Gemmily (norethindrone acetate-ethinyl estradiol/ferrous fumarate)

No dosing information is available for this tab.

Norethindrone acetate is administered orally.

Estrogen-progestin combination contraceptives are administered orally, intravaginally, and percutaneously by topical application of a transdermal system to the skin.

There is no enhanced messaging for this drug.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Agents Affecting Plasma Cortisol Levels/Cosyntropin

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Agents affecting plasma cortisol levels may impact the accuracy of the cosyntropin diagnostic test.(1)

CLINICAL EFFECTS: Concurrent use of agents affecting plasma cortisol levels may impact the accuracy of the cosyntropin diagnostic test.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of cosyntropin states accuracy of diagnosis using the cosyntropin diagnostic test may be complicated by concomitant medications affecting plasma cortisol levels.(1) Agents affecting plasma cortisol levels and recommendation to stop prior to cosyntropin diagnostic test include: - Glucocorticoids: May elevate plasma cortisol levels. Stop these drugs on the day of testing. Long-acting glucocorticoids may need to be stopped for a longer period before testing. - Spironolactone: May elevate plasma cortisol levels. Stop spironolactone on the day of testing. - Estrogen: May elevate plasma total cortisol levels. Discontinue estrogen containing drugs 4 to 6 weeks prior to testing to allow cortisol binding globulin levels to return to levels within the reference range. Alternatively, concomitant measurement of cortisol binding globulin at the time of testing can be done; if cortisol binding globulin levels are elevated, plasma total cortisol levels are considered inaccurate.(1)

DISCUSSION: Concurrent use of agents affecting plasma cortisol levels may impact the accuracy of the cosyntropin diagnostic test.(1)

Cyp1a2 Inhibitors/Fezolinetant

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Inhibitors of CYP1A2 may inhibit the metabolism of fezolinetant.(1-4)

CLINICAL EFFECTS: Concurrent use of a CYP1A2 inhibitor may increase levels of and adverse effects from fezolinetant.(1-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Recommendations for concurrent use of fezolinetant with CYP1A2 inhibitors differ in different regions. The US manufacturer of fezolinetant states that concurrent use with strong, moderate, and weak CYP1A2 inhibitors is contraindicated.(1) The Australian, Canadian, and UK manufacturers of fezolinetant state that concurrent use with strong and moderate CYP1A2 inhibitors is contraindicated, while weak CYP1A2 inhibitors are not predicted to cause clinically relevant changes in fezolinetant exposure.(2-4)

DISCUSSION: In a study, fluvoxamine, a strong CYP1A2 inhibitor, increased fezolinetant maximum concentration (Cmax) and area-under-curve (AUC) by 80% and 840%, respectively. Mexiletine (400 mg every 8 hours), a moderate CYP1A2 inhibitor, increased fezolinetant Cmax and AUC by 40% and 360%, respectively. Cimetidine (300 mg every 6 hours), a weak CYP1A2 inhibitor, increased fezolinetant Cmax and AUC by 30% and 100%, respectively.(1) Strong CYP1A2 inhibitors linked to this monograph include angelica root, ciprofloxacin, enasidenib, enoxacin, fluvoxamine, and rofecoxib. Moderate CYP1A2 inhibitors linked to this monograph include capmatinib, centanafadine, dipyrone, fexinidazole, genistein, hormonal contraceptives, methoxsalen, mexiletine, osilodrostat, phenylpropanolamine, pipemidic acid, rucaparib, troleandomycin, vemurafenib, and viloxazine. Weak CYP1A2 inhibitors linked to this monograph include acyclovir, allopurinol, artemisinin, belumosudil, caffeine, cannabidiol, cimetidine, curcumin, dan-shen, deferasirox, disulfiram, Echinacea, famotidine, ginseng, norfloxacin, obeticholic acid, parsley, piperine, propafenone, propranolol, ribociclib, simeprevir, thiabendazole, ticlopidine, triclabendazole, valacyclovir, verapamil, and zileuton.(5-7)

Estrogenic Agents/Tranexamic Acid (Oral)

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Tranexamic acid is an antifibrinolytic and estrogen-containing hormonal contraceptives are known to increase the risk of venous thromboembolism and arterial thromboses, including stroke and myocardial infarction. Concurrent use may increase the risk of these events.(1)

CLINICAL EFFECTS: Concurrent use of tranexamic acid in patients taking estrogen-containing agents or hormonal contraceptives may increase the risk of embolisms.(1)

PREDISPOSING FACTORS: The risk of thrombosis may be even greater in women who are obese or smoke, especially smokers over age 35.(1)

PATIENT MANAGEMENT: The concurrent use of oral tranexamic and and estrogen-containing hormonal contraception is contraindicated.(1) It would be prudent to follow this restriction with estrogen-replacement therapy as well.

DISCUSSION: There are no clinical trial data on the risk of concurrent therapy with tranexamic acid and hormonal contraceptives. There have been postmarketing reports of venous and arterial thrombotic events in women receiving combination therapy.(1) Women taking hormonal contraception were excluded from safety and efficacy trials of tranexamic acid.(1)

Estrogens/Selected Anti-Aromatase Agents

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Aromatase inhibitors(1-6) and inactivators(7-10) treat breast cancer by inhibiting estrogen synthesis therefore lowering serum estrone and estradiol levels. In postmenopausal women, androgens are metabolized to estrogens via the primary pathway of the aromatase enzyme.

CLINICAL EFFECTS: Concurrent administration of estrogen may decrease the effectiveness of aromatase inhibitors.(1-6)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The Canadian,(1) UK,(2) and US(3) manufacturers of anastrozole state that estrogen containing therapies should not be used during anastrozole therapy. The Australian,(7) Canadian,(8) UK,(9) and US(10) manufacturers of exemestane state that exemestane should not be administered with estrogen containing therapies. The Canadian(4) and UK(5) manufacturer of letrozole state that estrogen containing therapies should be avoided during letrozole therapy.

DISCUSSION: Many breast cancers have estrogen receptors and their growth can be stimulated by estrogen. Anastrozole is a potent and selective non-steroidal aromatase inhibitor that lowers serum estradiol levels. Concurrent use of estrogen may diminish the effects of anastrozole.(1-3) Exemestane is a steroidal aromatase inactivator that lowers serum estradiol levels. Concurrent use of estrogen may diminish the effects of exemestane.(7-10)

Estrogens/Sodium Tetradecyl Sulfate

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Patients taking estrogen-containing hormonal contraceptives or hormone replacement therapy have a higher risk of clotting problems.(1)

CLINICAL EFFECTS: Use of sodium tetradecyl sulfate on patients taking estrogen-containing hormonal contraceptives or hormone replacement therapy may increase the risk of deep vein thrombosis.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of sodium tetradecyl sulfate states that its use in patients taking contraceptives or hormone replacement therapy is contraindicated.(2)

DISCUSSION: Factors which may increase the risk of deep vein thrombosis after sclerotherapy should be avoided.(1) Therefore, its use in patients taking estrogen-containing contraceptives or hormone replacement therapy is contraindicated.(2)

Ethinyl Estradiol;Estetrol/Ombitasvir-Paritaprevir-Ritonavir

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The mechanism of action has not been described.

CLINICAL EFFECTS: In clinical trials, subjects receiving concomitant ethinyl estradiol-containing combinations had a significantly higher risk for ALT elevations > 5 times the upper limit of normal (ULN) than subjects receiving ombitasvir-paritaprevir-ritonavir with or without dasabuvir.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Due to the added risk for ALT elevations, the manufacturer of ombitasvir-paritaprevir-ritonavir states that medications which contain ethinyl estradiol such as oral contraceptives, contraceptive patches, or contraceptive vaginal rings must be discontinued prior to starting therapy with ombitasvir-paritaprevir-ritonavir. In clinical trials, 25% (4/16) women taking ethinyl estradiol containing medications had ALT elevations > 5 times the upper limit of normal (ULN).(1,2) Alternative methods of contraception, such as progestin only or non-hormonal methods are recommended during ombitasvir-paritaprevir-ritonavir therapy. Ethinyl estradiol and estetrol containing medications may be restarted 2 weeks after completion of ombitasvir-paritaprevir-ritonavir treatment.(1,2) Women taking estrogens other than ethinyl estradiol (e.g. estradiol or conjugated estrogens) had a 3% rate of ALT levels > 5 times ULN (2/59 subjects). The risk for similar ALT elevations in subjects not receiving estrogens was 1%. The manufacturer of ombitasvir-paritaprevir-ritonavir describes these rates as similar.(1,2)

DISCUSSION: During clinical trials, approximately 1% of subjects taking ombitasvir-paritaprevir-ritonavir had ALT elevations > 5 times the upper limit of normal. Women taking estrogens other than ethinyl estradiol (e.g. estradiol or conjugated estrogens) had a 3% rate of ALT levels > 5 times ULN (2/59 subjects). The manufacturer of ombitasvir-paritaprevir-ritonavir describes these rates as similar.(1,2) Although the number of exposed subjects was small, 4 of 16 women (25%) receiving ethinyl estradiol containing medications had ALT levels > 5 times ULN.(1,2)

Hormonal Contraceptives/Dipyrone

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Dipyrone is a moderate CYP3A4 and weak CYP2C9 inducer. Coadministration of dipyrone with hormonal contraceptives may lead to contraceptive failure or an increase in breakthrough bleeding due to decreased hormonal concentrations.(1-2)

CLINICAL EFFECTS: Concurrent use of dipyrone may reduce the effectiveness of hormonal contraceptives, except for intrauterine systems containing levonorgestrel.(1-2)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Avoid concomitant use with hormonal contraceptives except for intrauterine systems containing levonorgestrel. If contraception is needed or desired, an alternate contraceptive that is not affected by CYP inducers (e.g., an intrauterine system) or additional non-hormonal contraceptives (e.g., condoms) should be used when treated concomitantly with dipyrone and for at least 4 weeks after the last dose of dipyrone.(1) Women of reproductive age should be counseled not to rely on hormonal contraceptives (including oral contraceptives, patches, implants, and/or IUDs) for contraception.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if she does become pregnant.(3)

DISCUSSION: Dipyrone is a moderate CYP3A4 and weak CYP2C9 inducer.(1-2) In a study, dipyrone 1 gram 3 times daily decreased the area under curve (AUC) of midazolam (a CYP3A4 substrate) by 68% and of flurbiprofen (a CYP2C9 substrate) by 22%.(2)

Hormonal Contraceptives/Elafibranor

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Elafibranor is a weak CYP3A4 inducer. Coadministration of elafibranor with hormonal contraceptives may lead to contraceptive failure or an increase in breakthrough bleeding due to decreased hormonal concentrations.(1)

CLINICAL EFFECTS: Concurrent use of elafibranor may reduce the effectiveness of hormonal contraceptives.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concomitant use of hormonal contraceptives with elafibranor. Advise females of reproductive potential to use effective non-hormonal contraception (e.g., non-hormonal intrauterine system) or additional non-hormonal contraceptive (e.g., condoms) during treatment with elafibranor and for 21 days after the last dose. Women of reproductive age should be counseled not to rely on hormonal contraceptives (including oral contraceptives, patches, implants, and/or IUDs) for contraception.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if she does become pregnant.(2)

DISCUSSION: Elafibranor is a weak CYP3A4 inducer.(1) Coadministration of elafibranor with simvastatin (a CYP3A, OATP1B1, and OATP1B3 substrate) decreased the concentration maximum (Cmax) and area-under-curve (AUC) of simvastatin beta-hydroxyacid by 26% and 32%, respectively.(1)

Hormonal Contraceptives/Mobocertinib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Mobocertinib is a weak CYP3A4 inducer. Coadministration of mobocertinib with hormonal contraceptives may lead to contraceptive failure or an increase in breakthrough bleeding due to decreased hormonal concentrations.(1)

CLINICAL EFFECTS: Concurrent use of mobocertinib can lead to ineffective hormonal contraceptive and cause fetal harm when administered to a pregnant woman.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concomitant use of hormonal contraceptives with mobocertinib. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with mobocertinib and for 1 month after the last dose. Women of reproductive age should be counseled not to rely on hormonal contraceptives (including oral contraceptives, patches, implants, and/or IUDs) for contraception. Pregnant women and females of reproductive potential should be counseled on the potential risk to a fetus.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if she does become pregnant.(2)

DISCUSSION: Mobocertinib has not been studied with hormonal contraceptives. It can render some hormonal contraceptives ineffective and cause embryo-fetal harm. Women should use non-hormonal contraception during therapy and for one month after the last dose.(1) In an animal study, oral administration of mobocertinib to pregnant rats during the period of organogenesis resulted in embryolethality at maternal exposures approximately 1.7 times the human exposure based on area under the curve (AUC) at the 160 mg once daily clinical dose.(1) Coadministration of mobocertinib 160 mg once daily with oral or intravenous midazolam (a CYP3A substrate) decreased the AUC of midazolam by 32% and 16%, respectively.(1)

Hormonal Contraceptives/Omaveloxolone

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Omaveloxolone is a weak CYP3A4 inducer. Coadministration of omaveloxolone with hormonal contraceptives may lead to contraceptive failure or an increase in breakthrough bleeding due to decreased hormonal concentrations.(1)

CLINICAL EFFECTS: Concurrent use of omaveloxolone may reduce the effectiveness of hormonal contraceptives.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concomitant use of hormonal contraceptives with omaveloxolone. Advise females of reproductive potential to use effective non-hormonal contraception (e.g., non-hormonal intrauterine system) or additional non-hormonal contraceptive (e.g., condoms) during treatment with omaveloxolone and for 28 days after the last dose. Women of reproductive age should be counseled not to rely on hormonal contraceptives (including oral contraceptives, patches, implants, and/or IUDs) for contraception.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if she does become pregnant.(2)

DISCUSSION: Coadministration of omaveloxolone with midazolam (a CYP3A substrate) decreased the area-under-curve (AUC) of midazolam by 45%.(1)

Hormonal Contraceptives/Pacritinib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Pacritinib is a moderate CYP3A4 inducer. Coadministration of pacritinib with hormonal contraceptives may lead to contraceptive failure or an increase in breakthrough bleeding due to decreased hormonal concentrations.(1)

CLINICAL EFFECTS: Concurrent use of pacritinib may reduce the effectiveness of hormonal contraceptives, except for intrauterine systems containing levonorgestrel.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer of pacritinib states to avoid concomitant use with hormonal contraceptives except for intrauterine systems containing levonorgestrel. If contraception is needed or desired, an alternate contraceptive that is not affected by CYP3A4 inducers (e.g., an intrauterine system) or additional non-hormonal contraceptives (e.g., condoms) should be used when treated concomitantly with pacritinib and for 30 days after the last dose of pacritinib.(1) Women of reproductive age should be counseled not to rely on hormonal contraceptives (including oral contraceptives, patches, implants, and/or IUDs) for contraception.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if she does become pregnant.(2)

DISCUSSION: Pacritinib is a moderate CYP3A4 inducer.(1) Coadministration of pacritinib (200 mg twice daily at steady state) with a single dose of oral midazolam (2 mg) (a CYP3A4 substrate) decreased the concentration maximum (Cmax) and area-under-curve (AUC) of midazolam by 60% and 60%, respectively.(1)

Hormonal Contraceptives/Pexidartinib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Pexidartinib is a moderate CYP3A4 inducer and may increase the CYP3A4-mediated metabolism of both estrogen and progestin components of hormonal contraceptives.(1)

CLINICAL EFFECTS: Coadministration of pexidartinib with hormonal contraceptives can result in decreased concentrations and reduced efficacy.(1) Breakthrough bleeding and contraceptive failure/pregnancy may result. Pexidartinib may cause fetal harm if administered to pregnant women.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of pexidartinib recommends that female patients of reproductive potential use effective non-hormonal contraception during treatment with pexidartinib and for 1 month after the final dose.(1) Patients should be alerted to the risk for decreased effectiveness(e.g. contraceptive failure) of their hormonal contraceptive therapy. For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (i.e., a copper IUD).(2)

DISCUSSION: Coadministration of pexidartinib 400 mg twice daily with oral midazolam, a sensitive CYP3A4 substrate, in patients decreased midazolam area-under-curve (AUC) by 59% and maximum concentration (Cmax) by 28%.(1)

Hormonal Contraceptives/Sunvozertinib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Sunvozertinib is a weak CYP3A4 inducer. Coadministration of sunvozertinib with hormonal contraceptives may lead to contraceptive failure or an increase in breakthrough bleeding due to decreased hormonal concentrations.(1)

CLINICAL EFFECTS: Concurrent use of sunvozertinib may reduce the effectiveness of hormonal contraceptives, except for intrauterine systems containing levonorgestrel.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer of sunvozertinib states to avoid concomitant use with hormonal contraceptives. Use a non-hormonal contraceptive during treatment and for 2 weeks after the last dose.(1) Women of reproductive age should be counseled to use highly effective contraception due to the risk of fetal harm with sunvozertinib. Women of reproductive age should be counseled not to rely on hormonal contraceptives (including oral, implantable, injectable, or transdermal agents) for contraception because they may not be effective.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if she does become pregnant.(2)

DISCUSSION: Sunvozertinib is a weak CYP3A4 inducer.(1) Coadministration of sunvozertinib with midazolam (a CYP3A4 substrate) decreased the concentration maximum (Cmax) and area-under-curve (AUC) of midazolam by 15% and 23%, respectively.(1)

Hormonal Contraceptives/Vorasidenib

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Vorasidenib may induce the CYP3A4-mediated metabolism of hormonal contraceptives.(1) Hormonal contraceptives may inhibit the CYP1A2-mediated metabolism of vorasidenib.(1,2)

CLINICAL EFFECTS: Concurrent use of vorasidenib may reduce the blood concentrations and effectiveness of hormonal contraceptives. Vorasidenib may cause fetal harm when administered to pregnant women.(1) Concurrent use of moderate CYP1A2 inhibitors such as hormonal contraceptives may result in elevated levels of and effects from vorasidenib, including hepatotoxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of vorasidenib states that concurrent use of moderate CYP1A2 inhibitors should be avoided. If concurrent use of moderate CYP1A2 inhibitors cannot be avoided, monitor for increased risk of adverse reactions and modify the dose of vorasidenib as recommended in the prescribing information.(1) Women of reproductive age should be counseled to avoid hormonal contraception (including oral contraceptives, patches, implants, and/or IUDs) due to the risk of contraceptive failure. Women should use an effective non-hormonal method of contraception during and for 3 months after vorasidenib therapy.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (i.e., a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(3)

DISCUSSION: Vorasidenib is an inducer of CYP3A4 in vitro. Concomitant use of multiple doses of vorasidenib is predicted to decrease the concentration of CYP3A4 substrates, including hormonal contraceptives. Vorasidenib may cause fetal harm when administered to pregnant women.(1) Vorasidenib is primarily metabolized by CYP1A2. In a study, concurrent use of vorasidenib and ciprofloxacin (a moderate CYP1A2 inhibitor) increased vorasidenib Cmax 1.3-fold and AUC 2.5-fold.(1)

Iron/Dimercaprol

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Dimercaprol can complex with iron, forming a chelation compound that is more toxic than iron alone.(1)

CLINICAL EFFECTS: Concurrent use of dimercaprol and iron may result in toxicity, especially renal toxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Medicinal iron should not be administered to patients receiving dimercaprol.(1)

DISCUSSION: Because the dimercaprol-iron complex is more toxic than iron alone, especially to the kidneys, medicinal iron should not be administered to patients receiving dimercaprol.(1)

Selected Cyp1a2 Inhibitors/Rasagiline (> 0.5 Mg)

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Inhibitors of CYP1A2 may inhibit the metabolism of rasagiline.(1)

CLINICAL EFFECTS: Concurrent use of a CYP1A2 inhibitor may increase levels of and adverse effects from rasagiline.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of rasagiline states that patients receiving concurrent therapy with an inhibitor of CYP1A2 should receive no more than 0.5 mg of rasagiline daily.(1) Concurrent therapy with vemurafenib may require extended monitoring for interaction onset and severity because steady-state levels of vemurafenib are not attained for approximately 15 days.(2)

DISCUSSION: In a study in 12 healthy subjects, ciprofloxacin (500 mg twice daily) increased the area-under-curve (AUC) of rasagiline (2 mg twice daily) by 83%.(1) Strong CYP1A2 inhibitors linked to this monograph include angelica root, ciprofloxacin, enasidenib, enoxacin, and rofecoxib. Moderate CYP1A2 inhibitors linked to this monograph include capmatinib, dipyrone, fexinidazole, genistein, hormonal contraceptives, methoxsalen, mexiletine, osilodrostat, phenylpropanolamine, pipemidic acid, rucaparib, troleandomycin, and vemurafenib.(3-5)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Aluminum & Magnesium Antacids;Polyvalent Cations/Raltegravir

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Aluminum and/or magnesium containing antacids may alter raltegravir absorption by altering gastric pH. Magnesium antacids and supplements containing polyvalent cations may bind to raltegravir in the GI tract, preventing its absorption.(1)

CLINICAL EFFECTS: Aluminum and/or magnesium containing antacids and supplements containing polyvalent cations may reduce levels and clinical effectiveness of raltegravir.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of any formulation of raltegravir and aluminum and/or magnesium antacids is not recommended. Instruct patients not to use aluminum and/or magnesium containing antacids. Calcium carbonate may be used in place of aluminum and/or magnesium containing antacids in patients receiving raltegravir twice daily. Calcium carbonate is not recommended for patients receiving once daily raltegravir (1,200 mg daily).(1,2) The US HIV treatment guidelines state that if coadministration of other medications that contain polyvalent cations (e.g., Mg, Al, Fe, Ca, Zn, sucralfate) is necessary, administer raltegravir at least 2 hours before or at least 6 hours after polyvalent cations. Monitor for virologic response.(2)

DISCUSSION: Simultaneous administration of aluminum and magnesium hydroxide (20 ml) with raltegravir (400 mg BID) decreased raltegravir maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) by 44%, 49%, and 63%, respectively.(1) Administration of aluminum and magnesium hydroxide (20 ml) 2 hours before raltegravir (400 mg BID) decreased raltegravir Cmax, AUC, and Cmin by 51%, 51%, and 56%, respectively.(1) Administration of aluminum and magnesium hydroxide (20 ml) 2 hours after raltegravir (400 mg BID) decreased raltegravir Cmax, AUC, and Cmin by 22%, 30%, and 57%, respectively.(1) Administration of aluminum and magnesium hydroxide (20 ml) 4 hours before after raltegravir (400 mg BID) decreased raltegravir Cmax, AUC, and Cmin by 22%, 19%, and 60%, respectively.(1) Administration of aluminum and magnesium hydroxide (20 ml) 4 hours after after raltegravir (400 mg BID) decreased raltegravir Cmax, AUC, and Cmin by 30%, 32%, and 62%, respectively.(1) Administration of aluminum and magnesium hydroxide (20 ml) 6 hours before after raltegravir (400 mg BID) decreased raltegravir Cmax, AUC, and Cmin by 10%, 13%, and 50%, respectively.(1) Administration of aluminum and magnesium hydroxide (20 ml) 6 hours after after raltegravir (400 mg BID) decreased raltegravir Cmax, AUC, and Cmin by 10%, 11%, and 49%, respectively.(1) Administration of aluminum and magnesium hydroxide (20 ml) 12 hours after after raltegravir (1200 mg single dose) decreased raltegravir Cmax, AUC, and Cmin by 14%, 14%, and 58%, respectively.(1,3) Data from in vitro(3) and in vivo simulations(5) suggest that magnesium's effect on raltegravir may involve chelation as well as changes in pH.

Contraceptives/Atazanavir-Cobicistat

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The mechanism of this interaction is unknown. Both atazanavir and cobicistat may inhibit CYP3A4 but neither has been found to induce CYP3A4. Atazanavir also inhibits UGT1A1 and weakly inhibits CYP2C8 while cobicistat also inhibits CYP2D6, P-glycoprotein (P-gp), BCRP, OATP1B1 and OATP1B3.(1-3)

CLINICAL EFFECTS: Atazanavir-cobicistat has been shown to decrease ethinyl estradiol (EE) levels when used with EE-drospirenone, but did not change EE levels when used with EE-levonorgestrel.(4) The effect of atazanavir-cobicistat on other contraceptives is unknown.(1) Progestin concentrations may be increased with the use of atazanavir-cobicistat, which may increase the risk of insulin resistance, dyslipidemia, and acne.(1,4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of atazanavir-cobicistat states that no data is available to make recommendations on coadministration with oral or other hormonal contraceptives. Alternative nonhormonal forms of contraception should be considered.(1) The US Department of Health and Human Services HIV guidelines state that no dose adjustment is needed when atazanavir-cobicistat is used with oral contraceptives.(4) The CDC contraceptive guidelines state that intrauterine devices (copper or levonorgestrel) may be used with any antiretroviral agent.(5)

DISCUSSION: Concurrent use of atazanavir-cobicistat (300 mg - 150 mg once daily) increased the area-under-curve (AUC) of drospirenone (administered as drospirenone/ethinyl estradiol 3/0.02 mg single dose) by 2.3-fold.(2) Atazanavir-cobicistat (300 mg-150 mg once daily) did not change levonorgestrel concentrations or ethinyl estradiol AUC, and decreased ethinyl estradiol minimum concentration (Cmin) by 25%.(4) Concurrent administration of atazanavir (400 mg daily) with ethinyl estradiol-norethindrone (Ortho-Novum) increased the maximum concentration (Cmax), AUC, and Cmin of ethinyl estradiol by 15%, 48%, and 91%, respectively, and the Cmax, AUC, and Cmin of norethindrone by 67%, 210%, and 362%, respectively.(3)

Contraceptives/Chloramphenicol

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Estrogens and progesterones are extensively excreted in bile, principally as glycuronide conjugates. Subsequently, they undergo enterohepatic circulation where bacterial hydrolysis occurs, allowing for reabsorption of the oral contraceptives through the bowel wall and eventual urinary excretion. Treatment with antibiotics destroys the gut flora and prevents steroid reabsorption, resulting in lower than normal concentrations of the contraceptive and excretion via the feces rather than the urine. Chloramphenicol may also induce hepatic enzymes, resulting in increased metabolism of the contraceptive agent.

CLINICAL EFFECTS: May observe reduced pharmacologic effects of oral contraceptives with resultant breakthrough bleeding and pregnancy. Reduced effects may be seen for several days after discontinuation of antibiotic therapy.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: It is recommended that additional forms of birth control be used during concurrent administration of short courses of chloramphenicol. For longer courses, use another method of birth control. The patient should be asked to report any spotting or bleeding.

DISCUSSION: The manufacturer states that lower estrogen reabsorption and reduced efficacy may result in women taking oral contraceptives and chloramphenicol.

Contraceptives/Griseofulvin

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Unknown. However, possibly due to increased metabolism of oral contraceptives.

CLINICAL EFFECTS: Decreased effectiveness of oral contraceptives, producing breakthrough bleeding, amenorrhea and unintended pregnancy.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The patient should use an alternative method of contraception during and for one month after receiving griseofulvin. Increasing the dose of estrogen may be necessary in patients on low-dose estrogen. For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used an inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.

DISCUSSION: Loss of oral contraceptive efficacy has been reported following the addition of griseofulvin to the patient's drug therapy. Loss of efficacy was indicated by breakthrough bleeding, amenorrhea and unintended pregnancy.

Contraceptives/Selected Anticonvulsants; Barbiturates

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Barbiturates, hydantoins, and primidone may increase the metabolism of the contraceptives via CYP3A4 induction.

CLINICAL EFFECTS: May observe reduced contraceptive effects such as breakthrough bleeding, spotting, or pregnancy. Effects may be seen several days after discontinuation of the anticonvulsant or barbiturate. In addition, topiramate has been associated with an increased risk of birth defects, including cleft palate.

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: To avoid pregnancy, additional or alternative means of non-hormonal contraception should be utilized. Depo medroxyprogesterone may be an alternative, since its effectiveness is not decreased by anticonvulsants. Patients receiving perampanel at doses of 12 mg/day should use alternative contraception methods, such as an intra-uterine device or condom. Patients receiving topiramate may observe decreased contraceptive efficacy and increased breakthrough bleeding, especially at doses greater than 200 mg per day. Patients taking topiramate and estrogen containing or progestin-only contraceptives should be asked to report any change in their bleeding patterns.(20) Patients taking the combination of phentermine/topiramate for weight loss should be counseled that break-through bleeding may occur but is not expected to increase the risk of pregnancy. Instruct patients to report changes in bleeding patterns to their physician and to continue to take their hormonal contraceptive. Patients should not rely on hormonal contraceptives (other than implants or IUD) alone, but may use them in combination with a barrier contraceptive. It is necessary to use effective contraception with phentermine/topiramate, because the topiramate content of the product can cause birth defects. For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.

DISCUSSION: Decreased effectiveness of oral contraceptives, characterized by breakthrough bleeding and amenorrhea have been documented. Through August, 2010, Australia's Therapeutic Goods Association had received 32 reports of contraceptive failure leading to pregnancy as a result of a suspected interaction between etonogestrel implants and carbamazepine. In a randomized, open-label study in healthy women, concurrent topiramate (50 mg daily to 200 mg daily) and Ortho Novum 1/35 (ethinyl estradiol and norethindrone) resulted in no changes in levels of ethinyl estradiol or norethindrone. However, in another study, concurrent topiramate at doses of 200 mg daily, 400 mg daily, and 800 mg daily with valproic acid decreased the area-under-curve (AUC) of ethinyl estradiol by 18%, 21%, and 30%, respectively. There were no changes in norethindrone levels. The US manufacturer of topiramate states that the possibility of decreased contraceptive effectiveness should be considered. At doses of 12 mg/day, perampanel decreased the maximum concentration (Cmax) and AUC of levonorgestrel by 40% each. The Cmax of ethinyl estradiol was decreased by 18%. There were no effects on ethinyl estradiol AUC. Doses of perampanel of 4 mg/day and 8 mg/day had no effect on contraceptive levels. The combination of phentermine/topiramate (15 mg/92 mg for 15 days) increased the Cmax and AUC of norethindrone by 22% and 16%, respectively. The Cmax and AUC of ethinyl estradiol decreased 8% and 16%, respectively. Because contraceptive efficacy is primarily determined by the progestin component, no effect on contraceptive efficacy is expected, although breakthrough bleeding may occur. The effectiveness of depo medroxyprogesterone is not decreased by anticonvulsants or barbiturates.

Contraceptives/Selected Protease Inhibitors

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Ritonavir-boosted protease inhibitors(1-10), fosamprenavir(1), and nelfinavir(2) may induce the metabolism of estrogens. Unboosted atazanavir may inhibit the metabolism of estrogens and progestins.(3)

CLINICAL EFFECTS: Concurrent use of ritonavir-boosted protease inhibitors may result in decreased levels and effectiveness of estrogen and increased levels of progestins, which may increase the risk of insulin resistance, dyslipidemia, and acne.(1-10) Additionally, concurrent use of atazanavir-cobicistat with drospirenone-containing contraceptives may result in elevated levels of and effects from drospirenone, including hyperkalemia.(4) Atazanavir alone may result in elevated levels of estrogens.(3) Hormonal contraceptives may decrease the effectiveness of fosamprenavir.(1) Elevated liver enzymes may also occur.(1) Concurrent use with tipranavir may increase the risk of rash.(5)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US Department of Health and Human Services (DHHS) HIV guidelines recommend that concurrent use of oral contraceptives with atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir be done with a contraceptive product that contains at least 35 mcg ethinyl estradiol. If atazanavir is used without ritonavir, limit the dose of ethinyl estradiol to 30 mcg. Atazanavir/cobistat is contraindicated with drospirenone-containing products. No dose adjustment is needed when atazanavir/cobicistat is used with other oral contraceptives.(11) Most manufacturer recommendations differ from the DHHS guidelines. The manufacturer of atazanavir states that if an oral contraceptive agent containing either norgestimate or norethindrone is used with atazanavir without ritonavir, the contraceptive should contain no more than 30 mcg of ethinyl estradiol. These agents should be used with caution. Oral contraceptives containing progestins other than norethindrone or norgestimate and hormonal contraceptives other than oral (e.g. patches, rings, injections) have not been studied with atazanavir (boosted or unboosted), and alternative contraceptive methods are recommended.(3,4) The manufacturers of fosamprenavir,(1) darunavir,(5) and tipranavir(6) state that alternate methods of non-hormonal contraception are recommended. The manufacturers of the combination of lopinavir and ritonavir,(7) nelfinavir,(2) ritonavir,(8) and saquinavir(9) state that additional or alternate methods of contraception should be used in patients receiving these agents. The manufacturer of nirmatrelvir/ritonavir states that a non-hormonal method of contraception should be considered during nirmatrelvir/ritonavir therapy until one menstrual cycle after stopping therapy.(10) The CDC contraceptive guidelines state that intrauterine devices (copper or levonorgestrel) may be used with any antiretroviral agent.(12) The manufacturer of darunavir/cobicistat states that additional or alternative (non-hormonal) forms of contraception should be considered when estrogen-containing contraceptives are co-administered with darunavir/ritonavir.(17)

DISCUSSION: Concurrent administration of unboosted amprenavir (1200 mg twice daily) with ethinyl estradiol/norethindrone (0.035 mg/1 mg daily) decreased the amprenavir area-under-curve (AUC) and minimum concentration (Cmin) by 22% and 20%, respectively. The Cmin of ethinyl estradiol was increased by 32%. The AUC and Cmin of norethindrone were increased by 18% and 45%, respectively. Fosamprenavir is a prodrug of amprenavir.(1) In contrast, a study of fosamprenavir/ritonavir (700/100 mg twice daily) with ethinyl estradiol/norethindrone (0.035/0.5 mg daily) in 25 subjects had no effect on amprenavir levels. In addition, this combination decreased the Cmax and AUC of ethinyl estradiol by 28% and 37%, respectively. The Cmax, AUC, and Cmin of norethindrone decreased by 38%, 34%, and 26%, respectively.(1) Concurrent administration of atazanavir (400 mg daily) with ethinyl estradiol-norethindrone (Ortho-Novum) increased the maximum concentration (Cmax), AUC, and Cmin of ethinyl estradiol by 15%, 48%, and 91%, respectively, and the Cmax, AUC, and Cmin of norethindrone by 67%, 210%, and 362%, respectively.(3) Concurrent administration of atazanavir/ritonavir (300/100 mg daily) with ethinyl estradiol-norgestimate (Ortho Tri-Cyclen) decreased the maximum concentration (Cmax), AUC, and Cmin of ethinyl estradiol by 16%, 19%, and 37%, respectively, and increased the Cmax, AUC, and Cmin of norgestimate by 68%, 85%, and 202%, respectively.(3) In a study in 11 subjects, concurrent administration of darunavir/ritonavir (600/100 mg twice daily) with ethinyl estradiol/norethindrone (0.035/1 mg daily) decreased ethinyl estradiol Cmax, AUC, and Cmin by 32%, 44%, and 62%, respectively. The Cmax, AUC, and Cmin, of norethindrone decreased by 10%, 14%, and 30%, respectively.(6) The concurrent administration of nelfinavir (2250 mg daily) and ethinyl estradiol (35 mcg daily) and norethindrone (0.4 mg daily) decreased the AUC, Cmax, and Cmin of ethinyl estradiol by 47%, 28%, and 62%, respectively, and decreased the AUC and Cmin of norethindrone by 18% and 46%, respectively. There was no effect on the Cmax of norethindrone.(2) Concurrent administration of lopinavir/ritonavir (400/100 mg twice daily) and Ortho Novum (once daily) decreased the Cmax, AUC, and Cmin of ethinyl estradiol by 41%, 42%, and 58%, respectively. The Cmax, AUC, and Cmin, of norethindrone decreased by 16%, 17%, and 32%, respectively.(7) Concurrent administration of ritonavir (500 mg twice daily) and ethinyl estradiol (50 mcg single dose) decreased ethinyl estradiol AUC and Cmax by 40% and 32%, respectively.(8,14) In a study in 8 healthy females, ethinyl estradiol/gestodene (0.03/0.075 mg) had no effect on the pharmacokinetics of a single dose of saquinavir (600 mg).(15) In a study in 21 subjects, concurrent ethinyl estradiol/norethindrone (0.035/1 mg) and tipranavir-ritonavir (500/100 mg twice daily) decreased tipranavir Cmin by 27%. Ethinyl estradiol AUC and Cmax decreased by 48% and 48%, respectively. There were no significant effects on norethindrone levels. In a study in 13 subjects, concurrent ethinyl estradiol/ norethindrone (0.035/1 mg) and tipranavir-ritonavir (750/200 mg twice daily) had no significant effects on tipranavir levels. Ethinyl estradiol AUC and Cmax decreased by 52% and 43%, respectively. There were no significant effects on norethindrone levels.(6) Selected protease inhibitors linked to this monograph include: amprenavir, atazanavir, darunavir, fosamprenavir, lopinavir, nelfinavir, nirmatrelvir, and ritonavir. Although not directly linked, protease inhibitor regimens containing saquinavir and tipranavir also alert.

Contraceptives/Troglitazone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Troglitazone may induce the metabolism of the oral contraceptive by CYP3A4.(1,2)

CLINICAL EFFECTS: Concurrent administration may result in decreased levels of both the estrogen and progestin components of the oral contraceptive, which may result in breakthrough bleeding and loss of contraception.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Higher contraceptive dosages may be needed in patients receiving troglitazone therapy. Alternative methods of contraception should also be considered.(1,2) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(3)

DISCUSSION: In a study in 15 healthy women, concurrent troglitazone (600 mg daily) and Ortho Novum 1/35 (35 mcg ethinyl estradiol, 1 mg norethindrone) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of ethinyl estradiol by 29% and 32%, respectively. Concurrent therapy decreased the AUC and Cmax of norethindrone by 30% and 31%. Troglitazone decreased the plasma unbound AUC of norethindrone by 49%.(1,2)

Contraceptives/Troleandomycin

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Troleandomycin is a strong CYP3A4 inhibitor and may decrease metabolism of oral contraceptives.(1,2) Increased exposure to estrogens may result in decreased bile acid secretion and toxic accumulation of bile acids.

CLINICAL EFFECTS: The concurrent use of troleandomycin with contraceptive agents may result in intrahepatic cholestasis.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concurrent administration of these drugs.

DISCUSSION: Numerous case reports and one study document the occurrence of intrahepatic cholestasis in patients receiving oral contraceptives and troleandomycin concomitantly. This reaction appears to be reversible if the drugs are discontinued.

Estrogen-Containing Contraceptives/Lamotrigine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Estrogens increase glucuronidation mediated metabolism of lamotrigine. Lamotrigine may modestly induce the metabolism of hormonal contraceptives.(1,2)

CLINICAL EFFECTS: Concurrent use of lamotrigine and estrogen-containing contraceptives may result in decreased levels and effectiveness of both agents. Increased seizure rates have been reported in patients taking lamotrigine for epilepsy.(1,2)

PREDISPOSING FACTORS: Increased seizure risk is more likely when lamotrigine is used as monotherapy for treatment of epilepsy. The risk for an increase in seizure rate is lower in patients already stabilized on a combination of lamotrigine and an enzyme inducing agent such as carbamazepine, phenytoin, phenobarbital, or primidone. The risk for contraceptive failure may be greater in patients also taking other enzyme inducing agents such as carbamazepine, phenytoin, phenobarbital, primidone, or rifampin.

PATIENT MANAGEMENT: During initiation of lamotrigine therapy, no adjustments to the recommended lamotrigine dose escalation guidelines are recommended in patients taking estrogen-containing contraceptives.(1) Dose adjustments will be necessary in most patients who start or stop an estrogen-containing oral contraceptive in patients taking maintenance doses of lamotrigine. The lamotrigine dosage may need to be increased by as much as 2-fold according to clinical response when estrogen-containing contraceptives are initiated in patients NOT taking other drugs which induce glucuronidation such as carbamazepine, phenytoin, phenobarbital, primidone, lopinavir/ritonavir, atazanavir/ritonavir, or rifampin. If estrogen-containing contraceptives are discontinued, the dosage of lamotrigine may need to be decreased by 50%.(1) Initiate changes in lamotrigine dosage at the same time estrogen containing products are started or stopped.(1) In patients also taking carbamazepine, phenytoin, phenobarbital, primidone, lopinavir/ritonavir, atazanavir/ritonavir, or rifampin, no lamotrigine maintenance dosage adjustments should be necessary if estrogen-containing contraceptives are initiated or discontinued.(1) Patients should be instructed to promptly report any changes in their menstrual cycle, such as break-through bleeding.(1)

DISCUSSION: In a study in 16 females, concurrent ethinylestradiol (30 mcg) and levonorgestrel (150 mcg) with lamotrigine (300 mg per day) increased lamotrigine clearance by 2-fold, with a mean decrease in lamotrigine area-under-curve (AUC) and maximum concentration (Cmax) by 52% and 39%, respectively. Serum trough lamotrigine levels were two-fold higher at the end of the week of inactive tablets when compared to lamotrigine levels at the end of the active hormonal cycle. This effect should be expected in women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin.(1) In a study in 16 females, concurrent ethinylestradiol (30 mcg) and levonorgestrel (150 mcg) with lamotrigine (300 mg per day) had no effect on ethinylestradiol levels. Levonorgestrel AUC and Cmax decreased by 19% and 12%, respectively. Though there was no hormonal evidence of ovulation, there was some loss of suppression of the hypothalamic-pituitary-ovarian axis.(1) In a study, mean steady-state lamotrigine levels were 13 micro mol/L in 22 women taking oral contraceptives compared to 28 micro mol/L in 30 women who were not taking oral contraceptives. The lamotrigine dose/body weight/ plasma concentration was 2.1 L/kg/day in patients taking oral contraceptives compared to 0.8 L/kg/day in patients without oral contraceptives.(3) One set of authors reported seven cases of decreased lamotrigine levels in patients receiving oral contraceptives. Lamotrigine levels were decreased by 41% to 64%, average 49%. Most patients either experienced increased seizure frequency or recurrence of seizures after the addition of the oral contraceptive, or increased lamotrigine adverse effects following the discontinuation of the oral contraceptive.(4) A study in 45 females compared lamotrigine pharmacokinetics in patients taking an ethinyl estradiol-containing contraceptive (n=11) to patients taking a progestin-only contraceptive (n=16) and to patients taking no contraceptives (n=18). The lamotrigine serum concentration to dose ratio was significantly lower in patients taking ethinyl estradiol-containing contraceptives. There was no significant difference between patients taking progestin-only contraceptives and those using no contraceptives.(5) In a double-blind, placebo-controlled study, women with epilepsy were treated with lamotrigine monotherapy, or lamotrigine plus oral contraceptive. After 21 days, the mean dose-corrected lamotrigine concentration was 84% higher in the monotherapy group verses the combined treatment group.(6) Another study in 8 epileptic females assessed the pharmacokinetics of lamotrigine in combination with hormonal contraceptives. Serum samples were drawn on days 18 and 21 of hormonal contraceptive therapy and during days 5 and 7 of the placebo week (hormonal contraceptive free week). Analysis found statistically significant elevations (approximately 27%) in lamotrigine plasma concentrations during the hormone-free week, than during cycle intake.(7) In a study, 22 enrolled females took lamotrigine titrated up to 300 mg/d for a period of 130 days and either combined it with an oral contraceptive or took lamotrigine monotherapy. Both ethinyl estradiol and lamotrigine serum levels were drawn in the presence or absence of combined therapy. Laboratory serum data showed the ratios of lamotrigine AUC (0-24h) and Cmax at 0.48 for coadministration (lamotrigine plus oral contraceptive) and a ratio of 0.61 for lamotrigine monotherapy. There were no changes in ethinyl estradiol levels. Levonorgestrel levels decreased 19% and 7 of 22 patients reported break-through bleeding; however, suppression of ovulation was maintained.(8) In an interaction study, lamotrigine decreased exposure to the progestin component (levonorgestrel) of an oral contraceptive by 19%, but suppression of ovulation was not affected. The manufacturer of lamotrigine states that the possibility of decreased contraceptive efficacy in some patients cannot be excluded.(1) The 2010 CDC and 2015 WHO contraceptive guidelines do not mention evidence of reduced contraceptive efficacy with concurrent therapy with lamotrigine.(9,10) The 2018 Faculty of Sexual and Reproductive Healthcare contraceptive guidelines state that lamotrigine is not thought to be an enzyme-inducing drug but that contraceptive efficacy may be reduced by concurrent use with lamotrigine. The clinical significance of this effect is unknown. The guideline recommends caution when administering lamotrigine and contraceptives concurrently.(11)

Estrogen-Containing Contraceptives/Thalidomide Analogues

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Both the thalidomide analogues and estrogen-containing contraceptives are associated with an increased risk of thromboembolic disorders.(1-9) The US manufacturer of thalidomide states that it is unknown if these risks are additive.(1)

CLINICAL EFFECTS: Use of iberdomide, lenalidomide, pomalidomide, or thalidomide in patients taking estrogen-containing hormonal contraceptives may increase the risk of venous or arterial thromboembolism, including deep vein thrombosis (DVT), pulmonary embolism (PE), myocardial infarction (MI), and stroke.(1-10)

PREDISPOSING FACTORS: Previous history of thromboembolic events or concomitant administration of erythropoietic agents may increase the thrombotic risk. Modifiable risk factors (e.g., diabetes, hyperlipidemia, hypertension, smoking) should be minimized.(1-9)

PATIENT MANAGEMENT: The Canadian manufacturer of the thalidomide analogues states that use of hormonal contraceptives is not recommended.(2-4) The UK manufacturer of the thalidomide analogues states that concurrent combined hormonal contraceptives is not recommended and that patients should be switched to a progesterone-only or non-hormonal contraceptive (e.g., progestin-only pills, progestin implant or intrauterine device, depot medroxyprogesterone acetate, tubal sterilization).(5-7) The US manufacturer of the thalidomide analogues does not recommend against use of hormonal contraceptives but instead includes them as an option for highly effective contraception. Estrogen-containing therapies should be used with caution after assessment of their risks and benefits.(1,8-9) The risk of venous thromboembolism continues for 4-6 weeks after discontinuing combined oral contraception.(5-7) If the estrogen-containing contraceptive is not used, two other simultaneous, effective methods of contraception are still required in the US and Canada.(1-4,8,9) In the UK, at least one effective method of contraception is required.(5-7)

DISCUSSION: Iberdomide, lenalidomide, pomalidomide, and thalidomide can all cause thromboembolism. Concurrent use of other agents that may increase the risk of thrombosis, like estrogen-containing therapies, may result in an increased risk of thrombosis.

Estrogenic Agents/Tranexamic Acid (Injectable)

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Tranexamic acid is an antifibrinolytic and estrogen-containing hormonal contraceptives are known to increase the risk of venous thromboembolism and arterial thromboses, including stroke and myocardial infarction. Concurrent use may increase the risk of these events.(1,2)

CLINICAL EFFECTS: Concurrent use of tranexamic acid in patients taking estrogen-containing agents or hormonal contraceptives may increase the risk of embolisms.(1,2)

PREDISPOSING FACTORS: The risk of thrombosis may be even greater in women who are obese or smoke, especially smokers over age 35.(1)

PATIENT MANAGEMENT: The concurrent use of injectable tranexamic and and estrogen-containing hormonal contraception or estrogen replacement therapy should be approached with caution.(1)

DISCUSSION: There are no clinical trial data on the risk of concurrent therapy with tranexamic acid and hormonal contraceptives. There have been postmarketing reports of venous and arterial thrombotic events in women receiving combination therapy with oral tranexamic acid.(2) Women taking hormonal contraception were excluded from safety and efficacy trials of oral tranexamic acid.(2)

Estrogens/Tizanidine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Estrogen containing hormonal contraceptives or hormone replacement therapy may decrease the clearance of tizanidine by inhibiting CYP1A2.(1)

CLINICAL EFFECTS: Concurrent use of tizanidine and estrogen containing hormonal contraceptives or hormone replacement therapy may result in elevated levels of and effects from tizanidine, including hypotension, bradycardia, drowsiness, sedation, and decreased psychomotor function.

PREDISPOSING FACTORS: The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(2)

PATIENT MANAGEMENT: The manufacturer states that routine administration of tizanidine and estrogen containing hormonal contraceptives or hormone replacement therapy should be avoided.(1) If concurrent use is necessary, tizanidine should be initiated with a 2 mg dose and increased 2-4 mg daily based on patient response to therapy.(1) If adverse reactions such as hypotension, bradycardia, or excessive drowsiness occur, reduce or discontinue tizanidine therapy.(1)

DISCUSSION: In a retrospective analysis of population pharmacokinetic data, women taking oral contraceptives with tizanidine has a 50% lower clearance compared to women not on oral contraceptives.(1) In fifteen women using oral contraceptives, tizanidine (4 mg) increased the area-under-curve (AUC) and peak plasma tizanidine concentration, 3.9-fold and 3.0-fold respectively, compared to placebo. In one patient, the AUC of tizanidine exceeded twenty times the AUC of the placebo group.(3)

Estrogens/Tofacitinib (>=20 Mg Daily)

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Estrogens increase the risk of thrombosis, and combining estrogens with a higher dose of tofacitinib (greater than or equal to 10 mg twice daily, or 20 mg/day) may place patients at high risk of thromboembolism.(1-3)

CLINICAL EFFECTS: Concurrent use of estrogens with a higher dose of tofacitinib (greater than or equal to 10 mg twice daily, or 20 mg/day) may increase the incidence of pulmonary embolism and death.(1-3)

PREDISPOSING FACTORS: Additional risk factors include advanced age, obesity (BMI >30), smoking, prolonged immobilization, heart failure, hypercoagulable states, history of venous thromboembolism, malignancy, and major surgery.(1)

PATIENT MANAGEMENT: The European manufacturer states that the 10 mg twice daily dose of tofacitinib is not recommended in patients who are on combined hormonal contraceptives or hormone replacement therapy, or who are otherwise at high risk of pulmonary embolism, unless there are no suitable alternatives.(4) Patients at high risk of pulmonary embolism should be switched to alternative therapies. For the treatment of rheumatoid arthritis and psoriatic arthritis, the dose of tofacitinib should be limited to 5 mg twice daily or tofacitinib XR 11 mg daily.(1-4) The US FDA and Health Canada have not placed use restrictions specifically on concurrent use of tofacitinib with hormonal contraceptives or hormone replacement therapy. Both agencies advise avoiding tofacitinib in patients at increased risk of thrombosis. The US and Canadian manufacturers recommend against a dosage of tofacitinib 10 mg twice daily or weight-based equivalent twice daily or tofacitinib XR 22 mg once daily for rheumatoid arthritis, psoriatic arthritis, or polyarticular-course juvenile idiopathic arthritis. For the treatment of ulcerative colitis, the lowest effective dose for the shortest duration possible is recommended. Counsel patients on the risk of thrombosis and its signs and symptoms. Instruct patients to promptly report any symptoms of thrombosis and discontinue tofacitinib in patients with symptoms of thrombosis.(5-7) There is currently no use restriction on the combination of estrogens with lower doses of tofacitinib (less than 20 mg daily).

DISCUSSION: In an ongoing open-label study comparing the safety of tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, and a tumor necrosis factor (TNF) inhibitor in rheumatoid arthritis patients 50 years old and older, the incidence of pulmonary embolism (PE) was 6-fold higher in the tofacitinib 10 mg twice daily arm and 3-fold higher in the tofacitinib 5 mg twice daily arm compared to the TNF inhibitor arm (17 cases/3,123 patient-years, 9 cases/3,317 patient-years, and 3 cases/3,319 patient-years, respectively). All-cause mortality was also higher in the tofacitinib 10 mg twice daily and 5 mg twice daily arms compared to the TNF inhibitor arm (28 deaths/3,140 patient-years, 19 deaths/3,324 patient-years, and 9 deaths/3,323 patient-years, respectively).(3)

Ethinyl Estradiol (<= 20 Mcg)/Glecaprevir-Pibrentasvir

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The mechanism of action has not been described.

CLINICAL EFFECTS: Coadministration of greater than 20 mcg of ethinyl estradiol with glecaprevir-pibrentasvir may increase the risk of ALT elevations.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Due to the added risk for ALT elevations, the US manufacturer of glecaprevir-pibrentasvir states that medications which contain more than 20 mcg of ethinyl estradiol such as oral contraceptives are not recommended to be administered with glecaprevir-pibrentasvir. No dose adjustment is required when glecaprevir-pibrentasvir is coadministered with products containing 20 mcg or less of ethinyl estradiol.(1) The Canadian and UK manufacturers of glecaprevir-pibrentasvir state that ethinyl estradiol-containing products are contraindicated. The UK manufacturer of ethinyl estradiol/etonogestrel states that users must switch to an alternative method of contraception before starting therapy with glecaprevir-pibrentasvir. Ethinyl estradiol-etonogestrel can be restarted 2 weeks following completion of treatment with glecaprevir-pibrentasvir.(2,3) Alternative methods of contraception, such as progestin only or non-hormonal methods may be recommended during glecaprevir-pibrentasvir therapy.

DISCUSSION: Simultaneous administration of glecaprevir-pibrentasvir may increase the risk of ALT elevations.(1)

Hormonal Contraceptive Agents/Boceprevir

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Boceprevir may induce the metabolism of hormonal contraceptives by CYP3A4.

CLINICAL EFFECTS: Concurrent use of boceprevir and hormonal contraceptive agents may decrease the effectiveness of the hormonal contraceptive agent, which may result in contraceptive failure. Boceprevir is only indicated for use with ribavirin, a known teratogen.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Women receiving boceprevir therapy should not rely on hormonal contraceptive agents (including oral, implantable, injectable, or transdermal agents) because they may not be effective. Two alternative effective methods of contraception (e.g. intrauterine devices and/or barrier methods) should be used during combination treatment with ribavirin and for six months after completing therapy.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(2)

DISCUSSION: Concurrent use of boceprevir (800 mg three times daily for 7 days) decreased the area-under-curve (AUC) of ethinyl estradiol (administered as drospirenone/ethinyl estradiol 3/0.02 mg daily for 14 days) by 24%.(1) Concurrent use of boceprevir (800 mg three times daily for 21 days) decreased the AUC and maximum concentration (Cmax) of ethinyl estradiol (administered as norethindrone/ethinyl estradiol 1/0.035 mg daily for 21 days) by 26% and 21%, respectively. The AUC and Cmax of norethindrone decreased by 4% and 17%, respectively.(1)

Hormonal Contraceptive Agents/Bosentan

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Bosentan may induce the metabolism of hormonal contraceptive agents by CYP3A4.(1,2)

CLINICAL EFFECTS: Concurrent use of bosentan and hormonal contraceptive agents may decrease the effectiveness of the hormonal contraceptive agent, which may result in contraceptive failure.(1,2) Bosentan is likely to cause major birth defects if used by pregnant women.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Women receiving bosentan therapy should not rely solely on hormonal contraceptive agents (including oral, implantable, injectable, or transdermal agents) because they may not be effective. Consider consulting a gynecologist or similar expert for advice on adequate contraception.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.

DISCUSSION: Concurrent use of bosentan and Ortho-Novum (norethindrone and ethinyl estradiol) resulted in average decreases of norethindrone and ethinyl estradiol by 14% and 31%, respectively. However, individual subjects experienced decreases in norethindrone and ethinyl estradiol by as much as 56% and 66%, respectively. Therefore, hormonal contraceptive agents may not be reliable in patients taking bosentan.(1,2)

Hormonal Contraceptive Agents/Clobazam

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Clobazam may induce the metabolism of hormonal contraceptive agents by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of clobazam and hormonal contraceptive agents may decrease the effectiveness of the hormonal contraceptive agent, which may result in contraceptive failure. While there are no adequate studies in pregnant women, animal data suggests that clobazam use in pregnancy may result in development toxicity and fetal abnormalities.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Women receiving clobazam therapy should not rely on hormonal contraceptive agents (including oral, implantable, injectable, or transdermal agents) because they may not be effective. Women taking clobazam should use additional, non-hormonal forms of contraception during and for 28 days after discontinuing clobazam.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(2)

DISCUSSION: Clobazam decreased the maximum concentration (Cmax) and area-under-curve (AUC) of midazolam, a CYP3A4 substrate by 24% and 27%, respectively. Because some hormonal contraceptives are metabolized by CYP3A4, clobazam use may decrease their effectiveness.(1)

Hormonal Contraceptive Agents/Dabrafenib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Dabrafenib may induce the metabolism of hormonal contraceptive agents by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of dabrafenib and hormonal contraceptive agents may decrease the effectiveness of the hormonal contraceptive agent, which may result in contraceptive failure. Dabrafenib may cause birth defects and/or miscarriage if used by pregnant women.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Women receiving dabrafenib therapy should not rely solely on hormonal contraceptive agents (including oral, implantable, injectable, or transdermal agents) because they may not be effective. Women should be advised to use a highly effective non-hormonal method of contraception during and for 2 weeks after dabrafenib mono-therapy.(1-3) The Canadian and UK manufacturers of dabrafenib also state that an effective method of contraception should be continued for 16 weeks after the last dose of trametinib when given in combination dabrafenib.(2-3) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(4)

DISCUSSION: Dabrafenib is a moderate inducer of CYP3A4. In a clinical trial in 12 subjects, dabrafenib decreased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of midazolam, a sensitive CYP3A4 substrate) by 61% and 74%, respectively. Hormonal contraceptives are also metabolized by CYP3A4, therefore, hormonal contraceptive agents may not be reliable in patients taking dabrafenib.(1)

Hormonal Contraceptive Agents/Efavirenz; Nevirapine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Efavirenz(1) and nevirapine(2,3) may induce the metabolism of hormonal contraceptives via CYP3A4.

CLINICAL EFFECTS: Concurrent administration of efavirenz(1) or nevirapine(2,3) with a hormonal contraceptive agent may result in decreased plasma concentrations and clinical effectiveness of the contraceptive agent.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturers of efavirenz(1) and nevirapine(2) state that hormonal contraceptives should not be used as the sole method of contraception in women taking these agents. A reliable method of barrier contraception must be used in addition to hormonal contraception in women taking efavirenz.(1) Alternative or additional methods of contraception should be considered in women taking nevirapine.(2) Because of the long half-life of efavirenz, women should continue to use a barrier method of contraception in addition to hormonal contraception for 12 weeks after discontinuing efavirenz.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg.(4) Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.

DISCUSSION: In a study in 21 subjects, concurrent efavirenz (600 mg daily for 14 days) and ethinyl estradiol/norgestimate (0.035/0.25 mg for 14 days) had no effect on ethinyl estradiol levels. The maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of norelgestromin decreased by 46%, 64%, and 82%, respectively. The Cmax, AUC, and Cmin of levonorgestrel decreased by 80%, 83%, and 86%, respectively.(1) There have been reports of contraceptive failure in patients with etonogestrel implants who were receiving efavirenz.(1) In a study in 10 subjects taking Ortho-Novum 1/35, nevirapine decreased the AUC of ethinyl estradiol by 20% and the AUC and Cmax of norethindrone by 19% and 16%, respectively.(2) In a study in 16 HIV-positive females, concurrent nevirapine (200 mg daily, Days 2-15; 200 mg twice daily, Days 16-29) and ethinyl estradiol with norethindrone decreased the AUCs of ethinyl estradiol and norethindrone by 29% and 18%, respectively.(3) A study of 118 HIV-positive females compared levonorgestrel pharmacokinetics and safety between the following groups: 1. levonorgestrel 1.5 mg with dolutegravir-based antiretrovirals (ART)(control group), 2. levonorgestrel 1.5 mg with efavirenz-based ART, 3. levonorgestrel 3 mg with efavirenz-based ART, and 4. levonorgestrel 3 mg with rifampin. While both levonorgestrel 3 mg groups had Cmax and AUC(0-8h) similar to the control group, the half life of levonorgestrel was shorter, resulting in an AUC(inf) that was 53% lower in the efavirenz group and 37% lower in the rifampin group than the control group. Tolerability was similar between groups. No pregnancies were reported but it is unknown whether the correction of levonorgestrel levels early in the dosing period is sufficient to maintain overall emergency contraceptive effectiveness.(5)

Hormonal Contraceptive Agents/Encorafenib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Encorafenib may induce the metabolism of hormonal contraceptive agents by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of encorafenib and hormonal contraceptive agents may decrease the effectiveness of the hormonal contraceptive agent, which may result in contraceptive failure. Encorafenib may cause birth defects and/or miscarriage if used by pregnant women.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Women receiving encorafenib therapy should not rely solely on hormonal contraceptive agents (including oral, implantable, injectable, or transdermal agents) because they may not be effective. Women should be advised to use a highly effective non-hormonal method of contraception during and for 2 weeks after the final dose of encorafenib.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(2)

DISCUSSION: Based on in vitro data, encorafenib is an inducer of CYP3A4 at clinically relevant plasma concentrations.(1) Hormonal contraceptives are also metabolized by CYP3A4, therefore, hormonal contraceptive agents may not be reliable in patients taking encorafenib.(1)

Hormonal Contraceptive Agents/Lumacaftor

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Lumacaftor, a strong inducer of CYP3A4, may induce the metabolism of hormonal contraceptive agents.(1)

CLINICAL EFFECTS: Concurrent use of lumacaftor and hormonal contraceptive agents may decrease the effectiveness of the hormonal contraceptive agent, which may result in contraceptive failure. In addition, menstrual related adverse effects such as such as amenorrhea, dysmenorrhea, menorrhagia and irregular menses are common.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Women receiving lumacaftor therapy should not rely solely on hormonal contraceptive agents (including oral, implantable, injectable, or transdermal agents) because they may not be effective. The manufacturer recommends avoiding concomitant use unless the benefit outweighs the risk.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(2)

DISCUSSION: Lumacaftor is a strong inducer of CYP3A4. Hormonal contraceptives are metabolized by CYP3A4, therefore, hormonal contraceptive agents may not be reliable in patients taking lumacaftor.(1) Menstrual irregularities, e.g. amenorrhea, dysmenorrhea, menorrhagia and irregular menses were reported in 27% of lumacaftor patients also taking hormonal contraceptives vs. 3% of female patients not using hormonal contraceptives.(1)

Hormonal Contraceptive Agents/Telaprevir

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Telaprevir may induce the metabolism of hormonal contraceptives by CYP3A4.

CLINICAL EFFECTS: Concurrent use of telaprevir and hormonal contraceptive agents may decrease the effectiveness of the hormonal contraceptive agent, which may result in contraceptive failure. Telaprevir is only indicated for use with ribavirin, a known teratogen.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Women receiving telaprevir therapy should not rely on hormonal contraceptive agents (including oral, implantable, injectable, or transdermal agents) because they may not be effective during and for two weeks after completing telaprevir therapy. Two alternative effective methods of contraception (e.g. intrauterine devices and/or barrier methods) should be used during combination treatment with ribavirin and for six months after completing therapy.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(2)

DISCUSSION: In a study in 24 subjects, concurrent use of telaprevir (750 mg every 8 hours for 21 days) decreased the maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of ethinyl estradiol (administered as ethinyl estradiol/norethindrone 0.035/0.5 mg daily for 21 days) by 26%, 28%, and 33% respectively. The Cmax, AUC, and Cmin of norethindrone decreased by 15%, 11%, and 6%, respectively. There were no significant effects on telaprevir levels.(1,2)

Hormonal Contraceptives/Artemether

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Artemether may increase the metabolism of hormonal contraceptives.

CLINICAL EFFECTS: Concurrent use of artemether may result in reduced levels and clinical effectiveness of hormonal contraceptives. In the case of contraceptives, breakthrough bleeding and pregnancy may result.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving artemether should be alerted to the possibility of decreased effectiveness of their hormonal contraceptive. It is recommended that alternative or additional non-hormonal contraceptive methods be used during artemether therapy(1) and for 28 days after completing therapy.(2) The patient should be asked to report any spotting or bleeding. For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.

DISCUSSION: Artemether has been shown to weakly induce CYP2C19, CYP2B6, and CYP3A and may reduce the efficacy of hormonal contraceptives.(1)

Hormonal Contraceptives/Belzutifan

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Belzutifan is a weak to moderate CYP3A4 inducer. Coadministration of belzutifan with hormonal contraceptives may lead to contraceptive failure or an increase in breakthrough bleeding due to decreased hormonal concentrations.(1)

CLINICAL EFFECTS: Concurrent use of belzutifan can lead to ineffective hormonal contraceptive and cause fetal harm when administered to a pregnant woman.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Women of reproductive age should be counseled not to rely on hormonal contraceptives (including oral contraceptives, patches, implants, and/or IUDs) for contraception. Pregnant women and females of reproductive potential should be counseled on the potential risk to the fetus.(1) Advise females of reproductive potential to use effective non-hormonal contraception during treatment with belzutifan and for 1 week after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with belzutifan and for 1 week after the last dose.(1) Verify the pregnancy status of females of reproductive potential prior to initiating treatment with belzutifan.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(2)

DISCUSSION: Belzutifan has not been studied with hormonal contraceptives. It can render some hormonal contraceptives ineffective and cause embryo-fetal harm. Women should use non-hormonal contraception during therapy.(1) In an animal reproduction study, oral administration of belzutifan to pregnant rats during the period of organogenesis caused embryo-fetal lethality, reduced fetal body weight, and fetal skeletal malformations at maternal exposures greater than or equal to 0.2 times the human exposure (AUC) at the recommended dose of 120 mg daily.(1)

Hormonal Contraceptives/Bexarotene

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Bexarotene may induce the CYP3A4 mediated metabolism of both estrogen and progestin components of hormonal contraceptives.(1,2)

CLINICAL EFFECTS: Concurrent use of bexarotene may result in reduced levels and clinical effectiveness of hormone containing contraceptives. Breakthrough bleeding and contraceptive failure/pregnancy may result.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving bexarotene should be alerted to the risk for decreased effectiveness (e.g. contraceptive failure) of their hormonal contraceptive therapy and should be advised to use a reliable non-hormonal contraceptive option.(1) Due to bexarotene being teratogenic in animal studies and may cause fetal harm, the US prescribing information recommends that two reliable forms of contraception be used simultaneously one month before, during, and at least one month after bexarotene therapy. Females of reproductive potential should be advised to avoid becoming pregnant. If treatment with bexarotene is intended in a female with reproductive potential, it is strongly recommended that one of the two reliable forms of contraception should be non-hormonal. The patient should be asked to report any spotting or bleeding.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(3)

DISCUSSION: In a study of bexarotene 400 mg/m2 was administered orally with atorvastatin (another CYP3A4 substrate), the area-under-curve (AUC) of atorvastatin was decreased by 50%.(1) No studies have been conducted looking specifically at hormonal contraceptive use with bexarotene. However, due to the possibility of intended pregnancy the use of non-hormonal contraception needs to be considered.(1)

Hormonal Contraceptives/Cenobamate

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Cenobamate may induce the CYP3A4 mediated metabolism of hormonal contraceptives.(1)

CLINICAL EFFECTS: Concurrent use of cenobamate may reduce the effectiveness of hormonal contraceptives.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Women of reproductive age should be counseled not to rely on hormonal contraceptives for contraception. According to the US manufacturer, women should use additional or alternative non-hormonal methods of birth control during cenobamate therapy.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (i.e., a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if she does become pregnant.(2)

DISCUSSION: Cenobamate may induce the CYP3A4 mediated metabolism of hormonal contraceptives. The effectiveness of hormonal contraceptives may be reduced when administered concomitantly with cenobamate. Women should use additional or alternative non-hormonal birth control.(1)

Hormonal Contraceptives/Deferasirox

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Deferasirox may induce the CYP3A4 mediated metabolism of hormonal contraceptives.(1)

CLINICAL EFFECTS: Concurrent use of deferasirox may reduce the effectiveness of hormonal contraceptives.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Women of reproductive age should be counseled not to rely on hormonal contraception (including oral contraceptives, patches, implants, and/or IUDs) for contraception. Women should use a non-hormonal method of birth control during deferasirox therapy.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (i.e., a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if she does become pregnant.(2)

DISCUSSION: Deferasirox may induce the CYP3A4 mediated metabolism of hormonal contraceptives. Deferasirox may decrease the effectiveness of hormonal contraceptives, including oral contraceptives, patches, implants, and/or IUDs. Women should use a non-hormonal method of birth control during deferasirox therapy.(1)

Hormonal Contraceptives/Elagolix

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Based on the mechanism of action of elagolix, estrogen containing contraceptives are expected to reduce the efficacy of elagolix. The effect of progestin-only contraceptives on elagolix is unknown.(1) Elagolix is a weak to moderate inducer of CYP3A4 and may increase the metabolism of progestins. The mechanism of elagolix's interaction with estrogens is unknown.(1)

CLINICAL EFFECTS: Concurrent use of hormonal contraceptives may reduce the effectiveness of elagolix.(1) Elagolix 200 mg twice daily may increase the levels and toxicity of estrogens, including thromboembolic disorders and vascular events, while decreasing the levels and efficacy of progestin-containing hormonal contraceptives. Elagolix may cause birth defects and/or miscarriage if used by pregnant women.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Women of reproductive potential should use effective non-hormonal methods of contraception during elagolix therapy and for 28 days after discontinuing elagolix. Women of reproductive age should be counseled not to use hormonal contraception (including oral contraceptives, patches, implants, and/or IUDs) for contraception.(1)

DISCUSSION: Hormonal contraceptives may decrease the effectiveness of elagolix. Women should use a non-hormonal method of birth control during elagolix therapy.(1) Coadministration of elagolix 200 mg twice daily for 14 days with ethinyl estradiol 20 mcg-levonorgestrel 0.1 mg resulted in a 2.2-fold increase in ethinyl estradiol exposure and a 27% decrease in levonorgestrel exposure.(1) Coadministration of elagolix 150 mg daily did not affect exposure to norethindrone 0.35 mg once daily nor to ethinyl estradiol 35 mcg-triphasic norgestimate 0.18/0.215/0.25 mg once daily.(1)

Hormonal Contraceptives/Elvitegravir-Cobicistat

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown.

CLINICAL EFFECTS: Concurrent administration may result in increased effects from the progestin (insulin resistance, dyslipidemia, acne, and venous thrombosis) and decreased effects of the estrogen component.(1,2) Concurrent use of cobicistat-containing products may result in elevated levels of and adverse effects from drospirenone, including hyperkalemia.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of cobicistat-elvitegravir-emtricitabine-tenofovir recommends the use of non-hormonal methods of contraception.(1) The manufacturer of cobicistat-elvitegravir-emtricitabine-tenofovir alafenamide recommends clinical monitoring due to the potential for hyperkalemia when administered concurrently with drospirenone-ethinyl estradiol.(2)

DISCUSSION: Concurrent administration of cobicistat-elvitegravir-emtricitabine-tenofovir increased Cmax, AUC, and minimum concentration (Cmin) of norgestimate by 2.08-fold, 2.26-fold, and 2.67-fold, respectively. The Cmax, AUC, and Cmin of ethinyl estradiol decreased by 6%, 25%, and 44%, respectively.(1) Drospirenone has anti-mineralocorticoid activity comparable to a 25mg dose of spironolactone.

Hormonal Contraceptives/Enasidenib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Enasidenib may increase or decrease the metabolism of hormonal contraceptives.(1)

CLINICAL EFFECTS: Concurrent use of enasidenib may increase side effect from or reduce the effectiveness of hormonal contraceptives. Enasidenib may cause birth defects if used by pregnant women.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Women of reproductive age should be counseled not to rely on hormonal contraception (including oral contraceptives, patches, implants, and/or IUDs) for contraception. Women should use a back-up method of birth control during enasidenib therapy. Women of reproductive potential should use effective non-hormonal methods of contraception during enasidenib therapy and for at least 2 months after the final dose.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(2)

DISCUSSION: Enasidenib may increase or decrease metabolism of hormonal contraceptives. Enasidenib may increase or decrease the effectiveness of hormonal contraceptives, including oral contraceptives, patches, implants, and/or IUDs. Women should use a back-up method of birth control during enasidenib therapy and for at least 1 month after the final dose.(1)

Hormonal Contraceptives/Ixazomib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Ixazomib does not interact with hormonal contraceptives, but the dexamethasone used with ixazomib is a weak to moderate CYP3A4 inducer and may increase the CYP3A4 mediated metabolism of hormonal contraceptives.(1)

CLINICAL EFFECTS: Concurrent use of ixazomib with dexamethasone may reduce the effectiveness of hormonal contraceptives.(1) Ixazomib may cause birth defects and/or miscarriage if used by pregnant women.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Women of reproductive age should be counseled not to rely on hormonal contraceptives (including oral contraceptives, patches, implants, and/or IUDs) for contraception. Women should use an effective non-hormonal back-up method of birth control during and for 90 days after ixazomib-dexamethasone therapy.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(2)

DISCUSSION: Ixazomib-dexamethasone has not been studied with hormonal contraceptives. Dexamethasone may decrease the effectiveness of hormonal contraceptives, including oral contraceptives, patches, implants, and/or IUDs. Women should use a back-up method of birth control during ixazomib-dexamethasone therapy.(1)

Hormonal Contraceptives/Lesinurad

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Lesinurad may induce the CYP3A4 mediated metabolism of hormonal contraceptives.(1)

CLINICAL EFFECTS: Concurrent use of lesinurad may reduce the effectiveness of hormonal contraceptives.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Women of reproductive age should be counseled not to rely on hormonal contraception (including oral contraceptives, patches, implants, and/or IUDs) for contraception. Women should use a back-up method of birth control during lesinurad therapy.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(2)

DISCUSSION: Lesinurad may decrease the effectiveness of hormonal contraceptives, including oral contraceptives, patches, implants, and/or IUDs. Women should use a back-up method of birth control during lesinurad therapy.(1)

Hormonal Contraceptives/Lomitapide

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Hormonal contraceptives are weak inhibitors of CYP3A4 and may inhibit the metabolism of lomitapide.(1) Lomitapide is very susceptible to CYP3A4 inhibition. For example, in an interaction study with a strong CYP3A4 inhibitor (ketoconazole) lomitapide exposure was increased 27-fold.(2) Thus even weak CYP3A4 inhibitors may affect lomitapide exposure (AUC, area-under-curve).

CLINICAL EFFECTS: Concurrent use of a weak inhibitor of CYP3A4 may result in 2-fold increases in lomitapide levels and toxicity from lomitapide.(1)

PREDISPOSING FACTORS: This interaction may be more severe in patients with hepatic impairment or with end-stage renal disease.(1)

PATIENT MANAGEMENT: When initiating lomitapide in patients taking a stable dose of an oral contraceptive, follow the recommended dose and titration schedule per labeling. When initiating an oral contraceptive in patients taking lomitapide, decrease the dose of lomitapide by one-third. The maximum recommended lomitapide dose with concurrent weak CYP3A4 inhibitors should be: -Adults (age 18 years and older): 40 mg daily, -Age group 11 to 17 years: 30 mg daily, -Age group 2 to 10 years: 15 mg daily. Due to lomitapide's long half-life, it may take 1 to 2 weeks to see the full effect of this interaction.(1)

DISCUSSION: Lomitapide is very susceptible to CYP3A4 inhibition. For example, in an interaction study with a strong CYP3A4 inhibitor (ketoconazole) lomitapide exposure was increased 27-fold.(2) Based upon interactions with stronger inhibitors, weak inhibitors of CYP3A4 are predicted to increase lomitapide area-under-curve(AUC) 2-fold.(1)

Hormonal Contraceptives/Lorlatinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Lorlatinib may induce the CYP3A4 mediated metabolism of hormonal contraceptives.(1)

CLINICAL EFFECTS: Concurrent use of lorlatinib may reduce the effectiveness of hormonal contraceptives.(1) Lorlatinib may cause birth defects and/or miscarriage if used by pregnant women.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Women of reproductive age should be counseled not to rely on hormonal contraception (including oral contraceptives, patches, implants, and/or IUDs) for contraception. Women should use a back-up method of birth control during lorlatinib therapy and for at least 6 months after the final dose. Women of reproductive potential should use effective non-hormonal methods of contraception during lorlatinib therapy and for at least 6 months after the final dose.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(2)

DISCUSSION: Lorlatinib may induce the CYP3A4 mediated metabolism of hormonal contraceptives. Lorlatinib may decrease the effectiveness of hormonal contraceptives, including oral contraceptives, patches, implants, and/or IUDs. Women should use a back-up method of birth control during lorlatinib therapy and for at least 6 months after the final dose.(1)

Hormonal Contraceptives/Mifepristone

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Mifepristone is a progesterone-receptor antagonist, which will interfere mechanism of action of hormonal contraceptives (including oral, implantable, injectable, or transdermal agents).(1)

CLINICAL EFFECTS: Concurrent use of mifepristone may decrease the effectiveness of hormonal contraceptives. Mifepristone will result in the loss of any pregnancy that results from decreased hormonal contraceptive efficacy.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Females of reproductive age maintained on mifepristone for hyperglycemia secondary to hypercortisolism should use a non-hormonal form of contraception during and for 1 month after mifepristone therapy unless they have been surgically sterilized.(1)

DISCUSSION: Mifepristone is a progesterone-receptor antagonist, which will interfere mechanism of action of hormonal contraceptives. Mifepristone will result in the loss of any pregnancy that results from decreased hormonal contraceptive efficacy. Therefore, females of reproductive age maintained on mifepristone for hyperglycemia secondary to hypercortisolism should use a non-hormonal form of contraception during and for 1 month after mifepristone therapy unless they have been surgically sterilized.(1)

Hormonal Contraceptives/Mitapivat

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Mitapivat is a moderate CYP3A4 inducer. Coadministration of mitapivat with hormonal contraceptives may lead to contraceptive failure or an increase in breakthrough bleeding due to decreased hormonal concentrations.(1)

CLINICAL EFFECTS: Concurrent use of mitapivat can lead to ineffective hormonal contraceptive and cause unintended pregnancy.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Women of reproductive age should be counseled not to rely on hormonal contraceptives (including oral contraceptives, patches, implants, and/or IUDs) for contraception. Pregnant women and females of reproductive potential should be counseled on the potential risk to the fetus.(1) Advise females of reproductive potential to use effective non-hormonal contraception during treatment with mitapivat.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(2)

DISCUSSION: Mitapivat is a moderate CYP3A4 inducer. Mitapivat has not been studied with hormonal contraceptives. It can render some hormonal contraceptives ineffective and may cause unintended pregnancy. Women should use non-hormonal contraception during therapy.(1) In an animal reproduction study, oral administration of mitapivat to pregnant rats and rabbits during the period of organogenesis was not teratogenic at doses up to 13 and 3 times the maximum recommended ose.(1)

Hormonal Contraceptives/Mycophenolate

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown.

CLINICAL EFFECTS: Concurrent use of mycophenolate may result in decreased levels and effectiveness of hormonal contraceptives. The use of mycophenolate in pregnancy has been associated with an increased risk for first trimester pregnancy loss and and congenital malformations.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients should be informed that mycophenolate may reduce the effectiveness of hormonal contraceptives and that the use of mycophenolate in pregnancy has been associated with an increased risk for first trimester pregnancy loss and congenital malformations.(1,2) Female patients of childbearing potential should use two forms of contraception four weeks prior to initiating mycophenolate, during therapy, and for six weeks after completing mycophenolate therapy.(1,2)

DISCUSSION: In a study in 18 female patients, concurrent mycophenolate mofetil (1 gram twice daily) and oral contraceptives containing ethinyl estradiol (0.02 to 0.04 mg) with levonorgestrel (0.05 mg to 0.20 mg), desogestrel (0.15 mg), or gestodene (0.05 mg to 0.10 mg) decreased the area-under-curve (AUC) of levonorgestrel by 15%. There was large inter-patient variability in the data, especially for ethinyl estradiol. Mean serum levels of LH, FSH, and progesterone were not significantly affected. (1)

Hormonal Contraceptives/Pegaspargase

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: An indirect interaction may occur due to pegaspargase hepatotoxicity resulting in decreased hepatic clearance of hormonal contraceptives.(1,2) Both medicines may also cause thromboembolic events.

CLINICAL EFFECTS: Concurrent use of pegaspargase may result in increased levels and effects of hormonal contraceptives and increase the risk of venous thromboembolism.(3)

PREDISPOSING FACTORS: Patients with risk factors for thrombosis include those with advanced age, obesity (BMI >30), smoking, prolonged immobilization, heart failure, hypercoagulable states, history of venous thromboembolism, malignancy, and major surgery.

PATIENT MANAGEMENT: The Australian and UK manufacturers of pegaspargase state that hormonal contraceptives are not considered to be sufficiently safe in patients on pegaspargase. Concurrent use of hormonal contraceptives and pegaspargase is not recommended.(1,2) The US manufacturer of pegaspargase states that females of reproductive potential should be counseled to use an effective non-hormonal contraceptive method during and for 3 months after therapy with pegaspargase.(4) The UK manufacturer of pegaspargase recommends using non-oral contraceptives during and for 6 months after therapy with pegaspargase.(2)

DISCUSSION: Hepatotoxicity caused by pegaspargase may result in increased exposure to hormonal contraceptives and increase the risk of thromboembolism. Concurrent use of hormonal contraceptives is not recommended.(1-4)

Hormonal Contraceptives/Pitolisant

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Pitolisant may induce the CYP3A4 mediated metabolism of hormonal contraceptives.(1,2)

CLINICAL EFFECTS: Concurrent use of pitolisant may reduce the effectiveness of hormonal contraceptives.(1,2) Pitolisant may cause birth defects and/or miscarriage if used by pregnant women.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Women of reproductive age should be counseled not to rely on hormonal contraception (including oral contraceptives, patches, implants, and/or IUDs) for contraception. Women should use a back-up method of birth control during pitolisant therapy and for at least 21 days after the final dose. Women of reproductive potential should use effective non-hormonal methods of contraception during pitolisant therapy and for at least 21 days after the final dose.(1,2) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(3)

DISCUSSION: Pitolisant may induce the CYP3A4 mediated metabolism of hormonal contraceptives. Pitolisant may decrease the effectiveness of hormonal contraceptives, including oral contraceptives, patches, implants, and/or IUDs. Women should use a back-up method of birth control during pitolisant therapy and for at least 21 days after the final dose.(1,2)

Hormonal Contraceptives/Repotrectinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Repotrectinib may induce the CYP3A4-mediated metabolism of hormonal contraceptives.(1)

CLINICAL EFFECTS: Concurrent use of repotrectinib may reduce the blood concentrations and effectiveness of hormonal contraceptives. Repotrectinib may cause fetal harm when administered to pregnant women.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Women of reproductive age should be counseled to avoid hormonal contraception (including oral contraceptives, patches, implants, and/or IUDs) due to the risk of contraceptive failure. Women should use an effective non-hormonal method of contraception during and for 2 months after repotrectinib therapy.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (i.e., a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(2)

DISCUSSION: Repotrectinib is a moderate CYP3A4 inducer. In a study, repotrectinib decreased the area-under-curve (AUC) and maximum concentration (Cmax) of midazolam (a sensitive CYP3A4 substrate) by 69% and 48%, respectively. It may also decrease estrogen or progestin concentrations and reduce the effectiveness of hormonal contraceptives. Repotrectinib may cause fetal harm when administered to pregnant women.(1)

Hormonal Contraceptives/Rifamycins

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Rifamycins (rifampin, rifabutin and rifapentine) induce the CYP3A4 mediated metabolism of both estrogen and progestin components of hormonal contraceptives.

CLINICAL EFFECTS: Concurrent use of rifampin, rifabutin, or rifapentine may result in reduced levels and clinical effectiveness of hormone containing contraceptives. Breakthrough bleeding and contraceptive failure/pregnancy may result. Effects may be seen for several weeks after discontinuation of the rifamycin.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving rifamycins should be alerted to the risk for decreased effectiveness(e.g. contraceptive failure) of their hormonal contraceptive therapy. It is recommended that alternative or additional contraceptive methods be used during and for several weeks after rifamycin therapy. If a combined oral contraceptive is used, the preparation should contain at least 30 mcg of ethinyl estradiol should be used. The patient should be asked to report any spotting or bleeding. For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.

DISCUSSION: In an open-label, randomized crossover study, 22 healthy females received oral contraceptives for 21 days, then were randomized to receive rifampin or rifabutin (300 mg/d for 10 days). Rifampin and rifabutin decreased the area-under-curve (AUC) of ethinyl estradiol by 64% and 35%, respectively, and maximum concentration (Cmax) by 42% and 20%, respectively. Rifampin and rifabutin decreased the AUC of norethindrone by 60% and 20%, respectively. Incidences of spotting were much greater in the rifampin co-administration group. In a study, a single dose of oral contraceptive (ethinyl estradiol 50 mcg and norethindrone acetate 1 mg) was administered to 7 female patients with tuberculosis, both during TB treatment and one month after stopping rifampin (450-600 mg/d). Upon cessation of rifampin therapy, the AUC for ethinyl estradiol significantly increased by 70%, and terminal plasma half-life more than doubled. A similar study design analyzed the pharmacokinetics of norethisterone (1 mg) in 8 women receiving rifampin (450-600 mg/d). Upon termination of TB treatment, it was found that rifampin reduced the AUC of a single dose of norethisterone (1 mg) by approximately 40%, with a half-life reduction of 50%. In a study, male volunteers received 50 mcg iv of ethinyl estradiol, followed by rifampin (600 mg for 6 days). Ethinyl estradiol half-life decreased by approximately 55%. The upward titration of ethinyl estradiol to 100 mcg resulted in a more than 2-fold increase in ethinyl estradiol metabolism caused by rifampicin treatment. An analytical trial evaluated liver biopsies from four patients treated with rifampin 600 mg for a period of 6-10 days. Hepatic microsomes from the biopsies were incubated with hormone substrates, including oestradiol and ethinyl estradiol. Rifampin resulted in a fourfold increase in hydroxylation. Not only did rifampin increase the rate of hydroxylation through enzyme induction, it also caused an increase in cytochrome P-450. There are reports of breakthrough bleeding and unintended pregnancy during concurrent use. A study of 118 HIV-positive females compared levonorgestrel pharmacokinetics and safety between the following groups: 1. levonorgestrel 1.5 mg with dolutegravir-based antiretrovirals (ART)(control group), 2. levonorgestrel 1.5 mg with efavirenz-based ART, 3. levonorgestrel 3 mg with efavirenz-based ART, and 4. levonorgestrel 3 mg with rifampin. While both levonorgestrel 3 mg groups had Cmax and AUC(0-8h) similar to the control group, the half life of levonorgestrel was shorter, resulting in an AUC(inf) that was 53% lower in the efavirenz group and 37% lower in the rifampin group than the control group. Tolerability was similar between groups. No pregnancies were reported but it is unknown whether the correction of levonorgestrel levels early in the dosing period is sufficient to maintain overall emergency contraceptive effectiveness.(25)

Hormonal Contraceptives/Selected Anticonvulsants

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Carbamazepine is a strong inducer of CYP3A4; oxcarbazepine and rufinamide are weak inducers of CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use with carbamazepine, oxcarbazepine or rufinamide may result in decreased contraceptive levels, which may result in menstrual abnormalities or unintended pregnancy.

PREDISPOSING FACTORS: Intermittent compliance with oral contraceptives.

PATIENT MANAGEMENT: To avoid pregnancy, additional or alternative means of non-hormonal contraception should be utilized. If larger doses of hormonal contraceptives are utilized, titrating the dose against a response such as lack of spotting or breakthrough bleeding may not guarantee contraceptive efficacy. In women who wish to continue oral contraceptives with the addition of a second form of contraception, emphasize the importance of not missing doses of the oral contraceptive. For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.

DISCUSSION: In a study of four epileptic patients receiving an oral contraceptive containing ethinyl estradiol 50 mcg plus levonorgestrel 250 mcg carbamazepine reduced the area-under-curve (AUC) for ethinyl estradiol by 42% and for levonorgestrel by 40%. Pregnancy has been reported. Pregnancy has been reported in a woman receiving low-dose oral contraceptives six weeks after initiation of treatment with carbamazepine. In a randomized, open label study, concurrent administration of carbamazepine (600 mg daily) and Ortho Novum 1/35 (ethinyl estradiol, norethindrone) decreased the AUC of ethinyl estradiol and norethindrone by 42% and 58%, respectively. The apparent oral clearance of ethinyl estradiol and norethindrone increased by 127% and 69%, respectively. Concurrent use of rufinamide (800 mg twice daily) and ethinyl estradiol / norethindrone (35 mcg/1 mg) for 14 days decreased the AUC of ethinyl estradiol and norethindrone by 22% and 14%, respectively. The maximum concentration (Cmax) of ethinyl estradiol and norethindrone decreased by 31% and 18%, respectively. Double-blind, randomized, crossover study with 24 women (only 20 analyzed) given 20 micrograms ethinyl estradiol and 100 micrograms levonorgestrel and either carbamazepine 600 mg or a matched placebo for 4 months. Ethinyl estradiol and levonorgestrel levels were measured and mean AUC was significantly lower in those taking carbamazepine. Cmax of ethinyl estradiol was also significantly decreased. Additionally more cases of breakthrough bleeding and ovulation occurred with concurrent use of the carbamazepine. In a case report, a patient with an etonogestrel implant became pregnant while taking carbamazepine for epilepsy. Coadministration of immediate-release oxcarbazepine decreased mean ethinyl estradiol AUC levels in two different studies by 48% and 52%, respectively. Additionally, mean AUC of levonorgestrel was decreased in two different studies by 32% and 52%, respectively.

Hormonal Contraceptives/Selected Strong & Mod Cyp3a4 Inducer

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong and moderate CYP3A4 inducers may increase the CYP3A4-mediated metabolism of hormonal contraceptives.(1-2)

CLINICAL EFFECTS: Concurrent use of strong or moderate CYP3A4 inducers may reduce the effectiveness of hormonal contraceptives.(1-2) Apalutamide, enzalutamide, ivosidenib, and mitotane may cause birth defects and/or miscarriage if used by pregnant women.

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Women of reproductive age should be counseled not to rely on hormonal contraception (including oral contraceptives, patches, implants, and/or IUDs) for contraception. Women should use a back-up method of birth control during therapy with a CYP3A4 inducer. Women of reproductive potential should use effective non-hormonal methods of contraception during therapy with a CYP3A4 inducer. Continuation of an effective non-hormonal contraceptive after discontinuation of the CYP3A4 inducer is also advised for the period of time indicated below.(1-3) There is no specific recommendation for contraception in women on apalutamide or enzalutamide. Male patients with female partners of reproductive age are advised to continue effective contraception for 3 months after discontinuation of apalutamide or enzalutamide.(4,5) For patients taking fexinidazole: The manufacturer of fexinidazole recommends alternative contraceptive that is not affected by enzyme inducers or additional nonhormonal contraception during and for at least 5 days after treatment with fexinidazole.() For patients taking mitapivat: The manufacturer of mitotane recommends continuing effective contraception after discontinuation of mitotane for as long as mitotane plasma levels are detectable. Mitotane half life ranges from 18 to 159 days (median 53 days).(3) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(6)

DISCUSSION: Strong and moderate CYP3A4 inducers may increase the CYP3A4-mediated metabolism of hormonal contraceptives and decrease the effectiveness of hormonal contraceptives, including oral contraceptives, patches, implants, and/or IUDs. Women should use a back-up method of birth control during and after CYP3A4 inducer therapy.(1-3) An in vivo mechanism static model predicted strong interactions between ulipristal combined with enzalutamide or mitotane. Enzalutamide was predicted to lower ulipristal area-under-curve (AUC) by 85%, and mitotane was predicted to lower ulipristal AUC by 93%.(2) Strong and moderate CYP3A4 inducers linked include: apalutamide, enzalutamide, fexinidazole, ivosidenib, mitotane, nafcillin, sotorasib, telotristat, and thioridazine.(7,8)

Hormonal Contraceptives/St. John's Wort

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: St. John's wort may induce the metabolism of hormonal-containing contraceptives by CYP3A4.(1-8)

CLINICAL EFFECTS: The concurrent administration of St. John's wort may result in reduced levels and clinical effectiveness of hormonal-containing contraceptives.(1-8)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Women taking hormonal contraception should be alerted to the possibility of decreased effects of their hormonal-containing contraceptive if they take St. John's wort. Consider monitoring for menstrual irregularities and pregnancy during concurrent therapy. The dosage of the contraceptive may need to be adjusted if St. John's wort is added to or discontinued from concurrent therapy, or another form of birth control may need to be considered. St. John's wort may need to be discontinued. For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.

DISCUSSION: The FDA and CDC recommend that patients taking estrogen-containing oral contraceptives be alerted to the possibility of a drug interaction resulting in decreased levels and/or effects of the oral contraceptive.(1,2) In a study in 12 healthy women taking ethinyl estradiol-norethindrone, administration of St. John's wort (300 mg 3 times daily) increased the oral clearance of norethindrone and decreased the half-life of ethinyloestradiol. Serum concentrations of follicle-stimulating hormone, luteinizing hormone, and progesterone were not significantly affected by St. John's wort. Breakthrough bleeding occurred in 2 of 12 subjects in the control phase and 7 of 12 women during the St. John's wort phase.(3) In a study in 17 healthy women, subjects receiving ethinyloestradiol-desogestrel alone, with 300 mg St. John's wort twice daily, and with 300 mg St. John's wort 3 times daily. There was no significant changes in follicle maturation, serum estrogen, or serum progesterone concentrations during St. John's wort. During the control phase, 6 women reported breakthrough bleeding, compared with 13 women while taking St. John's wort twice daily and 15 women while taking St. John's wort 3 times daily. There were no changes in the area-under-curve (AUC) or maximum concentration (Cmax) of ethinyloestradiol. However, the AUC and Cmax of 3-ketodesogestrel decreased by 43.9% and by 17.8%, respectively during twice daily St. John's wort and by 41.7% and by 22.8%, respectively during 3 times daily St. John's wort.(4) In a study in 16 healthy women, concurrent St. John's wort (300 mg three times daily) decreased the exposure from Loestrin 1/20 (estradiol with norethindrone) by 13% to 15%. Breakthrough bleeding and evidence of follicle growth and probable ovulation increased during concurrent St. John's wort.(6) Unplanned pregnancies have been reported during concurrent St. John's wort and hormonal contraception.(4,7) In a study in 15 healthy women, concurrent St. John's wort and Loestrin 1/20 did not affect androgen levels when compared to Loestrin 1/20 alone, suggesting that concurrent therapy would not impair treatment of acne or hirsutism.(8)

Hormonal Contraceptives/Sugammadex

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Sugammadex may bind to hormonal contraceptives.(1,2)

CLINICAL EFFECTS: Use of sugammadex may result in decreased levels of hormonal contraceptive similar to those seen with a missed dose of an oral contraceptive, which may result in decreased hormonal contraceptive effectiveness.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of sugammadex recommends that all patients using hormonal contraceptives use an additional non-hormonal contraceptive method for 7 days following the administration of sugammadex.(1) The UK manufacturer of sugammadex recommends that patients taking oral hormonal contraceptives should be instructed to follow the missed dose instructions for their oral hormonal contraceptive on the day they receive sugammadex. Patients taking non-oral hormonal contraceptives should use an additional non-hormonal contraceptive method for 7 days following the administration of sugammadex and should refer to the advice in the package leaflet of their non-oral hormonal contraceptive.(2)

DISCUSSION: Use of sugammadex may result in decreased levels of hormonal contraceptive similar to those seen with a missed dose of an oral contraceptive, which may result in decreased hormonal contraceptive effectiveness.(1,2)

Hormonal Contraceptives/Tazemetostat

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Tazemetostat is a weak CYP3A4 inducer and may increase the CYP3A4-mediated metabolism of both estrogen and progestin components of hormonal contraceptives.(1)

CLINICAL EFFECTS: Coadministration of tazemetostat with hormonal contraceptives can result in decreased concentrations and reduced efficacy.(1) Breakthrough bleeding and contraceptive failure/pregnancy may result. Tazemetostat may cause fetal harm if administered to pregnant women.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of tazemetostat recommends that female patients of reproductive potential use effective non-hormonal contraception during treatment with tazemetostat and for 6 months after the final dose.(1) Patients should be alerted to the risk for decreased effectiveness(e.g. contraceptive failure) of their hormonal contraceptive therapy. For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (i.e., a copper IUD).(2)

DISCUSSION: Coadministration of tazemetostat 800 mg twice daily with oral midazolam, a sensitive CYP3A4 substrate, in patients decreased midazolam area-under-curve (AUC) by 40% and maximum concentration (Cmax) by 21%.(1)

Hormonal Contraceptives/Tovorafenib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Tovorafenib may induce the CYP3A4-mediated metabolism of hormonal contraceptives.(1)

CLINICAL EFFECTS: Concurrent use of tovorafenib may reduce the blood concentrations and effectiveness of hormonal contraceptives. Tovorafenib may cause fetal harm when administered to pregnant women.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Women of reproductive age should be counseled to avoid hormonal contraception (including oral contraceptives, patches, implants, and/or IUDs) due to the risk of contraceptive failure. Women should use an effective non-hormonal method of contraception during and for 28 days after tovorafenib therapy.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (i.e., a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(2)

DISCUSSION: A pharmacokinetic model predicted tovorafenib to decrease midazolam Cmax and AUC by at least 20%. Tovorafenib may also decrease estrogen or progestin concentrations and reduce the effectiveness of hormonal contraceptives and/or an increase in breakthrough bleeding. Tovorafenib may cause fetal harm when administered to pregnant women.(1)

Hormonal Contraceptives/Zanubrutinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Zanubrutinib is a weak CYP3A4 inducer. Coadministration of zanubrutinib with hormonal contraceptives may lead to contraceptive failure or an increase in breakthrough bleeding due to decreased hormonal concentrations.(1,2)

CLINICAL EFFECTS: Concurrent use of zanubrutinib may reduce the effectiveness of hormonal contraceptives.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Women of reproductive age should be counseled to use highly effective contraception due to the risk of fetal harm with zanubrutinib. Women of reproductive age should not rely on hormonal contraception (including oral contraceptives, patches, implants, and/or IUDs) due to the risk of contraceptive failure. Women who use hormonal methods of birth control must add a barrier method.(1) Advise females of reproductive potential to use effective non-hormonal contraception (e.g., non-hormonal intrauterine system) or additional non-hormonal contraceptive (e.g., condoms) during treatment with zanubrutinib and for 7 days after the last dose.(1,2) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if she does become pregnant.(3)

DISCUSSION: Zanubrutinib is a weak CYP3A4 inducer.(1,2) Coadministration of zanubrutinib with midazolam (a CYP3A substrate) decreased the concentration maximum (Cmax) and area-under-curve (AUC) of midazolam by 30% and 47%, respectively.(1,2)

Iron Salts, Oral/Levodopa

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Iron salts appear to decrease the absorption of levodopa by chelate formation.

CLINICAL EFFECTS: The therapeutic effect of levodopa may be decreased.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Separate the administration times of levodopa and iron by as much as possible. Observe the patient for a decrease in clinical response and adjust the dose of levodopa as necessary.

DISCUSSION: Ferrous sulfate administration produced decreases in the serum concentration of levodopa and area-under-curve (AUC). Patients receiving levodopa plus carbidopa also experienced a reduction in the serum concentration and AUC for carbidopa during concurrent administration of ferrous sulfate. In addition, a loss in therapeutic response was demonstrated.

Oral Contraceptives/Exenatide Microsphere

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Exenatide delays gastric emptying, which may result in decreased oral contraceptive absorption.(1,2)

CLINICAL EFFECTS: Exenatide may result in decreased levels and effectiveness of oral contraceptives.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of oral contraceptives with extended-release exenatide is not recommended. No recommendations are available for the timing of administration of extended-release exenatide and oral contraceptives.(1) Consider using non-sustained release exenatide. If using non-sustained release exenatide, oral contraceptives should be taken one hour before administering exenatide non-sustained release.(2)

DISCUSSION: In a study in 32 healthy females, administration of an oral contraceptive 30 minutes after exenatide (5 mcg BID) decreased the maximum concentration (Cmax) of ethinyl estradiol and levonorgestrel by 45% and 27%, respectively. Time to Cmax (Tmax) of ethinyl estradiol and levonorgestrel increased by 3 hours and 3.5 hours, respectively. Administering the oral contraceptive one hour before exenatide decreased the Cmax of ethinyl estradiol by 15%, but there was no effect on levonorgestrel. There was no significant effect on bioavailability with either regimen.(1-3)

Oral Contraceptives/Selected Glp-1 Receptor Agonists

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: GLP-1 receptor agonists delay gastric emptying, which may result in decreased oral contraceptive absorption.(1-3)

CLINICAL EFFECTS: GLP-1 receptor agonists may result in decreased levels and effectiveness of oral contraceptives.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturers of orforglipron and tirzepatide state patients should be advised to switch from oral hormonal contraceptives to a non-oral contraceptive method or to add a barrier method of contraception. Patients should use a non-oral contraceptive or barrier method of contraception for 4 weeks after starting a GLP-1 receptor agonist and for 4 weeks after each dose escalation of the GLP-1 receptor agonist.(1-3) Hormonal contraceptives that are not administered orally are not expected to be affected by GLP-1 receptor agonists.(1-3)

DISCUSSION: In a pharmacokinetic study, a single dose of tirzepatide 5 mg with combined oral contraceptive (0.035 mg ethinyl estradiol and 0.25 mg norgestimate) decreased the mean concentration maximum (Cmax) of ethinyl estradiol, norgestimate, and norelgestromin by 59%, 66%, and 55%, respectively, while mean area-under-curve (AUC) was reduced by 20%, 21%, and 23%, respectively.(1,2) A study in pregnant rats, tirzepatide caused fetal growth restrictions and fetal abnormalities at clinical exposure. A study in pregnant rabbits, tirzepatide caused fetal growth restrictions at clinically relevant exposures.(1) In a pharmacokinetic study, acetaminophen Cmax was decreased by 28% after the first dose of orforglipron 0.8 mg. This effect diminished after repeated dosing of orforglipron 17.2 mg.(3) A study in pregnant rabbits, orforglipron resulted in decreased fetal and placental weights and external malformations at a dose 14 times the clinical exposure from the maximum recommended human dose.(3)

Progestin-Containing Contraceptives/Ulipristal

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Ulipristal is a progesterone receptor modulator and binds to the progesterone receptor with high affinity.(1)(2)

CLINICAL EFFECTS: Concurrent use of ulipristal may make hormonal contraception (including combined hormonal products, progestin-only products, and levonorgestrel emergency contraception) ineffective.(1,2) These agents may also make ulipristal ineffective.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US and UK manufacturers of ulipristal recommends that patients who have received ulipristal use a reliable barrier method of contraception for subsequent acts of intercourse until the next menstrual cycle begins.(1)(2) The US manufacturer of ulipristal states that if a woman wishes to start or resume hormonal contraception after taking ulipristal, she should do so no sooner than 5 days afterwards. The UK manufacturer of ulipristal states that concurrent use with levonorgestrel emergency contraception is not recommended.(1)

DISCUSSION: Ulipristal is a progesterone receptor modulator and binds to the progesterone receptor with high affinity, thus it may interfere with the efficacy of hormonal contraception (including combined hormonal products, progestin-only products, and levonorgestrel emergency contraception) and progestin products.(1-2) These products may also make ulipristal ineffective.

Steroidal Contraceptives/Aprepitant; Fosaprepitant

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Aprepitant and fosaprepitant may induce the CYP3A4 mediated metabolism of hormonal contraceptives.(1,2)

CLINICAL EFFECTS: The effectiveness of hormonal contraceptives may be reduced during and for 28 days following aprepitant and fosaprepitant use.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients taking hormonal contraceptives should be instructed to use alternative or back-up methods of contraception while using aprepitant or fosaprepitant and for 1 month after the last dose of aprepitant or fosaprepitant.(1,2) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.

DISCUSSION: The concurrent use of aprepitant (100 mg daily for 14 days) with an oral contraceptive (ethinyl estradiol, 35 mcg and norethindrone, 1 mg) decreased the area-under-curve (AUC) of ethinyl estradiol and norethindrone by 43% and 8%, respectively.(1) In another study, an oral contraceptive (ethinyl estradiol and norethindrone, dosages not stated) was administered on Days 1 through 21. Subjects also received aprepitant (125 mg Day 8, 80 mg daily Days 9 and 10), ondansetron (32 mg Day 8), dexamethasone (12 mg Day 8, 8 mg daily Days 9 through 11). The AUC of ethinyl estradiol decreased by 19% on Day 10 and by as much as 64% on Days 9 through 21. There was no effect on the AUC of norethindrone on Day 10, but there was as much as a 60% decrease in norethindrone minimum concentration (Cmin) during Days 9 through 21.(1) In another study, an oral contraceptive (ethinyl estradiol and norgestimate, dosages not stated) was administered on Days 1 through 21. Subjects also received aprepitant (40 mg Day 8). The AUC of ethinyl estradiol decreased by 4% and 29% on Days 8 and 12, respectively. The AUC of norelgestromin (norgestimate is converted to norelgestromin) increased by 18% on Day 8 and decreased by 10% on Day 12. Trough concentrations of ethinyl estradiol and norelgestromin on Days 8 through 21 were generally lower following aprepitant.(1)

Steroidal Contraceptives/Armodafinil; Modafinil

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Modafinil may induce the CYP3A4 mediated metabolism of the steroidal contraceptive.(1-3) Armodafinil is the R-enantiomer of modafinil.(4)

CLINICAL EFFECTS: Armodafinil(4) or modafinil(1-3) may result in decreased levels of steroidal contraceptives and possibly decreased effectiveness of the contraceptive agent during and one(1,4) to two(2-3) months following armodafinil or modafinil therapy.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The United Kingdom manufacturer of modafinil states that when oral contraceptives are used concurrently with modafinil, a product containing 50 mcg or more of ethinyl estradiol should be used. Adequate contraception requires continuation of the oral contraceptive two months after the discontinuation of modafinil.(2) The Australian manufacturer of modafinil states that alternative or concomitant methods of contraception are recommended for patients on modafinil until 2 months after discontinuation of modafinil.(3) The United States manufacturer of armodafinil(4) and modafinil(1) states that because the effectiveness of steroidal contraceptives may be decreased during concurrent therapy, alternative or concomitant methods of contraception are recommended during therapy and for one month following discontinuation of armodafinil or modafinil. For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(5)

DISCUSSION: Modafinil is contraindicated during pregnancy and may induce the metabolism of oral,(2) depot, and implantable(1) contraceptives, thus decreasing their effectiveness. A placebo-controlled, single-blind study in 41 females evaluated the effect of modafinil on the pharmacokinetics of ethinyl estradiol. The study subjects were controlled on long-term oral contraceptive treatment (0.035 mg ethinyl estradiol) and norgestimate (0.180-0.250 mg). Pharmacokinetic profiles were obtained for ethinyl estradiol on the day before initiation and on the last day of modafinil (200 mg for 7 days, then 400 mg for 21 days) or placebo (28 days). A small, but significant decrease in the ethinyl estradiol area-under-curve (AUC) by 18%, and maximum concentration (Cmax) by 11% were reported.(6)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Aluminum, Iron, Zinc/Deferiprone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Deferiprone chelates polyvalent cations such as aluminum, iron, and zinc.(1)

CLINICAL EFFECTS: Deferiprone chelation with oral aluminum, iron or zinc containing products in the gastrointestinal tract may decrease the amount of free deferiprone available for systemic iron chelation. Zinc supplements prescribed to counteract deferiprone-induced zinc deficiency may not be effective if taken near time of deferiprone administration.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer recommends at least a four hour interval between deferiprone dose and administration of aluminum, iron or zinc containing medications or supplements.(1) Avoid use of iron-containing vitamins or nutritional supplements in patients who require chelation therapy for iron overload.

DISCUSSION: The US manufacturer has not studied this interaction. The recommendation to separate deferiprone and polyvalent cation doses by at least four hours is based upon the deferiprone mechanism of action.(1)

Calcium & Iron Containing Supplements/Bictegravir

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Calcium or iron containing supplements may bind to bictegravir in the GI tract, preventing its absorption.(1)

CLINICAL EFFECTS: Calcium or iron containing supplements may reduce levels and clinical effectiveness of bictegravir.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Bictegravir and calcium or iron containing supplements may be taken together with food. Routine administration of bictegravir under fasting conditions simultaneously with, or within 2 hours after, calcium or iron containing supplements is not recommended.(1) In pregnant patients, if bictegravir is taken on an empty stomach, take bictegravir at least 2 hours before or 6 hours after calcium or iron containing supplements.(1)

DISCUSSION: Simultaneous administration of aluminum and magnesium hydroxide (20 ml) in a fasted state with bictegravir (50 mg single dose) decreased bictegravir maximum concentration (Cmax) and area-under-curve (AUC) by 80% and 79%, respectively.(1) Administration of aluminum and magnesium hydroxide (20 ml) 2 hours after bictegravir (50 mg single dose) in a fasted state decreased bictegravir Cmax and AUC by 7% and 13%, respectively.(1) Administration of aluminum and magnesium hydroxide (20 ml) 2 hours before bictegravir (50 mg single dose) in a fasted state decreased bictegravir Cmax and AUC by 58% and 52%, respectively.(1) Simultaneous administration of aluminum and magnesium hydroxide (20 ml) in a fed state with bictegravir (50 mg single dose) decreased bictegravir Cmax and AUC by 49% and 47%, respectively.(1) Simultaneous administration of calcium carbonate (1200 mg single dose) in a fasted state with bictegravir (50 mg single dose) decreased bictegravir Cmax and AUC by 42% and 33%, respectively.(1) Simultaneous administration of calcium carbonate (1200 mg single dose) in a fed state with bictegravir (50 mg single dose) decreased bictegravir Cmax by 10% and increased AUC 3%, respectively.(1) Simultaneous administration of ferrous fumarate (324 mg single dose) in a fasted state with bictegravir (50 mg single dose) decreased bictegravir Cmax and AUC by 71% and 63%, respectively.(1) Simultaneous administration of ferrous fumarate (324 mg single dose) in a fed state with bictegravir (50 mg single dose) decreased bictegravir Cmax and AUC by 25% and 16%, respectively.(1)

Calcium; Iron; Sucralfate/Thyroid Preparations

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The mechanism by which malabsorption of thyroid preparations occurs from calcium-containing products is presumed to be a binding of the medication to the thyroid hormone, forming an insoluble or nonabsorbable complex.(1-3) Iron may form a ferric-thyroxine complex with thyroid agents, preventing their absorption from the gastrointestinal tract.(1,4) Sucralfate binds to other agents in the gastrointestinal tract and alters absorption of other drugs, including thyroid agents.(1,5)

CLINICAL EFFECTS: The simultaneous administration of thyroid preparations with calcium, iron, or sucralfate may result in decreased levels and clinical effects of thyroid preparations.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Instruct patients to separate the administration time of thyroid preparations from calcium or iron by as much time as possible, preferably by at least four hours.(1) Administer thyroid preparations at least 2 hours before sucralfate.(5) Patients taking thyroid preparations and calcium- or iron-containing products or sucralfate should be monitored for changes in thyroid function. The dosage of the thyroid preparation may need to be increased. Separating the administration times of the thyroid preparation and the calcium- or iron-containing products or sucralfate may decrease the effects of the interaction.(1-5)

DISCUSSION: In a pharmacokinetic study 8 healthy, euthyroid adults were given levothyroxine alone and levothyroxine coadministered with calcium carbonate, calcium citrate, or calcium acetate in doses containing 500 mg elemental calcium. The coadministration of each of the three calcium preparations significantly reduced levothyroxine absorption by about 20%-25% compared with levothyroxine given alone.(3) In a study in 14 subjects, the simultaneous administration of thyroxine with ferrous sulfate for 12 weeks resulted in an increase in the mean level of thyroid stimulating hormone (TSH) from 1.6+/-0.4 mU/L to 5.4+/-2.8 mU/L. Mixing thyroxine with ferrous sulfate in vitro resulted in a poorly soluble complex.(4) In a study in 20 hypothyroid patients, the simultaneous administration of levothyroxine and calcium carbonate (1200 mg) daily for three months resulted in reductions in the mean free T4 and total T4 levels. These values increased in most patients following the discontinuation of calcium carbonate. A concurrent in-vitro study found that calcium carbonate adsorbed levothyroxine in solution at a pH of 2, gastric pH, but not at a pH of 7.4.(6) One author reported three cases of decreased levothyroxine efficacy following the addition of calcium carbonate to therapy.(7) In a study in 5 healthy subjects, levothyroxine (five 200 mcg tablets) was administered in 3 different dosing regimens: after an overnight fast, with the fifth and final dose of sucralfate (1 gram every 6 hours) and 8 hours after the second and final dose of sucralfate (2 grams every 12 hours). When administered alone, 80% of levothyroxine was absorbed within 6 hours of administration, compared to 23% when administered concurrently with sucralfate. There was no difference in levothyroxine absorption when administered alone or 8 hours after sucralfate.(8) There are several case reports documenting decreased effects of thyroid supplementation as the result of simultaneous administration of sucralfate.(9,10) One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Calcium; Iron; Sucralfate/Tiratricol

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The mechanism by which malabsorption of thyroid preparations such as tiratricol occurs from calcium-containing products is presumed to be a binding of the medication to the thyroid hormone, forming an insoluble or nonabsorbable complex.(1,2) Iron may form a ferric-thyroxine complex with thyroid agents such as tiratricol, preventing their absorption from the gastrointestinal tract.(1,2) Sucralfate binds to other agents in the gastrointestinal tract and alters absorption of other drugs, including thyroid agents such as tiratricol.(1-3)

CLINICAL EFFECTS: The simultaneous administration of thyroid preparations with calcium, iron, or sucralfate may result in decreased levels and clinical effects of thyroid preparations.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Instruct patients to take iron and calcium supplements at the same time every day relative to tiratricol dosing.(6,7) Patients taking thyroid preparations and calcium- or iron-containing products or sucralfate should be monitored for changes in thyroid function. The dosage of the thyroid preparation may need to be increased. Separating the administration times of the thyroid preparation and the calcium- or iron-containing products or sucralfate may decrease the effects of the interaction.(1-3)

DISCUSSION: Iron and calcium may interfere with the absorption of tiratricol.(1,2)

Contraceptives/Tetracyclines; Tigecycline

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Not established.

CLINICAL EFFECTS: Reduced pharmacologic effects of oral contraceptives with resultant breakthrough bleeding and pregnancy may occur.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Current guidelines suggest that additional precautions are not necessary when non-enzyme inducing antibiotics are used concurrently with hormonal contraceptives; however, some patients may still prefer to use an additional method of contraception.

DISCUSSION: Evidence for this interaction is limited and conflicting; however, the CDC and the Faculty of Sexual and Reproductive Healthcare Clinical Effectiveness Unit no longer recommend use of a backup contraceptive method during use of a non-enzyme inducing antibiotic. Pregnancy has been reported following the addition of tetracycline to oral contraceptive therapy.(1) In contrast, a study in 7 healthy women found no effect of tetracycline on ethinyl estradiol or norethindrone levels.(2) A study in 24 healthy women found no significant effects of doxycycline on ethinyl estradiol, norethindrone, or progesterone levels. However, the authors noted that there large inter-patient and inter-patient variability in these levels and that the interaction may just manifest itself in a small proportion of women.(3)

Divalent & Trivalent Cations/Tetracyclines

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Di- and trivalent cations may form chelation complexes with tetracyclines, preventing their absorption.(1,2)

CLINICAL EFFECTS: Simultaneous administration of di- or trivalent cations may result in decreased levels of and therapeutics effects from tetracyclines.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Administer tetracyclines at least two hours before or after the di- or trivalent cations. When used for the treatment of H. pylori infection, tetracyclines and bismuth should be given simultaneously. The US manufacturer of omadacycline states to fast for at least four hours, administer omadacycline, and then wait four hours before taking di- or trivalent cations.(21) The US manufacturer of ferric maltose recommends separation of ferric maltose by at least 4 hours.(22)

DISCUSSION: Concurrent administration of aluminum hydroxide or divalent cations (such as calcium, magnesium, or zinc) has been shown to significantly decrease the gastrointestinal absorption of tetracycline.(3-5) Concurrent administration of tetracycline and magnesium-aluminum hydroxide gel has been shown to decrease the tetracycline area-under-curve (AUC) by 90%.(6) Magnesium-aluminum silicate has been shown to decrease the AUC of tetracycline by 27%.(7) Demeclocycline(8,9) methacycline,(10) chlortetracycline,(11) and oxytetracycline(10,12) have been shown to interact with aluminum hydroxide and/or dairy products. Doxycycline has been reported to interact with aluminum hydroxide gel.(13) Aluminum magnesium hydroxide has been shown to decrease doxycycline absorption by 84%.(14) Minocycline absorption has been shown to be impaired by aluminum, calcium, and magnesium.(15) Bismuth subsalicylate has been shown to decrease absorption of doxycycline and tetracycline by 37%(16) and 34%,(17) respectively. Since sucralfate is an aluminum salt of a sulfated disaccharide, it may also prevent absorption of tetracyclines. This complex has been used to provide site-specific delivery of tetracycline to gastric ulcers in the treatment of Helicobacter pylori gastric ulcer disease and may be useful in some indications.(18) Quinapril tablets contain a high percentage of magnesium and have been shown to decrease the absorption of tetracycline by 28-37%.(19) Lanthanum is expected to interact with tetracyclines as well.(20)

Estrogen/Raloxifene

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Raloxifene binds to estrogen receptors and activates certain estrogenic pathways while blocking others.(1)

CLINICAL EFFECTS: The concurrent use of raloxifene and estrogen may increase the risk of estrogen-related toxicities (bloating, vaginal bleeding, mood changes, cardiovascular events, thromboembolism, and breast cancer) and antagonize the anti-estrogenic effects of raloxifene.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of raloxifene does not recommend the use of systemic estrogen or hormone replacement therapy with raloxifene.(1)

DISCUSSION: Information on the interaction between raloxifene and estrogen is lacking and the manufacturer of raloxifene states that the concurrent use of these medications has not been studied in prospective clinical trials.(1)

Estrogens/Selected Human Immunoglobulins

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent use of human immunoglobulin with estrogens may have additive effects on clotting mechanisms.(1)

CLINICAL EFFECTS: Concurrent use of human immunoglobulin with estrogens may increase the risk of thrombosis. Thrombosis may occur regardless of the route of administration of the immunoglobulin.(1)

PREDISPOSING FACTORS: Additional risk factors include advanced age, prolonged immobilization, hypercoagulable states, history of arterial or venous thrombosis, indwelling central vascular catheter, hyperviscosity and cardiovascular risk factors (e.g. coronary artery disease, hypertension, diabetes).(1)

PATIENT MANAGEMENT: For patients at risk of thrombosis, administer the minimum concentration of immunoglobulin available at the minimum rate of infusion practicable. Ensure that patients are adequately hydrated before immunoglobulin is infused. Patients should be monitored for signs and symptoms of thrombosis. Assess blood viscosity in patients at risk for hyperviscosity. Counsel patients on the risk of thrombosis and its signs and symptoms. Instruct patients to promptly report any symptoms of thrombosis.(1)

DISCUSSION: Thrombosis has been associated with the use of human immunoglobulin and may occur without the presence of risk factors and regardless of the route of administration of the immunoglobulin. Risk factors known to increase the risk of thrombosis include the use of estrogens, advanced age, prolonged immobilization, hypercoagulable states, history of arterial or venous thrombosis, indwelling central vascular catheter, hyperviscosity and cardiovascular risk factors (e.g. coronary artery disease, hypertension, diabetes). For patients at risk of thrombosis, administer the minimum concentration of immunoglobulin available at the minimum rate of infusion practicable. Ensure that patients are adequately hydrated before immunoglobulin is infused. Patients should be monitored for signs and symptoms of thrombosis. Assess blood viscosity in patients at risk for hyperviscosity. Counsel patients on the risk of thrombosis and its signs and symptoms. Instruct patients to promptly report any symptoms of thrombosis.(1)

Estrogens/Thyroid Preparations

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Estrogens increase thyroxine-binding globulin (TBG) levels by increasing its biosynthesis and decreasing its clearance.(1) Hypothyroid patients who start estrogens may be unable to compensate for this increase and may have decreased serum free T4 (FT4) concentrations and increased TSH.(1,2)

CLINICAL EFFECTS: The coadministration of thyroid preparations and estrogens may result in decreased levels and clinical effects of thyroid hormones.(1-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients taking thyroid preparations and who start or stop estrogens should be monitored for changes in thyroid function. The dosage of the thyroid preparation may need to be increased.(1-4)

DISCUSSION: In a prospective observational study, 25 post-menopausal women with hypothyroidism on stable levothyroxine therapy for at least 9 months started on estrogen replacement therapy. After 12 weeks, mean serum FT4 levels decreased significantly from 1.7 +/- 0.4 ng/dL to 1.4 +/-0.3 mg/dL and TSH increased significantly from 0.9 +/-1.1 to 3.2 +/- 3.1 milli-units/L.(1)

Estrogens/Tofacitinib (<20 Mg Daily)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Estrogens increase the risk of thrombosis, and combining estrogens with a higher dose of tofacitinib (greater than or equal to 10 mg twice daily, or 20 mg/day) may place patients at high risk of thromboembolism.(1-3)

CLINICAL EFFECTS: Concurrent use of estrogens with a higher dose of tofacitinib (greater than or equal to 10 mg twice daily, or 20 mg/day) may increase the incidence of pulmonary embolism and death.(1-3)

PREDISPOSING FACTORS: Additional risk factors include advanced age, obesity (BMI greater than 30), smoking, prolonged immobilization, heart failure, hypercoagulable states, history of venous thromboembolism, malignancy, and major surgery.(1)

PATIENT MANAGEMENT: The European manufacturer states that the 10 mg twice daily dose of tofacitinib is not recommended in patients who are on combined hormonal contraceptives or hormone replacement therapy, or who are otherwise at high risk of pulmonary embolism.(4) Patients at high risk of pulmonary embolism should be switched to alternative therapies. For the treatment of rheumatoid arthritis and psoriatic arthritis, the dose of tofacitinib should be limited to 5 mg twice daily or tofacitinib XR 11 mg daily.(1-4) The US FDA and Health Canada have not placed use restrictions specifically on concurrent use of tofacitinib with hormonal contraceptives or hormone replacement therapy. Both agencies advise avoiding tofacitinib in patients at increased risk of thrombosis. The US and Canadian manufacturers recommend against a dosage of tofacitinib 10 mg twice daily or weight-based equivalent twice daily or tofacitinib XR 22 mg once daily for rheumatoid arthritis, psoriatic arthritis, or polyarticular-course juvenile idiopathic arthritis. For the treatment of ulcerative colitis, the lowest effective dose for the shortest duration possible is recommended. Counsel patients on the risk of thrombosis and its signs and symptoms. Instruct patients to promptly report any symptoms of thrombosis and discontinue tofacitinib in patients with symptoms of thrombosis.(5-7) There is currently no use restriction on the combination of estrogens with lower doses of tofacitinib (less than 20 mg daily).

DISCUSSION: In an ongoing open-label study comparing the safety of tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, and a tumor necrosis factor (TNF) inhibitor in rheumatoid arthritis patients 50 years old and older, the incidence of pulmonary embolism (PE) was 6-fold higher in the tofacitinib 10 mg twice daily arm and 3-fold higher in the tofacitinib 5 mg twice daily arm compared to the TNF inhibitor arm (17 cases/3,123 patient-years, 9 cases/3,317 patient-years, and 3 cases/3,319 patient-years, respectively). All-cause mortality was also higher in the tofacitinib 10 mg twice daily and 5 mg twice daily arms compared to the TNF inhibitor arm (28 deaths/3,140 patient-years, 19 deaths/3,324 patient-years, and 9 deaths/3,323 patient-years, respectively).(3)

Estrogens/Xanthine Derivatives

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Estrogens may inhibit the hepatic microsomal enzymes responsible for the metabolism of the theophyllines.

CLINICAL EFFECTS: Concurrent use of estrogens may result in an increase in the pharmacologic effects of xanthine derivatives as a result of elevated serum levels. Signs and symptoms of theophylline toxicity including anorexia, nausea, vomiting, nervousness, agitation, headache, tachycardia, arrhythmias, and convulsions.

PREDISPOSING FACTORS: Smoking.

PATIENT MANAGEMENT: Patients receiving concurrent estrogens should be monitored for elevated xanthine levels and signs of toxicity. Adjust dosages accordingly.

DISCUSSION: Although there are no reports of toxicity due to concurrent administration of oral contraceptives and theophylline, use of this combination has been associated with a decrease in the plasma clearance and an increase in the elimination half-life of theophylline. One study involving a small number of patients found that low dose oral contraceptive administration (i.e., 35 mcg) for up to 9 months, did not alter the pharmacokinetics of theophylline. Other studies demonstrate the effect of caffeine, a xanthine alkaloid chemically similar to theophylline, when administered to patients taking oral contraceptives or hormone replacement. Concomitant administration resulted in decreased caffeine metabolism by ethinyl estradiol's metabolic inhibition. A study of 20 healthy women evaluated the effect of caffeine elimination prior to and during one cycle of oral contraception. Compared to pretreatment values, it was determined that clearance of caffeine was reduced by approximately 55%. Another study evaluated the pharmacokinetics of caffeine in seven women receiving an oral depot contraceptive containing ethinyl estradiol. After six months, the oral contraceptive was found to significantly decrease the elimination half-life of caffeine: half-life prior to therapy was 4.9h, and after oral contraceptive therapy, the half-life of caffeine increased to 8.0h.

Ethinyl Estradiol (<= 20 Mcg)/Avapritinib

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The mechanism of action has not been described.

CLINICAL EFFECTS: Coadministration of ethinyl estradiol and avapritinib may increase the plasma concentrations and toxicities of ethinyl estradiol.(1)

PREDISPOSING FACTORS: Patients with risk factors for thrombosis may be at higher risk of adverse events, including those with advanced age, obesity (BMI >30), smoking, prolonged immobilization, heart failure, hypercoagulable states, history of venous thromboembolism, malignancy, and major surgery.

PATIENT MANAGEMENT: The manufacturer of avapritinib states that the daily dose of ethinyl estradiol should not exceed 20 mcg unless a higher dose is necessary.(1)

DISCUSSION: In a study, coadministration of ethinyl estradiol 30 mcg/levonorgestrel 0.15 mg once daily and avapritinib 25 mg once daily increased the area-under-curve (AUC) and maximum concentration (Cmax) of ethinyl estradiol by 1.15-fold and 1.46-fold, respectively.(1)

Ethinyl Estradiol (<= 30 Mcg)/Fostemsavir

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The mechanism of action has not been described.

CLINICAL EFFECTS: Coadministration of ethinyl estradiol and fostemsavir may increase the plasma concentrations and toxicities of ethinyl estradiol.(1)

PREDISPOSING FACTORS: Patients with risk factors for thrombosis may be at higher risk of adverse events, including those with advanced age, obesity (BMI >30), smoking, prolonged immobilization, heart failure, hypercoagulable states, history of venous thromboembolism, malignancy, and major surgery.

PATIENT MANAGEMENT: The manufacturer of fostemsavir states that the daily dose of ethinyl estradiol should not exceed 30 mcg when used in patients concurrently on fostemsavir.(1)

DISCUSSION: In a study, coadministration of ethinyl estradiol 30 mcg/norethindrone 1.5 mg once daily and fostemsavir 600 mg twice daily increased the area-under-curve (AUC) and maximum concentration (Cmax) of ethinyl estradiol by 1.4-fold and 1.39-fold, respectively. The exposure to norethindrone was not significantly different.(1)

Hormonal Contraceptives/Asunaprevir

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Asunaprevir is a weak CYP3A4 inducer and may increase the CYP3A4-mediated metabolism of both estrogen and progestin components of hormonal contraceptives.(1)

CLINICAL EFFECTS: Concurrent use of asunaprevir may result in reduced levels and clinical effectiveness of hormone containing contraceptives.(1) Breakthrough bleeding and contraceptive failure/pregnancy may result. Effects may be seen for several weeks after discontinuation of asunaprevir.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of asunaprevir recommends using a high-dose oral contraceptive containing at least 30 mcg ethinyl estradiol with norethindrone when use concurrently with asunaprevir.(1) Patients should be alerted to the risk for decreased effectiveness(e.g. contraceptive failure) of their hormonal contraceptive therapy. For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(2)

DISCUSSION: A study of 17 subjects found that asunaprevir 600 mg twice daily decreased the maximum concentration (Cmax) and area-under-curve (AUC) of ethinyl estradiol 35 mcg daily by 25% and 28%, respectively, and of norgestromin by 29% and 34%, respectively.(3) Another study of 36 subjects found that asunaprevir 100 mg twice daily did not significantly affect the kinetics of high-dose contraceptives consisting of ethinyl estradiol 30 mcg daily and norethindrone 1.5 mg daily.(3)

Hormonal Contraceptives/Cannabidiol

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Cannabidiol (CBD) may induce the CYP3A4-mediated metabolism of hormonal contraceptives.(1)

CLINICAL EFFECTS: Concurrent use of CBD may reduce the effectiveness of hormonal contraceptives.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Women of reproductive age should be counseled not to rely on hormonal contraception (including oral contraceptives, patches, implants, and/or IUDs) for contraception. Women should use an effective non-hormonal method of contraception or a back-up method of birth control during CBD therapy.(1) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(2)

DISCUSSION: An in vitro, CYP induction study showed that CBD may increase expression of CYP3A4. The effectiveness of hormonal contraceptives, including oral contraceptives, patches, implants, and/or IUDs may be decreased. Women should use a back-up method of birth control during CBD or THC therapy.(1)

Hormonal Contraceptives/Meropenem-Vaborbactam

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Meropenem-vaborbactam may induce the CYP3A4-mediated metabolism of hormonal contraceptives.(1,2)

CLINICAL EFFECTS: Concurrent use of meropenem-vaborbactam may reduce the blood concentrations and effectiveness of hormonal contraceptives.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Women of reproductive age should be counseled not to rely on hormonal contraception (including oral contraceptives, patches, implants, and/or IUDs) for contraception. Women should use an effective non-hormonal method of contraception or an additional method of birth control during and for 28 days after meropenem-vaborbactam therapy.(1,2) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (i.e., a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(2)

DISCUSSION: There have been no studies evaluating the potential of meropenem-vaborbactam to interact with other drugs. In vitro data suggest that both meropenem and vaborbactam are weak CYP3A4 inducers.(1,2)

Hormonal Contraceptives/Tecovirimat

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Tecovirimat may induce the CYP3A4-mediated metabolism of hormonal contraceptives.(1,2)

CLINICAL EFFECTS: Concurrent use of tecovirimat may reduce the effectiveness of hormonal contraceptives.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Women of reproductive age should be counseled not to rely on hormonal contraception (including oral contraceptives, patches, implants, and/or IUDs) for contraception. Women should use an effective non-hormonal method of contraception or a back-up method of birth control during and for 28 days after tecovirimat therapy.(1,2) For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.(3)

DISCUSSION: In a pharmacokinetic study, tecovirimat decreased the concentration maximum (Cmax) and area-under-curve (AUC) of midazolam (a CYP3A4 substrate) by 39% and 32%, respectively. The effectiveness of hormonal contraceptives, including oral contraceptives, patches, implants, and/or IUDs may be decreased. Women should use a back-up method of birth control during and for 28 days after tecovirimat therapy.(1)

Hormonal Contraceptives; Estrogens/Corticosteroids

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: It is speculated that hormonal contraceptives and estrogens inhibit hepatic metabolism of some corticosteroids as well as endogenous cortisol. Competitive protein binding may also contribute to elevations in serum corticosteroids.

CLINICAL EFFECTS: Concurrent use of hormonal contraceptives or estrogens may result in an increase in the therapeutic and toxic effects of corticosteroids.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent hormonal contraceptives or estrogen should be observed for symptoms of corticosteroid toxicity. A lower corticosteroid dose may be required.

DISCUSSION: In a study in 6 healthy females controlled on long-term oral contraceptives, subjects received either a placebo or high and low-dose prednisolone (0.53 and 0.14 mg/Kg iv). Both dosages of prednisolone decreased the total clearance, unbound clearance, and volume of distribution (Vd) at maximum concentration (Cmax) of total drug. Significant increases in half-life for free and unbound prednisolone and hydrocortisone concentrations were also observed in comparison to the placebo group. In a study in 8 females controlled on oral contraceptive therapy, 8 females not receiving contraceptive therapy, and 8 males, each subject received prednisolone 40 mg iv. The plasma clearance of total prednisolone in females on OC was 96 ml/min, which was significantly lower than those in both the male and female (205 and 187 ml/min, respectively) control groups. Prednisolone half-life and mean residence times were increased. The oral contraceptive group had a significantly higher (2-fold) concentration of transcortin, resulting in lower clearance, decreased Vd, and a 2-fold increase in the area-under-curve (AUC) for prednisolone. A clinical trial demonstrated the interaction between prednisolone (20 mg) and oral contraceptives containing ethinyl estradiol (30 mcg). The oral contraceptive users had an average plasma concentration of prednisolone 131% higher compared to the control group, and plasma cortisol levels were suppressed by approximately 90%. No differences were reported for ethinyl estradiol levels. In a study in 8 females taking oral contraceptives and 8 females who were were not, subjects received IV doses of prednisolone at 0.1 mg/Kg and 1.0 mg/Kg. Free prednisolone clearance was reduced by approximately 30% in the contraceptive receiving subjects compared to the control group, and plasma cortisol concentrations were reduced 2-fold compared to the control group. One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Iron Salts, Oral/Trientine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Trientine is a chelating agent. Concurrent administration with iron may reduce the absorption of both trientine and iron.

CLINICAL EFFECTS: Iron may decrease the levels and clinical effects of trientine, and trientine may reduce serum iron levels.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid use of iron salts within 2 hours of trientine dose. Monitor clinical status for decreased effectiveness and adjust the trientine dose if necessary.

DISCUSSION: Multivitamins with low doses of iron may decrease trientine absorption so ensure patient is aware of the risks. Also, as patients may be unaware which foods contain iron, instruct patients to take trientine on an empty stomach, at least one hour before meals or two hours after food or milk.

Moderate And Weak Cyp3a4 Inhibitors/Tacrolimus

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Moderate and weak inhibitors of CYP3A4 may inhibit the metabolism of tacrolimus.(1)

CLINICAL EFFECTS: Concurrent use of a CYP3A4 inhibitor may result in elevated levels of and toxicity from tacrolimus, including nephrotoxicity, neurotoxicity, and prolongation of the QTc interval and life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The US manufacturer of tacrolimus recommends monitoring tacrolimus whole blood trough concentrations and reducing tacrolimus dose if needed.(1) Consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a study of 26 renal transplant recipients, conjugated estrogens 3.75 mg daily increased the tacrolimus dose-corrected concentration of tacrolimus by 85.6%. Discontinuation of the conjugated estrogens led to a decrease in tacrolimus concentration of 46.6%.(3) A case report describes a 65-year-old kidney transplant recipient who was stable on tacrolimus 9 mg per day with trough levels of 5 to 7.5 ng/mL. Ten days after starting on estradiol gel 0.5 mg per day, her tacrolimus level rose to 18.3 ng/mL and serum creatinine (Scr) rose from 1.1 mg/dL at baseline to 2 mg/dL. Tacrolimus dose was reduced by 60%, and trough levels and Scr normalized after two weeks.(4) A study of 16 healthy volunteers found that elbasvir 50 mg/grazoprevir 200 mg daily increased the area-under-curve (AUC) of tacrolimus by 43%, while the maximum concentration (Cmax) of tacrolimus was decreased by 40%.(5) An analysis of FAERS data from 2004-2017, found a significant association between transplant rejection and concurrent use of tacrolimus and clotrimazole (reporting odds ratio 1.92, 95% CI). A retrospective study of 7 heart transplant patients on concurrent tacrolimus and clotrimazole troche showed a significant correlation between tacrolimus trough concentration and AUC after clotrimazole discontinuation. Tacrolimus clearance and bioavailability after clotrimazole discontinuation was 2.2-fold greater (0.27 vs. 0.59 L/h/kg) and the trough concentration decreased from 6.5 ng/mL at 1 day to 5.3 ng/mL at 2 days after clotrimazole discontinuation.(7) A retrospective study of 26 heart transplant patients found that discontinuation of concurrent clotrimazole with tacrolimus in the CYP3A5 expresser group had a 3.3-fold increase in apparent oral clearance and AUC of tacrolimus (0.27 vs. 0.89 L/h/kg) compared to the CYP3A5 non expresser group with a 2.2-fold mean increase (0.18 vs. 0.39 L/h/kg).(8) A study of 6 adult kidney transplant recipients found that clotrimazole (5-day course) increased the tacrolimus AUC 250% and the blood trough concentrations doubled (27.7 ng/ml versus 27.4 ng/ml). Tacrolimus clearance decreased 60% with coadministration of clotrimazole.(9) A case report describes a 23-year-old kidney transplant recipient who was stable on tacrolimus 5 mg twice daily, mycophenolate mofetil 30 mg daily, prednisone (30 mg daily tapered over time to 5 mg), and clotrimazole troche 10 mg four times daily. Discontinuation of clotrimazole resulted in a decrease in tacrolimus trough levels from 13.7 ng/ml to 5.4 ng/ml over a period of 6 days. Clotrimazole was restarted with tacrolimus 6 mg resulting in an increased tacrolimus level of 19.2 ng/ml.(10) A retrospective study in 95 heart transplant recipients on concurrent clotrimazole and tacrolimus found a median tacrolimus dose increase of 66.7% was required after clotrimazole discontinuation. Tacrolimus trough concentration was found to have decreased 42.5% after clotrimazole discontinuation.(11) A retrospective study in 65 pancreas transplant patients on concurrent tacrolimus, clotrimazole, cyclosporine, and prednisone found that clotrimazole discontinuation at 3 months after transplantation may cause significant tacrolimus trough level reductions.(12) A case report describes a 6-year-old kidney transplant recipient who was on a regimen of tacrolimus and mycophenolate mofetil. The patient was started letermovir 240 mg via G-tube 2 months post kidney transplant. One week after starting letermovir, the routine tacrolimus level showed a supratherapeutic concentration of 22.9 ng/L. A 36% dose reduction of tacrolimus was required. Upon discontinuation of letermovir, the tacrolimus level decreased by 42%.(13) Moderate CYP3A4 inhibitors linked to this monograph include: berotralstat, conivaptan, fluvoxamine, lenacapavir, letermovir, netupitant, nirogacestat, sevabertinib, stiripentol, and tofisopam.(6) Weak CYP3A4 inhibitors linked to this monograph include: avacopan, baikal skullcap, berberine, bicalutamide, blueberry, brodalumab, camizestrant, chlorzoxazone, cimetidine, cranberry juice, daclatasvir, daridorexant, delavirdine, diosmin, elinzanetant, estrogens, flibanserin, fostamatinib, ginkgo biloba, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lazertinib, linagliptin, lomitapide, lumateperone, lurasidone, peppermint oil, piperine, propiverine, ranitidine, resveratrol, rimegepant, simeprevir, sitaxsentan, skullcap, ticagrelor, tolvaptan, trofinetide, viloxazine, and vonoprazan-amoxicillin.(6)

Moderate Cyp1a2 Inhibitors/Pirfenidone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Pirfenidone is primarily metabolized by CYP1A2 which is responsible for about 50% of its conversion to inactive drug. CYP2C9, 2C19, 2D6 and 2E1 are additional minor contributors to pirfenidone metabolism.(1) Inhibitors of CYP1A2 may inhibit the metabolism of pirfenidone.(1)

CLINICAL EFFECTS: Concurrent pirfenidone use with moderate inhibitors of CYP1A2 may lead to increased systemic concentrations and toxicity from pirfenidone, including serious liver injury.(1)

PREDISPOSING FACTORS: A greater risk of adverse events may result from concomitant treatment with strong or moderate inhibitors of one or more other CYP isoenzymes involved in the metabolism of pirfenidone such as CYP2C9 (e.g. amiodarone, fluconazole), CYP2C19 (e.g. fluconazole, fluoxetine, ticlopidine) and CYP2D6 (e.g. fluoxetine, paroxetine).(1) The magnitude of this interaction may be reduced in cigarette smokers. Cigarette smoking induces production of CYP1A2 and, in the absence of a CYP1A2 inhibitor, leads to decreased systemic concentrations of pirfenidone.(1)

PATIENT MANAGEMENT: The manufacturer of pirfenidone states that for concurrent use with moderate inhibitors of CYP1A2, dose reduction is recommended. Reduce the dose of pirfenidone to two-267 mg capsules three times a day (total daily dose of 1602 mg/day).(1) Combinations of strong or moderate CYP1A2 inhibitors with strong or moderate CYP2C9, CYP2C19, and/or CYP2D6 inhibitors should be discontinued prior to and avoided during pirfenidone treatment.(1)

DISCUSSION: Pirfenidone is converted to inactive metabolites prior to elimination. CYP1A2 is responsible for approximately half of this metabolism. In an interaction study conducted in non-smokers and smokers, coadministration of pirfenidone with fluvoxamine (a strong CYP1A2 inhibitor), an agent which inhibits multiple pirfenidone elimination pathways (CYP1A2, CYP2C9, CYP2C19), led to an approximately 4-fold and 7-fold, respectively, increase in pirfenidone exposure.(1) In a single-dose study in 27 healthy subjects, coadministration of 801 mg of pirfenidone and 750 mg of ciprofloxacin on Day 6 (ciprofloxacin was dosed at 750 mg twice daily from Day 2 to Day 7) increased the exposure to pirfenidone by 81%.(1) Moderate CYP1A2 inhibitors linked to this monograph include: capmatinib, centanafadine, dipyrone, fexinidazole, genistein, hormonal contraceptives, methoxsalen, mexiletine, osilodrostat, phenylpropanolamine, pipemidic acid, rucaparib, troleandomycin, vemurafenib, and viloxazine.(2)

Oral Contraceptives/Colesevelam

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Colesevelam may bind to oral contraceptives in the gastrointestinal track, preventing their absorption.(1,2)

CLINICAL EFFECTS: Simultaneous administration of colesevelam may result in decreased levels and effectiveness of oral contraceptives.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Oral contraceptives should be administered four hours before colesevelam.(1)

DISCUSSION: When administered with colesevelam (3.75 g), the area-under-curve (AUC) and maximum concentration (Cmax) of ethinyl estradiol (0.035 mg) decreased by 24% and by 24%, respectively, and the AUC and Cmax of norethindrone (1 mg) decreased by 1% and 20%, respectively. When administered 1 hour prior to colesevelam, the AUC and Cmax of ethinyl estradiol decreased by 18% and 1%, respectively, the AUC of norethindrone increased by 5%, and the Cmax of norethindrone decreased by 3%. When administered 4 hours prior to colesevelam, the AUC of ethinyl decreased by 12% and the AUC and Cmax of norethindrone increased by 6% and 7%, respectively.(1,2)

Oral Contraceptives/Exenatide; Lixisenatide

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Exenatide and lixisenatide delay gastric emptying, which may result in decreased oral contraceptive absorption.(1,2)

CLINICAL EFFECTS: Exenatide and lixisenatide may result in decreased levels and effectiveness of oral contraceptives.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Oral contraceptives should be taken one hour before administering exenatide non-sustained release.(1) No recommendations are available for the timing of administration of extended-release exenatide and oral contraceptives.(3) Oral contraceptives should be taken one hour before or 11 hours after administering lixisenatide.(2)

DISCUSSION: In a study in 32 healthy females, administration of an oral contraceptive 30 minutes after exenatide (5 mcg BID) decreased the maximum concentration (Cmax) of ethinyl estradiol and levonorgestrel by 45% and 27%, respectively. Time to Cmax (Tmax) of ethinyl estradiol and levonorgestrel increased by 3 hours and 3.5 hours, respectively. Administering the oral contraceptive one hour before exenatide decreased the Cmax of ethinyl estradiol by 15%, but there was no effect on levonorgestrel. There was no significant effect on bioavailability with either regimen.(1,3,4) Administration of an oral contraceptive 1 hour before or 11 hours after lixisenatide had no effect on the pharmacokinetics of ethinyl estradiol or levonorgestrel. Administration of an oral contraceptive 1 hour or 4 hours after lixisenatide did not affect the area-under-curve (AUC) of ethinyl estradiol or levonorgestrel; however, the Cmax of ethinyl estradiol was decreased by 52% and 39%, respectively, and the Cmax of levonorgestrel decreased by 46% and 20%, respectively. Tmax was delayed by 1-3 hours.(2)

Oral Contraceptives/Penicillins

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Estrogens and progesterones are extensively excreted in bile, principally as glycuronide conjugates. Subsequently, they undergo enterohepatic circulation where bacterial hydrolysis occurs, allowing for reabsorption of the oral contraceptives through the bowel wall and eventual urinary excretion. Treatment with antibiotics destroys the gut flora and prevents steroid reabsorption, resulting in lower than normal concentrations of the contraceptive and excretion via the feces rather than the urine.

CLINICAL EFFECTS: May observe reduced pharmacologic effects of oral contraceptives with resultant breakthrough bleeding and pregnancy. Reduced effects may be seen for several days after discontinuation of antibiotic therapy.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Current guidelines suggest that additional precautions are not necessary when non-enzyme inducing antibiotics are used concurrently with hormonal contraceptives; however, some patients may still prefer to use an additional method of contraception.

DISCUSSION: Evidence for this interaction is limited and conflicting; however, the CDC and the Faculty of Sexual and Reproductive Healthcare Clinical Effectiveness Unit no longer recommend use of a backup contraceptive method during use of a non-enzyme inducing antibiotic. Reports of breakthrough bleeding and loss of contraceptive protection leading to unwanted pregnancies have occurred in women taking oral contraceptive agents who received concurrent ampicillin, amoxicillin, penicillin G, or oxacillin. Several studies have shown that the administration of ampicillin or penicillin to pregnant and nonpregnant women resulted in lowered urinary estrogen excretion, in some women as soon as three days after ampicillin therapy began. However in one small prospective study, plasma ethinyl estradiol concentrations showed a tendency to decrease during ampicillin administration on the third, fourth, and fifth morning of ampicillin administration, but were never lower than pretreatment values. In another small prospective study of women taking low dose combination contraceptives, concurrent ampicillin therapy neither altered the plasma levels nor the AUC of norethisterone and ethinyl estradiol. In addition, progesterone levels were in an anovulatory range. In another prospective study of 13 women taking long term oral contraceptive steroids, concurrent ampicillin was not associated with any significant changes in plasma concentrations of ethinyl estradiol, levonorgestrel, follicle stimulating hormone or progesterone, although lower concentrations of ethinyl estradiol were noted in two women.

Oral Contraceptives/Warfarin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The more potent warfarin S-enantiomer is metabolized by CYP2C9 while the weaker R-enantiomer is metabolized by several CYP enzymes including CYP1A2, CYP2C19, and CYP3A4.(1) Oral contraceptives are moderate inhibitors of CYP1A2 and weak inhibitors of CYP3A4.(2) Oral contraceptives (OC) have been shown to induce the activity of CYP2C9.(7)

CLINICAL EFFECTS: Concurrent use of oral contraceptives may result in increased or decreased levels of warfarin which may increase the risk of clotting or bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). Pharmacogenomic information: patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be more susceptible to this interaction. Although patients with a pre-existing CYP2C9 poor metabolizer genotype are expected to be less susceptible to effects from this drug combination, their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) result in an inherently higher warfarin half-life and risk for warfarin-associated bleeding. CYP2C9 poor metabolizers generally require lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective and safe anticoagulation than patients without these CYP2C9 variants.

PATIENT MANAGEMENT: Monitor INRs more frequently until stable in patients who start oral contraceptive therapy. Monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug. Discontinue anticoagulation in patients with active pathologic bleeding.

DISCUSSION: A case series of 3 adolescent females with a history of mechanical mitral valve replacement who developed heavy menstrual bleeding (HMB) found that starting norethindrone in combination with warfarin resulted in increased INRs.(3) -Patient 1, a 12-year-old female, who was stable on 42 mg warfarin weekly, started norethindrone 10 mg daily for HMB. The patient's INR became supratherapeutic (INR 4-6) and required a decrease in warfarin dose to 21 mg weekly (50% reduction).(3) -Patient 2, a 14-year-old female, who was stable on 35 mg warfarin weekly, started norethindrone for HMB (10 mg four times daily for 4 days followed by a maintenance dose of 15 mg daily). The patient required a 43% dose reduction of warfarin to 28 mg weekly.(3) -Patient 3, a 15-year-old female, was stable on 24.5 mg of warfarin weekly. After starting norethindrone 5 mg for 1 month and increasing norethindrone to 10 mg daily, the patient's warfarin requirement decreased to 17.5 mg weekly and eventually stabilized at 19 mg weekly (29% dose reduction). One year later, an intrauterine device was placed and norethindrone was tapered and discontinued over 2 months. The patient's warfarin requirement increased to 28 mg weekly once norethindrone was discontinued (47% increase).(3) A comparative pharmacokinetic study of 14 women found that administration of oral contraceptive steroids in combination with phenprocoumon resulted in decreased serum phenprocoumon concentrations. There was a significant increase in the mean clearance of phenprocoumon from 1.6 to 2.0 mL/min/kg (p <0.05).(4) A case report of a 33-year-old female on long-term anticoagulation following an aortic valve replacement found that stopping Ortho-Cyclen while on warfarin resulted in decreased INRs. While on warfarin (38.5 mg weekly) with a therapeutic INR, she was transitioned from Ortho-Cyclen to implantable progestin-only contraceptive. 19 days after insertion, her INR decreased to 1.8 and required a 55% warfarin dose increase (60 mg weekly). The patient had the implant removed 10 months later and 9 days following removal, her INR went up to 6.5 and finally returned to therapeutic once her dose was reduced to 55.5 mg weekly.(5) An observational study with 12 patients taking nicoumalone (coumarin derivative) and an OC (Neogynona, Microgynon, Eugynon, or Topasel) were assessed in 2 phases using British comparative thromboplastin (BCT). The therapeutic range for commercial thromboplastin ranges from 1.3-1.8, which corresponds to a PT INR of 2-3. Phase A consisted of patients taking both nicoumalone and an OC, while phase B consisted of patients only taking nicoumalone. The mean thromboplastin in phase A was higher than phase B (1.67 vs 1.50; p<0.01) and statistically significant. These findings coincide with a lesser mean requirement for anticoagulation in phase A (2.05 mg) compared to phase B (2.53 mg).(6) In a randomized crossover study with 10 healthy women, participants were started on the Cooperstown 5+1 cocktail (oral caffeine, oral dextromethorphan, oral omeprazole, IV midazolam, and oral warfarin + vitamin k) in 2 phases. There was a 2 month wash-out period between phase 1 and phase 2, with phase 2 adding oral Ortho-Tricyclen. All women in the study carried at least 1 normal-activity allele for CYP2C9, CYP2C19, and CYP2D6. The study found that CYP2C9 and 2D6 activity was increased when taking oral contraception, while CYP1A2, 2C19, and NAT-2 activity decreased.(7)

Oral Estrogens/Growth Hormone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Growth hormone (somatropin or lonapegsomatropin-tcgd) binds to growth hormone receptors and stimulates Janus activating tyrosine kinases (JAK 1 and 2) and signal transducer activators of transcription (STAT1, STAT3, STAT5) to increase gene transcription and metabolism to produce and secrete insulin like growth factor-1 (IGF-1). IGF-1 promotes cell growth, proliferation, and survival. Estrogens block STAT phosphorylation and inhibit IGF-1 secretion and production.(1,2) Higher quantities of growth hormone are required to raise serum IGF-1 concentrations to the normal range.

CLINICAL EFFECTS: Oral estrogens may reduce the IGF-1 response to growth hormone (somatropin and lonapegsomatropin-tcgd).(1-9)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of somatropin states a larger dose of somatropin may be required to achieve the treatment goal.(3-9) The manufacturer of lonapegsomatropin-tcgd states adults of any age concurrently taking oral estrogen should increase the dose of lonapegsomatropin-tcgd to 2.1 mg once weekly.(3) The American Association of Clinical Endocrinologists and American College of Endocrinology guidelines for growth hormone deficiency states that higher recombinant human growth hormone (rhGH) doses are advised in women on oral estrogen therapy and that switching women to transdermal estrogen patches may allow lower rhGH doses to be used for equivalent IGF-1 responses.(10)

DISCUSSION: A prospective study compared growth hormone replacement requirements in women with elevated estrogen (on oral estrogen), women without elevated estrogen (no estrogen therapy or on transdermal estrogen), and growth hormone treated adult hypopituitary males. Women on oral estrogen required 10.6 +/-0.7 mcg/kg/day or 867 +/- 45 mcg/day growth hormone, women not taking oral estrogen required 5.0 +/- 0.7 mcg/kg/day or 424 +/-57 mcg/day, and men required 4.1 +/- 0.6 mcg/kg/day or 376 +/-49 mcg/day.(1) A randomized cross-over study compared one month of treatment with ethinyl estradiol (20 mcg), conjugated equine estrogen (1.25 mg Premarin), and estradiol valerate (2 mg). All three formulations resulted in a significant reduction in IGF-1 levels compared to baseline.(11) A study compared IGF-1 concentrations in premenopausal women and postmenopausal women before and after 2 months of cyclical replacement therapy with either oral ethinyl estradiol (20 mcg daily) or transdermal 17 beta-estradiol (100 mcg patch applied twice weekly). Oral ethinyl estradiol significantly reduced circulating IGF-1 (0.70 +/- 0.09 to 0.47 +/- 0.04 units/mL, P < 0.02) levels. Transdermal 17-beta estradiol increased IGF-1 levels (0.86 +/- 0.15 to 1.10 +/- 0.14 units/mL, P < 0.005).(12) In a clinical trial, somapacitan administered once weekly was compared to somatropin once daily injections in patients with and without oral estrogen replacement therapy. Patients with oral estrogen therapy were administered 2 mg/wk compared to 1 mg/wk for patients without estrogen replacement therapy. Observed doses after titration for somapacitan and somatropin were highest for females on oral estrogen.(13) An open-label, randomized crossover study in growth hormone deficient women compared oral estrogen with transdermal estrogen treatment while on growth hormone. Women received incremental doses of growth hormone (0.5, 1.0, 2.0 units/day for 1 week; increased to next dose each week) for 8 weeks and estradiol valerate (2 mg/day) or transdermal estrogen patches (Estraderm-TTS 100 mcg). IGF-1 levels were significantly reduced during oral estrogen treatment and rose dose-dependently during growth hormone administration by a lower magnitude compared with transdermal treatment (change in IGF-1: 109 +/-43% vs. 135 +/-41%).(14)

Oral Iron Supplements/Antacids And Selected Minerals

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Some antacids may bind to iron, preventing its absorption. Alterations in gastric pH by antacids may also play a role. Iron may bind to other minerals such as calcium, manganese, tin, and zinc in the GI tract.

CLINICAL EFFECTS: Simultaneous administration of an antacid or minerals may decrease the absorption of orally administered iron.

PREDISPOSING FACTORS: The interaction with some combinations may be affected by the presence or absence of food.

PATIENT MANAGEMENT: Iron supplements should not be taken within 1 hour before or 2 hours after antacids, calcium, manganese, or zinc.(1) Some vitamin preparations may contain sufficient quantities of calcium and/or magnesium salts with antacid properties to interact as well.

DISCUSSION: Magnesium hydroxide has been shown to inhibit the absorption of elemental iron,(2) although other studies have shown conflicting results.(3,4) Sodium bicarbonate has been shown to decrease the absorption of iron by 50%.(3) In a study in 61 healthy subjects, calcium citrate, calcium carbonate, and calcium phosphate inhibited iron absorption when taken with food. However, in the fasted state, calcium carbonate had no effect on iron absorption. In the fasted state, calcium citrate and calcium phosphate decreased iron absorption by 49% and 62%, respectively,(6) In a study in 23 healthy subjects, calcium acetate and calcium carbonate decreased the area-under-curve (AUC) of elemental iron (65 mg) by 27% and 19%, respectively.(7) In a study, manganese decreased iron absorption. A ratio of 5:1 of zinc:iron decreased iron absorption by 56%.(8) In a study, inorganic iron decreased zinc absorption.(9) In another study, ferrous sulfate decreased the absorption of zinc sulfate in a concentration dependent manner; however, heme chloride had no effect on zinc sulfate.(10) In a study in premature infants, administration of liquid zinc and iron supplements between feedings decreased iron uptake; however, no effect was seen when the supplements were mixed with feedings.(11) One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Oral Iron Supplements/Entacapone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Entacapone may chelate with iron within the gastrointestinal tract, reducing the absorption of both drugs.

CLINICAL EFFECTS: Simultaneous administration of entacapone and orally administered iron may decrease the clinical effects of both medications.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Iron supplements should not be taken within 2-3 hours before or after entacapone to minimize the effects of this interaction.(1) Some multivitamin preparations that contain sufficient quantities of iron may interact and not be properly absorbed as well.

DISCUSSION: Entacapone may form chelates with iron in the gastrointestinal tract, and preparations should be taken at least 2-3 hours apart.(1) Although the impact on the body's iron stores is unknown, clinical studies showed decreasing serum iron concentrations with coadministration of entacapone.(2) In repeated dose toxicity studies, anemia was observed most likely due to the iron chelating properties of entacapone.(1) Prescribing information of entacapone/levodopa/carbidopa states chelation of entacapone with iron may decrease bioavailability of entacapone/levodopa/carbidopa.(3)

Oral Iron/Cefdinir

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Iron may form a chelation complex with cefdinir, preventing its absorption.(1,2)

CLINICAL EFFECTS: Simultaneous administration of cefdinir with iron may result in decreased levels and clinical effectiveness of cefdinir.(1,2) Concurrent use may also result in a reddish color of stools.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Cefdinir should be taken at least 2 hours before or after iron supplements, including multivitamins containing iron.(1) Patients should be counseled that their stool may turn reddish during treatment with cefdinir. Cefdinir may be administered simultaneously with iron-fortified infant formula.(1)

DISCUSSION: Simultaneous administration of cefdinir with a therapeutic iron supplement containing 60 mg of elemental iron as ferrous sulfate or vitamins containing 10 mg of elemental iron decreased cefdinir absorption by 80% and 31%, respectively.(1) Simultaneous administration of iron with cefdinir (200 mg) decreased cefdinir area-under-curve (AUC) by 93%.(2) There have been reports of reddish stools in patients taking cefdinir, most of these patients were taking iron-containing products.(1)

Oral Iron/Oral Methyldopa

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Iron, in several forms, binds strongly to methyldopa, producing iron complexes thereby reducing methyldopa absorption.

CLINICAL EFFECTS: Concomitant use of methyldopa with iron supplementation may decrease the clinical efficacy of methyldopa.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients requiring iron supplementation should be advised to take methyldopa two hours prior to any iron products.

DISCUSSION: In a randomized crossover trial with 12 subjects, concurrent use of methyldopa (500 mg daily) and ferrous sulfate (325 mg daily) showed a 28.4% decrease in the proportion of "free" methyldopa (p<0.01), a 28% increase in the proportion excreted as methyldopa sulfate (p<0.01), and a 21.2% decrease in total absorbed methyldopa (p<0.01). Similar results were found when administering ferrous gluconate (600 mg daily). Antihypertensive effects of methyldopa while taking ferrous sulfate were also assessed in five patients chronically taking methyldopa. All participants showed an increase in systolic blood pressure (p=0.03) after two weeks of ferrous sulfate administration. Diastolic blood pressure increased in four patients (p>0.05). After 14 days, three patients had an increase in systolic pressure greater than 15 mm Hg and two patients had an increase of greater than 10 mm Hg in diastolic blood pressures. Both systolic and diastolic pressures decreased after ferrous sulfate was discontinued.(2)

Oral Multivalent Cations/Oral Bisphosphonates

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Multivalent cations may bind to and inhibit the absorption of oral bisphosphonates.(1-6)

CLINICAL EFFECTS: Simultaneous administration of products containing multivalent cations may result in decreased levels of and clinical effects from oral bisphosphonates.(1-6)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Instruct patients to separate the administration times of products containing multivalent cations and oral bisphosphonates. Manufacturer recommendations regarding the separation of administration times of oral bisphosphonates and multivalent cations vary. Do NOT give multivalent cation-containing products: - until at least 30 minutes after taking alendronate(1) - within 2 hours of etidronate(2) - until at least 1 hour after taking ibandronate(3) - until at least 30 minutes after taking risedronate(4) - within 2 hours of tiludronate(5)

DISCUSSION: Multivalent cations may bind to and inhibit the absorption of oral bisphosphonates, resulting in decreased levels of and clinical effects from these agents.(1-6) Administration of aluminum- or magnesium-containing antacids 1 hour before tiludronate decreased the bioavailability of tiludronate by 60%.(5)

Polyvalent Cations And Phosphate Binders/Vadadustat

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Vadadustat may form a chelate with iron supplements, phosphate binders, and other medicinal products whose primary component consists of polyvalent cations such as aluminum, calcium, magnesium, selenium, and zinc.(1)

CLINICAL EFFECTS: Simultaneous administration of vadadustat and polyvalent cations and phosphate binders decreases the exposure and effectiveness of vadadustat.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of vadadustat states that it should be administered at least 1 hour before or 2 hours after any medications or products whose primary component consists of iron, phosphate binders and polyvalent cations.(1)

DISCUSSION: Two studies evaluating the pharmacokinetics, safety, and tolerability of a single oral dose of vadadustat coadministered with a phosphate binder or iron supplement were conducted in healthy adult participants. Vadadustat exposure was reduced by coadministration with sevelamer carbonate, calcium acetate, ferric citrate, and ferrous sulfate. Geometric least squares mean ratios for area under the concentration-time curve (AUC) were reduced 37% to 55% by phosphate binders and 46% by ferrous sulfate. However, when vadadustat was administered 1 hour before phosphate binders, 90% confidence intervals for vadadustat exposure were within the no-effect boundaries of +50% to -33%, indicating that drug-drug interactions can be reduced by administering vadadustat 1 hour before phosphate binders.(2)

Polyvalent Cations/Baloxavir

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Aluminum, calcium, iron, magnesium, selenium, and zinc may form chelation compounds with baloxavir.(1)

CLINICAL EFFECTS: Simultaneous administration of products containing aluminum, calcium, iron, magnesium, selenium, and zinc may result in decreased levels of and clinical effects from baloxavir.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid concurrent administration of baloxavir with cation-containing products.(1)

DISCUSSION: A significant decrease in baloxavir exposure was observed when baloxavir was coadministered with calcium, aluminum, magnesium, or iron in monkeys. No studies have been conducted in humans.(1)

Polyvalent Cations/Cabotegravir

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Cabotegravir chelates polyvalent cations such as aluminum, calcium, iron, magnesium, selenium, and zinc.(1)

CLINICAL EFFECTS: Simultaneous administration of cabotegravir and polyvalent cations may decrease the absorption and clinical effects of cabotegravir.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of cabotegravir states that it should be administered at least 4 hours before or 2 hours after any medications or products containing polyvalent cations such as antacids or mineral supplements.(1)

DISCUSSION: Clinical studies have not been conducted. Prescribing information states cabotegravir levels may be decreased when coadministered with antacids containing polyvalent cations (examples include aluminum or magnesium hydroxide, calcium carbonate) suggesting cabotegravir is susceptible to chelation.(1)

Polyvalent Cations/Eltrombopag

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Eltrombopag chelates polyvalent cations such as aluminum, calcium, iron, magnesium, selenium, and zinc.(1)

CLINICAL EFFECTS: Simultaneous administration of eltrombopag and polyvalent cations may decrease the absorption and clinical effects of eltrombopag.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of eltrombopag states that it should be administered at least 2 hours before or 4 hours after any medications or products containing polyvalent cations such as antacids or mineral supplements.(1)

DISCUSSION: In a crossover study in 25 healthy subjects, administration of eltrombopag with an antacid (1524 mg aluminum hydroxide/1425 mg magnesium carbonate/sodium alginate) decreased eltrombopag levels by 70%.(1,2)

Polyvalent Cations/Penicillamine, Oral

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Penicillamine chelates with polyvalent cations such as aluminum, calcium, iron, magnesium, and zinc in the GI tract reducing the absorption of the penicillamine.

CLINICAL EFFECTS: Reduced (to 30% of fasting) bioavailability of penicillamine with decreased pharmacologic response.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: In order to assure systemic absorption and maximal effectiveness from penicillamine, counsel patient to separate penicillamine by at least 1 hour before or 1 hours after any medications or products containing polyvalent cations such as antacids or mineral supplements. Monitor clinical status for decreased effectiveness and adjust the penicillamine dose if necessary.

DISCUSSION: Clinical studies with polyvalent cations have not been conducted. Multivitamins with low doses of cations including iron and zinc may decrease penicillamine absorption so insure patient is aware of the risks.

Polyvalent Cations/Roxadustat

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Roxadustat chelates polyvalent cations such as aluminum, calcium, iron, magnesium, selenium, and zinc.(1)

CLINICAL EFFECTS: Simultaneous administration of roxadustat and polyvalent cations may decrease the absorption and clinical effects of roxadustat.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of roxadustat states that it should be administered at least 1 hour before or 1 hour after any medications or products containing polyvalent cations such as antacids or mineral supplements.(1)

DISCUSSION: Clinical studies with polyvalent cations have not been conducted. In a study in health subjects, concurrent use of roxadustat with sevelamer carbonate or calcium acetate decreased roxadustat area-under-curve (AUC) by 67% and 46% and concentration maximum (Cmax) by 66% and 52%, respectively.(1)

Sel Oral Cations; Antacids; H2 Antag/Dolutegravir-Rilpivirin

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Aluminum, calcium, iron, lanthanum, magnesium, sucralfate, and zinc may form chelation compounds with dolutegravir.(1) Rilpivirine requires an acidic medium for absorption. Antacid or H2 antagonist induced decrease in gastric pH may result in decrease in rilpivirine absorption.(1)

CLINICAL EFFECTS: Simultaneous administration or administration of products containing aluminum, calcium, iron, lanthanum, magnesium, and/or sucralfate close to the administration time of dolutegravir may result in decreased absorption and clinical effectiveness of dolutegravir.(1) Simultaneous administration of an antacid or a H2 antagonist may result in decreased levels and effectiveness of rilpivirine, as well as the development of resistance.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If possible, avoid concurrent therapy with dolutegravir-rilpivirine and cation-containing products. If it is necessary to use these agents concurrently, dolutegravir-rilpivirine should be administered 4 hours before or 6 hours after taking these medications.(1) Alternatively, dolutegravir-rilpivirine and supplements containing calcium or iron can be taken together with food.(1) In patients maintained on dolutegravir-rilpivirine, administer dolutegravir-rilpivirine at least 4 hours before or 6 hours after antacids .(1) In patients maintained on dolutegravir-rilpivirine, administer dolutegravir-rilpivirine at least 4 hours before or 12 hours after H2 antagonists.(1) Concurrent use of proton pump inhibitors will dolutegravir-rilpivirine is contraindicated.(1)

DISCUSSION: In a study in 16 subjects, the administration of an antacid (Maalox - aluminum and magnesium hydroxide) simultaneously with dolutegravir (50 mg single dose) decreased the maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of dolutegravir by 72%, 74%, and 74%, respectively.(1) In a study in 16 subjects, the administration of an antacid (Maalox - aluminum and magnesium hydroxide) 2 hours after dolutegravir (50 mg single dose) decreased dolutegravir Cmax, AUC, and Cmin by 18%, 26%, and 30%, respectively.(1) In a study in 16 subjects, the administration of a multiple vitamin (One-A-Day) simultaneously with dolutegravir (50 mg single dose) decreased dolutegravir Cmax, AUC, and Cmin by 35%, 33%, and 32%, respectively.(1) In a study in 16 subjects, omeprazole (20 mg daily) decreased the Cmax, AUC, and Cmin of rilpivirine (150 mg daily) by 40%, 40%, and 33%, respectively. The Cmax and AUC of omeprazole decreased by 14% and 14%, respectively.(1) In a study in 24 subjects, famotidine (40 mg single dose) administered 12 hours before a single dose of rilpivirine (150 mg) had no significant effect on rilpivirine Cmax or AUC.(1) In a study in 23 subjects, famotidine (40 mg single dose) administered 2 hours before a single dose of rilpivirine (150 mg) decreased the rilpivirine Cmax and AUC by 85% and 76%, respectively.(1) In a study in 24 subjects, famotidine (40 mg single dose) administered 4 hours before a single dose of rilpivirine (150 mg) increased the rilpivirine Cmax and AUC by 21% and 13%, respectively.(1)

Selected Cyp1a2 Inhibitors/Rasagiline (<= 0.5 Mg)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Inhibitors of CYP1A2 may inhibit the metabolism of rasagiline.(1)

CLINICAL EFFECTS: Concurrent use of a CYP1A2 inhibitor may increase levels of and adverse effects from rasagiline.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of rasagiline states that patients receiving concurrent therapy with an inhibitor of CYP1A2 should receive no more than 0.5 mg of rasagiline daily.(1) Concurrent therapy with vemurafenib may require extended monitoring for interaction onset and severity because steady-state levels of vemurafenib are not attained for approximately 15 days.(2)

DISCUSSION: In a study in 12 healthy subjects, ciprofloxacin (500 mg twice daily) increased the area-under-curve (AUC) of rasagiline (2 mg twice daily) by 83%.(1) Strong CYP1A2 inhibitors linked to this monograph include: angelica root, ciprofloxacin, enasidenib, enoxacin, and rofecoxib. Moderate CYP1A2 inhibitors linked to this monograph include: capmatinib, dipyrone, fexinidazole, genistein, hormonal contraceptives, methoxsalen, mexiletine, osilodrostat, phenylpropanolamine, pipemidic acid, rucaparib, troleandomycin, and vemurafenib.(3-5)

Selected Oral Cations/Dolutegravir

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Aluminum, calcium, iron, lanthanum, magnesium, sucralfate, and zinc may form chelation compounds with dolutegravir.(1)

CLINICAL EFFECTS: Simultaneous administration or administration of products containing aluminum, calcium, iron, lanthanum, magnesium, and/or sucralfate close to the administration time of dolutegravir may result in decreased absorption and clinical effectiveness of dolutegravir.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If possible, avoid concurrent therapy with dolutegravir and cation-containing products. If it is necessary to use these agents concurrently, dolutegravir should be administered 2 hours before or 6 hours after taking these medications.(1) Alternatively, dolutegravir and supplements containing calcium or iron can be taken together with food.(1)

DISCUSSION: In a study in 16 subjects, the administration of an antacid (Maalox - aluminum and magnesium hydroxide) simultaneously with dolutegravir (50 mg single dose) decreased the maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of dolutegravir by 72%, 74%, and 74%, respectively.(1) In a study in 16 subjects, the administration of an antacid (Maalox - aluminum and magnesium hydroxide) 2 hours after dolutegravir (50 mg single dose) decreased dolutegravir Cmax, AUC, and Cmin by 18%, 26%, and 30%, respectively.(1) In a study in 16 subjects, the administration of a multiple vitamin (One-A-Day) simultaneously with dolutegravir (50 mg single dose) decreased dolutegravir Cmax, AUC, and Cmin by 35%, 33%, and 32%, respectively.(1)

Selected Oral Cations/Elvitegravir

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: The exact mechanism is unknown, but aluminum, calcium, iron, lanthanum, magnesium, sucralfate, and zinc may bind to elvitegravir in GI tract.

CLINICAL EFFECTS: Simultaneous administration or administration of products containing aluminum, calcium, iron, lanthanum, magnesium, and/or sucralfate may result in decreased levels and effectiveness of elvitegravir, as well as the development of resistance.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Separate the administration of elvitegravir and products containing aluminum, calcium, iron, lanthanum, magnesium, and/or sucralfate by at least 2 hours.(1) Some vitamin preparations may contain sufficient quantities of calcium and/or magnesium salts with antacid properties to interact as well.

DISCUSSION: Administration of an antacid (exact formulation not stated) 2 hours before elvitegravir (50 mg) decreased the maximum concentration (Cmax), area-under-curve (AUC), or minimum concentration (Cmin) of elvitegravir by 18%, 15%, and 10%, respectively.(1) Administration of an antacid 2 hours after elvitegravir (50 mg) decreased the Cmax, AUC, or Cmin of elvitegravir by 21%, 20%, and 20%, respectively.(1) Administration of an antacid 4 hours before elvitegravir (50 mg) decreased the Cmax and AUC of elvitegravir by 5%, and 4%, respectively.(1) Administration of an antacid 4 hours before elvitegravir (50 mg) decreased both the Cmax and AUC of elvitegravir by 2%.(1)

Selected Oral Cations/Selected Oral Quinolones

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Aluminum, calcium, iron, lanthanum, magnesium, and zinc may form chelation compounds with the quinolones.(1-40) MECHANISM OF ACTION: Aluminum, iron, lanthanum, magnesium, and zinc may form chelation compounds with the quinolones.(1-23)

CLINICAL EFFECTS: Simultaneous administration or administration of products containing aluminum, calcium, iron, lanthanum, magnesium, and/or zinc close to the administration time of an oral quinolone may result in decreased absorption and clinical effectiveness of the quinolone. CLINICAL EFFECTS: Simultaneous administration or administration of products containing aluminum, iron, lanthanum, magnesium, and/or zinc close to the administration time of an oral quinolone may result in decreased absorption and clinical effectiveness of the quinolone

PREDISPOSING FACTORS: None determined. PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If possible, avoid concurrent therapy with quinolones and cation-containing products. If it is necessary to administer these agents concurrently, follow the manufacturers' recommendations regarding timing of administration of the quinolone and cation-containing products. Manufacturer recommendations regarding the separation of administration times of quinolones and products containing aluminum, calcium, iron, lanthanum, magnesium, and/or zinc vary: ---Do not give ciprofloxacin for at least 2 hours before or 6 hours after oral cations.(1) ---Do not give delafloxacin for at least 2 hours before or 6 hours after oral cations.(2) ---Do not give enoxacin for at least 2 hours before or 8 hours after oral cations.(3) ---Do not give levofloxacin for at least 2 hours before or 2 hours after oral cations.(4) ---Do not give nalidixic acid for at least 2 hours before or 2 hours after oral cations.(5) ---Do not give norfloxacin for at least 2 hours before or 2 hours after oral cations.(6) ---Do not give ofloxacin for at least 2 hours before or 2 hours after oral cations.(7) ---Do not give sparfloxacin for at least 4 hours before oral cations.(8) ---Do not give sitafloxacin for at least 2 hours before or 2 hours after oral cations.(9) The US manufacturer of lanthanum recommends that quinolones be taken at least 1 hour before or 4 hours after lanthanum;(10) however, it would be prudent to follow the specific quinolone manufacturers' recommendations regarding concurrent administration of cations. The US manufacturer of ferric maltose recommends separation of ferric maltose by at least 4 hours. For quinolones not listed above, separate their administration from oral cations by as much time as feasible. PATIENT MANAGEMENT: If possible, avoid concurrent therapy with quinolones and cation-containing products. If it is necessary to administer these agents concurrently, follow the manufacturers' recommendations regarding timing of administration of the quinolone and cation-containing products. Manufacturer recommendations regarding the separation of administration times of quinolones and products containing aluminum, iron, lanthanum, magnesium, and/or zinc vary: ---Do not give gatifloxacin for at least 4 hours before oral cations(1) ---Do not give gemifloxacin for at least 2 hours before or 3 hours after oral cations.(2) ---Do not give lomefloxacin for at least 2 hours before or 4 hours after oral cations.(3) ---Do not give moxifloxacin for at least 4 hours before or 8 hours after oral cations.(4) ---Do not give trovafloxacin for at least 2 hours before or after oral cations.(5) ---Do not give prulifloxacin for at least 2 hours before or 4 hours after oral cations.(23) The US manufacturer of lanthanum recommends that quinolones be taken at least 1 hour before or 4 hours after lanthanum;(6) however, it would be prudent to follow the specific quinolone manufacturers' recommendations regarding concurrent administration of cations. The US manufacturer of ferric maltose recommends separation of ferric maltose by at least 4 hours. For quinolones not listed above, separate their administration from oral cations by as much time as feasible.

DISCUSSION: Aluminum, calcium, iron, magnesium, and zinc products have been shown to form chelation compounds with quinolone antibiotics, resulting in decreased absorption of the quinolone.(1-40) Treatment failures have been reported.(11-12) In a study in 12 healthy subjects, simultaneous administration of didanosine chewable tablets, which contain aluminum and magnesium, decreased ciprofloxacin area-under-curve (AUC) and maximum concentration (Cmax) by 92% and 98%, respectively.(14) The administration of ciprofloxacin 2 hours prior to Videx chewable/dispersible tablets decreased ciprofloxacin concentrations by 26%.(15,16) In a study in healthy subjects, pretreatment with an antacid containing aluminum-magnesium hydroxide at 5-10 minutes, 2 hours, and 4 hours before a single dose of ciprofloxacin decreased ciprofloxacin AUC by 84.9%, 76.8%, and 30%, respectively. There was no effect when the antacid was administered 6 hours before or 2 hours after.(17) In a study in 12 healthy subjects, aluminum hydroxide decreased ciprofloxacin AUC by 85%.(18) In a study in patients on continuous ambulatory peritoneal dialysis, peak levels of ciprofloxacin were decreased by 67% to 92% in patients receiving aluminum-containing antacids.(19) In a study in 15 healthy subjects, simultaneous administration of calcium acetate decreased the bioavailability of ciprofloxacin by 51%.(20) In a study in 6 healthy males, simultaneous administration of calcium carbonate decreased ciprofloxacin Cmax and AUC by 40% and 43%, respectively.(21) In a study in 12 healthy subjects, calcium carbonate decreased ciprofloxacin AUC by 40%.(18) In a study in 13 healthy males, calcium carbonate had no effect on ciprofloxacin bioavailability when administered 2 hours prior to the antibiotic.(22,23) In a study in healthy males, simultaneous administration of calcium polycarbophil decreased ciprofloxacin AUC by 50%.(24) In a study in 8 healthy males, simultaneous administration of ferrous fumarate (200 mg) decreased ciprofloxacin AUC by 70%.(25) In a study in healthy subjects, ferrous gluconate decreased ciprofloxacin bioavailability by 50%; however, no significant effects were seen with iron-ovotransferrin.(26) In a study in 8 healthy subjects, ferrous sulfate decreased the Cmax and AUC of simultaneously administered ciprofloxacin by 54% and 57%, respectively.(27) In a study in 8 healthy subjects, administration of ferrous sulfate decreased the Cmax and AUC of ciprofloxacin by 33% and 46%, respectively. Administration of ferrous gluconate decreased the Cmax and AUC of ciprofloxacin by 57% and 67%, respectively. Administration of a multivitamin product containing calcium, copper, iron, magnesium, manganese, and zinc decreased the Cmax and AUC of ciprofloxacin by 53% and 56%, respectively.(28) In a study in 12 healthy males, ferrous sulfate decreased ciprofloxacin AUC by 63%.(29) In a study in 12 healthy subjects, lanthanum carbonate decreased the area-under-curve (AUC) and maximum concentration (Cmax) of concurrently administered ciprofloxacin by 54% and 56%, respectively.(30) In a study in 12 healthy males, a multivitamin containing zinc decreased ciprofloxacin AUC by 22%.(29) In a study in 12 healthy subjects, an antacid containing aluminum-magnesium hydroxide had no effect on the pharmacokinetics of intravenous enoxacin.(31) In a study in 10 healthy subjects, administration of an aluminum-magnesium hydroxide antacid 0.5 hours or 2 hours before oral enoxacin (400 mg single dose) decreased the AUC of enoxacin by 73% and 43%, respectively. There were no significant effects on enoxacin AUC when the antacid was administered 8 hours before or 2 hours after enoxacin.(32) In a study in 9 healthy subjects, colloidal aluminum phosphate had no effect on the amount of enoxacin absorbed; however, ferrous sulfate (1050 mg) decreased the amount of enoxacin absorption by 10%.(33) In a study in 5 healthy subjects and 5 patients with cystic fibrosis, separation of levofloxacin (750 mg) and calcium carbonate (500 mg 3 times daily with meals) by 2 hours resulted in no interaction in healthy subjects; however, levofloxacin levels were not bioequivalent in patients with cystic fibrosis.(34) Concurrent magnesium-aluminum hydroxide or calcium have been shown to decrease the bioavailability of norfloxacin by 91.0% and 63.5%, respectively.(35) Concurrent zinc has been shown to decrease the bioavailability of norfloxacin.(36) In a study in 8 healthy subjects, ferrous sulfate decreased the Cmax and AUC of simultaneously administered norfloxacin by 75% and 73%, respectively.(27) Simultaneous aluminum phosphate was found to decrease the rate, but not the extent, of absorption of ofloxacin.(37) In a study in 8 healthy subjects, ferrous sulfate decreased the Cmax and AUC of simultaneously administered norfloxacin by 36% and 25%, respectively.(27) In an in vitro study, ferrous sulfate, aluminum hydroxide, and calcium carbonate decreased ofloxacin availability by 32.6%, 30.7%, and 26.2%, respectively. However, in vivo tests showed a significant effect with only aluminum hydroxide.(38) In a study in 9 healthy subjects, simultaneous administration colloidal aluminum phosphate had no effect on ofloxacin (200 mg) absorption; however, ferrous sulfate (1050 mg) decreased the ofloxacin fraction of dose absorbed by 10.85%.(33) In a study in 16 subjects, administration of either aluminum-magnesium hydroxide or calcium carbonate at least 2 hours before or after ofloxacin administration had no significant effects on ofloxacin levels.(39) The administration of an antacid containing aluminum hydroxide and magnesium hydroxide 2 hours before, 2 hours after, and 4 hours after sparfloxacin decreased sparfloxacin levels by 23%, 17%, and 5%, respectively.(40) One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology. DISCUSSION: Magnesium and aluminum compounds have been shown to form chelation compounds with quinolone antibiotics, resulting in decreased absorption of the quinolone.(1-22) Treatment failures during concurrent use of cations and gatifloxacin(7) and pefloxacin(8) have been reported. In a study in 24 healthy subjects, administration of an aluminum-magnesium hydroxide antacid simultaneously, 2 hours before, or 2 hours after decreased the area-under-curve (AUC) of a single dose of gatifloxacin (400 mg) by 42%, 64%, or 18%, respectively. There were no affects on gatifloxacin AUC when the antacid was administered 4 hours after gatifloxacin.(9) In a study in 16 healthy males, administration of an aluminum-magnesium hydroxide antacid 10 minutes before or 3 hours after a single dose of gemifloxacin (320 mg) decreased the gemifloxacin AUC by 85% and 15%, respectively. There was no affect when the antacid was administered 2 hours after gemifloxacin.(10) In a study in 16 subjects, simultaneous administration of calcium carbonate decreased the maximum concentration (Cmax) and AUC of a single dose of gemifloxacin (320 mg) by 17% and 21%, respectively. There was no effect of calcium carbonate when administered either 2 hours before or after gemifloxacin.(11) In a study in 27 healthy males, the administration of ferrous sulfate (325 mg) 3 hours before a single dose of gemifloxacin (320 mg) decreased the Cmax and AUC of gemifloxacin by 20% and 11%, respectively. There were no effects when ferrous sulfate was administered 2 hours after gemifloxacin.(12) In a study in 8 healthy subjects, ferrous sulfate (100 mg elemental iron) decreased the Cmax and AUC of a single dose of lomefloxacin by 26% and 13%, respectively. There were no effects with concurrent calcium carbonate (500 mg calcium).(13) Magnesium- and aluminum-containing antacids have been shown to decrease the bioavailability of lomefloxacin by 40%.(14) Administration of moxifloxacin 2 hours before, simultaneously, or 4 hours after a magnesium- and aluminum-containing antacid decreased moxifloxacin AUC by 26%, 60%, and 23%, respectively.(15) Simultaneous administration of moxifloxacin and ferrous sulfate (100 mg) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of moxifloxacin by 39% and 59%, respectively.(16) Concurrent administration of calcium had no affect on moxifloxacin pharmacokinetics.(17) In a study in 10 healthy subjects, an aluminum-magnesium hydroxide antacid decreased the bioavailability of pefloxacin (400 mg) by 44.4%.(18) The administration of an antacid containing aluminum hydroxide and magnesium hydroxide 5 minutes before rufloxacin decreased rufloxacin levels by 36%. Administration of the antacid 4 hours after rufloxacin decreased rufloxacin levels by 13%.(19) Magnesium- and aluminum-containing antacids have been shown to decrease the bioavailability of temafloxacin by 40%.(20) Aluminum hydroxide has been shown to decrease the bioavailability of tosufloxacin by 31.6%.(21) Administration of an antacid containing aluminum hydroxide and magnesium hydroxide 30 minutes before trovafloxacin decreased trovafloxacin levels by 66%.(22) One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Strong And Moderate Cyp1a2 Inhibitors/Ropinirole

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Ropinirole is a CYP1A2 substrate. Strong and moderate CYP1A2 inhibitors may decrease the metabolism of ropinirole.(1-3)

CLINICAL EFFECTS: The concurrent administration of strong or moderate CYP1A2 inhibitors and ropinirole may result in elevated levels of ropinirole, increased clinical effects, and signs of toxicity.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: In patients receiving strong or moderate CYP1A2 inhibitors who are started on ropinirole, ropinirole may be titrated to effect according to the manufacturer's dosage instructions. If the strong or moderate CYP1A2 inhibitor is started or discontinued in a patient receiving ropinirole, the dosage of ropinirole may need to be adjusted.(1-2)

DISCUSSION: In a study in 12 subjects, the concurrent administration of ropinirole with ciprofloxacin resulted in increases in the maximum concentration (Cmax) and area-under-curve (AUC) of ropinirole by 84% and 60%, respectively. The major pathway for ropinirole metabolism has been shown to be CYP1A2.(1-3) Strong CYP1A2 inhibitors linked to this monograph include: Angelica dahurica, enasidenib, enoxacin, and fluvoxamine. Moderate CYP1A2 inhibitors linked to this monograph include: capmatinib, centanafadine, ciprofloxacin, dipyrone, fexinidazole, genistein, estrogen-containing contraceptives, methoxsalen, mexiletine, osilodrostat, phenylpropanolamine, pipemidic acid, rucaparib, troleandomycin, vemurafenib, and viloxazine.(4)

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• Carcinoma of breast
• Cerebrovascular accident
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Coronary artery disease
• Deep venous thrombosis
• Estrogen-dependent neoplasm
• Malignant neoplasm of liver
• Migraine with aura
• Nephrotic syndrome
• Porphyria
• Pulmonary thromboembolism
• Sickle cell disease
• Thrombophilia

• Benign hepatic cell adenoma
• Cardiomyopathy
• Diabetes mellitus
• Disease of liver
• Hereditary angioedema
• History of deep vein thrombosis
• History of pulmonary embolism
• History of roux-en-Y gastric bypass
• Hyperlipidemia
• Hypertension
• Invasive surgical procedure
• Obesity
• Retinal thrombosis
• Tobacco smoker
• Valvular heart disease

• Chloasma
• Gallbladder disease

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Less Frequent

• Deep venous thrombosis
• Hyperlipidemia
• Hypertension

Rare or Very Rare

• Acute myocardial infarction
• Acute occlusion of mesenteric vein
• Anaphylaxis
• Angioedema
• Arterial thrombosis
• Benign hepatic cell adenoma
• Biliary calculus
• Cerebrovascular accident
• Colitis
• Dysplasia of cervix
• Dyspnea
• Focal nodular hyperplasia of liver
• Gallbladder disease
• General weakness
• Hemolytic uremic syndrome
• Hemorrhagic stroke
• Hepatic vein thrombosis
• Hepatitis
• Hypersensitivity drug reaction
• Hypertriglyceridemia
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Liver cell carcinoma
• Mesenteric artery thrombosis
• Neoplasm of breast
• Neoplasm of liver
• Obstructive hyperbilirubinemia
• Optic neuritis
• Ovarian cyst
• Pancreatitis
• Pulmonary thromboembolism
• Retinal thrombosis
• Thromboembolic disorder
• Thrombophlebitis
• Thrombotic disorder
• Unconsciousness
• Uterine leiomyoma

More Frequent

• Abdominal distension
• Acne vulgaris
• Body fluid retention
• Dizziness
• Headache disorder
• Mastalgia
• Nausea

Less Frequent

• Abdominal pain with cramps
• Abnormal glucose tolerance
• Acute abdominal pain
• Bronchitis
• Chloasma
• Cystitis
• Gynecomastia
• Libido changes
• Menorrhagia
• Migraine
• Pharyngitis
• Skin photosensitivity
• Urinary tract infection
• Vomiting
• Vulvovaginal candidiasis
• Weight gain

Rare or Very Rare

• Abnormal vaginal bleeding
• Alopecia
• Amenorrhea
• Appetite changes
• Back pain
• Cataracts
• Cervical discharge
• Change in corneal curvature
• Depression
• Diarrhea
• Dysmenorrhea
• Edema
• Endometrial hyperplasia
• Erythema multiforme
• Erythema nodosum
• Fatigue
• Folate deficiency
• Galactorrhea not associated with childbirth
• Hirsutism
• Increased libido
• Insomnia
• Irregular menstrual periods
• Mood changes
• Muscle spasm
• Nervousness
• Oligomenorrhea
• Pelvic pain
• Peripheral edema
• Premenstrual syndrome
• Pruritus of skin
• Raynaud's phenomenon
• Skin rash
• Symptoms of anxiety
• Urticaria
• Vaginal dryness
• Vaginitis
• Varicose veins
• Weight loss

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Although progestins have been used beginning in the first trimester of pregnancy to prevent habitual abortion or to treat threatened abortion, there is no adequate evidence from well-controlled studies to substantiate the efficacy of progestins for these uses; however, there is evidence of potential adverse effects on the fetus when these drugs are administered during the first 4 months of pregnancy. In addition, in most women, the cause of abortion is a defective ovum, which progestins could not be expected to influence. Because of their uterine-relaxant effects, progestins may delay spontaneous abortion of fertilized defective ova. Masculinization of the female fetus has reportedly occurred when progestins were used during pregnancy. Clitoral hypertrophy and fusion of the labia have been reported in a few female neonates born to women who had received medroxyprogesterone during pregnancy; hypospadias in male neonates born to women receiving progestational agents occurs at approximately twice the rate of occurrence in male neonates born to women not receiving the drugs. An association between intrauterine exposure to female sex hormones and congenital anomalies, including cardiovascular and limb defects, has been suggested. (See Cautions: Pregnancy, Fertility, and Lactation, in Estrogen-Progestin Combinations 68:12.) Use of progestins, including norethindrone, is not recommended during the first 4 months of pregnancy. If a woman becomes pregnant while receiving norethindrone or is inadvertently exposed to the drug during the first 4 months of pregnancy, she should be advised of the potential risks to the fetus.

Norethindrone should not be used to induce withdrawal bleeding as a test for pregnancy.

Although preliminary evidence suggested that oral contraceptives could cause serious fetal toxicity when administered to pregnant women, current evidence does not suggest an association between inadvertent use of oral contraceptives in early pregnancy and teratogenic effects (including cardiovascular and limb defects, which have been reported following use of sex hormones). In addition, extensive epidemiologic studies have revealed no increased risk of birth defects in neonates born to women who used estrogen-progestin contraceptives prior to pregnancy. However, since the risks of estrogen-progestin contraceptive use clearly outweigh any possible benefit in women who are pregnant, these agents are contraindicated in such women. Although estrogens and/or progestins were previously used to treat threatened or habitual abortion, there is considerable evidence that estrogens are ineffective and no evidence from well-controlled studies that progestins are effective for these uses. Progestin-only or estrogen-progestin contraceptives should not be used to induce withdrawal bleeding as a test of pregnancy.

Data concerning pregnancy outcomes following unsuccessful emergency postcoital contraception with estrogen-progestin combinations are limited, in part because such women may choose abortion following failure of postcoital contraception. Pooled data from several controlled trials that followed pregnancies that occurred despite postcoital estrogen-progestin combinations indicate delivery of 45 healthy neonates, 1 neonate with absent left kidney, and 2 neonates with minor anomalies. In addition, numerous studies evaluating teratologic risk of conception during cyclic (routine) oral contraceptive regimens (for both currently available low-dose oral contraceptive regimens and older, high-dose preparations (e.g., 150 mcg of ethinyl estradiol daily) that are no longer available) indicate no increased fetal risks. Exposure to the amount of estrogen-progestin in postcoital contraceptive regimens is not large when compared with the total amount of the estrogen-progestin cyclic (routine) oral contraceptive regimens, and there currently is no evidence of substantial risk to the fetus with such short-term exposure. Estrogen-progestin postcoital contraceptive regimens are contraindicated in pregnancy because of lack of efficacy, not because of adverse effects on the fetus.

In women who have missed 2 consecutive menstrual periods during estrogen-progestin conventional-cycle contraceptive use, the drug should be withheld until pregnancy has been ruled out. In women using a fixed-combination extended-cycle oral contraceptive (e.g., LoSeasonique(R), Seasonale(R), Seasonique(R)), the possibility of pregnancy should be considered after one missed menstrual period. When the woman has not adhered to the prescribed oral contraceptive regimen, the possibility of pregnancy should be considered after one missed menstrual period and the drug should be withheld until pregnancy has been ruled out. A back-up method of contraception should be instituted until the possibility of pregnancy has been eliminated. If pregnancy is confirmed, the woman should be informed of the potential hazard to the fetus and the advisability of continuing the pregnancy should be weighed against the risks of exposure of the fetus to the drugs.

Progestins are reportedly distributed into milk. The manufacturers warn that the possible effects of progestins in milk on nursing infants have not been determined.

Estrogen-progestin contraceptives may decrease the quantity and quality of milk if given in the immediate postpartum period. Small amounts of the hormonal agents in estrogen-progestin contraceptives are distributed into milk and adverse effects such as jaundice and breast enlargement have been reported in nursing infants of women receiving cyclic regimens; therefore, because of the theoretical risk, some clinicians recommend that lactating women receiving high-dose postcoital contraceptive regimens use alternative milk sources for their infants for at least 24 hours after completion of the regimen. When possible, the use of cyclic estrogen-progestin contraceptives should be deferred until the infant has been weaned. Long-term follow-up after oral contraceptive use showed no apparent clinical effect on breast-feeding mothers or children whose mothers were breast-feeding and using oral contraceptives.

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