Ethinyl Estradiol; Norethindrone with Carbamazepine Interaction Details

Brand Names Associated with Carbamazepine

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

Carbamazepine is a strong CYP3A4 inducer and concomitant use with hormonal contraceptives may significantly decrease exposure and contraceptive efficacy. Coadministration of carbamazepine and oral ethinyl estradiol/norethindrone significantly decreased AUC and increased clearance of the contraceptive in a randomized study. In a study, concomitant use of a CYP3A4 inducer disproportionally increased unplanned pregnancy rate with oral and implanted contraceptives, but not with intrauterine devices or intravaginal rings; therefore, consider intrauterine or intravaginal routes if coadministration is required . Because breakthrough bleeding and significantly increased pregnancy rates have been reported with coadministration, consider an alternative to carbamazepine, or employ alternative or backup contraceptive methods  during coadministration and for at least 28 days after discontinuation of carbamazepine .

Severity

Major

Onset

Delayed

Evidence

Established

How To Manage Interaction

Concomitant use of carbamazepine (a strong CYP3A4 inducer) with hormonal contraceptives (oral and subdermal implant) has resulted in breakthrough bleeding and pregnancies. Consider an alternative to carbamazepine, or employ alternative or backup contraceptive methods 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) In a study in healthy women (N=10 evaluable; 18 to 45 years) using an etonogestrel implant for 13 to 34 months, 3 weeks of coadministered carbamazepine titrated up to 300 mg twice daily resulted in a significant median 61% decrease in etonogestrel levels from 158 picogram (pg)/mL (range, 127.9 to 347.3 pg/mL) to 50.8 pg/mL (range 39.4 to 202.3 pg/mL). In 8 women, the etonogestrel level was below the threshold for ovulatory suppression (less than 90 pg/mL) after carbamazepine coadministration. There was no significant change in the number of ovarian follicle-like structures or endometrial thickness. No pregnancies were reported during the study period .

C) A randomized, open-label, five-group study concluded that carbamazepine significantly decreased the mean AUC and Cmax values of oral contraceptives containing ethinyl estradiol and norethindrone. In two, 28-day cycles, five groups of female subjects received oral doses of ethinyl estradiol and norethindrone (Ortho-Novum 1/35(R)) alone in the first cycle and then in combination with topiramate or carbamazepine during the second cycle. When carbamazepine 600 mg/day was coadministered with ethinyl estradiol and norethindrone, a significant 42% and 58% decrease was observed in the mean AUC of both oral contraceptives, respectively, as was the mean Cmax by 19.2%. However, oral clearance significantly increased in both contraceptives by 127% and 69%, respectively. Coadministration of topiramate at daily doses for nonobese (50 mg, 100 mg, and 200 mg) and obese (200 mg) women resulted in a nonsignificant change in the AUC of ethinyl estradiol by -12%, +5%, -11% and -9%, respectively, when compared with the oral contraceptive alone. Norethindrone results were similar with plasma levels and AUC not significantly changed .

D) 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. 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 special concern, a moderate dose formulation (50 mcg ethinyl estradiol) 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 contraceptives .

E) Carbamazepine reduced the AUC of ethinyl estradiol by 6% to 60% in 4 women taking carbamazepine 300 to 600 mg daily within 8 to 12 weeks of initiation of therapy. Norgestrel AUCs were also significantly reduced to 29% to 57% of baseline. The authors suggest that breakthrough bleeding can be controlled for most women with use of oral contraceptives containing 80 to 100 mcg ethinyl estradiol .

F) Accidental pregnancy occurred in a 20-year-old patient with epilepsy who was using phenytoin 400 mg daily plus carbamazepine 400 mg daily. The plasma concentration of levonorgestrel in this patient was very low (107 to 120 picograms (pg)/mL) when compared with controls (325 +/- 135 pg/mL). Carbamazepine appears to decrease plasma levonorgestrel concentrations by enhancing the hepatic metabolism of the steroid via enzyme induction. Levonorgestrel should not be relied upon as the sole means of contraception in patients on anticonvulsant therapy .

Carbamazepine Overview

• Carbamazepine is used alone or in combination with other medications to control certain types of seizures in people with epilepsy. It is also used to treat trigeminal neuralgia (a condition that causes facial nerve pain). Carbamazepine extended-release capsules (Equetro brand only) are also used to treat episodes of mania (frenzied, abnormally excited or irritated mood) or mixed episodes (symptoms of mania and depression that happen at the same time) in patients with bipolar I disorder (manic-depressive disorder; a disease that causes episodes of depression, episodes of mania, and other abnormal moods). Carbamazepine is in a class of medications called anticonvulsants. It works by reducing 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:

• 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.