Idiosyncratic drug-induced liver injury (DILI) is traditionally thought not to be dose-related. However, it has been pointed out that most medicines that were withdrawn from marketing or received a black-box warning because of hepatotoxicity were prescribed at daily doses greater than 50 mg/day. To examine the relationship between daily dose of medications and idiosyncratic DILI, we conducted a study with two aims. First, using two pharmaceutical databases, we examined the relationship between daily dose of commonly prescribed medicines in the United States and reported frequency of their selected hepatic adverse events. Second, we examined serious DILI cases reported to the Swedish Adverse Drug Reactions Advisory Committee (1970-2004) for any signals supporting the relationship between daily dose and idiosyncratic DILI. Medications were categorized into < or =10 mg/day, 11-49 mg/day, and > or =50 mg/day groups. Among US prescription medicines, a statistically significant relationship was observed between daily dose of oral medicines and reports of liver failure (P = 0.009), liver transplantation (P < 0.001), and death caused by DILI (P = 0.004) but not alanine aminotransferase (ALT) > 3 x upper limit of normal (P = 0.10) or jaundice (P = 0.16). Of 598 eligible Swedish DILI cases, 9% belonged to the < or =10 mg/day group, 14.2% to the 11-49 mg/day group, and 77% of cases were caused by medications given at dose > or =50 mg/day. A statistically significant relationship was noted between daily dose and poor outcome (death or liver transplantation) of Swedish DILI cases (2%, 9.4%, and 13.2% in < or =10, 11-49, and > or =50 mg/day groups, respectively, P = 0.03).
Conclusion: These data suggest a relationship between daily doses of oral prescription medications and idiosyncratic DILI. More studies are needed to validate these observations and to explore their implications.