Ethinyl Estradiol; Norethindrone with Rifampin Interaction Details

Brand Names Associated with Rifampin

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Nov 12, 2023

Interaction Effect

Decreased hormonal contraceptive exposure and increased risk of contraceptive failure

Interaction Summary

Contraceptive effectiveness may be reduced when hormonal contraceptives are coadministered with drugs that increase the metabolism of contraceptive steroids, such as rifampin. This could result in unintended pregnancy or breakthrough bleeding. In a 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 . Rifampin may alter intestinal flora, which alters the enterohepatic circulation of oral contraceptives. Concomitant use has been associated with unintended pregnancies and menstrual changes . If coadministration is required, use an alternative method of contraception during coadministration and for at least 28 days after discontinuation of a CYP3A4 inducer .

Severity

Major

Onset

Delayed

Evidence

Established

How To Manage Interaction

Concomitant use of rifampin and a hormonal contraceptive may decrease plasma concentrations of the contraceptive and diminish effectiveness. If coadministration is required, use an alternative method of contraception during coadministration and for at least 28 days after discontinuation of a CYP3A4 inducer. Use of intrauterine or intravaginal contraceptives may be preferable during coadministration with a CYP3A inducer .

Mechanism Of Interaction

Induction of CYP3A4-mediated metabolism of hormonal contraceptives

Literature Reports

A) 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 .

B) An open-label, randomized, three-way crossover study was conducted on 28 healthy females to determine the impact of concomitant rifabutin and rifampin therapy on the pharmacokinetics of an oral contraceptive containing ethinyl estradiol and norethindrone (Ortho-Novum 1/35(R)). Twenty-two women completed all three phases of the study. All women received the oral contraceptive for 21 days for the first cycle, which served as the control. They were then randomized to one of two sequences to receive concomitant rifampin or rifabutin 300 mg daily for 10 days. When evaluating the pharmacokinetics of ethinyl estradiol, women receiving rifampin had a decreased Cmax (243.1 picograms (pg)/mL vs. 416.1 pg/mL) and a decreased AUC (1220.7 pg/hr/mL vs. 3362 pg/hr/mL) when compared with controls. Similarly, the Cmax of norethindrone was 16.5 nanograms (ng)/mL in the rifampin group and 22.61 ng/mL in control, and the AUC of norethindrone was 65.08 ng/hr/mL during the rifampin phase and 159.09 ng/hr/mL during control. The incidence of spotting was 3.7% during the control cycle and increased to 36.4% during rifampin therapy. However, there was no clear evidence of ovulation in this study .

C) The effects of rifampin and rifabutin on an oral contraceptive were examined in a randomized, 2-period crossover trial involving 12 females. All subjects were on a stable contraceptive regimen that contained ethinyl estradiol 35 mcg and norethindrone 1 mg (Ortho-Novum(R) 1/35). Each participant was randomized to receive 14 days of therapy with rifampin 600 mg daily or rifabutin 300 mg daily on days 7 through 21 of their menstrual cycle. Rifampin decreased the mean trough ethinyl estradiol concentration (Cmin) by 79% and decreased the mean Cmax by 43%. Mean norethindrone Cmin values decreased by 89%, while Cmax did not significantly change. Luteinizing hormone levels were not statistically altered by rifampin, while follicle stimulating hormone values increased by 69%. Despite these profound pharmacokinetic alterations, all subjects remained anovulatory after rifampin therapy as indicated by undetectable progesterone levels .

Rifampin Overview

• Rifampin is used with other medications to treat tuberculosis (TB; a serious infection that affects the lungs and sometimes other parts of the body). Rifampin is also used to treat some people who have Neisseria meningitidis (a type of bacteria that can cause a serious infection called meningitis) infections in their noses or throats. These people have not developed symptoms of the disease, and this treatment is used to prevent them from infecting other people. Rifampin should not be used to treat people who have developed symptoms of meningitis. Rifampin is in a class of medications called antimycobacterials. It works by killing the bacteria that cause infection.

• Antibiotics such as rifampin will not work for colds, flu, or other viral infections. Using antibiotics when they are not needed increases your risk of getting an infection later that resists antibiotic treatment.

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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.