By Rebecca H. Allen, MD, MPH, Editor
SYNOPSIS: In this retrospective cohort study, women taking low-dose topiramate (< 200 mg per day) and oral contraception did not have more contraceptive failures compared to women taking other headache remedies (propanolol, metoprolol, amitriptyline, venlafaxine, or verapamil), with an adjusted rate difference of 0.00 (95% confidence interval, -0.3, 0.3).
SOURCE: Sarayani A, Winterstein A, Cristofoletti R, et al. Real-world effect of a potential drug-drug interaction between topiramate and oral contraceptives on unintended pregnancy outcomes. Contraception 2023;120:109953.
Certain anti-epileptic drugs (AEDs), such as phenytoin, carbamazepine, barbiturates, primidone, and oxcarbazepine, are known to reduce the efficacy of oral contraceptives.1 Whether topiramate should be included in this category has been controversial. Topiramate also is used to treat migraines and other types of headaches and, therefore, is a common medication among women. The authors of this study sought to identify actual unintended pregnancies resulting from concomitant use of oral contraceptives and topiramate rather than just conducting pharmacokinetic studies on hormonal levels.
This was a retrospective cohort study that compared the unintended pregnancy rate for combined oral contraceptives while also taking topiramate and other therapies for chronic migraines and headaches. The study used a national private health insurance database (IBM MarketScan) that included data from medical and pharmacy encounters from 2005 to 2018. Included in the study were women ages 12 to 48 years who had been enrolled in the insurance program for at least six months with at least two claims for migraine or other chronic headache. The exclusion criteria included women diagnosed with infertility, ovarian dysfunction, and hirsutism who might be using oral contraceptives for other indications.
Prescription data were used to determine overlapping use of topiramate and other headache therapies (propanolol, metoprolol, amitriptyline, venlafaxine, or verapamil) and oral contraceptives, which included both combined oral contraceptives and progestin-only oral contraceptives. The overlap had to be at least 14 days to enter the cohort. The primary outcome was a claim related to pregnancy while using the drugs concomitantly. Pregnancy claims (live birth, stillbirth, miscarriage, termination, or prenatal visits) were used to determine the conception date of the pregnancy. Patients were followed in the cohort up to one year or until the end of concomitant medication use, the occurrence of pregnancy, teratogenic drug use, hormonal dysfunction diagnosis, or lack of insurance eligibility. Pregnancy rates were calculated and adjusted for confounding factors.
There were 63,649 episodes of oral contraceptives and topiramate use (> 95% with < 200 mg of topiramate daily) and 59,012 episodes of oral contraceptives and other headache medication use. The mean age of both groups was 29 years and the mean follow-up time was 68 days. Both cohorts had similar demographics and comorbidities. There were 158 pregnancies in the topiramate group and 144 pregnancies in the other headache therapy group. Most pregnancies were identified by claims for births (55%) and abortions (20%). In the adjusted analysis, the contraception failure rates were 1.3 (95% confidence interval [CI], 1.1, 1.6) person-years in the topiramate group and 1.3 (95% CI, 1.1, 1.6) person-years in the other group. The rate difference was 0.00 (95% CI, -0.3, 0.3).
COMMENTARY
The authors of this study demonstrated that the concomitant use of oral contraceptives and low-dose topiramate did not increase the unintended pregnancy rate compared to a control group of patients taking other medications for headaches. Certain AEDs are known to interfere with hormonal contraceptive efficacy through the CYP3A4 hepatic metabolism pathway. Topiramate is a moderate CYP3A4 enzyme inducer. Often these drug-drug interactions are evaluated with pharmacokinetic studies looking at contraceptive hormone levels. Previous pharmacokinetic studies indicated that topiramate’s effects on progestin and estrogen levels likely are dose-dependent, with no effect at the < 200 mg per day range.2,3 This now has been confirmed in a clinical study looking at actual pregnancy rates.
Of course, this study does have significant limitations that need to be taken into account. As a database study, the findings are based on diagnosis codes and pharmacy records. Adherence to the medication is assumed. In addition, dating a pregnancy based on these types of records is challenging. Therefore, whether conception actually occurred when both drugs were being taken is not 100% reliable. The authors estimated that the gestational age estimation accuracy is > 90% for live births but only 60% to 80% for other pregnancy outcomes.
In addition, pregnancies could have been missed. For example, pregnancies may not have been captured in the database if the patient paid out of pocket for an abortion. Finally, the frequency of sexual activity or risk of pregnancy cannot be ascertained in this dataset.
Nevertheless, drug-drug interactions with hormonal contraceptives are important to study. AEDs of concern include phenytoin, carbamazepine, barbiturates, primidone, and oxcarbazepine. Lamotrigine is unique because combined oral contraceptives actually can decrease lamotrigine levels, which is clinically important.
The United States Medical Eligibility Criteria (USMEC) for Contraceptive Use from the Centers for Disease Control and Prevention rates combined hormonal contraception as Category 3 (risks outweigh the benefits) for these AEDs, as well as topiramate.1 They recommend if a patient does use combined oral contraceptives concomitantly that at least a 30 mcg ethinyl estradiol pill be prescribed. They may end up changing their recommendations regarding topiramate because of the emerging data that doses < 200 mg are likely to have no effect. Other medications known to interfere with the efficacy of hormonal contraception include rifampin and rifabutin, which also are rated Category 3, and various anti-retrovirals used to treat human immunodeficiency virus/acquired immunodeficiency syndrome. However, most other antibiotics and antifungals have no effect on the effectiveness of oral contraceptives and are rated Category 1 (no restriction on use) by the USMEC.
REFERENCES
- Curtis KM, Tepper NK, Jatlaoui TC, et al. U.S. Medical Eligibility Criteria for Contraceptive Use, 2016. MMWR Recomm Rep 2016;65:1-104.
- Doose DR, Wang SS, Padmanabhan M, et al. Effect of topiramate or carbamazepine on the pharmacokinetics of an oral contraceptive containing norethindrone and ethinyl estradiol in healthy obese and nonobese female subjects. Epilepsia 2003;44:540-549.
- Rosenfeld WE, Doose DR, Walker SA, Nayak RK. Effect of topiramate on the pharmacokinetics of an oral contraceptive containing norethindrone and ethinyl estradiol in patients with epilepsy. Epilepsia 1997;38:317-323.
