Hepatic Safety Considerations in the Use of Ulipristal Acetate for Symptomatic Uterine Fibroids

Annika Semmler,1,2,* Maria E de Lange,2,* Joost PH Drenth,3 Niels S Vermeer,4 Pierre M Bet,4 Judith AF Huirne,1,2 Wouter JK Hehenkamp1,2 1Amsterdam Reproduction & Development Research Institute, Amsterdam, the Netherlands; 2Department of Obstetrics and Gynecology, Amsterdam University Medical Center, location AMC and VUMC, Amsterdam, the Netherlands; 3Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism (AGEM), Amsterdam University Medical Center, Location VUMC, Amsterdam, the Netherlands; 4Department of Clinical Pharmacology and Pharmacy, Amsterdam University Medical Center, Amsterdam, the Netherlands*These authors contributed equally to this workCorrespondence: Maria E de Lange, Department of Obstetrics and Gynecology, Amsterdam University Medical Centers, Meibergdreef 9, Amsterdam, 1105 AZ, the Netherlands, Tel +31205667481, Email [email protected]: Ulipristal acetate (UPA, 5 mg) demonstrated efficacy in symptom reduction for patients with symptomatic fibroids. While registration and post-marketing trials assessing UPA identified few hepatic concerns, post-marketing concerns about potential drug-induced liver injury (DILI) led to significant restrictions, including indication restriction, warning labels and mandatory liver function monitoring. These measures, along with two marketing suspensions, resulted in a decline in UPA use, ultimately leading to the withdrawal of its marketing authorization previously in Canada, Australia, as well as Singapore and in 2024, at the request of the marketing authorization holder for commercial reasons, also for the European Union.Methods: This narrative review critically evaluates the hepatic safety considerations associated with UPA.Results: On reassessment, the risk of severe DILI with UPA is low at 13.5:100.000, with an incidence of 1 in 200,000 for liver transplantation. These numbers are lower than with many other widely prescribed medications, where no regular liver monitoring is recommended. UPA was subjected to strict liver test monitoring although proof of effectiveness of these measures in preventing serious DILI was lacking. While the risk of severe hepatotoxic events is important to consider, a balanced approach to safety measures is needed, particularly in light of the higher risks associated with alternative treatment options such as surgical intervention.Conclusion: While UPA had a unique place in the treatment of uterine fibroids, overly cautious regulatory measures due to exceedingly rare DILI incidences led to the withdrawal of its marketing authorization in most parts of the world. There is a need for an improved understanding of DILI mechanisms and causality assessments to aid in the development of more proportional regulatory responses, balancing patient safety and sustained access to effective innovative treatment.Keywords: leiomyoma, drug-induced liver injury, safety pharmacology, selective progesterone receptor modulator, pharmacovigilance, ulipristal