By Rebecca H. Allen, MD, MPH
Associate Professor, Department of Obstetrics and Gynecology, Warren Alpert Medical School of Brown University, Women & Infants Hospital, Providence, RI
SYNOPSIS: Women taking low-dose topiramate (< 200 mg per day) and oral contraception did not experience more contraceptive failures compared to women taking other headache remedies (propranolol, metoprolol, amitriptyline, venlafaxine, or verapamil).
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 is a common medication among women. Sarayani et al sought to identify actual unintended pregnancies resulting from concomitant use of oral contraceptives and topiramate rather than just conducting pharmacokinetic studies on hormonal levels.
In this retrospective cohort study, the authors compared the unintended pregnancy rate for combined oral contraceptives while also taking topiramate and other therapies for chronic migraines and headaches. Researchers used a national private health insurance database (IBM MarketScan) that included data from medical and pharmacy encounters from 2005 to 2018. The authors included women ages 12-48 years who had been enrolled in the insurance program for at least six months and had filed at least two claims for migraine or other chronic headache. Exclusion criteria included women diagnosed with infertility, ovarian dysfunction, and hirsutism who might be using oral contraceptives for other indications.
Researchers used prescription data to determine overlapping use of topiramate and other headache therapies (propranolol, 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. Investigators used pregnancy claims (live birth, stillbirth, miscarriage, termination, or prenatal visits) to determine the conception date. The authors followed patients 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. Researchers calculated and adjusted pregnancy rates 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 featured 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% 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 to 0.3).
COMMENTARY
Sarayani et al demonstrated the concomitant use of oral contraceptives and low-dose topiramate did not increase the unintended pregnancy rate compared to a control group 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 of contraceptive hormone levels. The results of previous pharmacokinetic studies indicated topiramate’s effects on progestin and estrogen levels likely are dose-dependent, with no effect at the lower than 200 mg per day range.2,3 This has been confirmed in a clinical study of actual pregnancy rates.
There were significant limitations that must 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 taken is not 100% reliable. The authors noted 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 here.
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 CDC 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 clinicians prescribe at least a 30 mcg ethinyl estradiol pill. They may end up changing their recommendations regarding topiramate because of the emerging data indicating doses < 200 mg are likely to produce 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 HIV/acquired immunodeficiency syndrome. However, most other antibiotics and antifungals do not affect oral contraceptives and are rated Category 1 (no restriction on use) by the USMEC.
REFERENCES
1. Curtis KM, Tepper NK, Jatlaoui TC, et al. U.S. Medical Eligibility Criteria for Contraceptive Use, 2016. MMWR Recomm Rep 2016;65:1-104.
2. 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.
3. 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.
Women taking low-dose topiramate (< 200 mg per day) and oral contraception did not experience more contraceptive failures compared to women taking other headache remedies (propranolol, metoprolol, amitriptyline, venlafaxine, or verapamil).
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