolix is unknown. Advise women to use nonhormonal contraceptives during treatment with elagolix and for 1 week after discontinuing elagolix.

              ethinylestradiol decreases effects of elagolix by pharmacodynamic antagonism. Avoid or Use Alternate Drug. Based on the mechanism of action of elagolix, estrogen-containing contraceptives are expected to reduce elagolix efficacy. Effects of progestin-only contraceptives on the efficacy of elagolix is unknown. Advise women to use nonhormonal contraceptives during treatment with elagolix and for 1 week after discontinuing elagolix.

            • elvitegravir

              elvitegravir will decrease the level or effect of ethinylestradiol by unknown mechanism. Avoid or Use Alternate Drug. Consider alternative nonhormonal methods of contraception to add or replace combination oral contraceptive

            • encorafenib

              encorafenib will decrease the level or effect of levonorgestrel transdermal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration of encorafenib with hormonal contraceptives (CYP3A4 substrates) can result in decreased concentrations and loss of hormonal contraceptive efficacy. Since encorafenib can cause fetal harm, advise women of childbearing potential to use a highly effective nonhormonal contraceptive during treatment and for 2 weeks after final encorafenib dose.

            • encorafenib

              encorafenib will decrease the level or effect of ethinylestradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration of encorafenib with hormonal contraceptives (CYP3A4 substrates) can result in decreased concentrations and loss of hormonal contraceptive efficacy. Since encorafenib can cause fetal harm, advise women of childbearing potential to use a highly effective nonhormonal contraceptive during treatment and for 2 weeks after final encorafenib dose.

            • enoxaparin

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

            • enzalutamide

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

            • eslicarbazepine acetate

              eslicarbazepine acetate will decrease the level or effect of ethinylestradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Use additional or alternative nonhormonal birth control.

            • exemestane

              ethinylestradiol decreases effects of exemestane by pharmacodynamic antagonism. Avoid or Use Alternate Drug. Exemestane should not be given concurrently with any estrogens or estrogen-containing products.

            • fedratinib

              ethinylestradiol will increase the level or effect of fedratinib by Other (see comment). Avoid or Use Alternate Drug. Avoid coadministration of fedratinib (a CYP3A4 and CYP2C19 substrate) with dual CYP3A4 and CYP2C19 inhibitor. Effect of coadministration of a dual CYP3A4 and CYP2C19 inhibitor with fedratinib has not been studied.

            • fexinidazole

              fexinidazole will increase the level or effect of ethinylestradiol by affecting hepatic enzyme CYP2E1 metabolism. Avoid or Use Alternate Drug. Fexinidazole inhibits CYP3A4. Coadministration may increase risk for adverse effects of CYP3A4 substrates.

            • fosamprenavir

              fosamprenavir, ethinylestradiol. unspecified interaction mechanism. Avoid or Use Alternate Drug. Coadministration may decrease amprenavir AUC, and may lead to loss of virologic response. Coadministration of fosamprenavir with ethinyl estradiol may alter hormone levels. Alternative methods of nonhormonal contraception are recommended.

            • griseofulvin

              griseofulvin will decrease the level or effect of ethinylestradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. The efficacy of hormonal contraceptives may be reduced. Use of a nonhormonal contraceptive is recommended.

            • heparin

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

            • idelalisib

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

            • indinavir

              indinavir, ethinylestradiol. Other (see comment). Avoid or Use Alternate Drug. Comment: Significant changes (increase or decrease) can occur in estrogen plasma levels. Efficacy of hormonal contraceptives may be reduced. Use of a nonhormonal contraceptive is recommended. .

            • isavuconazonium sulfate

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

            • ivosidenib

              ivosidenib will decrease the level or effect of ethinylestradiol 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.

            • leniolisib

              leniolisib will increase the level or effect of ethinylestradiol by Other (see comment). Avoid or Use Alternate Drug. Leniolisib, a BCRP inhibitor, may increase systemic exposure of BCRP substrates

            • lesinurad

              lesinurad decreases effects of ethinylestradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Use additional methods of nonhormonal contraception. Do not rely on hormonal contraception alone when taking lesinurad.

            • letrozole

              ethinylestradiol decreases effects of letrozole by pharmacodynamic antagonism. Avoid or Use Alternate Drug. Letrozole should not be given concurrently with any estrogens or estrogen-containing products.

            • lonafarnib

              ethinylestradiol will increase the level or effect of lonafarnib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. If coadministration of lonafarnib (a sensitive CYP3A substrate) with weak CYP3A inhibitors is unavoidable, reduce to, or continue lonafarnib at starting dose. Closely monitor for arrhythmias and events (eg, syncope, heart palpitations) since lonafarnib effect on QT interval is unknown.

            • lopinavir

              lopinavir, ethinylestradiol. Other (see comment). Avoid or Use Alternate Drug. Comment: Significant changes (increase or decrease) can occur in estrogen plasma levels. Efficacy of hormonal contraceptives may be reduced. Use of a nonhormonal contraceptive is recommended. .

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

            • lumacaftor/ivacaftor

              lumacaftor/ivacaftor will decrease the level or effect of ethinylestradiol by unspecified interaction mechanism. 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).

            • mavacamten

              mavacamten will decrease the level or effect of ethinylestradiol 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.

            • metyrapone

              ethinylestradiol decreases effects of metyrapone by unspecified interaction mechanism. Avoid or Use Alternate Drug. A subtherapeutic response to metyrapone can be seen in patients on estrogens, including oral contraceptives, that contain estrogen therapy. It may be advisable to discontinue estrogens prior to and during metyrapone administration.

            • mifepristone

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

            • mobocertinib

              mobocertinib will decrease the level or effect of ethinylestradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration of mobocertinib with hormonal contraceptives may lead to contraceptive failure or increased breakthrough bleeding. Advise females of reproductive potential to use effective non-hormonal contraception.

            • mycophenolate

              mycophenolate decreases effects of ethinylestradiol by unknown mechanism. Avoid or Use Alternate Drug. Patients should consider using an alternative or additional form of contraception.

            • nelfinavir

              nelfinavir, ethinylestradiol. Other (see comment). Avoid or Use Alternate Drug. Comment: Significant changes (increase or decrease) can occur in estrogen plasma levels. Efficacy of hormonal contraceptives may be reduced. Use of a nonhormonal contraceptive is recommended. .

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

            • nevirapine

              nevirapine will decrease the level or effect of ethinylestradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. The efficacy of hormonal contraceptives may be reduced. Use of a nonhormonal contraceptive is recommended.

            • omaveloxolone

              omaveloxolone will decrease the level or effect of levonorgestrel transdermal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Omaveloxolone may reduce efficacy of hormonal contraceptives (eg, pill, patch, ring), implants, and progestin-only pills owing to weak CYP3A4 induction.

              omaveloxolone will decrease the level or effect of ethinylestradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Omaveloxolone may reduce efficacy of hormonal contraceptives (eg, pill, patch, ring), implants, and progestin-only pills owing to weak CYP3A4 induction.

            • oxcarbazepine

              oxcarbazepine will decrease the level or effect of ethinylestradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. The efficacy of hormonal contraceptives may be reduced. Use of a nonhormonal contraceptive is recommended.

            • pentobarbital

              pentobarbital will decrease the level or effect of ethinylestradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. The efficacy of hormonal contraceptives may be reduced. Use of a nonhormonal contraceptive is recommended.

            • phenobarbital

              phenobarbital will decrease the level or effect of ethinylestradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. The efficacy of hormonal contraceptives may be reduced. Use of a nonhormonal contraceptive is recommended.

            • phenytoin

              phenytoin will decrease the level or effect of ethinylestradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. The efficacy of hormonal contraceptives may be reduced. Use of a nonhormonal contraceptive is recommended.

            • primidone

              primidone will decrease the level or effect of ethinylestradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. The efficacy of hormonal contraceptives may be reduced. Use of a nonhormonal contraceptive is recommended.

            • quinidine

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

            • ranolazine

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

            • rifabutin

              rifabutin will decrease the level or effect of ethinylestradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. The efficacy of hormonal contraceptives may be reduced. Use of a nonhormonal contraceptive is recommended.

            • rifampin

              rifampin will decrease the level or effect of ethinylestradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. The efficacy of hormonal contraceptives may be reduced. Use of a nonhormonal contraceptive is recommended.

            • rifapentine

              rifapentine will decrease the level or effect of ethinylestradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. The efficacy of hormonal contraceptives may be reduced. Use of a nonhormonal contraceptive is recommended.

            • ritonavir

              ritonavir, ethinylestradiol. Other (see comment). Avoid or Use Alternate Drug. Comment: Significant changes (increase or decrease) can occur in estrogen plasma levels. Efficacy of hormonal contraceptives may be reduced. Use of a nonhormonal contraceptive is recommended. .

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

            • saquinavir

              saquinavir, ethinylestradiol. Other (see comment). Avoid or Use Alternate Drug. Comment: Significant changes (increase or decrease) can occur in estrogen plasma levels. Efficacy of hormonal contraceptives may be reduced. Use of a nonhormonal contraceptive is recommended. .

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

            • secobarbital

              secobarbital will decrease the level or effect of ethinylestradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. The efficacy of hormonal contraceptives may be reduced. Use of a nonhormonal contraceptive is recommended.

            • St John's Wort

              St John's Wort will decrease the level or effect of ethinylestradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. The efficacy of hormonal contraceptives may be reduced. Use of a nonhormonal contraceptive is recommended.

            • sugammadex sodium

              sugammadex sodium decreases effects of ethinylestradiol by receptor binding competition. Avoid or Use Alternate Drug. In vitro binding studies showed that sugammadex may bind to progestogen, thereby decreasing progestogen exposure. Therefore, a sugammadex bolus dose is considered to be equivalent to missing dose(s) of hormonal contraceptives containing an estrogen or progestogen. If an oral contraceptive is taken on the same day of sugammadex, or the patient has a transdermal or implant hormonal contraceptive, the patient must use an additional, nonhormonal contraceptive method or back-up method of contraception (eg, condoms and spermicides) for the next 7 days.

            • tipranavir

              tipranavir, ethinylestradiol. Other (see comment). Avoid or Use Alternate Drug. Comment: Significant changes (increase or decrease) can occur in estrogen plasma levels. Efficacy of hormonal contraceptives may be reduced. Use of a nonhormonal contraceptive is recommended. .

            • topiramate

              topiramate will decrease the level or effect of ethinylestradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. The efficacy of hormonal contraceptives may be reduced. Use of a nonhormonal contraceptive is recommended.

            • tucatinib

              tucatinib will increase the level or effect of ethinylestradiol 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 ethinylestradiol 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 (86)

            • albiglutide

              ethinylestradiol 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.

            • alosetron

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

            • alprazolam

              ethinylestradiol will increase the level or effect of alprazolam by Mechanism: decreasing metabolism. Use Caution/Monitor. Ethinyl estradiol may inhibit the clearance of benzodiazepines that undergo oxidation, thereby increasing serum concentrations of concomitantly administered benzodiazepines.

            • aminocaproic acid

              ethinylestradiol, aminocaproic acid. Other (see comment). Use Caution/Monitor. Comment: Concomitant use may lead to additive hypercoagulability. Estrogens increase clotting factor production and platelet aggregation; aminocaproic acid inhibits fibrinolysis and activity of plasminogen.

            • amoxicillin

              amoxicillin will decrease the level or effect of ethinylestradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Use Caution/Monitor. Antibiotics may decrease hormonal contraceptive efficacy.

            • ampicillin

              ampicillin will decrease the level or effect of ethinylestradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Use Caution/Monitor.

            • artemether/lumefantrine

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

            • atogepant

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

            • atorvastatin

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

            • axitinib

              ethinylestradiol increases levels of axitinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • bendamustine

              ethinylestradiol increases levels of bendamustine by decreasing metabolism. Use Caution/Monitor. Bendamustine is metabolized to minimally active metabolites by CYP1A2. Ethinyl estradiol is a weak CYP1A2 inhibitor and concurrent administration may increase bendamustine concentrations in plasma. .

            • caffeine

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

            • cefaclor

              cefaclor will decrease the level or effect of ethinylestradiol 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 ethinylestradiol 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 ethinylestradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Use Caution/Monitor.

            • cefdinir

              cefdinir will decrease the level or effect of ethinylestradiol 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 ethinylestradiol 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 ethinylestradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Use Caution/Monitor.

            • cefotaxime

              cefotaxime will decrease the level or effect of ethinylestradiol 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 ethinylestradiol 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 ethinylestradiol 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 ethinylestradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Use Caution/Monitor.

            • cefuroxime

              cefuroxime will decrease the level or effect of ethinylestradiol 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 ethinylestradiol 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 levonorgestrel transdermal 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 levonorgestrel transdermal by unspecified interaction mechanism. Modify Therapy/Monitor Closely. Advise women to use additional or alternative non-hormonal birth control when concomitantly using cenobamate with oral contraceptives.

              cenobamate will decrease the level or effect of ethinylestradiol by unspecified interaction mechanism. Modify Therapy/Monitor Closely. Advise women to use additional or alternative non-hormonal birth control when concomitantly using cenobamate with oral contraceptives.

            • cephalexin

              cephalexin will decrease the level or effect of ethinylestradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Use Caution/Monitor.

            • cyclosporine

              levonorgestrel transdermal, cyclosporine. Either increases levels of the other by decreasing metabolism. Use Caution/Monitor. Combined oral contraceptives containing EE may inhibit the metabolism and increase plasma concentrations of cyclosporine.

            • ceritinib

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

            • chloramphenicol

              chloramphenicol will decrease the level or effect of ethinylestradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Use Caution/Monitor.

            • cimetidine

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

            • ciprofloxacin

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

            • clindamycin

              clindamycin will decrease the level or effect of ethinylestradiol 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 ethinylestradiol 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.

            • clonazepam

              ethinylestradiol will increase the level or effect of clonazepam by Mechanism: decreasing metabolism. Use Caution/Monitor. Ethinyl estradiol may inhibit the clearance of benzodiazepines that undergo oxidation, thereby increasing serum concentrations of concomitantly administered benzodiazepines.

            • cyclosporine

              ethinylestradiol increases levels of cyclosporine by unknown mechanism. Use Caution/Monitor.

            • dabrafenib

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

            • darunavir

              darunavir will decrease the level or effect of ethinylestradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Significant changes (increase or decrease) can occur in estrogen plasma levels. Efficacy of hormonal contraceptives may be reduced. Use of a nonhormonal contraceptive is recommended.

            • dasatinib

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

            • deferasirox

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

            • demeclocycline

              demeclocycline will decrease the level or effect of ethinylestradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Use Caution/Monitor.

            • diazepam

              ethinylestradiol will increase the level or effect of diazepam by Mechanism: decreasing metabolism. Use Caution/Monitor. Ethinyl estradiol may inhibit the clearance of benzodiazepines that undergo oxidation, thereby increasing serum concentrations of concomitantly administered benzodiazepines.

            • dicloxacillin

              dicloxacillin will decrease the level or effect of ethinylestradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Use Caution/Monitor.

            • doxycycline

              doxycycline will decrease the level or effect of ethinylestradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Use Caution/Monitor.

            • elagolix

              elagolix will decrease the level or effect of ethinylestradiol 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.

            • eltrombopag

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

            • elvitegravir/cobicistat/emtricitabine/tenofovir DF

              elvitegravir/cobicistat/emtricitabine/tenofovir DF increases levels of ethinylestradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Cobicistat is a CYP3A4 inhibitor; contraindicated with CYP3A4 substrates for which elevated plasma concentrations are associated with serious and/or life-threatening events.

            • encorafenib

              encorafenib will increase the level or effect of ethinylestradiol by Other (see comment). Modify Therapy/Monitor Closely. Encorafenib (a BCRP inhibitor) may increase the concentration and toxicities of BCRP substrates. Closely monitor for signs and symptoms of increased exposure and consider adjusting the dose of these substrates.

            • erythromycin base

              erythromycin base will decrease the level or effect of ethinylestradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Use Caution/Monitor. Antibiotics may decrease hormonal contraceptive efficacy.

            • erythromycin ethylsuccinate

              erythromycin ethylsuccinate will decrease the level or effect of ethinylestradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Use Caution/Monitor. Antibiotics may decrease hormonal contraceptive efficacy.

            • erythromycin lactobionate

              erythromycin lactobionate will decrease the level or effect of ethinylestradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Use Caution/Monitor. Antibiotics may decrease hormonal contraceptive efficacy.

            • erythromycin stearate

              erythromycin stearate will decrease the level or effect of ethinylestradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Use Caution/Monitor. Antibiotics may decrease hormonal contraceptive efficacy.

            • etravirine

              etravirine will decrease the level or effect of ethinylestradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. The efficacy of hormonal contraceptives may be reduced. Use of a nonhormonal contraceptive is recommended.

            • exenatide injectable solution

              ethinylestradiol, 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

              ethinylestradiol, 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 ethinylestradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Adjust dose of drugs that are CYP3A4 substrates as necessary.

            • finerenone

              ethinylestradiol will increase the level or effect of finerenone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Monitor serum potassium during initiation and dosage adjustment of either finererone or weak CYP3A4 inhibitors. Adjust finererone dosage as needed.

            • flibanserin

              ethinylestradiol will increase the level or effect of flibanserin by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Increased flibanserin adverse effects may occur if coadministered with multiple weak CYP3A4 inhibitors.

            • fluconazole

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

            • fluvoxamine

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

            • fostemsavir

              fostemsavir will increase the level or effect of ethinylestradiol by Other (see comment). Modify Therapy/Monitor Closely. Fostemsavir inhibits BCRP transporters. If possible, avoid coadministration or modify dose of BCRP substrate coadministered with fostemsavir. Do not ethinyl estradiol dose of exceed 30 mcg/day.

            • gemifloxacin

              gemifloxacin will decrease the level or effect of ethinylestradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Use Caution/Monitor.

            • grapefruit

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

            • green tea

              ethinylestradiol increases levels of green tea by decreasing elimination. Use Caution/Monitor.

            • hemin

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

            • hyaluronidase

              ethinylestradiol 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.

            • iloperidone

              iloperidone increases levels of ethinylestradiol 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.

            • insulin aspart

              ethinylestradiol decreases effects of insulin aspart 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.

            • insulin degludec

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

            • insulin degludec/insulin aspart

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

            • insulin detemir

              ethinylestradiol decreases effects of insulin detemir 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.

            • insulin glargine

              ethinylestradiol decreases effects of insulin glargine 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.

            • insulin glulisine

              ethinylestradiol decreases effects of insulin glulisine 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.

            • insulin inhaled

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

            • insulin lispro

              ethinylestradiol decreases effects of insulin lispro 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.

            • insulin NPH

              ethinylestradiol decreases effects of insulin NPH 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.

            • insulin regular human

              ethinylestradiol decreases effects of insulin regular human 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.

            • isavuconazonium sulfate

              ethinylestradiol will increase the level or effect of isavuconazonium sulfate by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • istradefylline

              istradefylline will increase the level or effect of ethinylestradiol 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 ethinylestradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. CYP3A4 inhibitors such as itraconazole may increase plasma hormone levels.

            • ketoconazole

              ketoconazole will increase the level or effect of ethinylestradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. CYP3A4 inhibitors such as ketoconazole may increase plasma hormone levels.

            • lamotrigine

              ethinylestradiol decreases levels of lamotrigine by increasing hepatic clearance. Use Caution/Monitor. Combination oral contraceptives have been shown to significantly decrease plasma concentrations of lamotrigine, likely due to induction of lamotrigine glucuronidation.

            • lapatinib

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

            • lemborexant

              ethinylestradiol will increase the level or effect of lemborexant by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Lower nightly dose of lemborexant recommended if coadministered with weak CYP3A4 inhibitors. See drug monograph for specific dosage modification.

            • lenacapavir

              lenacapavir will increase the level or effect of ethinylestradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Lencapavir (a moderate CYP3A4 inhibitor) may increase CYP3A4 substrates initiated within 9 months after last SC dose of lenacapavir, which may increase potential risk of adverse reactions of CYP3A4 substrates.

              lenacapavir will increase the level or effect of levonorgestrel transdermal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Lencapavir may increase CYP3A4 substrates initiated within 9 months after last SC dose of lenacapavir, which may increase potential risk of adverse reactions of CYP3A4 substrates.

            • levofloxacin

              levofloxacin will decrease the level or effect of ethinylestradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Use Caution/Monitor.

            • warfarin

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

            Minor (31)

            • acetazolamide

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

            • amitriptyline

              ethinylestradiol, 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

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

            • anastrozole

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

            • antipyrine

              ethinylestradiol will increase the level or effect of antipyrine by affecting hepatic enzyme CYP1A2 metabolism. Minor/Significance Unknown.

            • asenapine

              ethinylestradiol will increase the level or effect of asenapine by affecting hepatic enzyme CYP1A2 metabolism. Minor/Significance Unknown.

            • clarithromycin

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

            • clomipramine

              ethinylestradiol will increase the level or effect of clomipramine by affecting hepatic enzyme CYP1A2 metabolism. Minor/Significance Unknown.

            • cyclophosphamide

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

            • desipramine

              ethinylestradiol, desipramine. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Oxidative metabolism of TCAs may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Potential for increased TCA adverse effects.

            • dosulepin

              ethinylestradiol, dosulepin. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Oxidative metabolism of TCAs may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Potential for increased TCA adverse effects.

            • doxepin

              ethinylestradiol, doxepin. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Oxidative metabolism of TCAs may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Potential for increased TCA adverse effects.

            • duloxetine

              ethinylestradiol will increase the level or effect of duloxetine by affecting hepatic enzyme CYP1A2 metabolism. Minor/Significance Unknown.

            • enasidenib

              enasidenib, ethinylestradiol. unknown mechanism. Minor/Significance Unknown. Coadministration of enasidenib may increase or decrease the concentrations of combined hormonal contraceptives. Clinical significance of this interaction is unknown.

            • eplerenone

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

            • felbamate

              felbamate decreases levels of ethinylestradiol by unknown mechanism. Minor/Significance Unknown.

            • frovatriptan

              ethinylestradiol will increase the level or effect of frovatriptan by affecting hepatic enzyme CYP1A2 metabolism. Minor/Significance Unknown.

            • imipramine

              ethinylestradiol, imipramine. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Oxidative metabolism of TCAs may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Potential for increased TCA adverse effects.

            • larotrectinib

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

            • mineral oil

              mineral oil decreases levels of ethinylestradiol by inhibition of GI absorption. Applies only to oral form of both agents. Minor/Significance Unknown.

            • naratriptan

              ethinylestradiol increases effects of naratriptan by unspecified interaction mechanism. Minor/Significance Unknown. The clinical implication of these interactions is unknown.

            • nefazodone

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

            • nortriptyline

              ethinylestradiol, nortriptyline. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Oxidative metabolism of TCAs may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Potential for increased TCA adverse effects.

            • protriptyline

              ethinylestradiol, protriptyline. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Oxidative metabolism of TCAs may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Potential for increased TCA adverse effects.

            • ramelteon

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

            • rosuvastatin

              rosuvastatin increases levels of ethinylestradiol by unspecified interaction mechanism. Minor/Significance Unknown.

            • ruxolitinib

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

            • ruxolitinib topical

              ethinylestradiol will increase the level or effect of ruxolitinib topical by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.

            • tizanidine

              ethinylestradiol increases levels of tizanidine by unspecified interaction mechanism. Minor/Significance Unknown.

            • trazodone

              ethinylestradiol, trazodone. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Oxidative metabolism of TCAs may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Potential for increased TCA adverse effects.

            • trimipramine

              ethinylestradiol, trimipramine. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Oxidative metabolism of TCAs may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Potential for increased TCA adverse effects.

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            Adverse Effects

            1-10%

            Application site disorder (6.2%)

            Nausea (4.1%)

            Headache (3.6%)

            Dysmenorrhea (2.3%)

            Increased weight (2%)

            <1%

            Cholelithiasis

            Cholecystitis

            Major depression

            Suicidal ideation

            Appendicitis

            Ectopic pregnancy

            Pneumonia

            Gastroenteritis

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            Warnings

            Black Box Warnings

            Cigarette smoking and serious cardiovascular events

            • Cigarette smoking increases risk of serious cardiovascular events from combined hormonal comtraceptive (CHC) use
            • This risk increases with age, particularly in women aged ≥35 yr, and with the number of cigarettes smoked
            • For this reason, CHCs are contraindicated in women aged ≥35 yr of age who smoke

            Contraindicated with BMI 30 kg/m2 or greater

            • Contraindicated in women with BMI ≥30 kg/m2
            • Compared with lower BMI, women with a BMI ≥30 kg/m2 had reduced effectiveness and may have a higher risk for venous thromboembolism events (VTEs)

            Contraindications

            Have headaches with focal neurological symptoms, migraine headaches with aura

            Women aged >35 yr with any migraine headache

            BMI ≥30 kg/m2; reduced effectiveness and may have higher risk for VTEs compared with women with lower BMI

            Liver tumors (benign or malignant), acute viral hepatitis, severe (decompensated) cirrhosis, or liver disease

            Undiagnosed abnormal uterine bleeding

            Pregnancy, given there is no reason to use CHCs during pregnancy

            Breast cancer or other estrogen- or progestin-sensitive cancer, now or in the past

            Hypersensitivity to any components; observed reactions include itching and irritation at application site

            Use of hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, owing to potential for elevated ALT

            High risk for arterial or VTEs

            • Examples include women who
              • Smoke, if over aged ≥35 yr
              • Have current or history of DVT or PE
              • Have cerebrovascular disease
              • Have coronary artery disease
              • Have thrombogenic valvular or thrombogenic rhythm heart diseases (eg, SBE with valvular disease, atrial fibrillation)
              • Have inherited or acquired hypercoagulopathies
              • Have uncontrolled hypertension or hypertension with vascular disease
              • Have diabetes mellitus and are aged ≥35 yr, diabetes mellitus with hypertension, or vascular disease or other end-organ damage, or diabetes mellitus of >20 years' duration

            Cautions

            Contraindicated with benign or malignant liver tumors, acute viral hepatitis, or severe cirrhosis; discontinue if jaundice occurs

            Increased ALT observed in women taking ethinyl estradiol-containing medications with certain hepatitis C drug regimens (ie, ombitasvir/paritaprevir/ritonavir, with or without dasabuvir)

            Contraindicated with uncontrolled hypertension or hypertension with vascular disease; if administered to women with well-controlled hypertension, monitor blood pressure; discontinue immediately if blood pressure increases significantly

            Consider age-related risk factors for CV disease (eg, hypertension, diabetes, dyslipidemia, obesity)

            Increase risk of gall bladder disease among CHC users

            Contraindicated in diabetic women aged ≥35 yr, or women who have diabetes with hypertension, nephropathy, retinopathy, or neuropathy, other vascular disease, or women with diabetes >20 yr duration

            Contraindicated in women who have headaches with focal neurological symptoms or have migraine headaches with aura, and women aged ≥35 yr who have migraine headaches with or without aura

            Carefully observe women with history of depression; discontinue if depression recurs to a serious degree

            Some studies suggest that CHCs are associated with increased risk of cervical cancer or intraepithelial neoplasia; controversial whether these findings are caused by CHCs or sexual behavior and other factors

            Estrogen may raise serum concentrations of thyroxine-binding globulin, sex hormone-binding globulin, and cortisol-binding globulin; dose of replacement thyroid hormone or cortisol therapy may need to be increased

            Exogenous estrogens may induce or exacerbate symptoms of angioedema

            Chloasma may occur, especially in women with a history of chloasma gravidarum; avoid sun exposure or ultraviolet radiation

            Thromboembolic disorders and other vascular conditions

            • Women are at increased risk for VTE when using CHCs
            • VTE risk may be greater with BMI ≥30 kg/m2 compared with lower BMI and CHCs are contraindicated in obese patients
            • Additional information
              • Discontinue if an arterial or VTE occurs
              • Discontinue if unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions occurs; evaluate for retinal vein thrombosis immediately
              • Discontinue during prolonged immobilization and resume treatment based on clinical judgement; if feasible, stop at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of thromboembolism
              • Start no earlier than 4 weeks after delivery in women who are not breastfeeding; risk of postpartum thromboembolism decreases after the third postpartum week, whereas the likelihood of ovulation increases after the third postpartum week
              • Before initiating, evaluate any medical history or family history of thromboembolism or thromboembolic disorders; consider whether the history suggests an inherited or acquired hypercoagulopathy
              • Contraindicated in women with high risk of arterial or VTE, including women aged ≥35 yr who smoke

            Bleeding irregularities and amenorrhea

            • Bleeding and spotting
              • Women may experience unscheduled (breakthrough or intracyclic) bleeding and spotting, especially during the first 3 months of use
              • Bleeding irregularities may resolve over time or by changing to a different contraceptive product
              • If bleeding persists or occurs after previously regular cycles, evaluate for causes (eg, pregnancy, malignancy)
            • Amenorrhea and oligomenorrhea
              • Women may experience absence of scheduled (withdrawal) bleeding, even if they are not pregnant
              • If scheduled bleeding does not occur, consider the possibility of pregnancy
              • Evaluate adherence and rule out pregnancy

            Drug interaction overview

            • Drugs that decrease systemic exposure of hormonal contraceptives
              • Enzyme inducers: May decrease plasma concentrations of estrogen and/or progestin component of CHCs
              • Colesevelam: Coadministration significantly decreases systemic exposure of ethinyl estradiol
              • HIV protease inhibitors (eg, nelfinavir, ritonavir, darunavir/ritonavir, fosamprenavir/ritonavir, lopinavir/ritonavir, and tipranavir/ritonavir) and some non-nucleoside reverse transcriptase inhibitors (eg, nevirapine)
            • Drugs that increase systemic exposure of hormonal contraceptives
              • HIV protease inhibitors (eg, indinavir, atazanavir/ritonavir) and with other non-nucleoside reverse transcriptase inhibitors (eg, etravirine)
              • Atorvastatin or rosuvastatin increase systemic exposure of ethinyl estradiol by ~20-25%
              • Ascorbic acid and acetaminophen may increase systemic exposure of ethinyl estradiol, possibly by inhibition of conjugation
              • CYP3A4 inhibitors (eg, itraconazole, voriconazole, fluconazole, grapefruit juice, ketoconazole) may increase systemic exposure of estrogen and/or progestin
            • CHC effect on other drugs
              • Lamotrigine systemic exposure may be significantly decreased owing to induction of lamotrigine glucuronidation; lamotrigine dose adjustment may be required
              • Thyroid hormone: CHCs may increase systemic exposure of thyroid-binding globulin; thyroid hormone dose may need to be increased
              • Corticosteroids: CHCs may increase systemic exposure of cortisol-binding globulin; corticosteroid dose may need to be increased
              • CHCs may decrease systemic exposure of acetaminophen, morphine, salicylic acid, and temazepam
              • CHCs may increase systemic exposure of cyclosporine, prednisolone, theophylline, tizanidine, and voriconazole
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            Pregnancy & Lactation

            Pregnancy

            Contraindicated

            Discontinue if pregnancy occurs

            Epidemiologic studies and meta-analyses have not found an increased risk of genital or nongenital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to CHCs before conception or during early pregnancy

            Lactation

            Contraceptive hormones and/or metabolites are present in human milk

            CHCs can reduce milk production in breastfeeding women, but this is less likely to occur once breastfeeding is well established

            Advise breastfeeding women to use another method of contraception until breastfeeding discontinued

            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

            Combination hormonal contraceptives lower the risk of becoming pregnant primarily by suppressing ovulation

            Ethinyl estradiol: Reduces LHRH release from hypothalamus and reduces gonadotropin release from pituitary; increases synthesis of DNA, RNA, and various proteins in target tissues; other possible mechanisms include changes in cervical mucus that cause inhibition of sperm penetration and endometrial changes that reduce likelihood of implantation

            Levonorgestrel transdermal: Synthetic progestin; ovulation is inhibited from a negative feedback mechanism on hypothalamus, leading to reduced secretion of FSH and LH

            Absorption

            Concentration at steady-state

            • Cycle 1
              • Average steady-state concentration, levonorgestrel: 842 pg/mL (week 1); 2009 pg/mL (week 3)
              • Average steady-state concentration, ethinyl estradiol: 31.9 pg/mL (week 1); 34.8 pg/mL (week 3)
              • AUC levonorgestrel: 120 ng⋅h/mL (week 1); 339 ng⋅h/mL (week 3)
              • AUC ethinyl estradiol: 5040 pg⋅h/mL (week 1); 6210 pg⋅h/mL (week 3)
            • Cycle 2
              • Average steady-state concentration, levonorgestrel: 1389 pg/mL (week 1); 2209 pg/mL (week 3)
              • Average steady-state concentration, ethinyl estradiol: 38.6 pg/mL (week 1); 40.3 pg/mL (week 3)
              • AUC levonorgestrel: 207 ng⋅h/mL (week 1); 378 ng⋅h/mL (week 3)
              • AUC ethinyl estradiol: 6060 pg⋅h/mL (week 1); 7120 pg⋅h/mL (week 3)

            Distribution

            Protein bound

            • Levonorgestrel: Primarily bound to sex hormone-binding globulin (SHBG)
            • Ethinyl estradiol: 97% bound to plasma albumin; does not bind to SHBG, but induces SHBG synthesis

            Metabolism

            Since it is applied transdermally, first-pass metabolism (via GI tract and/or liver) of levonorgestrel and ethinyl estradiol that would be expected with PO administration does not occur

            Levonorgestrel

            • The most important hepatic metabolic pathways are reduction of the delta-4-3-oxo group and hydroxylation at positions 2-alpha, 1-beta, and 16-beta, followed by conjugation
            • Most circulating metabolites are sulfates of 3-alpha, 5-beta-tetrahydro-levonorgestrel, while excretion is mostly in the form of glucuronides

            Ethinyl estradiol

            • CYP3A4 metabolism in the liver is responsible for 2-hydroxylation that is the major oxidative reaction
            • 2-Hydroxy metabolite is further transformed by methylation and glucuronidation before urinary and fecal excretion

            Elimination

            Half-life

            • Elimination half-life
              • Levonorgestrel: 38.2 hr (cycle 1, week 3); 40.5 hr (cycle 2, week 3)
              • Ethinyl estradiol: 19.7 hr (cycle 1, week 3); 20.5 hr (cycle 2, week 3)
            • Mean terminal half-life
              • Levonorgestrel: 41 hr
              • Ethinyl estradiol: 21 hr

            Excretion

            • Levonorgestrel: 40-68% urine; 16-48% feces
            • Ethinyl estradiol: Excreted in urine and feces and glucuronide and sulfate conjugates; undergoes enterohepatic recirculation
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            Administration

            Transdermal Administration

            Application

            • For transdermal use only
            • To achieve maximum contraceptive effectiveness, transdermal system (TDS) must be used exactly as directed; failure rate may increase when TDS application is delayed/missed or when TDS is applied incorrectly
            • Apply TDS to clean, dry, and intact skin on abdomen, buttock, or upper torso (excluding breasts)
            • When applying a new TDS, do not apply the new TDS directly over the previous TDS site
            • Do not apply to skin that has been exposed to powder, oil, moisturizer, or lotion
            • Advise women not to routinely use large amounts of body lotions or oils at application sites
            • Prolonged exposure to water may interfere with TDS adherence
            • Do not cut or alter TDS in any way; apply whole TDS; if TDS is cut or damaged or altered in size, contraceptive efficacy may be impaired
            • Discard by folding used TDS so that the adhesive side sticks to itself and safely discard in the trash
            • Used TDS still contains some active hormones; should not be flushed down the toilet

            TDS edge lifts up

            • Press down firmly on TDS with the palm of the hand for 10 seconds, making sure that the whole TDS is adhered to skin
            • Then run fingers over the entire surface area to smooth out any wrinkles around the edges of the TDS
            • If lifted edge of TDS does not stick completely after attempted readhesion, remove TDS and replace with new TDS
            • Do not tape or wrap TDS to skin or reapply a TDS that is partially adhered to clothing

            TDS has been off or partially off

            • <1 day
              • Try to reapply TDS; if TDS does not adhere completely, apply new TDS immediately
              • No back-up contraception is needed and the Patch Change Day will stay the same
            • >1 day or unsure of timeframe
              • Woman may not be protected from pregnancy
              • Reduce pregnancy risk by applying new TDS and start a new 4-week cycle
              • The woman will now have a new Patch Change Day and MUST use nonhormonal back-up contraception (eg, condoms and spermicide, diaphragm and spermicide) for the first 7 days of the new cycle

            Starting in women with no current hormonal contraceptive

            • Day 1 start
              • Apply first TDS during the first 24 hr of menstruation
              • Apply a new TDS each week for 3 weeks (21 total days) on the same day each week
              • No TDS is worn during Week 4
              • If a TDS is applied after the first 24 hr of menstruation, use nonhormonal back-up contraception (eg, condoms and spermicide, diaphragm and spermicide) concurrently for first 7 days of first cycle only

            Switching from an oral combination hormonal contraceptive

            • Complete the current pill cycle and apply the first TDS on the day the next pill cycle would normally start
            • If menses does not occur within a week after taking the last active pill, instruct the woman to consult with a healthcare professional to be sure that pregnancy has not occurred
            • If no pregnancy has occurred, TDS may be started for contraception
            • If initiated >1 week after taking the last active pill, use nonhormonal back-up contraception (eg, condoms and spermicide, diaphragm and spermicide) concurrently for first 7 days

            Switching from a transdermal hormonal contraceptive

            • Complete current TDS cycle and apply the first Twirla TDS on the day the next TDS cycle would normally start
            • If menses does not occur within a week after removing the last TDS, consult with a healthcare professional to ensure pregnancy has not occurred
            • If no pregnancy has occurred, Twirla TDS may be started for contraception
            • If Twirla TDS is applied >1 week after removal of the last TDS, use nonhormonal back-up contraception (eg, condoms and spermicide, diaphragm and spermicide) concurrently for first 7 days

            Switching from vaginal ring

            • Complete vaginal ring cycle and apply the first TDS on the day the next vaginal ring would normally start
            • If menses does not occur within a week after removing vaginal ring, consult with a healthcare professional to ensure pregnancy has not occurred
            • If no pregnancy has occurred, TDS may be started for contraception
            • If TDS is applied >1 week after vaginal ring removal, use nonhormonal back-up contraception (eg, condoms and spermicide, or diaphragm and spermicide) concurrently for first 7 days

            Injection, intrauterine system, implant, or progestin-only pill

            • Injection: Apply first TDS on the day the next injection would normally occur
            • Intrauterine system or implant: Apply first TDS on the day of intrauterine system/implant removal
            • Progestin-only pill: Apply first TDS on the day the next progestin-only pill cycle would normally start

            Starting after abortion or miscarriage

            • First trimester abortion or miscarriage
              • May be started immediately within the first 5 days following a complete first trimester abortion or miscarriage without additional back-up contraception
              • If >5 days have elapsed from the first trimester abortion or miscarriage, use nonhormonal contraception (eg, condoms and spermicide, diaphragm and spermicide) and follow instructions for starting TDS for the first time
              • Ovulation may occur within 10 days of an abortion or miscarriage
            • Second trimester abortion or miscarriage
              • Do not start earlier than 4 weeks after a second trimester abortion or miscarriage owing to increased risk of thromboembolism

            Starting after childbirth

            • For women who elect not to breastfeed, do not start sooner than 4 weeks after childbirth owing to increased risk of thromboembolism
            • If a woman begins using TDS postpartum and has not yet had a period, consider possibility of ovulation and pregnancy; obtain pregnancy test to guide action
            • If not pregnant, use nonhormonal back-up contraception (eg, condoms and spermicide, diaphragm and spermicide) for the first 7 days of TDS use

            Missed doses

            • Forgetting to change TDS
              • At the start of any TDS cycle (Week 1/Day 1): May not be protected from pregnancy; apply the first TDS as soon as possible (this now starts a new 4-week cycle and is now the new Patch Change Day); use nonhormonal back-up contraception for 7 days
              • In the middle of TDS cycle (Week 2/Day 8 or Week 3/Day 15), for up to 48 hr: Apply new TDS immediately; apply next TDS on the usual Patch Change Day; no back-up contraception needed
              • ≥48 hr: May not be protected from pregnancy; stop current TDS cycle and start a new 4-week cycle immediately by applying a new TDS (this is now a new Patch Change Day); use nonhormonal back-up contraception for 7 days
              • At end of TDS cycle Week 3 (Day 22): If the woman forgets to remove her TDS, she should take it off as soon as she remembers; start next cycle on the usual Patch Change Day, which is the day after Day 28; no back-up contraception needed

            Storage

            Store in original pouch until application time

            Store at room temperature 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)

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            Patient Handout

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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.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
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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.