Ella (ulipristal acetate)
Contraceptives Oral Tablet
Last reviewed · Source: First Databank (FDB) drug data
Overview
Ulipristal acetate, a synthetic selective progesterone receptor modulator, is a postcoital contraceptive.
Ulipristal acetate is a synthetic selective progesterone receptor modulator and a derivative of 19-norprogesterone. The drug is structurally and pharmacologically related to mifepristone. Ulipristal, like mifepristone, exhibits antagonist activity at progesterone receptors and inhibits progesterone from binding to its receptors; however, the drug also possesses partial agonist activity at the progesterone receptor.
Animal studies indicate that the antiglucocorticoid activity of ulipristal is lower than its antiprogestin activity. The exact mechanism of action of ulipristal is unknown, but may involve inhibition or delay of ovulation or inhibition of follicular growth or rupture; alterations to the endometrium that may affect implantation also may contribute to efficacy. However, in doses used for postcoital contraception (30 mg), ulipristal acetate has no clinically important effect on the endometrium.
Peak plasma concentrations of ulipristal acetate and its active metabolite, monodemethyl ulipristal acetate, are reached 60-90 minutes following a single oral dose under fasting conditions. Administration of ulipristal with a high-fat meal reduced mean peak plasma concentrations by 40-45% and delayed the time to peak plasma concentration from a median of 0.75 to 3 hours. However, the differences resulting from administration of the drug with food are not expected to result in clinically important effects on efficacy or safety.
Ulipristal acetate is more than 94% bound to plasma proteins, mainly high density lipoprotein (HDL)-cholesterol, alpha-1-acid glycoprotein, and albumin. In vitro data show that ulipristal is metabolized mainly by the cytochrome P-450 (CYP) 3A4 isoenzyme to mono-demethylated and di-demethylated metabolites. The terminal half-life of ulipristal acetate is approximately 32 hours following oral administration.
USES: Ulipristal 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 who are overweight (for example, body mass index greater than 30) or if you are using certain other medications. 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).
Generic name: ulipristal acetate
Pronunciation: (UE-li-PRIS-tal)
Drug class: Contraceptives
Therapeutic class: Contraceptives
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
Today’s intelligence on Ella
Indications
The following indications are listed for Ella:
- Postcoital Contraception
Also known as: Emergency Contraception.
Dosing
The recommended adult dosage of ulipristal acetate for the prevention of unintended pregnancy following unprotected intercourse is a single 30-mg dose administered as soon as possible within 120 hours of unprotected intercourse or known or suspected contraceptive failure.
Ulipristal acetate is administered orally without regard to meals. The drug may be used at any time during the menstrual cycle.
If vomiting occurs within 3 hours after administration, a repeat dose should be considered.
| Drug label | Dosing type | Instructions |
|---|---|---|
| Ella 30 Mg Tablet | Maintenance | Take 1 tablet (30 mg) by oral route once; as soon as possible within 120 hrs (5 days) after unprotected intercourse or contraceptive failure. |
No dosing information is available for this tab.
Drug interactions
No formal drug interaction studies have been performed to date.
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/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/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/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)
Selected Hormonal Contraceptives/Suzetrigine
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Suzetrigine may induce the metabolism of hormonal contraceptives containing progestins other than levonorgestrel and norethindrone.(1)
CLINICAL EFFECTS: Concurrent use of suzetrigine and hormonal contraceptives containing progestins other than levonorgestrel or norethindrone may result in decreased levels and effectiveness of the contraceptive.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The manufacturer of suzetrigine advises that suzetrigine-treated patients using hormonal contraceptives containing progestins other than levonorgestrel and norethindrone should either: - Use additional non-hormonal contraceptives, - Use alternative contraceptives such as a combined oral contraceptive containing ethinyl estradiol as the estrogen and levonorgestrel or norethindrone as the progestin, or - Use an intrauterine system The alternative birth control method should be used during treatment with suzetrigine and for 28 days after discontinuation of suzetrigine.(1)
DISCUSSION: Suzetrigine did not result in clinically significant changes in the pharmacokinetics of ethinyl estradiol and levonorgestrel when used concomitantly with an oral contraceptive containing ethinyl estradiol and levonorgestrel.(1) Suzetrigine administered 50 mg every 12 hours at steady state decreased the area-under-curve (AUC) of midazolam (a CYP3A4 substrate) by 48% and maximum concentration (Cmax) by 37%.(1)
Selected Sensitive Cyp3a4 Substrates/Oral Lefamulin
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Lefamulin is considered a moderate inhibitor of CYP3A4. FDA defines a moderate inhibitor as a drug which increases the area-under-curve (AUC) of a sensitive substrate by 2- to 5-fold.(1,3)
CLINICAL EFFECTS: Concurrent use of oral lefamulin may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway.(1)
PREDISPOSING FACTORS: With darifenacin, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(4)
PATIENT MANAGEMENT: If oral lefamulin must be coadministered with a sensitive CYP3A4 substrate, it is recommended to closely monitor for adverse effects of the CYP3A4 substrate.(1) Drug-specific recommendations: The manufacturer of abemaciclib recommends monitoring for adverse reactions and considering a dose reduction of abemaciclib in 50 mg decrements as detailed in prescribing information (based on starting dose, previous dose reductions, and combination or monotherapy use) with concurrent use of moderate CYP3A4 inhibitors.(2)
DISCUSSION: In a study, oral lefamulin tablets administered concomitantly with and at 2 or 4 hours before oral midazolam (a CYP3A4 substrate) increased the area-under-curve (AUC) and maximum concentration (Cmax) of midazolam by 200% and 100%, respectively. No clinically significant effect on midazolam pharmacokinetics was observed when co-administered with lefamulin injection.(1) Sensitive CYP3A4 substrates linked to this monograph include: abemaciclib, acalabrutinib, alprazolam, atorvastatin, brotizolam, budesonide, buspirone, cobimetinib, darifenacin, ebastine, eletriptan, elvitegravir, everolimus, lovastatin, lurasidone, maraviroc, midazolam, nisoldipine, paritaprevir, sildenafil, simvastatin, ticagrelor, triazolam, and ulipristal.(1,3,5)
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)
Ulipristal/Progestin Replacement Therapy
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 progesterone products ineffective.(1,2) These agents may also make ulipristal ineffective.(3)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: Products containing progestin should not be used within 12 days of ulipristal discontinuation.(3)
DISCUSSION: Ulipristal is a progesterone receptor modulator and binds to the progesterone receptor with high affinity, thus it may interfere with the efficacy of progestin products.(1-3) These products may also make ulipristal ineffective.(3)
Ulipristal/Progestin-Containing Contraceptives
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.
Ulipristal/Rifamycins
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Rifamycins (rifabutin, rifampin, rifapentine) may induce the metabolism of ulipristal by CYP3A4.(1)
CLINICAL EFFECTS: Concurrent use or use of rifamycins within the previous 2-3 weeks may result in decreased levels and effectiveness of ulipristal.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US and UK manufacturers of ulipristal state that concurrent use with CYP3A4 inducers such as rifampin is not recommended. Decreased effectiveness of ulipristal may occur even 2-3 weeks after discontinuation of rifamycins.(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). Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.
DISCUSSION: CYP3A4 inducers may decrease levels and effectiveness of ulipristal. Enzyme induction may take 2-3 weeks to wear off. Plasma levels of ulipristal may be reduced even if the CYP3A4 inducer was discontinued in the previous 2-3 weeks.(1) Concurrent administration of ulipristal 30 mg and rifampin 600 mg for 9 days decreased the maximum concentration (Cmax) and area-under-the-curve (AUC) by 90% and 93%, respectively. The Cmax and AUC of monodemethyl-ulipristal decreased by 84% and 90% respectively.(2)
Ulipristal/Selected Anticonvulsants
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Eslicarbazepine, mephenytoin, oxcarbazepine, rufinamide, and topiramate may induce the metabolism of ulipristal by CYP3A4.(1,2)
CLINICAL EFFECTS: Concurrent use or use of eslicarbazepine, mephenytoin, oxcarbazepine, rufinamide, or topiramate within the previous 2-3 weeks may result in decreased levels and effectiveness of ulipristal.(1,2) In addition, topiramate has been associated with an increased risk of birth defects, including cleft palate.(3)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US and UK manufacturers of ulipristal states that concurrent use with CYP3A4 inducers such as eslicarbazepine, mephenytoin, oxcarbazepine, rufinamide, or topiramate is not recommended. Decreased effectiveness of ulipristal may occur even 2-3 weeks after discontinuation of these agents.(1,2)
DISCUSSION: CYP3A4 inducers may decrease levels and effectiveness of ulipristal. Enzyme induction may take 2-3 weeks to wear off. Plasma levels of ulipristal may be reduced even if the CYP3A4 inducer was discontinued in the previous 2-3 weeks.(1) Concurrent administration of ulipristal 30 mg and rifampin 600 mg, another CYP3A4 inducer, for 9 days decreased the maximum concentration (Cmax) and area-under-the-curve (AUC) by 90% and 93%, respectively. The Cmax and AUC of monodemethyl-ulipristal decreased by 84% and 90%, respectively.(2)
Ulipristal/Selected Strong Cyp3a4 Inducers
SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.
MECHANISM OF ACTION: Strong CYP3A4 inducers may induce the metabolism of ulipristal by CYP3A4.(1)
CLINICAL EFFECTS: Concurrent use or use of strong CYP3A4 inducers within the previous 2-3 weeks may result in decreased levels and effectiveness of ulipristal.(1)
PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.
PATIENT MANAGEMENT: The US and UK manufacturers of ulipristal states that concurrent use with CYP3A4 inducers such as barbiturates, carbamazepine, phenobarbital, phenytoin or primidone is not recommended. Decreased effectiveness of ulipristal may occur even 2-3 weeks after discontinuation of these agents.(1,2)
DISCUSSION: CYP3A4 inducers may decrease levels and effectiveness of ulipristal. Enzyme induction may take 2-3 weeks to wear off. Plasma levels of ulipristal may be reduced even if the CYP3A4 inducer was discontinued in the previous 2-3 weeks.(1) Concurrent administration of ulipristal 30 mg and rifampin 600 mg, another CYP3A4 inducer, for 9 days decreased the maximum concentration (Cmax) and area-under-the-curve (AUC) by 90% and 93%, respectively. The Cmax and AUC of monodemethyl-ulipristal decreased by 84% and 90%, respectively.(2) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, and primidone.(3)
Ulipristal/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 ulipristal by CYP3A4.(1)
CLINICAL EFFECTS: Concurrent use or use of St. John's wort within the previous 2-3 weeks may result in decreased levels and effectiveness of ulipristal.(1)
PREDISPOSING FACTORS: None determined.
PATIENT MANAGEMENT: The US and UK manufacturers of ulipristal state that concurrent use with CYP3A4 inducers such as St. John's wort is not recommended. Decreased effectiveness of ulipristal may occur even 2-3 weeks after discontinuation of St. John's wort.(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). Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.
DISCUSSION: CYP3A4 inducers may decrease levels and effectiveness of ulipristal. Enzyme induction may take 2-3 weeks to wear off. Plasma levels of ulipristal may be reduced even if the CYP3A4 inducer was discontinued in the previous 2-3 weeks.(1) Concurrent administration of ulipristal 30 mg and rifampin 600 mg, another CYP3A4 inducer, for 9 days decreased the maximum concentration (Cmax) and area-under-the-curve (AUC) by 90% and 93%, respectively. The Cmax and AUC of monodemethyl-ulipristal decreased by 84% and 90% respectively.(2)
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 Sensitive Cyp3a4 Substrates/Schisandra
SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.
MECHANISM OF ACTION: Schisandra is considered a moderate inhibitor of CYP3A4. FDA defines a moderate inhibitor as a drug which increases the area-under-curve (AUC) of a sensitive substrate by 2- to 5-fold.(1,2)
CLINICAL EFFECTS: Concurrent use of Schisandra may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway.(3-7)
PREDISPOSING FACTORS: With darifenacin, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(8)
PATIENT MANAGEMENT: If Schisandra must be coadministered with a sensitive CYP3A4 substrate, it is recommended to closely monitor the CYP3A4 substrate and adjust its dose as appropriate.(3-7) The US manufacturer of sirolimus protein-bound injection (Fyarro) states a dose reduction to 56 mg/m2 is recommended when used concurrently with moderate or weak CYP3A4 inhibitors. Concurrent use with strong CYP3A4 inhibitors should be avoided.(8)
DISCUSSION: A study in 12 healthy volunteers found that Schisandra led to an increase in midazolam area-under-curve (AUC) and maximum concentration (Cmax) of 2.05- and 1.65-fold, respectively, compared to midazolam administered alone.(3) In a study of 18 healthy volunteers, sirolimus AUC and Cmax increased by 2.07-fold and 1.96-fold, respectively when given with Schisandra compared to sirolimus administered alone.(4) The effect of Schisandra on tacrolimus has been examined in several small pharmacokinetic studies in healthy volunteers as well as liver and kidney transplant patients. Compared to tacrolimus given alone, tacrolimus AUC when administered with Schisandra was consistently increased by 2.1-fold, while the increase in Cmax varied between 1.83- and 2.11-fold in the transplant studies(5-6) and 3-fold in the study on healthy subjects.(7) In the study with kidney transplant patients, a decrease in tacrolimus dose of 40.9 % was required to bring tacrolimus levels into the therapeutic range.(5)
Contraindications
Known or suspected pregnancy.
- Disease of liver
- Pregnancy
There are no severe contraindications for this drug.
There are no moderate contraindications for this drug.
Adverse reactions
The most common adverse effects reported in clinical trials of ulipristal are headache, abdominal pain, nausea, dysmenorrhea, fatigue, and dizziness.
Less Frequent
- Bradycardia
- Ovarian cyst
Rare or Very Rare
- Abnormal hepatic function tests
- Hepatic failure
- Hepatocellular damage
More Frequent
- Acute abdominal pain
- Dizziness
- Drug-induced hot flash
- Dysmenorrhea
- Fatigue
- Headache disorder
- Menstrual disorder
- Nausea
- Upper abdominal pain
Less Frequent
- Alopecia
- Amenorrhea
- Endometrial hyperplasia
- Endometrial thickening
- Hypercholesterolemia
- Mastalgia
- Vaginal discharge
- Vertigo
Rare or Very Rare
- Acne vulgaris
- Edema
- Pruritus of skin
- Skin rash
- Urticaria
Precautions
No enhanced messaging available.
Safety and efficacy of ulipristal have been established in women of reproductive age. Safety and efficacy are expected to be identical for postpubertal adolescents younger than 18 years of age and women 18 years of age or older. Ulipristal is not intended for use before menarche.
Category X. (See Fetal/Neonatal Morbidity and Mortality under Warnings/Precautions: Warnings and also see Contraindications, in Cautions.)
Distributed into milk in rats; not known whether distributed into human milk. Not recommended for use in nursing women.
Ulipristal has not been evaluated in women 65 years of age or older and is not intended for use for postmenopausal women.
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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