ethinyl estradiol/levonorgestrel transdermal (Rx)

Brand and Other Names:Twirla
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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

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Interactions

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            Contraindicated (2)

            • 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 (18)

            • abametapir

              abametapir will increase the level or effect of ethinylestradiol 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.

            • 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.

            Monitor Closely (147)

            • 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.

            • 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.

            • 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.

            • levoketoconazole

              levoketoconazole 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.

            • liraglutide

              ethinylestradiol 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.

            • lixisenatide

              lixisenatide will decrease the level or effect of ethinylestradiol by inhibition of GI absorption. Applies only to oral form of both agents. Modify Therapy/Monitor Closely. GLP1 agonists delay gastric emptying, which may affect absorption of concomitantly administered oral medications. Oral contraceptives should be taken at least 1 hr before lixisenatide administration or 11 hr after lixisenatide.

            • lomitapide

              ethinylestradiol increases levels of lomitapide by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Lomitapide dose should not exceed 30 mg/day.

            • lonapegsomatropin

              ethinylestradiol will decrease the level or effect of lonapegsomatropin by Other (see comment). Use Caution/Monitor. Oral estrogens may reduce serum insulin-like growth factor-1 response to lonapegsomatropin. Patients receiving oral estrogen replacement may require higher lonapegsomatropin dosages.

            • lorlatinib

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

            • lumefantrine

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

            • metformin

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

            • metronidazole

              metronidazole 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.

            • mexiletine

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

            • midazolam

              ethinylestradiol will increase the level or effect of midazolam 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.

            • midazolam intranasal

              ethinylestradiol will increase the level or effect of midazolam intranasal by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Coadministration of mild CYP3A4 inhibitors with midazolam intranasal may cause higher midazolam systemic exposure, which may prolong sedation.

            • mifepristone

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

            • minocycline

              minocycline 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.

            • mitotane

              mitotane decreases levels of ethinylestradiol 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 ethinylestradiol 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 ethinylestradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.

            • neomycin PO

              neomycin PO 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.

            • nicardipine

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

            • nilotinib

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

            • nirmatrelvir

              nirmatrelvir will decrease the level or effect of ethinylestradiol by increasing metabolism. Modify Therapy/Monitor Closely. Consider using additional nonhormonal contraceptive method for remainder of cycle. Mechanism unknown, but possibly by ritonavir CYP2C9 or CYP1A2 induction.

            • nirmatrelvir/ritonavir

              nirmatrelvir/ritonavir will decrease the level or effect of ethinylestradiol by increasing metabolism. Modify Therapy/Monitor Closely. Consider using additional nonhormonal contraceptive method for remainder of cycle. Mechanism unknown, but possibly by ritonavir CYP2C9 or CYP1A2 induction.

            • nitrofurantoin

              nitrofurantoin 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.

            • ofloxacin

              ofloxacin 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.

            • olanzapine

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

            • oteseconazole

              oteseconazole will increase the level or effect of ethinylestradiol by Other (see comment). Modify Therapy/Monitor Closely. Otesezonale, a BCRP inhibitor, may increase the effects and risk of toxicities of BCRP substrates. Use lowest starting dose of BCRP substrate, or consider reducing BCRP substrate dose.

            • paromomycin

              paromomycin 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.

            • penicillin G aqueous

              penicillin G aqueous decreases levels of ethinylestradiol by increasing metabolism. Use Caution/Monitor. Risk of oral contraceptive failure.

            • penicillin VK

              penicillin VK 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.

            • pioglitazone

              pioglitazone decreases levels of ethinylestradiol by unknown mechanism. Use Caution/Monitor.

            • posaconazole

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

            • quinupristin/dalfopristin

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

            • ramelteon

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

            • rasagiline

              ethinylestradiol will increase the level or effect of rasagiline by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor. Recommended dose of rasagiline is 0.5mg daily in combination with CYP1A2 inhibitors.

            • ribociclib

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

            • romidepsin

              romidepsin decreases effects of ethinylestradiol by receptor binding competition. Use Caution/Monitor.

            • ropinirole

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

              ethinylestradiol increases levels of ropinirole by unspecified interaction mechanism. Use Caution/Monitor.

            • rucaparib

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

            • rufinamide

              rufinamide decreases effects of ethinylestradiol 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. .

            • selegiline

              ethinylestradiol increases levels of selegiline by Other (see comment). Use Caution/Monitor. Comment: Oral contraceptives inhibit the N demethylatin of selegiline.

            • selegiline transdermal

              ethinylestradiol increases levels of selegiline transdermal by Other (see comment). Use Caution/Monitor. Comment: Oral contraceptives inhibit the N demethylatin of selegiline.

            • siltuximab

              siltuximab, ethinylestradiol. 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.

            • stiripentol

              stiripentol, ethinylestradiol. 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.

            • sulfadiazine

              sulfadiazine 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.

            • sulfamethoxazole

              sulfamethoxazole 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.

            • sulfisoxazole

              sulfisoxazole 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.

            • tacrolimus

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

            • tazemetostat

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

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

            • tecovirimat

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

            • teriflunomide

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

            • tetracycline

              tetracycline 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.

            • theophylline

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

            • ticarcillin

              ticarcillin 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.

            • tigecycline

              tigecycline 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.

            • tinidazole

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

            • tizanidine

              ethinylestradiol will increase the level or effect of tizanidine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor. Monitor for tizanidine adverse effects (eg, hypotension or bradycardia)

            • tolterodine

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

            • triazolam

              ethinylestradiol will increase the level or effect of triazolam 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.

            • trimethoprim

              trimethoprim 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.

            • ursodiol

              ethinylestradiol decreases effects of ursodiol by pharmacodynamic antagonism. Use Caution/Monitor.

            • valproic acid

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

            • vardenafil

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

            • voriconazole

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

            • warfarin

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

            Minor (27)

            • 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.

            • 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.

            • 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.

            • 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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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

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