Original Article
Copyright ©2014 Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Aug 27, 2014; 6(8): 601-612
Published online Aug 27, 2014. doi: 10.4254/wjh.v6.i8.601
Assessing liver injury associated with antimycotics: Concise literature review and clues from data mining of the FAERS database
Emanuel Raschi, Elisabetta Poluzzi, Ariola Koci, Paolo Caraceni, Fabrizio De Ponti
Emanuel Raschi, Elisabetta Poluzzi, Ariola Koci, Paolo Caraceni, Fabrizio De Ponti, Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, I-40126 Bologna BO, Italy
Author contributions: Raschi E and De Ponti F conceived the study; Koci A extracted data and performed statistical analysis; Raschi E drafted the first version of the manuscript; Poluzzi E, Caraceni P and De Ponti F provided substantial contribution to the discussion; all authors provided comments to the first draft and approved the final version of the manuscript.
Correspondence to: Fabrizio De Ponti, MD, PhD, Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Via Irnerio, 48, I-40126 Bologna BO, Italy. fabrizio.deponti@unibo.it
Telephone: +39-051-2091805  Fax: +39-051-2091780
Received: February 10, 2014
Revised: March 26, 2014
Accepted: July 17, 2014
Published online: August 27, 2014
Processing time: 199 Days and 13 Hours
Abstract

AIM: To inform clinicians on the level of hepatotoxic risk among antimycotics in the post-marketing setting, following the marketing suspension of oral ketoconazole for drug-induced liver injury (DILI).

METHODS: The publicly available international FAERS database (2004-2011) was used to extract DILI cases (including acute liver failure events), where antimycotics with systemic use or potential systemic absorption were reported as suspect or interacting agents. The reporting pattern was analyzed by calculating the reporting odds ratio and corresponding 95%CI, a measure of disproportionality, with time-trend analysis where appropriate.

RESULTS: From 1687284 reports submitted over the 8-year period, 68115 regarded liver injury. Of these, 2.9% are related to antimycotics (1964 cases, of which 112 of acute liver failure). Eleven systemic antimycotics (including ketoconazole and the newer triazole derivatives voriconazole and posaconazole) and terbinafine (used systemically to treat onychomicosis) generated a significant disproportionality, indicating a post-marketing signal of risk.

CONCLUSION: Virtually all antimycotics with systemic action or absorption are commonly reported in clinically significant cases of DILI. Clinicians must be aware of this aspect and monitor patients in case switch is considered, especially in critical poly-treated patients under chronic treatment.

Keywords: Drug-induced hepatotoxicity; Antimycotics; Drug safety; Pharmacovigilance; Spontaneous reporting systems

Core tip: The recent regulatory interventions (United States restriction and Europe suspension) concerning ketoconazole for drug-induced liver injury (DILI) poses a prescribing challenge to clinicians, who should now carefully consider safer therapeutic alternatives. Data mining of FAERS database (2004-2011) highlighted that: (1) antimycotics are involved in approximately 3% of DILI cases (including acute liver failure events); (2) virtually all systemic antimycotics (e.g., azole derivatives), are associated with disproportionality signals; careful monitoring is therefore recommended, especially in critical poly-treated patients with multiple comorbidities; and (3) topical antimycotics, as expected, do not generate a post-marketing signal of DILI, thus indicating the accuracy of our approach.