Telithromycin-associated hepatotoxicity: Clinical spectrum and causality assessment of 42 cases

✍ Scribed by Allen D. Brinker; Ronald T. Wassel; Jenna Lyndly; Jose Serrano; Mark Avigan; William M. Lee; Leonard B. Seeff

• Publisher: John Wiley and Sons
• Year: 2008
• Tongue: English
• Weight: 153 KB
• Volume: 49
• Category: Article
• ISSN: 0270-9139
• DOI: 10.1002/hep.22620

✦ Synopsis

Telithromycin is the first of a new class of ketolide antibiotics with increased activity against penicillin-resistant and erythromycin-resistant pneumococci. This agent received approval by the United States Food and Drug Administration (FDA) in 2004 for treatment of upper and lower respiratory infections. Following market introduction, spontaneous reports of telithromycin-associated hepatotoxicity, including frank liver failure, were received. To address these reports, an ad hoc group with expertise in spontaneous adverse events reporting and experience in evaluating drug-induced liver injury was formed, including members of the FDA, other federal agencies, and academia. The primary objective of this group was to adjudicate case reports of hepatic toxicity for causal attribution to telithromycin. After an initial screening of all cases of liver injury associated with telithromycin reported to FDA as of April 2006 by one of the authors, 42 cases were comprehensively reviewed and adjudicated. Five cases included a severe outcome of either death (n ‫؍‬ 4) or liver transplantation (n ‫؍‬ 1); more than half were considered highly likely or probable in their causal association with telithromycin. Typical clinical features were: short latency (median, 10 days) and abrupt onset of fever, abdominal pain, and jaundice, sometimes with the presence of ascites even in cases that resolved. Concurrence in assignment of causality increased after agreement on definitions of categories and interactive discussions. Conclusion: Telithromycin is a rare cause of drug-induced liver injury that may have a distinctive clinical signature and associated high mortality rate. Consensus for attribution of liver injury to a selected drug exposure by individual experts can be aided by careful definition of terminology and discussion. (HEPATOLOGY 2009;49:250-257.)

A ntibiotics have been linked to post-marketing cases of drug-induced liver injury more frequently than have other drug classes. [1][2][3] Telithromycin, a ketolide, is the first of a new class of antimicrobials that are structurally related to macrolide antibiotics. Approximately 5.2 million prescriptions for telithromycin were dispensed from retail pharmacies in the United States between July 2004 and April 2006. 4 Telithromycin was initially approved by the U.S. Food and Drug Administration (FDA) for the oral treatment of acute bacterial sinusitis, acute exacerbation of chronic bronchitis, and community-acquired pneumonia with dosage regimens of 800 mg once daily for 5 days for both acute bacterial sinusitis and acute bacterial exacerbations of chronic bronchitis, and 800 mg once daily for 7 to 10 days for community-acquired pneumonia. 5 In December 2006, the FDA-approved indications for use of telithromycin were reduced to community-acquired pneumonia only. Acute bacterial sinusitis and acute bacterial exacerbations of chronic bronchitis were removed from the prescribing information because the balance of benefits and risks no longer supported approval of the drug for these indications. 6 Before its approval, concern had been raised that telithromycin might be associated with idiosyncratic druginduced liver injury. 7 In phase I studies, a few elderly