underlying diseases differed between hepatic and non-hepatic ADR groups. Patients with hepatic ADEs suffered more frequent- ly with tuberculosis (6.9%), pneumonia (4.9%), intracranial in- jury including skull fracture (4.5%), HIV (3.4%), subarachnoid hemorrhage (2.8%), and osteoporosis (2.4%). Patients with he- patic ADEs experienced serious ADEs more frequently than pa- tients in the other groups because of liver disease (13.2% vs 6.8%). ADEs were classified into WHO-ART categories and are shown in Table 2. The suspected drugs for hepatic ADEs were classi- fied according to the WHO Anatomical Therapeutic Chemical (ATC) code. Anti-infectives (code-J, 55.6%), nervous system drugs (code-N, 16.6%) musculoskeletal system drugs (code-M, 6.0%) and cardiovascular system drugs (code-C, 4.4%) comprised the majority of causative drugs (Table 3). Each culprit drug was analyzed in detail (Table 4). The anti- tuberculosis drugs were the most common triggers for hepatic toxicity: isoniazid (5.5%), rifampicin (4.9%), and pyrazinamide (4.6%). Their mean relative ROR for hepatic ADRs compared with non-hepatic ADRs was 5.1 (4.1-6.4, P < 0.001). Although Table 2. Preferred criteria of the WHO-Adverse Reaction Terminology for hepatic ADE reports Number Percent (%) Hepatic ADR WHO-ART Hepatic enzyme levels increased * Bilirubin levels increased † Hepatitis Hepatic function abnormal Hepatic disease Hepatotoxicity Unknown Total * Alanine aminotransferase level was increased at least more than two-fold compared to baseline; †total bilirubin level was increased at least more than two-fold compared to baseline. ADE, adverse drug events; WHO-ART, World Health Organization-Adverse Reaction Terminology. Table 3. WHO-Anatomical Therapeutic Chemical codes of drugs causing hepatic ADRs 266 21 93 64 5 3 115 567 Hepatic ADR frequency (%) 315 (55.6) 94 (16.6) 34 (6.0) 25 (4.4) 20 (3.5) 16 (2.8) 13 (2.3) 10 (1.8) 10 (1.8) 3 (0.5) 3 (0.5) 1 (0.2) 0 0 6 (1.1) 17 (3.0) 567 (100) 46.9 3.7 16.4 11.3 0.9 0.5 20.3 100 Total ADR frequency (%) 3,173 (33.9) 2,052 (21.9) 801 (8.6) 466 (5.0) 344 (3.7) 745 (8.0) 244 (2.6) 434 (4.6) 126 (1.3) 8 (0.1) 78 (0.8) 11 (0.1) 17 (0.2) 9 (0.1) 683 (7.3) 169 (1.8) 9,360 (100) Drugs or system(s) treated (ATC code) Anti-infectives for systemic use (J) Nervous system (N) Musculoskeletal system (M) Cardiovascular system (C) Anti-neoplastics and immune modulators (L) Alimentary tract and metabolism (A) Blood and blood-forming organs (B) Respiratory system (R) Systemic hormonal preparation (H) Herbal medicines Genitourinary system (G) Anti-parasitic/insecticides (P) Dermatologic (D) Sensory organs (S) Various (V) Unidentified medicines Total 270 http://jkms.org Kwon H, et al. • Spontaneously Reported Hepatic Adverse Drug Events the cephalosporins (9.5%), penicillins (5.1%), quinolones (5.1%), carbapenems (1.6%), and glycopeptide antibiotics (2.3%) also caused hepatic ADRs, their ROR values were between 0.7 and 1.9. Only one case of hepatic ADRs induced by amoxillin/clavu- lanic acid was reported in this study. NSAIDs were important Table 4. Causative drugs and their reporting odd ratios (RORs) for hepatic ADRs Drugs Anti-tuberculosis agents Rifampicin Isoniazid Pyrazinamide Ethambutol Aminosalicylic acid Protionamide Cephalosporins Carbapenems Penicillins Amoxacillin/clavulanate Piperacillin/tazobactam Quinolones Sulphonamides Glycopeptide antibiotics Aminoglycosides Macrolides Clindamycin Antimycotics Amphotericin B Fluconazole Itraconazole Antivirals Protease inhibitors Atazanavir Nucleoside RT inhibitors Anti-epileptics Valproic acid Topiramate Phenytoin Carbamazepine Lamotrigine Gabapentin Anti-psychotics NSAIDs Salicylates Anilides Acetaminophen Acetaminophen/ tramadol Propacetamol Acetic acid derivatives Propionic acid derivates Coxibs Nabumetone Allopurinol Antineoplastics and immune modulator Propylthiouracil Lipid-modifying agents HMG CoA inhibitors Fibrates Herbal medicines Hepatic ADR (%) [n = 567] 112 (19.8) 28 (4.9) 31 (5.5) 26 (4.6) 17 (3.0) 4 (0.7) 3 (0.5) 54 (9.5) 9 (1.6) 29 (5.1) 1 (0.2) 20 (3.5) 29 (5.1) 2 (0.4) 13 (2.3) 5 (0.9) 6 (1.1) 6 (1.1) 6 (1.1) 1 (0.2) 2 (0.4) 3 (0.5) 12 (2.1) 7 (1.7) 7 (1.2) 4 (0.7) 55 (9.7) 33 (5.8) 8 (1.4) 1 (0.2) 6 (1.1) 2 (0.4) 2 (0.4) 7 (1.2) 24 (4.2) 2 (0.4) 13 (2.3) 1 (0.2) 7 (1.2) 5 (0.9) 4 (0.7) 4 (0.7) 1 (0.2) 10 (1.8) 4 (0.7) 20 (3.5) 2 (0.4) 10 (1.8) 7 (1.2) 2 (0.4) 3 (0.5) Non-hepatic ADR (%) [n = 8,793] 405 (4.6) 118 (1.3) 96 (1.1) 69 (0.8) 91 (1.0) 7 (0.1) 9 (0.1) 885 (10.1) 88 (1.0) 322 (3.7) 92 (1.0) 110 (1.3) 248 (2.8) 34 (0.4) 305 (3.5) 64 (0.7) 98 (1.1) 29 (0.3) 25 (0.2) 10 (0.1) 6 (0.1) 4 (< 0.1) 109 (1.2) 22 (0.3) 6 (0.1) 26 (0.3) 281 (3.2) 81 (0.9) 15 (0.2) 28 (0.3) 50 (0.6) 32 (0.4) 24 (0.3) 95 (1.1) 494 (5.6) 152 (1.7) 209 (2.4) 71 (0.8) 126 (1.4) 12 (0.1) 182 (2.1) 177 (2.0) 17 (0.2) 36 (0.4) 33 (0.4) 324 (3.7) 2 (< 0.1) 59 (0.7) 36 (0.4) 9 (0.1) 5 (0.1) ROR (95% CI) 5.1 (4.1-6.4) 3.8 (2.5-5.8) 5.2 (3.5-7.9) 6.1 (3.8-9.6) 3.0 (1.7-5.0) 8.9 (2.6-30.6) 5.2 (1.4-19.2) 0.9 (0.7-1.3) 1.6 (0.8-3.2) 1.4 (1.0-2.1) 0.2 (0.0-1.2) 2.9 (1.8-4.7) 1.9 (1.3-2.8) 0.9 (0.2-3.8) 0.7 (0.4-1.1) 1.2 (0.5-3.0) 0.9 (0.4-2.2) 3.2 (1.3-7.8) 3.8 (1.5-9.2) 1.6 (0.2-12.1) 5.2 (1.0-25.7) 11.7 (2.6-52.3) 1.7 (0.9-3.1) 5.0 (2.1-11.7) 18.3 (6.1-54.7) 2.4 (0.8-6.9) 3.3 (2.4-4.4) 6.6 (4.4-10.1) 8.4 (3.5-19.8) 0.6 (0.1-4.1) 1.9 (0.8-4.4) 1.0 (0.2-4.1) 1.3 (0.3-5.5) 1.1 (0.5-2.5) 0.7(0.5-1.1) 0.2 (0.1-0.8) 1.0 (0.5-1.7) 0.2 (0.0-1.6) 0.9 (0.4-1.8) 6.5 (2.3-18.5) 0.3 (0.1-0.9) 0.3 (0.1-0.9) 0.9 (0.1-6.9) 4.4 (2.2-8.8) 1.9 (0.7-5.3) 1.0 (0.6-1.5) P value < 0.001 < 0.001 < 0.001 < 0.001 < 0.001 0.003 0.032 0.678 0.181 0.078 0.043 < 0.001 0.002 0.898 0.151 0.610 0.901 0.017 0.010 0.673 0.025 0.006 0.073 0.001 < 0.001 0.105 < 0.001 < 0.001 < 0.001 0.555 0.151 0.966 0.670 0.732 0.162 0.013 0.898 0.095 0.699 0.003 0.024 0.028 0.929 < 0.001 0.282 0.847 15.6 (2.2-110.7) < 0.001 2.7 (1.4-5.2) 0.008 3.0 (1.3-6.9) 0.014 3.5 (0.7-16.0) 0.140 9.3 (2.2-39.2) 0.010 http://dx.doi.org/10.3346/jkms.2012.27.3.268