Kwon H, et al. • Spontaneously Reported Hepatic Adverse Drug Events macovigilance data from nine Regional Pharmacovigilance Cen- ters in Korea. MATERIALS AND METHODS For this study, 9,360 cases of adverse drug events (ADEs) were collected from nine Regional Pharmacovigilance Centers in Korea from January 2007 to December 2008. Each regional cen- ter collected ADEs from both general hospitals (90%) and gen- eral practitioners from private clinics or pharmacies (10%). The method of reporting ADEs was a voluntary system that relied on written reports submitted via fax, website, or electrical med- ical recording systems generated by physicians, pharmacists, and nurses. ADEs were coded using the World Health Organi- zation (WHO) Adverse Reaction Terminology (ART) (16), which consists of four components: preferred terms, high-level terms, systemic organ class, and included terms. We evaluated the cau- sality of these ADE cases according to WHO Uppsala Monitor- ing Center (UMC) criteria (17) at each regional center. WHO- UMC criteria classify ADEs as certain, probable, possible, un- likely, conditional and unassessable. The causality was assessed by the physicians majored in Internal Medicine. Once causality was assessed, the ADRs were characterized by severity as either serious or non-serious (17). The serious category included life- threatening, disabling, or permanent disabilities or prolonged hospitalization. The ADRs were further classified by the type of reactions (17). Type A reactions were usually dose-related, pre- dictable, preventable, and rarely life threatening, while Type B reactions were not dose-related and were idiosyncratic, unpre- ventable, and potentially life threatening. Type C reactions were both dose- and time-related. Hepatic ADRs were considered when the levels of serum alanine aminotransferase, alkaline phosphatase, or total bilirubin were increased to at least 2-fold higher than baseline without other plausible causes. All data of reported ADE are submitted to central office of the pharmaco- vigilance centers. Descriptive statistics were performed to assess the ADR cases. An association between drugs and hepatic ADRs was assessed by comparing hepatic ADRs with non-hepatic ADRs and calcu- Characteristics Mean age (yr) Gender (M:F) Seriousness of ADRs Underlying diseases (%) Tuberculosis Pneumonia Intracranial injury & skull fracture HIV Subarachnoid hemorrhage Osteoporosis ROR, reporting odds ratio; HIV, human immunodeficiency virus. http://dx.doi.org/10.3346/jkms.2012.27.3.268 50.2 ± 17.5 259:308 75 (13.2%) 6.9 4.9 4.5 3.4 2.8 2.4 Table 1. Clinical characteristics of the patients with spontaneously reported adverse drug reactions (ADR) Hepatic ADRs (n = 567) Non-hepatic ADRs (n = 8,793) ROR (95% CI) lating the ROR as a measure of disproportion. Comparisons of these two groups were performed using an independent t test or chi-square test. ROR values were calculated using the equation shown below. The basic assumption is that no relationship exists between the reported suspected ADR and the suspected drug, and the mea- sure of disproportionality can be calculated by means of the Pois- son probability (14, 15). Reports with Reports without hepatic ADE hepatic ADE Reports with the suspected drug All other drugs a c b d ROR = (a/c)/(b/d) = ad/bc 95% confidence interval of ROR = e ln(ROR) ± 1.96 √(1/a+1/b+1/c+1/d) All calculations were performed using the statistical software package SPSS 15.0 (Statistical Package for the Social Sciences, Chicago, IL, USA). Ethics statement The study protocol was reviewed by the institutional review board of Severance Hospital Clinical Trials Center (IRB No. 4-2011- 0372) and got permission for exemption. RESULTS Causality assessment using WHO-UMC classified the 9,360 cases to certain (n = 942, 10.1%), probable (n = 3,444, 36.8%), possible (n = 4,252, 45.4%), unlikely (n = 661, 7.1%), and unac- cessable (n = 61, 0.6%) groups. Hepatic ADRs comprised 6.1% (567 cases) of all enrolled ADRs (9,360 cases). Thirty-eight per- cent (n = 215) of hepatic ADE patients also had non-hepatic ADEs. WHO-UMC causality assessment of hepatic ADEs was as like; certain (6.9%), probable (22.6%), possible (60.7%), un- likely (9.5%) and unassessable (0.03%). There were no differ- ences in age or gender of patients with hepatic or non-hepatic ADEs (Table 1). Enrolled subjects had an average of 1.7 under- lying diseases that required treatment, and the patterns of these 49.9 ± 18.9 4,172:4,621 602 (6.8%) 0.9 1.7 0.9 0.4 0.5 1.4 2.1 (1.6-2.7) 8.4 (5.5-12.9) 3.0 (1.9-4.7) 5.3 (3.2-8.7) 9.1 (5.0-16.6) 6.4 (3.4-11.9) 1.8 (1.0-3.3) P value 0.672 0.414 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 0.049 http://jkms.org 269