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An Evaluation of Postmarketing Reports of Serious Idiosyncratic Liver Injury Associated with Ulipristal Acetate for the Treatment of Uterine Fibroids

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A Commentary to this article was published on 09 October 2020

Abstract

Introduction

Ulipristal acetate (ulipristal) is a selective progesterone receptor modulator that has been marketed for daily use in Europe and Canada to reduce symptoms caused by uterine fibroids. Long-term use of some other members of this class of 19-norprogesterone-derived agents has been associated with idiosyncratic hepatotoxicity.

Objective

We analyzed postmarketing reports of suspected drug-induced liver injury associated with the daily use of 5 mg of ulipristal to treat symptoms of uterine fibroids.

Methods

We searched for reports of serious liver injury associated with ulipristal, submitted to the US Food and Drug Administration through 31 January, 2020. Cases of liver injury temporally associated with long-term ulipristal exposure that reported combined increases of serum aminotransferases and bilirubin were individually assessed using a five-tier categorical scale of likelihood for a causal association with the drug by individuals with expertise in drug-induced liver injury evaluation. Individual cases that did not culminate in liver failure, death, or liver transplantation were also assessed for their causal association with ulipristal by the Roussel Uclaf Causality Assessment Method.

Results

We identified nine non-US cases that met the criteria for inclusion in our search for cases of serious liver injury associated with ulipristal. Five cases reported clinical outcomes of liver transplantation and/or death and all were assessed to have a probable causal association with ulipristal acetate. Evaluation of the other four cases reporting resolution of liver injury after treatment discontinuation revealed a possible or probable causal relationship with ulipristal.

Conclusions

We identified postmarketing cases of serious acute drug-induced liver injury causally associated with ulipristal used to treat uterine fibroids, some with outcomes of liver transplant and/or death. The presence of common structural features identified with certain selective progesterone receptor modulators in the treatment of chronic conditions may indicate a liability for idiosyncratic drug-induced liver injury.

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Acknowledgements

The authors acknowledge Drs. Neha Gada, Christina Chang, Christine Nguyen, and Lisa Soule for their careful reviews of the manuscript and valuable feedback.

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Authors and Affiliations

  1. Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA

    Sarah Kang, Allen Brinker, S. Christopher Jones & Mark I. Avigan

  2. Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA

    Lara Dimick-Santos

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  1. Sarah Kang
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  2. Allen Brinker
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  4. Lara Dimick-Santos
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Contributions

All authors contributed to the study. All authors read and approved the final manuscript. The views expressed are those of the authors and do not necessarily represent those of, nor imply endorsement from the US Food and Drug Administration or the US Government.

Corresponding author

Correspondence to Sarah Kang.

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Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflict of interest

Sarah Kang, Allen Brinker, S. Christopher Jones, Lara Dimick-Santos, and Mark I. Avigan have no conflicts of interest that are directly relevant to the content of this article.

Ethics Approval

This study was granted an exemption for review by the US Food and Drug Administration Institutional Review Board.

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All data generated and analyzed during this research are included in this article and its supplementary information files.

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Kang, S., Brinker, A., Jones, S.C. et al. An Evaluation of Postmarketing Reports of Serious Idiosyncratic Liver Injury Associated with Ulipristal Acetate for the Treatment of Uterine Fibroids. Drug Saf 43, 1267–1276 (2020). https://doi.org/10.1007/s40264-020-00960-1

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