Ethinyl Estradiol; Norethindrone with St John's Wort Interaction Details

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Last updated Nov 12, 2023

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Interaction Effect

Decreased hormonal contraceptive exposure and increased risk of contraceptive failure

Interaction Summary

Concomitant use of St. John's wort and hormonal contraceptives may decrease plasma concentrations of the contraceptive and diminish effectiveness. Pregnancy and breakthrough bleeding have been reported when St. John's wort was taken concurrently with hormonal contraceptives . 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 . Use an alternative method of contraception during coadministration and for at least 28 days after discontinuation of St. John's wort .

Severity

Major

Onset

Delayed

Evidence

Established

How To Manage Interaction

Concomitant use of St. John's wort and hormonal contraceptives 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 St. John's wort. 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; induction of intestinal P-glycoprotein drug transporter by St. John's wort

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) In a systematic review of studies of pharmacokinetic interactions involving St John's Wort, concomitant use with ethinyl estradiol in 4 studies resulted in no change in ethinyl estradiol AUC with products containing hyperforin dosages of 0.4 mg/day, and a decrease in ethinyl estradiol AUC of 10% to 34% with hyperforin dosages of 2.4 to 33 mg/day .

C) In a systematic review of studies of pharmacokinetic interactions involving St John's Wort, concomitant use with norethindrone in 2 studies resulted in a 11% to 12% decrease in norethindrone AUC with products containing hyperforin dosages of 27 to 33 mg/day .

D) In a systematic review of studies of pharmacokinetic interactions involving St John's Wort, concomitant use with desogestrel in 2 studies resulted in a 42% decrease in the AUC of ketodesogestrel, the active desogestrel metabolite with products containing hyperforin dosages of 4.8 to 7.5 mg/day and no change in AUC with 0.4 mg/day .

E) There have been 8 reports of breakthrough bleeding and 1 case of changed menstrual bleeding by women 23 to 31 years of age who were taking St. John's wort and oral contraceptives. Most of the women had been taking oral contraceptives for a long time. The time between coadministration of St. John's wort and onset of problems was approximately 1 week for most patients. Induction of CYP3A4, which metabolizes steroids, is suggested to be the cause .

F) Three case reports detail women taking ethinyloestradiol and desogestrel combination contraceptives who experienced breakthrough bleeding while taking hypericum. The author cites the possible mechanism of this interaction as a CYP3A4 induction by St. John's wort, causing increased metabolism and consequent lowering of ethinyloestradiol concentrations .

G) St. John's wort caused breakthrough bleeding in 7 of 12 women taking oral contraceptives. Twelve healthy female subjects received a combination oral contraceptive (ethinyl estradiol/norethindrone) for three months. During months 2 and 3, St. John's wort 300 mg was administered 3 times daily. Follicle stimulating hormone (FSH), luteinizing hormone (LH), progesterone, ethinyl estradiol, and norethindrone concentrations as well as CYP3A enzyme activity were assessed in months 1 and 3. FSH, LH and progesterone concentrations on days 11 through 16 were not altered by St. John's wort. St. John's wort significantly increased the oral clearance of norethindrone from 8.2 to 9.5 L/hr . Seven of 12 subjects experienced breakthrough bleeding during month 3, compared with 2 of twelve in month 1. The authors conclude that long-term St. John's wort administration alters the efficacy and disposition of combination oral contraceptives due to the ability of St. John's wort to induce intestinal wall CYP3A .

H) Two women experienced unintended pregnancy within 5 months of starting St. John's wort. Both had used oral contraceptives for more than 8 years .

I) A 36-year-old female experienced an unplanned pregnancy associated with the concomitant use of St. John's wort and an oral hormonal contraceptive (ethinyl estradiol/dienogest (Valette(R))). She had self-medicated with St. John's wort extract (Helarium(R) 425, Bionorica) up to 1700 mg daily for approximately 3 months before conception. She was on no other medications .

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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.

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

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