Econtra One-Step (levonorgestrel)
Contraceptives Oral Tablet
Last reviewed · Source: First Databank (FDB) drug data
Overview
Etonogestrel, levonorgestrel, and norethindrone are synthetic progestin contraceptives.
USES: Levonorgestrel is used by women to prevent pregnancy after birth control failure (such as a broken condom) or unprotected sex. This medication is an emergency contraceptive and should not be used as a regular form of birth control. Using this medication will not stop an existing pregnancy or protect you or your partner against sexually transmitted diseases (such as HIV, gonorrhea, chlamydia).
This medication may not work well in women over a certain weight (for example, greater than 164 pounds or 74 kilograms), or if you have used certain other medications within the past month. This effect can result in pregnancy. Talk to your doctor for more details and to see if this medication is right for you (see also Drug Interactions section).
Check the ingredients on the label even if you have used the product before. The manufacturer may have changed the ingredients. Also, products with similar names may contain different ingredients meant for different purposes.
Taking the wrong product could harm you.
Generic name: levonorgestrel
Pronunciation: (LEE-voe-nor-JES-trel)
Drug class: Contraceptives
Therapeutic class: Contraceptives
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
Today’s intelligence on Econtra One-Step
Indications
The following indications are listed for Econtra One-Step:
- Postcoital Contraception
Also known as: Emergency Contraception.
Dosing
No dosing information is available for this tab.
Norethindrone is administered orally once daily. The tablets should be taken at the same time each day and continued daily without interruption, including throughout all bleeding episodes. Women should be advised to inform a clinician if prolonged bleeding, amenorrhea, or severe abdominal pain occurs.
Levonorgestrel is administered orally or as a levonorgestrel-releasing intrauterine device.
If vomiting occurs within 2 hours following administration of levonorgestrel (e.g., Plan B One-Step(R), Next Choice One Dose(R)) for postcoital contraception, a clinician should be contacted to discuss the need for repeating the dose. If vomiting occurs within 2 hours following administration of the first or second dose of the levonorgestrel 2-dose regimen for emergency contraception, a clinician should be contacted to discuss the need for taking another dose.
Levonorgestrel-releasing intrauterine system should be inserted into the uterine cavity under strict aseptic conditions following a complete review of the patient's medical and social histories, exclusion of pregnancy, and physical examination (including pelvic examination, Papanicolaou test (Pap smear), and appropriate laboratory tests for other genital diseases (e.g., gonorrhea, chlamydia) as indicated). Special attention should be given to determining whether the woman is at risk for ectopic pregnancy or pelvic inflammatory disease (PID). Patients should be reexamined shortly after the first menstrual period following insertion of the device to verify that the device is properly positioned. The manufacturer's labeling should be consulted for proper methods of inserting and removing the levonorgestrel-releasing intrauterine system and for associated precautions.
Etonogestrel is administered as a nonbiodegradable implant that is inserted subcutaneously in the inner aspect of the upper arm. The manufacturer's labeling should be consulted for the proper method of administration and associated precautions.
| Drug label | Dosing type | Instructions |
|---|---|---|
| Econtra One-Step 1.5 Mg Tablet | Maintenance | Take 1 tablet (1.5 mg) by oral route once as soon as possible within 72 hours (3 days) after unprotected intercourse. |
| Drug label | Dosing type | Instructions |
|---|---|---|
| Levonorgestrel 1.5 Mg Tablet | Maintenance | Take 1 tablet (1.5 mg) by oral route once as soon as possible within 72 hours (3 days) after unprotected intercourse. |
Drug interactions
For information on drug interactions associated with oral contraceptives, see Drug Interactions in Estrogen-Progestin Combinations 68:12.
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)
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/Mavacamten
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: Mavacamten is a moderate CYP3A4 inducer. Coadministration of mavacamten 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 mavacamten can lead to ineffective hormonal contraceptive and cause unintended pregnancy. Mavacamten may cause fetal harm when administered to a pregnant woman.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Avoid concomitant use of hormonal contraceptives with mavacamten. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with mavacamten and for 4 months after the last dose.(1) Hormonal contraceptives containing a combination of ethinyl estradiol and norethindrone may be used with mavacamten.(1) 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) 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.(3)
DISCUSSION: Mavacamten is a moderate CYP3A4 inducer.(1) Concurrent use of a 16-day course of mavacamten (25 mg on days 1 and 2, followed by 15 mg for 14 days) resulted in a decrease in midazolam area-under-curve (AUC) and concentration maximum (Cmax) by 13% and 7%, respectively, in healthy CYP2C19 normal metabolizers. Concurrent use of mavacamten once daily in patients with hypertrophic cardiomyopathy, midazolam AUC and Cmax are predicted to decrease by 21 to 64% and 13 to 48%, respectively, depending on the dose of mavacamten and CYP2C19 phenotype.(1) Mavacamten 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, mavacamten administration resulted in decreases in mean fetal body weight, reductions in fetal ossification of bones, and increases in post-implantation loss as well as increases in skeletal malformations at doses similar to maximum recommended human doses.(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)
Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
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/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.
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/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)
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.
Progestin-Only Oral Contraceptives/Selected Retinoids
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 may result in increased progesterone levels and interference with the effect of the contraceptive. Major fetal abnormalities have been reported with the administration of acitretin(1) and isotretinoin.(2)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Use of "mini-pill" progestin preparations are not recommended. Patients on acitretin(1) or isotretinoin(2) therapy should be using two reliable methods of contraception and should be advised that progestin-only mini-pills may fail. Consider switching to a combination estrogen-progestin contraceptive agent; intrauterine device (IUD); or injected, implanted, or inserted hormonal birth control products. Two methods of contraception are still required.
DISCUSSION: According to the manufacturer of acitretin, this interaction has been documented in one patient who received concurrent therapy with acitretin and a progestin-only mini-pill.(1) Given the severe consequences of contraceptive failure during acitretin or isotretinoin therapy, caution is warranted. All females of reproductive age should use two reliable forms of contraception unless they have undergone a hysterectomy or practice abstinence.(1,2) In a study in 26 healthy women, concurrent use of isotretinoin and Ortho Novum 7/7/7 (ethinyl estradiol and norethindrone) resulted in small, inconsistent, although statistically significant, decreases in ethinyl estradiol (9%) and norethindrone (11%). However, there was large variability of pharmacokinetic and pharmacodynamic markers and the authors stressed that their results reinforced the need for additional contraceptive measures during therapy.(3)
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.
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)
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)
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)
Selected Progestin-Only Contraceptives/Lamotrigine
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Lamotrigine may induce the metabolism of levonorgestrel and norethindrone.(1-4)
CLINICAL EFFECTS: Concurrent use of lamotrigine and levonorgestrel or norethindrone-only contraceptives may result in decreased levels and effectiveness of the contraceptive. Agents linked to this monograph contain only levonorgestrel or norethindrone.
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Lamotrigine may decrease progestin concentration by approximately 20%. While this modest decrease does not appear to affect the efficacy of estrogen-progestin contraceptive combinations, it may be important in progestin-only oral or implanted contraceptives. Thus, contraceptive efficacy may be lower than described in prescribing information. Patients receiving lamotrigine may have a progestin-only contraceptive prescribed to avoid the effects of estrogens on lamotrigine concentrations. Although studies have not been performed to evaluate this interaction, it would be prudent to counsel patients on the importance of not missing doses of oral contraceptives. Theoretically, the efficacy of implanted progestins may be lower than expected at the end of the dosing interval as progestin concentrations wane.
DISCUSSION: Lamotrigine induces glucuronidation pathways including UGT1A4, a pathway associated with progestin metabolism.(3,4) In a study, 16 females took lamotrigine titrated up to 300 mg/d for a period of 130 days and either combined it with an estrogen-progestin oral contraceptive or took lamotrigine monotherapy. Levonorgestrel and lamotrigine serum levels were drawn in the presence or absence of combined therapy. Levonorgestrel AUC and Cmax decreased by 19% and 12%, respectively.(1,2)
Contraindications
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- Porphyria
- Body weight greater than 74 kg (164 lbs)
- Diabetes mellitus
Adverse reactions
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Less Frequent
- Abnormal vaginal bleeding
- Amenorrhea
- Menorrhagia
More Frequent
- Abdominal pain with cramps
- Dizziness
- Fatigue
- Headache disorder
- Nausea
- Vomiting
Less Frequent
- Mastalgia
- Menstrual disorder
Rare or Very Rare
- Migraine
Precautions
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ICD codes
| Code | Type | Description |
|---|---|---|
| Postcoital contraception | ||
| Z30.012 | ICD10CM | Encounter for prescription of emergency contraception |
ICD code information from First Databank (FDB).
Formulary status
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Last reviewed · Source: First Databank (FDB) drug data
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