Combined oral contraceptives and pharmacokinetic drug interactions: impact on efficacy and safety

INTRODUCTION: Combined oral contraceptives (COCs), commonly referred to as the 'pill,' are a reliable form of contraception used by a vast majority of women of reproductive potential. COCs contain two primary components: estrogens and progestins. In addition to protection against pregnancy, COCs also confer several significant non-contraceptive benefits, such as the treatment of polycystic ovary syndrome. Given that polypharmacy is a common practice, drug interactions between COCs and concomitant therapies can adversely impact efficacy and safety. AREAS COVERED: This article systematically reviews literature published up to December 2025, from PubMed and Scopus on drug-metabolizing enzymes and transporters in the disposition of key COC components, drug-COC interactions (DCIs), and clinically relevant safety concerns. EXPERT OPINION: Progestins are primarily metabolized through phase I enzymes, especially CYP3A4, whereas estrogen metabolism relies on a combination of both phase I and phase II pathways. Nevertheless, the contribution of phase II enzymes to the clearance of COCs remains underappreciated. Much of the existing studies have focused on characterizing metabolic pathways and pharmacokinetic effects rather than assessing meaningful clinical outcomes. While pharmacokinetic interactions can theoretically predict potential adverse effects, robust DCI studies that incorporate real-world clinical outcomes are still critically needed.