Clinical

Risks of hepatotoxicity increased with voriconazole and itraconazole

Last Updated: 2010-04-01 19:35:59 -0400 (Reuters Health)

By Ted Agres

NEW YORK (Reuters Health) - Voriconazole, itraconazole and amphotericin B formulations carry higher risks of liver injury than fluconazole and the echinocandins, new data show.

For a systematic comparison of liver toxicity and other adverse effects from newer antifungal agents, researchers in Taiwan performed a meta-analysis of 39 randomized controlled trials published from 1989-2009. The studies involved nearly 9000 patients receiving treatment for invasive fungal infection or persistent febrile neutropenia.

According to their March 22nd online report in Antimicrobial Agents and Chemotherapy, the pooled risk estimates for treatment discontinuation due to adverse effects were highest for itraconazole (18.8%), amphotericin B formulations (13.4%) and voriconazole (9.5%) and were lowest for caspofungin (3.8%), micafungin (3.6%) and fluconazole (2.2%).

Antifungal agents with the highest risks for liver enzyme elevations not requiring treatment cessation were voriconazole (19.7%) and itraconazole (17.4%). Lowest were anidulafungin (2.0%), micafungin (3.0%) and caspofungin (7.0%).

"This study is reassuring for clinicians and patients that the risk of harm to the liver from echinocandins and fluconazole is low," lead author Dr. Jiun-Ling Wang of the E-Da Hospital/I-Shou University in Taiwan told Reuters Health by email. But Dr. Wang was surprised by the relatively high percentage of adverse effects, including liver toxicity, from voriconazole, a relatively new antifungal, which he said had not been highlighted in other studies.

Safety risks associated with identical antifungal agents varied substantially among the various clinical trials, but the pooled results were similar when stratified by empirical or definitive antifungal therapy, the researchers report.

"The key limitation (of the study) is that the drugs were used in very different settings and often also for very different indications -- one might well expect different background rates of hepatic signals in patients with aspergillosis vs. candidiasis, for example," said Dr. John H. Rex, an editor of the journal who reviewed the manuscript.

"But the authors do note and analyze for this and did a thorough, thoughtful review of the available studies," Dr. Rex told Reuters Health by email. (Dr. Rex is a medical director at AstraZeneca Pharmaceuticals in the UK, which has also sponsored research involving antifungal agents.)

Antimicrob Agents Chemother 2010.