A Pharmacoepidemiologic Approach to Evaluate Real-world Effectiveness of Hormonal Contraceptives in the Presence of Drug–drug Interactions

Abstract

Background: Accurate estimation of conception is critical in the assessment of the effects of drugs used during pregnancy or to prevent pregnancy. In a novel application, we studied the effectiveness of oral contraceptives (OCs), where misclassification of conception relative to OC exposure may obscure effect estimates. Methods: We studied OC failure, in a large claims database, among women who used antiepileptic drugs with metabolizing enzyme-inducing properties (carbamazepine or oxcarbazepine), which reduce OC’s effectiveness or enzyme-neutral properties (lamotrigine or levetiracetam), with no expected impact on OC effectiveness. We compared conception rates in women 12–48 years of age concomitantly using OCs and enzyme-inducing drugs with rates in concomitant users of OCs and enzyme-neutral drugs. We measured conception with a validated algorithm that estimates gestational age based on pregnancy endpoints. We estimated relative and attributable risk using generalized estimating equation models after standardized mortality ratio weighting. Results: We identified 89,777 concomitant use episodes with adjusted contraceptive failure rates of 1.6 (95% confidence interval (CI) = 1.4, 1.8) per 100 person–years among users of enzyme-neutral drugs and 18,964 episodes with a rate of 2.3 (1.9, 2.8) among users of enzyme-inducing drugs. The relative risk of conception for enzyme-inducing group was 1.4 (1.1, 1.8), and the rate difference was 0.7 (0.2, 1.2). Conclusions: OCs in combination with antiepileptic drugs that interact with metabolic enzymes were associated with increased contraceptive failure rates. Measurement of conception in claims data had adequate accuracy to uncover a strong drug–drug interaction, offering promise for broader application in comparative effectiveness studies on hormonal contraceptives to inform clinical and regulatory decisionmaking.

Antiseizure medications and oral contraceptives: Impact of enzyme inducers on pregnancy outcomes and costs

“…The pregnancy-outcomes model estimated the number of unintended pregnancies and the associated costs because of DDIs for women with epilepsy who are taking an OC combined with an EI antiseizure medication rather than combined with an EN antiseizure medication. Similar estimates of the risk of unintended pregnancies for women taking an OC and an EI antiseizure medication have been shown in a registry study [12] and in an observational database study [13]. The clinical effectiveness and costeffectiveness in terms of seizure control of various antiseizure medications have been previously studied in the SANAD [14] and SANAD II [15] trials.…”

“…Using an alternative approach, a similar estimate of the size of the population at risk was derived. Third, the estimate of OC failure rates with EI and EN medications used in this article was developed by Sarayani et al [13] in a study of women taking one of four medications: carbamazepine and oxcarbazepine for EI medications and lamotrigine and levetiracetam for EN medications. More research is needed on the impact of DDIs on hormonal contraceptive failure rates in women taking antiseizure medication, including those taking multiple medications.…”

“…A recent commercial claims database analysis has estimated the contraceptive failure rates among users of concomitant EI and EN antiseizure medications [13]. This study showed an increased rate of contraceptive failure among women with epilepsy or bipolar disorder taking concomitant EI antiseizure medications.…”

“…Incidence of unintended pregnancies was estimated from the published literature [13] on unintended pregnancy rates in women taking OC + EI antiseizure medications or OC + EN antiseizure medications. The Pearl Index was used to derive from the literature the annual probability of contraceptive failure [5,18,19].…”

“…The Pearl Index was used to derive from the literature the annual probability of contraceptive failure [5,18,19]. Sarayani and colleagues [13] used US commercial claims data from IBM Mar-ketScan Ò from 2005 to 2017 to estimate unintended pregnancy rates among 108,741 users of either EN or EI antiseizure medications (specifically carbamazepine [EI], oxcarbazepine [EI], lamotrigine [EN], or levetiracetam [EN]) during episodes in which an OC was concomitantly taken. Based on the data analyzed by Sarayani et al [13], we assumed that EN and EI antiseizure medications were not taken simultaneously and that the antiseizure medications and OCs were taken concomitantly, which means that the potential for interaction of the drugs would be at its highest.…”