Kwon H, et al. • Spontaneously Reported Hepatic Adverse Drug Events causes of hepatic ADRs with different ROR values, comprising 4.2% of all drugs causing hepatic ADRs. Six cases of hepatic ADEs associated with systemic anti-fungal agents (1 case by ampho- tericin, 2 cases by fluconazole and 3 cases by itraconzole) were reported; but ROR values for fluconazole and itraconazole are especially higher (5.2-11.7). Antiviral agents were also emerging as the important causes of hepatic ADEs. Seven cases of hepatic ADE associated with atazanavir, protease inhibitor used for HIV infection, were reported (ROR 5.0, P < 0.001). Anti-epileptics, such as valproic acid (5.8%, ROR 6.6, P < 0.001), were also major culprits. The mean overall ROR of NSAIDs was 0.7 (0.5-1.1 ADRs by anilides [acetaminophen, a mixture including acetaminophen, and propacetamol], which included 2.3% of hepatic ADRs with low RORs [1.0]). Nabumetone com- prised 1.8% of hepatic ADRs and had the highest ROR values (4.4, P < 0.001) among all the NSAIDs. In this study, only two cases of hepatic ADEs associated with propylthiouracil were re- ported, but their ROR value is especially high to 15.6 (P < 0.001). Lipid-modifying agents, such as statins (ROR 3.0 P = 0.014), were also frequently associated with hepatic ADEs. Herbal medicines have been reported as the important causes of hepatic ADRs in Korea and other Asian countries. But in this study, herbal medi- cines comprised only 0.5% of hepatic ADRs with high mean ROR values (9.3, P = 0.010). However, we could not identify the details of the herbal medicines prescribed. DISCUSSION This is the first study of hepatic ADRs based on the spontaneous reporting program in Korea. Our spontaneous reporting system collected data from doctors, nurses, and pharmacists working in general hospitals or private clinics. Spontaneous reporting systems are important for the surveillance hepatic ADRs but have several weak points. However, the incidence of ADRs can- not be estimated from the data of spontaneous ADR monitor- ing systems. Underreporting is a well-known problem in spon- taneous reporting (13), and as denominators were unknown, our data cannot be used for estimations of hepatic ADR inci- dence. Our program for pharmacovigilance is mainly designed for the monitoring the ADEs inevitably occurred by adequately prescribed in hospitals and private clinics. The program did not include medication errors or drug abuse, and professionals for oriental medicine are not participating to the program. These features imperatively affected the results. The hepatotoxicity of drugs may be related to overdose of medication. In this study, the patients were prescribed to the therapeutic dosages. The major suspected drugs for hepatic ADRs in this study are anti- microbials, central nervous system drugs, and NSAIDs. These results are similar to reports from the United States and Europe (10) but differ from previous studies done in Korea (5-7) and East Asia (8). We hypothesize that this may be the reason why http://dx.doi.org/10.3346/jkms.2012.27.3.268 the incidence of hepatic ADRs after treatment with herbal med- icines is lower than the incidences found in other Asian studies (5-8). Herbal medicines comprise 0.5% of suspected hepatic ADRs with high ROR values for hepatic ADR in this study, sug- gesting that herbal medications could be an important cause of hepatic ADRs in Korea, where the oriental medicine is popular (18). WHO and the Uppsala Monitoring Centre have emphasized the monitoring of herbal products for coordinated regional phar- macovigilance centers (19). We think that the activity is espe- cially important in Korea, and now extend our activities to cover the herbal medicines prescribed by oriental medicine profes- sionals and herbal foods purchased from market. There is an- other point that should be considered. This pharmacovigilance program started in 2006 from the educating general hospitals hosting the Regional Pharmacovigilance Centers and is now spreading to general practitioners in private clinics or pharma- cies. The number of reported ADEs from private clinics or phar- macies is increasing, but the portion is still minor. About 90% of the reported ADE cases came from the 9 educating general hos- pitals, and this feature may explain the low incidence of ADEs in suspect of amoxicillin/clavulanic acid. Contrary to other reports (9), only one case of hepatic ADR induced by amoxicillin/clavu- lanic acid and another case due to phenytoin were reported in this study. Amoxicillin/clavulanic acid is still the first line anti- biotics for acute sinusitis and other infectious diseases for gen- eral practitioners in Korea. However multi-drugs resistant Strep- tococcus pneumoniae or methicillin resistance Staphylococcus aureus are big problems for the community acquired infections in Korea and prescriptions of anti-streptococcal quinolones or other classes of antibiotics are increasing instead of amoxicil- lin/clavulanic acid (20). Phenytoin is a well known culprit for hepatic ADRs. In Korea, phenytoin rarely prescribed due to var- ious ADRs and drug interactions, in addition to hepatic ADRs. Instead of phenytoin, other newly developed safe and effective anti-epileptics are popularly used. In Western countries and the United States, acetaminophen is a common cause of dose related drug-induced hepatic inju- ry: it is the most common cause of liver transplantation for acute liver failure in the United States (1, 21). Acetaminophen over- dose is often used for suicide attempts in Western societies, which is not a familiar concept in Korea. While acetaminophen use is popular in Korea, only a few cases of acetaminophen-induced hepatitis were reported in this study. This result may be due to the characteristics of the enrolled cases, which are primarily from the general hospital with adequately regulated prescrip- tions and a pharmacovigilance program that does not include patient drug abuse. There is another limitation to this study. Aithal et al. (22) re- ported that approximately 50% of spontaneously reported he- patic ADRs are misdiagnosed. We enrolled nine Regional Phar- macovigilance Centers, but their activities, experiences, capa- http://jkms.org 271