title: Relationship between daily dose of oral medications and idiosyncratic drug-induced liver injury: search for signals.
abstract: 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 However, it has been pointed out that most medicines that were withdrawn from marketing or received a black-box warning because of hepatotoxicity were prescribed at daily doses greater than 50 mg/day.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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Lammert
authors.forename: Stefan
authors.initials: S
authors.lastname: Einarsson
authors.forename: Chandan
authors.initials: C
authors.lastname: Saha
authors.forename: Anna
authors.initials: A
authors.lastname: Niklasson
authors.forename: Einar
authors.initials: E
authors.lastname: Bjornsson
authors.forename: Naga
authors.initials: N
authors.lastname: Chalasani
mesh_terms: D000284:Administration, Oral; D056486:Chemical and Drug Induced Liver Injury; D003625:Data Collection; D019992:Databases as Topic; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions / Q000175:diagnosis / Q000209:etiology*; D006801:Humans; D008099:Liver / Q000187:drug effects*; D008107:Liver Diseases / Q000175:diagnosis; D017093:Liver Failure / Q000139:chemically induced / Q000175:diagnosis; D016015:Logistic Models; D004364:Pharmaceutical Preparations / Q000008:administration & dosage; D015995:Prevalence; D011379:Prognosis; D011446:Prospective Studies; D013548:Sweden; D014481:United States
chemical_list: D004364:Pharmaceutical Preparations