Ethinyl Estradiol; Norethindrone with Phenytoin Interaction Details
Brand Names Associated with Phenytoin
- Dilantin®
- Phenytek®
- Phenytoin
Medical Content Editor Dr. Brian Staiger, PharmD
Last updated
Nov 12, 2023
Interaction Effect
Decreased hormonal contraceptive exposure and increased risk of breakthrough bleeding and/or contraceptive failure
Interaction Summary
Concomitant use of phenytoin and hormonal contraceptives may decrease plasma concentrations of the hormonal contraceptive. Breakthrough bleeding, spotting, and pregnancy have been reported in women taking phenytoin concurrently with hormonal contraceptives . Oral contraceptives have also been reported to increase or decrease phenytoin levels . If coadministration is required, use an alternative method of contraception during coadministration and for at least 28 days after discontinuation of a CYP3A4 inducer . 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 .
Severity
Major
Onset
Delayed
Evidence
Probable
How To Manage Interaction
Concomitant use of phenytoin and hormonal contraceptives may decrease plasma concentrations of the hormonal contraceptive. Breakthrough bleeding, spotting, and pregnancy have been reported in women taking phenytoin concurrently with hormonal contraceptives . 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) Concomitant administration of oral contraceptives with enzyme-inducing anticonvulsant agents, primarily phenobarbital, phenytoin, carbamazepine, or primidone, has been reported to result in an increased failure rate of contraception . One study found that the use of phenytoin and/or phenobarbital increased the frequency of pregnancy 25-fold in patients taking oral contraceptives . The benzodiazepines and valproic acid have not been associated with increased failure rates in women receiving oral contraceptives. Increasing the dose of ethinyl estradiol or mestranol in oral contraceptives may diminish breakthrough bleeding and decrease the risk of conception. However, higher doses of estrogens may also increase the risk of vascular side effects, primarily in patients where enzyme induction does not occur. It is recommended that low doses of estrogen and progestin be given initially in patients receiving an enzyme-inducing anticonvulsant; however, if unplanned pregnancy is a particular concern, a moderate dose formulation (ethinyl estradiol 50 mcg) should be considered. If breakthrough bleeding occurs with low-dose contraception, progressive increases in the dose of mestranol or its equivalent (up to 80 mcg) should be considered. If spotting occurs, it is suggested that the contraceptive not be discontinued, but rather that a traditional method of barrier contraception be initiated during the remainder of that cycle. Switching to a lower dose oral contraceptive is recommended if enzyme-inducing anticonvulsants are discontinued in women receiving moderate or high-dose contraceptive steroids to reduce the risk of vascular disease .
C) Contraception by levonorgestrel subdermal capsules is not reliable in patients on anticonvulsant therapy. In addition to levonorgestrel therapy, 2 patients took phenytoin, 3 took phenytoin plus carbamazepine, 2 used carbamazepine only, 1 used clonazepam, and 1 used phenytoin plus sodium valproate. At 3 to 12 months, the mean plasma levonorgestrel concentration was significantly lower in the 6 patients with epilepsy using phenytoin alone or in combination with other anticonvulsants (203 +/- 128 picograms/milliliter [pg/mL]) than in controls using levonorgestrel implants only (325 +/- 135 pg/mL). Two of the 9 patients with epilepsy became pregnant; 1 was taking phenytoin 250 mg daily and the second phenytoin 400 mg daily and carbamazepine 400 mg daily . A 26-year-old woman receiving phenytoin 300 mg/day became pregnant after 9 months of implant use. It appears that phenytoin, and probably carbamazepine, decrease plasma levonorgestrel concentrations by enhancing the hepatic metabolism of the steroid via enzyme induction . Phenytoin also induces sex hormone binding globulin (SHBG) and thereby decreases the amounts of biologically active levonorgestrel. Levonorgestrel should not be relied upon as the sole means of contraception in patients on anticonvulsants.
Phenytoin Overview
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Phenytoin is used to control certain type of seizures, and to treat and prevent seizures that may begin during or after surgery to the brain or nervous system. Phenytoin is in a class of medications called anticonvulsants. It works by decreasing abnormal electrical activity in the brain.
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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:
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.