Evaluation of the safety profile of prolonged-release EE/DNG oral contraceptives: a critical appraisal.

Abstract

Recent publications have suggested that a novel prolonged-release formulation of ethinylestradiol (EE) 20 µg and dienogest (DNG) 2 mg offers improved bleeding profiles and minimal impact on coagulation. These conclusions, however, are based on incomplete safety assessments and potentially misleading pharmacokinetic assumptions. This critical appraisal highlights several concerns: (1) discrepancies between published and regulatory data on bleeding/spotting rates compared to established EE/DRSP combinations; (2) inappropriate reliance on clotting-time-based activated protein C resistance (APCr) assays that fail to detect contraceptive-induced hypercoagulability; and (3) a strikingly high incidence of venous thromboembolism (VTE) reported in clinical trials of prolonged-release EE/DNG, significantly exceeding rates associated with both traditional EE-based and newer body-identical estrogen-containing contraceptives. Furthermore, these VTE cases are not transparently discussed in the peer-reviewed literature, raising ethical concerns about selective reporting. The pharmacokinetic profile of this formulation does not appear to mitigate estrogenic hepatic effects in a clinically meaningful way. Robust evaluation using validated thrombin generation assays such as the endogenous thrombin potential (ETP)-based APCr test, alongside independent post-marketing studies, is essential before asserting a neutral or favorable safety profile. Until then, claims regarding improved safety remain unsubstantiated.