Clinical Drug Interaction Studies with Combined Oral Contraceptives

This guidance is intended to help sponsors of investigational new drug applications (INDs) and new drug applications (NDAs) evaluate the drug drug interaction (DDI) effects of their investigational drugs on combined oral contraceptives (COCs), design DDI studies, and determine how to communicate DDI study results and risk mitigation strategies in labeling to address potential risks associated with increased or decreased exposure of COCs.

Reference is made to the FDA guidances entitled "Clinical Drug Interaction Studies – Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions (January 2020)" for general principles in assessing the clinical DDI potential and "In Vitro Drug Interaction Studies — Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions (January 2020)" for in vitro experimental approaches to evaluate the interaction potential for investigational drugs that involve metabolizing enzymes and/or transporters.

This guidance focuses solely on specific recommendations relevant to metabolism based drug interactions with COCs. Other mechanisms that can cause an interaction (e.g., absorption-based) are not addressed in this guidance but should be considered by sponsors and investigators.

In addition, this guidance does not discuss DDIs with progestin-only pills (POPs) and contraceptives administered via non-oral routes (e.g., transdermal systems). However, a DDI study with a COC could inform the impact on other types of contraceptives containing the same progestin. COCs usually contain two synthetic steroid hormones, a progestin and an estrogen. COCs are highly effective in preventing pregnancy when used correctly.

However, drug interactions with concomitant therapies can adversely impact the efficacy and safety of COCs by affecting enzymes involved in the metabolism of progestins and estrogens. For example, decreased progestin concentrations can lead to unintended pregnancy (loss of efficacy).

In addition, decreased estrogen concentrations could cause breakthrough bleeding and may also adversely affect the efficacy of COCs. Increased estrogen or progestin concentrations can increase the risk of venous thromboembolisms (VTEs), a rare but serious adverse event.

Because COCs are widely used in females of reproductive potential, and many investigational drugs are co-prescribed with COCs after approval, the DDI potential between an investigational drug and COCs should be evaluated during drug development and communicated in the labeling.

Cytochrome P450 (CYP) 3A is responsible for the metabolism of most commonly used progestins, although the relative contribution of CYP3A to the clearance of different progestins varies. Other metabolic enzymes, including CYP2C19, and certain isoforms of uridine 5'-diphospho-glucuronosyltransferases (UGTs) and sulfotransferases (SULTs), are also involved in the metabolism of certain progestins. These enzymes share gene expression regulation pathways (e.g., pregnane X receptor, PXR) with CYP3A, although the induction of UGTs and SULTs is less well understood compared to CYPs. 

In general, CYP3A is more sensitive to induction than other enzymes involved in the metabolism of progestins such as CYP2C19, UGTs, and SULTs. Therefore, an investigational drug’s induction effect on CYP3A can inform its potential to affect the pharmacokinetics of progestins in humans.