Hepatic safety of the antifungal triazole agent posaconazole: characterization of adverse event reports in a manufacturer’s safety database

ABSTRACT

Background

Second generation triazoles including posaconazole are efficacious for prophylaxis and salvage treatment of life-threatening invasive fungal diseases but have been associated with hepatic adverse events (AEs). This report evaluated hepatic AEs in posaconazole-treated patients.

Research design and methods

Hepatobiliary AEs occurring after posaconazole exposure in the company’s global safety database were analyzed to characterize underlying medical conditions and concomitant drug exposure.

Results

As of October 2019, 516 cases (168 from clinical trials, 348 from postmarketing use) containing 618 hepatobiliary AEs were reported regardless of causality. Frequently reported terms were hyperbilirubinemia, hepatic failure, and hepatic function abnormal (clinical trial reports) and hepatotoxicity, hepatocellular injury, and hepatic function abnormal (postmarketing reports). Cases reporting concurrent medications associated with drug-induced liver injury (DILI) included 8% with verified severe DILI (vMost-DILI) concern, 24% with verified mild to moderate DILI (vLess-DILI) concern, and 37% received both vMost-DILI and vLess-DILI-concern medications in the DILIrank data set.

Conclusions

Use of concomitant medications with known risks for hepatic injury appears to be an important contributor for the development of hepatotoxicity in patients treated with posaconazole.

KEYWORDS:

• Posaconazole
• adverse reactions
• antifungals
• azole antifungals
• liver toxicity

Abbreviations

AE, adverse event; DILI, drug-induced liver injury; DILIrank, Drug Induced Liver Injury Rank; FDA, US Food and Drug Administration; GVHD, graft-versus-host disease; HSCT, hematopoietic stem cell transplant; IA, invasive aspergillosis; IFIs, invasive fungal infections; MedDRA, Medical Dictionary for Regulatory Activities; PT, preferred term; SAE, serious adverse event; vLess-DILI, mild to moderate drug-induced liver injury; vMost-DILI, verified severe drug-induced liver injury

Acknowledgments

The authors thank Mary Frances Schubert, MD (Merck & Co., Inc., Kenilworth, NJ, USA), for her guidance on and expert input into the manuscript. Medical writing and/or editorial assistance was provided by Jennifer M. Kulak, PhD, and Tim Peoples, MA, ELS, of ApotheCom (Yardley, PA, USA), and funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Declaration of interests

R O’Flynn, Y-P Zhou, H Waskin, and R Leong are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. W Strauss was an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, at the time of writing. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Ethics approval

The global safety database of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (MSD), contains all spontaneous adverse event (AE) cases (including those in the literature) and noninterventional study AE cases reported to the company in the postmarketing period, as well as all serious AEs reported in company-sponsored interventional clinical trials and investigator-initiated studies. MSD clinical trials are run in accordance with the Declaration of Helsinki, Good Clinical Practice requirements, and applicable country and/or local statutes and regulations regarding Institutional Ethics Committee review, written informed consent, and protection of human participants in biomedical research.

Data sharing statement

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (MSD), is committed to providing qualified scientific researchers access to anonymized patient-level data and clinical study reports from the company’s clinical trials for the purpose of conducting legitimate scientific research. The company is also obligated to protect the rights and privacy of trial participants and, as such, has a procedure in place for evaluating and fulfilling requests for sharing company clinical trial data with qualified external scientific researchers. The process includes submission of data requests to the MSD data sharing website (available at: http://engagezone.msd.com/ds_documentation.php). Data will be made available for request after product approval in the US and EU or after product development is discontinued. There are circumstances that may prevent MSD from sharing the requested data.

Additional information

Funding

This work was supported by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. The funder, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (MSD), was involved in the design, execution, analysis, and reporting of the research insofar as the authors are employees of MSD and the company’s global safety database was used as the data source. Medical writing and/or editorial assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.