Mitotane with Levonorgestrel Interaction Details

Brand Names Associated with Mitotane

Brand Names Associated with Levonorgestrel

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Dec 29, 2023

Interaction Effect

Decreased levonorgestrel exposure and increased risk of breakthrough bleeding and/or contraceptive failure

Interaction Summary

Concomitant use of a CYP3A4 inducer and a hormonal contraceptive may decrease contraceptive exposure, which may lead to breakthrough bleeding and/or contraceptive failure. If coadministration is required, use an alternative non-hormonal method of contraception or a back-up method during and for at least 28 days after discontinuation of a CYP3A inducer. In a study, patients with obesity (BMI of 30 kg/m(2) or greater) had an increased risk of unplanned pregnancy with coadministration of a CYP3A inducer compared with patients with a BMI less than 25 mg/kg(2) . In another study, concomitant use of a CYP3A4 inducer disproportionally increased the rate of unplanned pregnancy with oral and implanted contraceptives; therefore, consider intrauterine or intravaginal routes if coadministration is required ; the contraceptive effect of levonorgestrel intrauterine system occurs via direct release into the uterine cavity and is unlikely to be affected by drug interactions mediated by enzyme induction .

Severity

Major

Onset

Delayed

Evidence

Probable

How To Manage Interaction

Concomitant use of a hormonal contraceptive, such as levonorgestrel, and a CYP3A4 inducer may decrease contraceptive exposure and lead to breakthrough bleeding and/or contraceptive failure. If coadministration is required, use an alternative non-hormonal method of contraception or a back-up method during coadministration and for at least 28 days after use of a CYP3A4 inducer. Patients with obesity (BMI of 30 kg/m(2) or greater) have an increased risk of unplanned pregnancy with coadministration of a CYP3A inducer compared with patients with a BMI less than 25 mg/kg(2) . Use of intrauterine or intravaginal contraceptives may be preferable during coadministration with a CYP3A inducer ; the contraceptive effect of levonorgestrel intrauterine system occurs via direct release into the uterine cavity and is unlikely to be affected by drug interactions mediated by enzyme induction .

Mechanism Of Interaction

Induction of CYP3A4-mediated metabolism of levonorgestrel

Literature Reports

A) Participants with HIV who received double-dose levonorgestrel (3 mg; n=35) in combination with efavirenz-based antiretroviral therapy (ART) had a similar levonorgestrel AUC and Cmax 8 hours after dosing compared with control (levonorgestrel 1.5 mg plus dolutegravir-based ART; n=32) in an open-label partially randomized 48-hour pharmacokinetic study. Similar results were seen with rifampicin plus levonorgestrel 3 mg in those without HIV receiving tuberculosis therapy (n=34), except levonorgestrel Cmax was 27% higher than control. Participants receiving the standard dose of levonorgestrel (1.5 mg; n=17) plus efavirenz experienced a 50% lower AUC compared with control. Compared with efavirenz plus levonorgestrel 1.5 mg, those receiving efavirenz plus levonorgestrel 3 mg had an AUC that remained 88% to 90% higher 24- and 48-hours after dosing and Cmax was 61% higher. Adverse events were similar between groups, and were reported in 4% for levonorgestrel 1.5 mg (Grade 2 nausea and heavy menstrual bleeding) and 3% for levonorgestrel 3 mg (Grade 2 nausea and intermenstrual bleeding, and Grade 3 headache). Participants were without an indication for emergency contraception and were not on hormonal contraception; median age was 34 years and BMI was 23.2 kg/m(2). Levonorgestrel is a CYP3A4 substrate, and administration of double-dose levonorgestrel has been suggested in patients receiving CYP3A4 inducers (such as efavirenz and rifampicin). It is not known if the AUC correction over the first 8 hours of dosing with levonorgestrel 3 mg in combination with efavirenz-based ART is adequate to maintain emergency contraceptive efficacy .

B) In an integrated physiologically-based pharmacokinetic (PBPK) modeling and model-based metaanalysis (10 studies; N=26,887 patients over 1 year/13 cycles), simulated coadministration of oral levonorgestrel and strong CYP3A4 inducers predicted significantly decreased levonorgestrel exposure of 50% to 65% in patients with BMI less than 25 kg/m(2) and 70% to 75% in patients with obesity (BMI 30 kg/m(2) or greater). Studies included use of combination oral contraceptives containing levonorgestrel and ethinyl estradiol 150 mcg/30 mcg (LNG150) or 100 mcg/20 mcg (LNG100), except for 1 study using levonorgestrel 30 mcg (progestin only pill). With coadministration of a CYP3A4 inducer and LNG150 or LNG100, mean Pearl Index increased 1.2 to 1.3 or 1.8 to 2.1 pregnancies/100 women years with BMI less than 25 kg/m(2) (incidence rate ratios [IRRs], 1.7 to 2.2) and 1.6 to 1.8 or 2.4 to 2.85 in patients with obesity (IRRs, 2.2 to 3), respectively. CYP3A4 inducer simulations included daily doses of rifampin 100 mg, carbamazepine 400 mg, and efavirenz 600 mg .

C) Concomitant use of a CYP3A4 inducer with oral or implantable contraceptive products containing levonorgestrel (684 events) or etonogestrel/desogestrel (864 events) was associated with a disproportionately higher rate of unintended pregnancy compared to all other event types reported to the FDA Adverse Event Reporting System (FAERS) between 1971 and 2020 [levonorgestrel (14,504 total events); etonogestrel/desogestrel (9348 total events)]. When compared between CYP3A4 inducer exposure vs no exposure, cases of unintended pregnancy made up a significantly higher proportion of total events when levonorgestrel was administered orally (32.8% vs 10.5%) or as an implant (51.9% vs 11.9%), and a similar association was identified with implanted etonogestrel products (42.5% vs 13.1%). However, when contraceptives were administered as an intrauterine device (levonorgestrel, 10.3% vs 11.5%) or intravaginal ring (etonogestrel, 10.9% vs 8.7%), no significant associations were identified. Oral desogestrel (pro-drug of etonogestrel) in combination with ethynyl estradiol also was not significantly affected (11.8% vs 17.4%). Intrauterine and vaginal ring products may be preferred in lieu of oral and implantable contraceptive products in women concomitantly receiving CYP3A4 inducers .

Mitotane Overview

• Mitotane is used to treat cancer of the adrenal gland that can not be treated with surgery. Mitotane is in a class of medications called antineoplastic agents. It works by slowing growth or reducing the size of the tumor.

Levonorgestrel Overview

• Levonorgestrel is used to prevent pregnancy after unprotected sexual intercourse (sex without any method of birth control or with a birth control method that failed or was not used properly [e.g., a condom that slipped or broke or birth control pills that were not taken as scheduled]). Levonorgestrel should not be used to prevent pregnancy on a regular basis. This medication is to be used as an emergency contraceptive or backup in case regular birth control fails or is used incorrectly. Levonorgestrel is in a class of medications called progestins. It works by preventing the release of an egg from the ovary or preventing fertilization of the egg by sperm (male reproductive cells). It also may work by changing the lining of the uterus (womb) to prevent development of a pregnancy. Levonorgestrel may prevent pregnancy, but it will not prevent the spread of human immunodeficiency virus (HIV, the virus that causes acquired immunodeficiency syndrome [AIDS]) and other sexually transmitted diseases.

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Definitions

Severity Categories

Contraindicated

These drugs, generally, should not be used together simultaneously due to the high risk of severe adverse effects. Combining these medications can lead to dangerous health outcomes and should be strictly avoided unless otherwise instructed by your provider.

Major

This interaction could result in very serious and potentially life-threatening consequences. If you are taking this drug combination, it is very important to be under close medical supervision to minimize severe side effects and ensure your safety. It may be necessary to change a medication or dosage to prevent harm.

Moderate

This interaction has the potential to worsen your medical condition or alter the effectiveness of your treatment. It's important that you are monitored closely and you potentially may need to make adjustments in your treatment plan or drug dosage to maintain optimal health.

Minor

While this interaction is unlikely to cause significant problems, it could intensify side effects or reduce the effectiveness of one or both medications. Monitoring for changes in symptoms and your condition is recommended, and adjustments may be made if needed to manage any increased or more pronounced side effects.

Onset

Rapid: Onset of drug interaction typically occurs within 24 hours of co-administration.

Delayed: Onset of drug interaction typically occurs more than 24 hours after co-administration.

Evidence

Level of documentation of the interaction.

Established: The interaction is documented and substantiated in peer-reviewed medical literature.

Theoretical: This interaction is not fully supported by current medical evidence or well-documented sources, but it is based on known drug mechanisms, drug effects, and other relevant information.

How To Manage The Interaction

Provides a detailed discussion on how patients and clinicians can approach the identified drug interaction as well as offers guidance on what to expect and strategies to potentially mitigate the effects of the interaction. This may include recommendations on adjusting medication dosages, altering the timing of drug administration, or closely monitoring for specific symptoms.

It's important to note that all medical situations are unique, and management approaches should be tailored to individual circumstances. Patients should always consult their healthcare provider for personalized advice and guidance on managing drug interactions effectively.

Mechanism Of Interaction

The theorized or clinically determined reason (i.e., mechanism) why the drug-drug interaction occurs.

Disclaimer: The information provided on this page is for informational purposes only and should not be considered medical advice. Always consult with a qualified healthcare professional regarding your specific circumstances and medical conditions.

Where Does Our Information Come From?

Information for our drug interactions is compiled from several drug compendia, including:

• Gold Standard Drug Database
• Micromedex
• Lexicomp
• DrugBank

The prescribing information for each drug, as published on DailyMED, is also used. 

Individual drug-drug interaction detail pages contain references specific to that interaction. You can click on the reference number within brackets '[]' to see what reference was utilized.

The information posted is fact-checked by HelloPharmacist clinicians and reviewed quarterly.