Drugs associated with hepatotoxicity and their reporting frequency of liver adverse events in VigiBase: unified list based on international collaborative work.
BACKGROUND
Challenges exist in the clinical diagnosis of drug-induced liver injury (DILI) and in obtaining information on hepatotoxicity in humans.


OBJECTIVE
(i) To develop a unified list that combines drugs incriminated in well vetted or adjudicated DILI cases from many recognized sources and drugs that have been subjected to serious regulatory actions due to hepatotoxicity; and (ii) to supplement the drug list with data on reporting frequencies of liver events in the WHO individual case safety report database (VigiBase).


METHODS
(i) Drugs identified as causes of DILI at three major DILI registries; (ii) drugs identified as causes of drug-induced acute liver failure (ALF) in six different data sources, including major ALF registries and previously published ALF studies; and (iii) drugs identified as being subjected to serious governmental regulatory actions due to their hepatotoxicity in Europe or the US were collected. The reporting frequency of adverse events was determined using VigiBase, computed as Empirical Bayes Geometric Mean (EBGM) with 90% confidence interval for two customized terms, 'overall liver injury' and 'ALF'. EBGM of >or=2 was considered a disproportional increase in reporting frequency. The identified drugs were then characterized in terms of regional divergence, published case reports, serious regulatory actions, and reporting frequency of 'overall liver injury' and 'ALF' calculated from VigiBase.


RESULTS
After excluding herbs, supplements and alternative medicines, a total of 385 individual drugs were identified; 319 drugs were identified in the three DILI registries, 107 from the six ALF registries (or studies) and 47 drugs that were subjected to suspension or withdrawal in the US or Europe due to their hepatotoxicity. The identified drugs varied significantly between Spain, the US and Sweden. Of the 319 drugs identified in the DILI registries of adjudicated cases, 93.4% were found in published case reports, 1.9% were suspended or withdrawn due to hepatotoxicity and 25.7% were also identified in the ALF registries/studies. In VigiBase, 30.4% of the 319 drugs were associated with disproportionally higher reporting frequency of 'overall liver injury' and 83.1% were associated with at least one reported case of ALF.


CONCLUSIONS
This newly developed list of drugs associated with hepatotoxicity and the multifaceted analysis on hepatotoxicity will aid in causality assessment and clinical diagnosis of DILI and will provide a basis for further characterization of hepatotoxicity.
Suzuki
Ayako
A
Division of Gastroenterology, Duke University, Durham, North Carolina 27710, USA. suzuk004@mc.duke.edu
Andrade
Raul J
RJ
Bjornsson
Einar
E
Lucena
M Isabel
MI
Lee
William M
WM
Yuen
Nancy A
NA
Hunt
Christine M
CM
Freston
James W
JW
D016907:Adverse Drug Reaction Reporting Systems / Q000706:statistics & numerical data*; D056486:Chemical and Drug Induced Liver Injury / Q000453:epidemiology / Q000209:etiology*; D004335:Drug and Narcotic Control / Q000706:statistics & numerical data; D005060:Europe / Q000453:epidemiology; D006801:Humans; D007391:International Cooperation; D055553:Prescription Drugs / Q000009:adverse effects*; D056737:Safety-Based Drug Withdrawals / Q000706:statistics & numerical data; D014481:United States / Q000453:epidemiology; D014944:World Health Organization
D055553:Prescription Drugs