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1 w wz 19«1y Kor. J. Clin. Pharm., Vol. 19, No ü t y BÁ CÁ wc B Ÿ w w w C w w w ( Á Á ) Analysis of Drug Interaction Information Young Sook Lee, Ji Seon Lee and Sukhyang Lee a Wonkwang University, College of Pharmacy b Sookmyung Women's University, Graduate College of Clinical pharmacy (Received February 5, 2009ÁRevised June 10, 2009ÁAccepted June 25, 2009) Adverse drug reactions (ADR) caused by inappropriate prescription are responsible for major socioeconomic loss. Drugdrug interactions (DDI) has been recognized as a major part of ADRs and, therefore, healthcare professionals should prevent possible DDIs to minimize preventable ADRs. This study aimed to examine DDI information in drug information references and Korea Food & Drug Administration (KFDA) drug labeling information. Drug ingredients from the formulary of Health Insurance Review and Assessment Service in Korea (HIRA) were included for the study. DDI information source used for the study were Drugdex and Drug Information Facts (DIF) with the DDI severity level of moderate or more. The DDI information in KFDA drug labeling were collected and compared. Drug ingredients were classified with KFDA Drug Classification and ATC Classification of WHO for the analysis. Among the total 1,355 drug ingredients satisfying inclusion criteria, 738 ingredients involved at least one DDI, which was described in and/or DIF. Drug Ingredients of 176 involved DDI only described in KFDA drug labeling, but not nor DIF. Drug ingredients of 35 which DDIs were described in or DIF did not have DDI based on KFDA drug labeling. and DIF retrieved 7,582 and 3,071 DDIs, respectively 57.6% and 58.5% of DDIs were also described in KFDA drug labeling. Central nervous system (CNS) drugs, cardiovascular system (CVS) drugs and the antiinfectives appeared to have higher frequency of DDIs among all drug classes. The highest number of DDIs with high severity level ( contraindicated or major ) were the DDIs of CNS drugs. The antiinfectives are the second drug group having serious DDIs. The DDI pairs of the CNS drug and the antiinfective had the highest contraindication risk (13.6%). DDI information from and DIF were not consistent with the result that only 465 ingredients' DDIs are common in both literature (total DDI numbers were 715 vs 488, respectively). And 1,652 DDI information are common in both references among 7,582 vs 3,071 DDIs, respectively. Only 55.2% of DDI information in the database contained in the KFDA drug labeling. Prescribers and pharmacists should pay attention to the drugs for CV system, CNS and infections because of higher risk of possible DDIs compared to other drug classes. KFDA drug labeling is not likely to be recommended as a good information source for DDI due to significant inconsistency of information. Drug information providers should be aware that DDI information from different sources are not consistent and therefore multiple references should be used. Key words - drug interaction, DUR, database y w w, wù z ƒ ƒw ù, w, w n w y x w Correspondence to : w w w w 304y z ¼ 52 Tel: , Fax: slee@sdic.sookmyung.ac.kr š w w w. y y ƒ y ƒ y e w w ƒ ƒw w x ƒw. w x z» w ƒ w y w wš» w y ƒ w ƒ ƒwš y ƒ j. mw, w sƒ(dur, Drug 1

2 2 Kor. J. Clin. Pharm., Vol. 19, No. 1, 2009 Utilization Reviw) ù x š. DUR x w DUR w wš, l v w. ü DUR w 2004 y» w t t š mw. ü t y w t x mw y l w, m y w p w ƒ w y,,,» p, w w. mw y w w œwš w. ü t w l w. t t, ü,, sww. w w yw (amoxicillin clavulanic acid w clavulanic acid ) w (amoxicillin + clavulanic acid) w. l ƒ œ», w l w. l y p w» w ü t l ƒ s ƒ sw g. ü t s ƒ y w., y s ƒ sw sw g. w. t»» (WHO) ATC(Anatomical Therapeutic Chemical) w œ, international non-proprietary name(inn) w š(aspirin INN acetylsalicylic acid),, z, t w (diclofenac sodium diclofenac potassium w t diclofenac ). ATC sw ü w œ w š, n, x, w w w. x y ü t ( t, xƒ ), Drugdex(TM)(Thomson, Green wood, CO, USA, version w ), Drug Interaction Facts(Facts and Comparisons, St. Louis, MO, USA, w DIF) w. ü t t p( w w šw. Drugdex» ü w 3 x š, Drug Interaction Facts y t 3 x k. y ¾ w w š, ¾. y ù» ƒ š w ƒ (severity, significance) w, y», y, y x»(onset) w., y» w» w w Áyw y (chemical incompatibility) w š, w» w w y (pharmacokinetic interaction), w» w w y (pharmacodynamic interaction) w sw g. y ƒ (severity)»( contraindicated ) w y w w, minor w w l sww š, w. y WHO ATC (ATC/DDD System, version 2007) w. y, w š w. m. (114) (110) w» w (Table 1). ATC ATC w wš ATC 1» w (Table 2). l w» w, x, n ƒ wù w š, ù w( y sw), 2 t w w. DIF y w» w y ( y w, wù y ) w š, ƒ x» ƒ x ew w. ü t (xƒ w ) l y y ƒ» y w» w»(contraindicated) w, vw, š n w, w, w

3 ü t y 3 Table 1. KFDA Drug Classification and 34 Drug Groups First Second Third 100 Nervous System and Sensory System Drugs 110 Central Nervous System Drugs 114 Antipyretics, Analgesic, & Antiinflammatory Drugs 120 Peripheral Sensory Nervous System Drugs 130 Sensory Organ Drugs 140 Antiallergic Drugs 190 Miscellaneous Nervous System and Sensory System Drugs 200 Other Organ Drugs 210 Cardiovascular System Drugs 220 Respiratory System Drugs 230 Digestive System Drugs 240 Hormones (Including Antihormones) 250 Genitourinary System Drugs & Anal Suppositories 260 Topically Applied Products 290 Miscellaneous Other Organ Drugs 300 Metabolic Drugs 310 Vitamins 320 Tonics 330 Blood & Body Fluid Products 340 Artificial Irrigation Products 390 Miscellaneous Metabolic Drugs 400 Tissue or Cell Functional Drugs 410 Tissue Revitalization Drugs 420 Antineplastic Drugs 430 Drugs for Treatment or Diagnosis of Tissues or Cells 490 Miscellaneous Tissue or Cell Functional Drugs 600 Anti-Microorganism Drugs 610 Antibiotics 620 Anti-microorganism Chemicals 630 Biologicals 640 Antiparasites 690 Miscellaneous Anti-Microorganism Drugs 700 Drugs or Products Not Purposed for Disease Treatment 710 Inactive Ingredients 720 Diagnostic Agents or Kits 730 Drugs for Public Hygiene 740 Related Products 790 Drugs Not Purposed for Disease Treatment 800 Opiods 810 Natural Alkaloid Opioids 820 Non-Alkaloid Opioids Table 2. WHO Anatomical Therapeutic Chemical (ATC) Classification 1st Level, Anatomical Main Group A Alimentary Tract And Metabolism B Blood And Blood Forming Organs C Cardiovascular System D Dermatologicals G Genito-Urinary System And Sex Hormones H J L M N P R S V Systemic Hormonal Preparations, Excl. Sex Hormones And Insulins Antiinfectives For Systemic Use Antineoplastic And Immunomodulating Agents Musculo-Skeletal System Nervous System Antiparasitic Products, Insecticides And Repellents Respiratory System Sensory Organs Various wš, n ( major or moderate ) y n w «w ü w, DIF y ƒ w. w DIF y ƒ ü t (xƒ w)» w. t w ƒq ( š ) sw 1,355. 1,251 1 y w š, ù y w ( w,, v t w). y (210) w 185 (12.5%) ƒ š, (110) 122 (8.3%), w (610)ƒ 117 (7.9%) (Table 3). 1,355 1,098 ATC sw. ATC 1» 1 w 949, ù (2-6 ) w

4 4 Kor. J. Clin. Pharm., Vol. 19, No. 1, 2009 Table 3. Drug Interaction from Two Drug Interaction Literatures according to KFDA Drug Classification Total DIF or DIF Ingredient 1, Class Ingredient (%) Ingredient (%) Ingredient (%) Ingredient (%) (8.3) 100 (12.1) 97 (12.2) 74 (13.2) (4.3) 45 (5.5) 44 (5.5) 34 (6.1) (4.1) 35 (4.2) 31 (3.9) 23 (4.1) (6.2) 45 (5.5) 44 (5.5) 27 (4.8) (2.8) 19 (2.3) 19 (2.4) 10 (1.8) (12.5) 128 (15.5) 122 (15.3) 94 (16.8) (4.0) 20 (2.4) 20 (2.5) 9 (1.6) (7.3) 38 (4.6) 37 (4.6) 26 (4.6) (4.4) 37 (4.5) 37 (4.6) 29 (5.2) (2.2) 16 (1.9) 16 (2.0) 7 (1.3) (6.2) 39 (4.7) 37 (4.6) 28 (5.0) (0.1) (1.3) 11 (1.3) 10 (1.3) 10 (1.8) (0.9) 4 (0.5) 4 (0.5) 2 (0.4) (2.5) 16 (1.9) 14 (1.8) 10 (1.8) (0.3) 2 (0.2) 2 (0.3) 1 (0.2) (6.8) 43 (5.2) 42 (5.3) 29 (5.2) (0.1) (5.4) 56 (6.8) 56 (7.0) 30 (5.4) (1.5) 4 (0.5) 3 (0.4) 1 (0.2) (0.1) (7.9) 73 (8.9) 73 (9.1) 50 (8.9) (4.2) 51 (6.2) 50 (6.3) 35 (6.3) (2.0) 12 (1.5) 11 (1.4) 4 (0.7) (0.9) 7 (0.8) 7 (0.9) 5 (0.9) (0.2) (2.4) 11 (1.3) 10 (1.3) 10 (1.8) (0.3) (0.1) 1 (0.1) 1 (0.1) 1 (0.2) (0.3) 5 (0.6) 5 (0.6) 5 (0.9) (0.4) 6 (0.7) 6 (0.8) 6 (1.1) Total 1, Nervous System (N) 170 (12.8%) ƒ š, Antiinfectives For Systemic Use (J) 158 (11.9%), Cardiovascular System (C) 149 (11.2%) (Table 4). y DIF w 1, (54.5%) y š, 176 (13.0%) ü t (xƒ w) y. DIF y ü t (xƒ w) y. DIF y 738 y (210) 128 (15.5%) ƒ š, (110) 100 (12.1%), w (610)ƒ 73 (8.9%) (Table 3). y ATC w, Nervous System (N) 145 (16.5%) ƒ š, Cardiovascular System (C) 118 (13.4%), Antiinfectives For Systemic Use (J) 106 (12.0%) (Table 4).JDSPNFEFY y w 715 moderate y š, y (210) 122 (15.3%) ƒ š, (110) 97 (12.2%), w (610)ƒ 73 (9.1%) (Table 3) ATC w, Nervous System (N) 142 (16.6%) ƒ š, Cardiovascular System (C) 114 (13.3%), Antiinfectives For Systemic Use (J) 105 (12.3%) (Table 4). 715 s³ 21.2 y (Table 6), wafarin 193 y ƒ. ciclosporin(cyclosporine INN) 144, phenytoin 129 š, 100 y ùkü 10 (1.4%), y ùkü 86 (12.0%), y ùkü 283 (39.6%), 10 y ùkü 336 (47.0%) (Table 5). y e (820) s³ 48.7 ƒ š, ATC Cardiovascular System (C) s³ 29.0 ƒ (Table 6, 7). y ƒ 10 y (210) 23.0% ƒ š, ATC Nervous System (N) 19.8% ƒ (Table 8, 9). ƒ moderate y 7,582 (Table 10). y (210) 3,552

5 ü t y 5 Table 4. Drug Interaction from Two Drug Interaction Literatures according to ATC Classification Total or DIF DIF Ingredient 1, Class Ingredient(%)Ingredient(%)Ingredient(%)Ingredient(%) A 139 (10.5) 78 (8.9) 74 (8.7) 60 (10.0) B 66 (5.0) 40 (4.5) 37 (4.3) 22 (3.7) C 149 (11.2) 118 (13.4) 114 (13.3) 90 (15.0) D 101 (7.6) 52 (5.9) 47 (5.5) 35 (5.8) G 79 (6.0) 39 (4.4) 39 (4.6) 25 (4.2) H 30 (2.3) 21 (2.4) 21 (2.5) 16 (2.7) J 158 (11.9) 106 (12.0) 105 (12.3) 77 (12.8) L 102 (7.7) 82 (9.3) 82 (9.6) 42 (7.0) M 70 (5.3) 56 (6.4) 55 (6.4) 36 (6.0) N 170 (12.8) 145 (16.5) 142 (16.6) 108 (17.9) P 16 (1.2) 9 (1.0) 9 (1.1) 8 (1.3) R 89 (6.7) 47 (5.3) 46 (5.4) 25 (4.2) S 99 (7.5) 66 (7.5) 65 (7.6) 44 (7.3) V 58 (4.4) 21 (2.4) 18 (2.1) 14 (2.3) Total 1, Table 5. Number of Drug Interaction Pairs Per Ingredient DIF Number of Drug Interaction Pairs Ingredient (%) Ingredient (%) (1.4) 2 (0.4) (12.0) 13 (2.7) (39.6) 194 (39.8) (47.0) 279 (57.2) Total (20.5%) ƒ š(table 11), ATC Nervous System (N) 3,997 (22.0%) ƒ (Table 12). y y (210) y (210) y 7.4% ƒ š, (110) (110) y 5.3%, (110) y (210) y 4.0% (Table 13). ATC Nervous System (N) Nervous System (N) y 8.8% ƒ š, Cardiovascular System (C) Cardiovascular System (C) y 5.6%, Cardiovascular System (C) Nervous System (N) y 4.6% (Table 14). Table 6. Number of Drug Interaction Pairs per Drug Ingredient according to KFDA Classification KFDA Class of Drug Ingredient Number of Drug Interaction Pairs from Number of Drug Interaction Pairs from DIF Total y 7,582 y ƒ contraindicated ƒ 474 (6.3%), major 2864 (37.8%), moderate ƒ 4244 (56.0%) (Table 10). ƒ ƒ contraindicated y ƒ 33.5% w y (110) y š, yw (620)ƒ 15.3%, w. m. (114)ƒ 12.3%. ƒ major y (110) 21.4% ƒ š, y (210) 19.2%, yw (620)ƒ 7.7% š, moderate y y (210) 22.8% ƒ š, (110)ƒ 13.8,%, w. m. (114)ƒ 8.9% (Table 11). ATC

6 6 Kor. J. Clin. Pharm., Vol. 19, No. 1, 2009 Table 7. Number of Drug Interaction Pairs per Each Drug Ingredient according to ATC Classification ATC Classification of Drug Ingredient Number of Drug Interaction Pairs from Number of Drug Interaction Pairs from DIF A B C D G H J L M N P R S V Total contraindicated y 40.5%ƒ Nervous System (N) y ƒ š, Antiinfectives For Systemic Use (J) 20.5%, Cardiovascular System (C) 6.9%. ƒ major y Nervous System (N) 28.3% ƒ š, Cardiovascular System (C) 16.4%, Antiinfectives For Systemic Use (J) 11.8% š, moderate Cardiovascular System (C) 20.5% ƒ š, Nervous System (N) 16.2,%, Antiinfectives For Systemic Use (J) 11.2% (Table 12). (110) yw (620) y contraindicated y ƒ ƒ š(13.6%), (110) (110) y major y ƒ (6.5%), moderate y y (210) y (210) y ƒ (7.2%)(Table 13). ATC Antiinfectives For Systemic Use (J) Nervous System (N) y contraindicated y ƒ š(22.3%), major y Nervous System (N) Nervous System (N) y ƒ (14.6%), moderate y Cardiovascular System (C) Cardiovascular System (C) y ƒ (6.6%) (Table 14).» y x»(onset) 7,582 y rapid y 1,953 (25.8%), delayed 3,342 (44.1%), unspecified ƒ 2,287 (30.2%) (Table 10). x»ƒ rapid y ƒ w y (210, 30.2%) š, (110, 13.1%), yw (620, 8.3%). Delayed x» ƒ y y (210) ƒ š (17.5%), (110, 13.4%), w. m. (114, 9.3%). unspecified x» ƒ y (110) ƒ š(28.7%), y (210, 16.9%), yw (620, 6.8%) (Table 11). ATC rapid x» y Table 8. More than 10 Drug Interactions per Ingredient according to KFDA Drug Classification DIF Class Ingredient(%) Ingredient(%) (15.0) 45(17.8) (8.9) 23(9.1) (3.0) 6(2.4) (5.6) 19(7.5) 140 6(1.4) 4(1.6) (23.0) 47(18.6) (2.3) 2(0.8) (2.3) 7(2.8) (4.7) 15(5.9) 250 5(1.2) 3(1.2) (5.2) 18(7.1) 310 4(0.9) 1(0.4) 320 2(0.5) 2(0.8) (2.3) 4(1.6) (4.0) 11(4.3) (3.0) 3(1.2) (6.3) 19(7.5) (6.6) 19(7.5) 630 1(0.2) (0.9) 2(0.8) 720 1(0.2) 1(0.4) 790-1(0.4) 810 4(0.9) (1.4) 1(0.4) Total

7 ü t y 7 Table 9. More than 10 Drug Interactions per Ingredient according to ATC Classification DIF Class Ingredient(%) Ingredient(%) A 34(7.3) 25(8.7) B 22(4.7) 6(2.1) C 89(19.2) 53(18.4) D 23(5.0) 18(6.3) G 20(4.3) 11(3.8) H 14(3.0) 9(3.1) J 51(11.0) 37(12.8) L 20(4.3) 7(2.4) M 37(8.0) 25(8.7) N 92(19.8) 54(18.8) P 5(1.1) 2(0.7) R 20(4.3) 10(3.5) S 37(8.0) 30(10.4) V - 1(0.3) Total Cardiovascular System (C) ƒ š(28.3%), Nervous System (N, 18.1%), Antiinfectives For Systemic Use (J, 10.9%). x»ƒ delayed y Nervous System (N) ƒ š (15.9%), Cardiovascular System (C, 15.5%), Antiinfectives For Systemic Use (J, 12.7%). x» ƒ w ( unspecified ) y Nervous System (N) ƒ (35.5%) (Table 12). Table 10. Drug Interaction Severity and Onset DIF Drug Interactions(%) Drug Interactions(%) Severity Contraindicated 474 (6.3) NA* Major 2,864 (37.8) 551 (17.9) Moderate 4,244 (56.0) 2,520 (82.1) Onset Rapid 1,953 (25.8) 735 (23.9) Delayed 3,342 (44.1) 2,336 (76.1) Unspecified 2,287 (30.2) NA** Total 7,582 3,071 * DIF's the hjghest severity level is Major, that is, does not have contraindicated level. ** no data.jdspnfefypousbjoejdbufe y» y ƒ contraindicated y» r w y y 201 (42.4%), y 8 (1.7%) š, w y ƒ 196 (41.4%), ¼w 9 (1.9%), w ƒ (unknown) 60 (12.7%) w» w» w wš. w j y y 191 cytochrome P450(CYP) 3A4 w (ergot alkaloid, benzodiazepine, pimozide ) CYP 3A4 z (microslide w azole w ³, protease inhibitor, fluoxetine, fluvoxamine selective serotonin reuptake inhibitor ) w w y. ergot alkaloid w w y ƒ š(41.3%), benzodiazepine y (33.8%). y 191 y 143 y w «wš, 48 y w l w w «wš. y 9 z. w e w wš e q w x w y 8 w «wš, 1 14 š n w «wš. ƒ y» w 8 St John s wortƒ t. w P-glycoprotein w k x û e q k x w «wš. w y ƒ x s j y 196 QT,, e j w s j ƒ ƒ (51.5%). yz (monoamine oxidase inhibitor, MAOI) yz (monoamine oxidase, MAO) w k m (selective serotonin reuptake inhibitor, SSRI), y w (tricyclic antidepressant, TCA), z (sympathomimetic) w y (23.8%). m, v v, v v ƒ g šx, m z ƒw w. k

8 8 Kor. J. Clin. Pharm., Vol. 19, No. 1, 2009 Table 11. Characteristics of Drug Interactions from according to KFDA Classification Class Total (%) Contraindicated (%) Major (%) Moderate (%) Rapid (%) Delayed (%) Unspecified (%) 110 3,059 (17.7) 349 (33.5) 1,329 (21.4) 1,381 (13.8) 575 (13.1) 1,067 (13.4) 1,416 (28.7) (7.5) 128 (12.3) 280 (4.5) 893 (8.9) 278 (6.3) 744 (9.3) 279 (5.7) (2.1) 6 (0.6) 207 (3.3) 152 (1.5) 179 (4.1) 73 (0.9) 113 (2.3) 130 1,063 (6.1) 45 (4.3) 302 (4.9) 716 (7.1) 347 (7.9) 556 (7.0) 160 (3.2) (1.9) 4 (0.4) 103 (1.7) 220 (2.2) 45 (1.0) 239 (3.0) 43 (0.9) 210 3,552 (20.5) 73 (7.0) 1,193 (19.2) 2,286 (22.8) 1,325 (30.2) 1,393 (17.5) 834 (16.9) (1.8) 9 (0.9) 220 (3.5) 90 (0.9) 52 (1.2) 89 (1.1) 178 (3.6) (2.4) 5 (0.5) 83 (1.3) 327 (3.3) 119 (2.7) 205 (2.6) 91 (1.8) (4.5) 22 (2.1) 151 (2.4) 604 (6.0) 67 (1.5) 581 (7.3) 129 (2.6) (1.0) 36 (3.5) 20 (0.3) 112 (1.1) 65 (1.5) 59 (0.7) 44 (0.9) (5.5) 50 (4.8) 177 (2.8) 725 (7.2) 123 (2.8) 632 (7.9) 197 (4.0) (0.5) 5 (0.5) 12 (0.2) 64 (0.6) 20 (0.5) 46 (0.6) 15 (0.3) (0.3) 1 (0.1) 2 (0.0) 56 (0.6) 36 (0.8) 19 (0.2) 4 (0.1) (2.9) (4.5) 228 (2.3) 145 (3.3) 197 (2.5) 165 (3.3) (0.1) (0.1) - 7 (0.1) 2 (0.0) (4.6) 19 (1.8) 234 (3.8) 551 (5.5) 298 (6.8) 437 (5.5) 69 (1.4) (2.9) 21 (2.0) 273 (4.4) 207 (2.1) 65 (1.5) 321 (4.0) 115 (2.3) (0.0) - 1 (0.0) 6 (0.1) 4 (0.1) 2 (0.0) 1 (0.0) (5.3) 53 (5.1) 375 (6) 497 (5) 154 (3.5) 470 (5.9) 301 (6.1) 620 1,343 (7.8) 159 (15.3) 478 (7.7) 706 (7) 365 (8.3) 642 (8.1) 336 (6.8) (0.2) - 29 (0.5) 13 (0.1) 6 (0.1) 18 (0.2) 18 (0.4) (1.3) 31 (3.0) 90 (1.4) 98 (1.0) 23 (0.5) 88 (1.1) 108 (2.2) (0.2) 9 (0.9) 2 (0.0) 25 (0.2) 28 (0.6) 7 (0.1) 1 (0.0) (0.0) - 1 (0.0) 4 (0.0) 5 (0.1) (1.0) 8 (0.8) 144 (2.3) 13 (0.1) 13 (0.3) 29 (0.4) 123 (2.5) (1.7) 8 (0.8) 237 (3.8) 47 (0.5) 50 (1.1) 54 (0.7) 188 (3.8) Total 17, ,222 10,030 4,387 7,975 4,930 m z (5HT-1 agonist) ƒ e x s y, ketolorac NSAID (, x) s y. y 143 y w «wš, 53 y š n w «wš, 30 5 w. w y ¼w w y 9 naltrexone opioid analgesic y. opioid receptor w opioid š ùkú, w» w w 7 10 š n w «w š.» 60 y 31 y w «wš, 29 y 2 14 š n w «wš (Table 15) %SVH*OUFSBDUJPO'BDUT y 1,355 DIF 488 moderate y, y (210) 94 (16.8%) ƒ š, (110, 74, 13.2%), w (610, 50, 8.9%) (Table 3). 476 ATC w, Nervous System (N) 108 (17.9%) ƒ š, Cardiovascular System (C) 90 (15.0%), Antiinfectives For Systemic Use (J) 77 (12.8%) (Table 4).

9 ü t y 9 Table 12. Characteristics of Drug Interactions from according to ATC Classification Class Total (%) Contraindicated (%) Major (%) Moderate (%) Rapid (%) Delayed (%) Unspecified (%) A 1,367 (7.5) 34 (3.1) 335 (5.2) 998 (9.4) 428 (9.6) 792 (9.2) 147 (2.9) B 836 (4.6) 2 (0.2) 453 (7.0) 381 (3.6) 207 (4.6) 298 (3.5) 331 (6.5) C 3,307 (18.2) 77 (6.9) 1,065 (16.4) 2,165 (20.5) 1,262 (28.3) 1,335 (15.5) 710 (13.8) D 886 (4.9) 66 (5.9) 234 (3.6) 586 (5.5) 109 (2.4) 577 (6.7) 200 (3.9) G 712 (3.9) 67 (6.0) 84 (1.3) 561 (5.3) 151 (3.4) 418 (4.9) 143 (2.8) H 458 (2.5) 13 (1.2) 98 (1.5) 347 (3.3) 26 (0.6) 345 (4.0) 87 (1.7) J 2,175 (12.0) 227 (20.5) 762 (11.8) 1,186 (11.2) 485 (10.9) 1,094 (12.7) 596 (11.6) L 883 (4.9) 23 (2.1) 383 (5.9) 477 (4.5) 94 (2.1) 632 (7.4) 157 (3.1) M 1,304 (7.2) 53 (4.8) 367 (5.7) 884 (8.4) 319 (7.2) 682 (7.9) 303 (5.9) N 3,997 (22.0) 449 (40.5) 1,834 (28.3) 1,714 (16.2) 808 (18.1) 1,367 (15.9) 1,822 (35.5) P 175 (1.0) 12 (1.1) 121 (1.9) 42 (0.4) 10 (0.2) 41 (0.5) 124 (2.4) R 695 (3.8) 19 (1.7) 330 (5.1) 346 (3.3) 128 (2.9) 315 (3.7) 252 (4.9) S 1,345 (7.4) 60 (5.4) 414 (6.4) 871 (8.2) 407 (9.1) 684 (8.0) 254 (5.0) V 40 (0.2) 8 (0.7) 4 (0.1) 28 (0.3) 24 (0.5) 13 (0.2) 3 (0.1) Total 18,180 1,110 6,484 10,586 4,458 8,593 5,129 ATC Not Assigned 1, y s³ 12.6 y (Table 6), wafarin 141 y ƒ š, phenytoin 108, digoxin y 2 (0.4%), y 13 (2.7%), y 194 (39.7%), 10 y 279 (57.2%) (Table 5). y x (330) s³ 21.5 ƒ š, ATC Sensory Organs (S) s³ 17.4 ƒ (Table 6, 7). y ƒ 10 y (210) 18.6% ƒ š, ATC Nervous System (N) 18.8% ƒ (Table 8, 9). DIF moderate ƒ y 3,071 Table 13. KFDA Drug Classification of Drug Interactions from Total Contraindicated Major Moderate KFDA Class Drug Interactions (%) KFDA Class Drug Interactions (%) KFDA Class Drug Interactions (%) KFDA Class Drug Interactions (%) (7.4) (13.6) (6.5) (7.2) (5.3) (10.8) (5.2) (4.4) (4.0) (4.8) (4.1) (3.0) (3.6) (4.2) (4.0) (3.0) (2.8) (4.2) (3.1) (2.6) (2.6) (3.8) (3.0) (2.6) (2.5) (3.8) (2.8) (2.6) (2.4) (3.2) (2.5) (2.3) (2.1) (2.7) (2.5) (2.2) (1.9) (2.7) (2.4) (2.2) Total 9,914 Total 660 Total 4,013 Total 7,249

10 10 Kor. J. Clin. Pharm., Vol. 19, No. 1, 2009 Table 14. ATC Drug Classification of Drug Interactions from Total Contraindicated Major Moderate Class Drug Interactions (%) Class Drug Interactions (%) Class Drug Interactions (%) Class Drug Interactions (%) N - N 958 (8.8) J - N 144 (22.3) N - N 536 (14.6) C - C 438 (6.6) C - C 610 (5.6) N - N 104 (16.1) C - N 233 (6.4) N - N 318 (4.8) C - N 502 (4.6) D - N 46 (7.1) C - J 179 (4.9) C - M 289 (4.4) J - N 498 (4.6) C - J 37 (5.7) C - C 171 (4.7) C - N 238 (3.6) C - J 423 (3.9) C - N 31 (4.8) J - N 164 (4.5) A - C 230 (3.5) A - J 350 (3.2) G - N 31 (4.8) A - J 161 (4.4) M - N 221 (3.3) M - N 334 (3.1) M - S 28 (4.3) C - R 136 (3.7) C - J 207 (3.1) C - M 319 (2.9) M - M 23 (3.6) B - B 127 (3.5) C - S 202 (3.1) C - S 295 (2.7) N - S 22 (3.4) M - N 109 (3.0) J - N 190 (2.9) A - C 275 (2.5) G - J 21 (3.3) B - M 104 (2.8) A - J 189 (2.9) Total 10,926 Total 646 Total 3661 Total 6,619 ATC Not Assigned 708 ATC Not Assigned 19 ATC Not Assigned 138 ATC Not Assigned 551 (Table 10). (110) 1,381 (19.0%) ƒ š, y (210) 1,313 (18.1%), w (610)ƒ 761 (10.5%) (Table 16). ATC Nervous System (N) 1,676 (20.6%) ƒ š, Cardiovascular System (C) 1,309 (16.1%), Antiinfectives For Systemic Use (J) 1,236 (15.2%) (Table 17) DIF y y (210) y (210) Table 15. Contraindicated Drug Interaction Mechanism and Management Management Mechanism Inhibition Metabolism Induction Inhibition & Induction Absorption & Metabolism Synergy Antagonism Unknown Total Never Coadministered Monitorin and/or Dosage Adjustment Required Should be Administered Apart Each Medication 30 Minutes Hours Hours 9 7~10 Days or 14 Days Days Days Days or 5 Weeks* 5 5 Total (%) 201 (42.4) 8 (1.7) 196 (41.4) 9 (1.9) 60 (12.7) 474 * The time lapse between the time when one drug should be discontinued and the time when the other drug would be started is not the same as the time lapse of the other way.

11 ü t y 11 y 5.5% ƒ š, (110) y (210) y 5.1%, (110) (110) y 4.8% (Table 18). ATC Nervous System (N) Cardiovascular System (C) y 6.1% ƒ š, Antiinfectives For Systemic Use (J) Nervous System (N) y 5.5%, Nervous System (N) Nervous System (N) y 5.5% (Table 19). DIF y ƒ 3,071 y major ƒ 551 (17.9%), moderate ƒ 2,520 (82.1%) (Table 10). ƒ major y (210) 18.1% ƒ š, w (610)ƒ 14.4%, (110) 13.9%, moderate w y (110) 20.1% ƒ š, y (210) 18.1%, w (610)ƒ 9.7% (Table 16). ATC major y Antiinfectives For Systemic Use (J) 21.5% ƒ š, Nervous System (N) 18.3%, Cardiovascular System (C) 16.6%, moderate w y Nervous System (N) 21.1% ƒ š, Cardiovascular System (C) 16.0%, Antiinfectives For Systemic Use (J) 13.8% (Table 17). ƒ y w r major y y (210) y (210) y major y 7.9%, moderate y (110) y (210) y 5.9% ƒ (Table 18). ATC Table 16. Characteristics of Drug Interactions from Drug Interaction Facts According to KFDA Classification Class Total (%) Major (%) Moderate (%) Rapid (%) Delayed (%) 110 1,381 (19) 177 (13.9) 1,204 (20.1) 291 (17.2) 1,090 (19.6) (7.2) 88 (6.9) 432 (7.2) 107 (6.3) 413 (7.4) (3.0) 45 (3.5) 176 (2.9) 155 (9.1) 66 (1.2) (6.3) 96 (7.5) 363 (6.1) 97 (5.7) 362 (6.5) (1.5) 15 (1.2) 97 (1.6) 39 (2.3) 73 (1.3) 210 1,313 (18.1) 231 (18.1) 1,082 (18.1) 458 (27.0) 855 (15.4) (1.1) 2 (0.2) 77 (1.3) 17 (1.0) 62 (1.1) (2.9) 38 (3.0) 175 (2.9) 64 (3.8) 149 (2.7) (3.9) 43 (3.4) 240 (4.0) 37 (2.2) 246 (4.4) (1.0) 14 (1.1) 56 (0.9) 22 (1.3) 48 (0.9) (6.6) 57 (4.5) 419 (7.0) 71 (4.2) 405 (7.3) (0.4) 2 (0.2) 25 (0.4) 3 (0.2) 24 (0.4) (0.5) - 36 (0.6) 21 (1.2) 15 (0.3) (3.0) 57 (4.5) 158 (2.6) 12 (0.7) 203 (3.7) (0.1) - 8 (0.1) - 8 (0.1) (3.4) 17 (1.3) 232 (3.9) 35 (2.1) 214 (3.8) (2.3) 39 (3.1) 126 (2.1) 11 (0.6) 154 (2.8) (0.0) - 1 (0.0) - 1 (0.0) (10.5) 183 (14.4) 578 (9.7) 94 (5.5) 667 (12.0) (6.3) 129 (10.1) 330 (5.5) 72 (4.3) 387 (7.0) (0.1) 4 (0.3) 2 (0.0) 3 (0.2) 3 (0.1) (1.2) 15 (1.2) 73 (1.2) 25 (1.5) 63 (1.1) (0.5) 8 (0.6) 27 (0.5) 27 (1.6) 8 (0.1) (0.2) - 13 (0.2) - 13 (0.2) (0.3) 5 (0.4) 19 (0.3) 14 (0.8) 10 (0.2) (0.5) 10 (0.8) 29 (0.5) 19 (1.1) 20 (0.4) Total 7,253 1,275 5,978 1,694 5,559

12 12 Kor. J. Clin. Pharm., Vol. 19, No. 1, 2009 Table 17. Characteristics of Drug Interactions from Drug Interaction Facts According to ATC Classification ATC Total (%) Major (%) Moderate (%) Rapid (%) Delayed (%) A 635 (7.8) 107 (7.2) 528 (7.9) 139 (7.3) 496 (7.9) B 311 (3.8) 69 (4.7) 242 (3.6) 55 (2.9) 256 (4.1) C 1,309 (16.1) 245 (16.6) 1,064 (16.0) 458 (24.2) 851 (13.6) D 514 (6.3) 101 (6.8) 413 (6.2) 107 (5.7) 407 (6.5) G 304 (3.7) 42 (2.8) 262 (3.9) 40 (2.1) 264 (4.2) H 181 (2.2) 29 (2.0) 152 (2.3) 31 (1.6) 150 (2.4) J 1,236 (15.2) 318 (21.5) 918 (13.8) 187 (9.9) 1,049 (16.8) L 299 (3.7) 52 (3.5) 247 (3.7) 32 (1.7) 267 (4.3) M 573 (7.0) 66 (4.5) 507 (7.6) 172 (9.1) 401 (6.4) N 1,676 (20.6) 271 (18.3) 1,405 (21.1) 416 (22.0) 1,260 (20.2) P 37 (0.5) 4 (0.3) 33 (0.5) 3 (0.2) 34 (0.5) R 272 (3.3) 24 (1.6) 248 (3.7) 75 (4.0) 197 (3.2) S 766 (9.4) 143 (9.7) 623 (9.4) 164 (8.7) 602 (9.6) V 28 (0.3) 9 (0.6) 19 (0.3) 13 (0.7) 15 (0.2) Total 8,141 1,480 6,661 1,892 6,249 ATC Not Assigned major y Antiinfectives For Systemic Use (J) Nervous System (N) y š 9.4% ƒ š, moderate y Cardiovascular System (C) Nervous System (N) y 7.2% w ƒ (Table 19). DIF y x» 3,071 y rapid 735 (23.9%), delayed 2,336 (76.1%) (Table 10). x»ƒ rapid y y (210) ƒ š(27.0%), (110, 17.2%), (120, 9.1%) š, delayed y (110) ƒ š(19.6%), y (210, 15.4%), w (610, 12.0%) (Table 16). ATC rapid y Cardiovascular System (C) ƒ š (24.2%), Nervous System (N, 22.0%), Antiinfectives For Systemic Use (J, 9.9%). Delayed y Nervous System (N) 20.2% ƒ š, Antiinfectives For Systemic Use (J) 16.8%, Cardiovascular System (C) 13.6% (Table 17)..JDSPNFEFY %SVH*OUFSBDUJPO'BDUT y 1,355 moderate ƒ y 715, DIF 488, š 465 y x œm (Table 20). w ƒ w y w s³ 21.2, DIF s³ 12.6, y ƒ 10 w w 6 sw. 7,582 y DIF 3,071 y 1,625 y w ( 21.4%, DIF 52.9%)(Table 21, 22). DIF œm w 1,625 y ƒ w contraindicated ³ w 138 y DIF 99 (71.7%) major, 39 (28.3%) moderate w š, major" ³ w 364 y DIF 187 (51,4%) major, 177 (48.6%) moderate w, moderate ³ w 1,123 y DIF 104 (9.3%) major, 1,018 (90.7%) moderate w. 1,625 y 99 (6.1%) contraindicated š, DIF major, 187 (11.5%) x major, 1019 (62.7%) x moderate, contraindicate major y w DIF e 80.3% (Table 23). DIF œm w 1,625 y x» w rapid ùkù 408 y DIF rapid ƒ

13 ü t y 13 Table 18. KFDA Drug Classification of Drug Interactions from Drug Interaction Facts Total Major Moderate Class Drug Interactions (%) Class Drug Interactions (%) Class Drug Interactions (%) (5.5) (7.9) (5.9) (5.1) (5.1) (5.0) (4.8) (4.5) (4.8) (3.5) (4.5) (3.6) (3.3) (4.2) (3.1) (2.8) (3.7) (3.1) (2.6) (3.6) (2.6) (2.4) (3.6) (2.5) (2.2) (3.6) (2.4) (2.2) (3.3) (2.3) Total 8,562 Total 1,460 Total 7, (63.0%), delayed ƒ 151 (37.0%) š, delayed ùkù 875 y DIF rapid ƒ 114 (13.0%), delayed ƒ 761 (87.0%), unspecified ùkù 342 y DIF rapid ƒ 21 (6.1%), delayed ƒ 321 (93.9%). x» 62.6% e ùkþ (Table 24). DIF ƒ x» e w y ƒ contraindicated DIF major ew w 1,625 y % e ùkþ. üxƒ w.jdspnfefy %SVH*OUFSBDUJPO'BDUT y ùkù 7,582 y 57.6%, DIF ùkù 3,071 y 58.5%, w 9,028 y 55.2%ƒ ü t (xƒ w)». DIF y ƒ, ü t (xƒ w)» Table 19. ATC Drug Classification of Drug Interactions from Drug Interaction Facts Total Major Moderate Class Drug Interactions (%) Class Drug Interactions (%) Class Drug Interactions (%) C - N 654 (6.1) J - N 186 (9.4) C - N 622 (7.2) J - N 588 (5.5) C - J 142 (7.2) N - N 468 (5.4) N - N 586 (5.5) C - C 126 (6.4) J - N 402 (4.6) C - C 404 (3.8) N - N 118 (6.0) J - S 306 (3.5) J - S 372 (3.5) D - J 70 (3.6) M - N 298 (3.4) C - J 354 (3.3) C - S 68 (3.5) C - C 278 (3.2) N - S 330 (3.1) J - J 68 (3.5) N - S 278 (3.2) M - N 312 (2.9) J - S 66 (3.4) A - J 246 (2.8) A - J 304 (2.9) A - J 58 (2.9) A - C 230 (2.6) J - J 298 (2.8) J - M 56 (2.8) D - N 230 (2.6) Total 10,654 Total 1,970 Total 8,684 ATC Not Assigned 436 ATC Not Assigned 26 ATC Not Assigned 410

14 14 Kor. J. Clin. Pharm., Vol. 19, No. 1, 2009 Table 20. Common Drug Interactions from both and Drug Interaction Facts according to KFDA Drug Classification KFDA Class Both DIF Total (13.2) 26(9.9) 3(11.5) (6.2) 11(4.2) 1(3.8) (3.5) 12(4.6) 4(15.4) (4.9) 18(6.9) 1(3.8) (1.9) 9(3.4) (16.4) 34(13.0) 6(23.1) 220 9(1.7) 11(4.2) (4.7) 12(4.6) 1(3.8) (5.4) 8(3.1) (1.3) 9(3.4) (5.0) 10(3.8) 2(7.7) 310 9(1.7) 1(0.4) 1(3.8) 320 2(0.4) 2(0.8) (1.5) 6(2.3) 2(7.7) 340 1(0.2) 1(0.4) (5.2) 14(5.3) 1(3.8) (5.6) 26(9.9) (1.1) 1(3.8) (9.3) 23(8.8) (6.3) 16(6.1) 1(3.8) 630 3(0.6) 8(3.1) 1(3.8) 640 6(1.1) 1(0.4) (1.7) 1(0.4) 1(3.8) 790 1(0.2) (0.9) (1.1) - - Total contraindicated 71.3%, major 47.9%, moderate 62.6% š, DIF major 70.1%, moderate 56.0% x ùkù ƒ ƒ w ü t (xƒ w)» w (Table 24). ü t (xƒ w) y» n w x w ü t (xƒ w)»» y contraindicated 46.6%, major 12.7%, moderate 5.7% š, DIF major 27.2%, moderate 7.5% ƒ ƒ w y ü t ( Table 21. KFDA Classification of Drug Interactions Described in and Drug Interaction Facts KFDA Class Both Only DIF Only Total 1,625 5,957 1, (21.0) 2,251(16.8) 573(16.9) (7.4) 1016(7.6) 235(6.9) (2.3) 275(2.0) 131(3.9) (6.0) 830(6.2) 226(6.7) (2.0) 249(1.9) 34(1.0) (18.7) 2,831(21.1) 592(17.4) (0.8) 287(2.1) 47(1.4) (3.0) 300(2.2) 98(2.9) (4.8) 592(4.4) 98(2.9) (0.9) 134(1.0) 36(1.1) (6.4) 704(5.2) 228(6.7) (0.6) 59(0.4) 5(0.1) (0.6) 34(0.3) 11(0.3) (3.6) 368(2.7) 76(2.2) 340 4(0.1) 5(0.0) 4(0.1) (2.8) 697(5.2) 142(4.2) (2.2) 416(3.1) 80(2.4) 430-7(0.1) 1(0.0) (6.6) 670(5.0) 506(14.9) (7.1) 1,070(8.0) 186(5.5) 630 4(0.1) 38(0.3) 2(0.1) (1.4) 164(1.2) 33(1.0) (0.6) 12(0.1) 11(0.3) 790 3(0.1) 2(0.0) 10(0.3) 810 8(0.2) 157(1.2) 16(0.5) (0.6) 269(2.0) 16(0.5) Total 3,856 13,437 3,397 xƒ w)» ƒ w. ü t (xƒ w) n y contraindicated 24.7%, major 35.2%, moderate 56.9% ƒ ƒ û y, DIF major 42.8%, moderate 48.5% j ƒ (Table 25). ü t (xƒ w)» y 2,543 y DIF moderate š y ( minor ù y )» y 358 (14.1%), n y 2,185(85.9%).

15 ü t y 15 Table 22. ATC Classification of Drug Interactions Described in and Drug Interaction Facts Class Both Only DIF Only Total 1,547 4,957 1,371 A 287(6.8) 1,080(7.7) 348(8.9) B 188(4.4) 648(4.6) 123(3.1) C 722(17.1) 2,585(18.5) 587(15.0) D 268(6.3) 618(4.4) 246(6.3) G 175(4.1) 537(3.8) 129(3.3) H 111(2.6) 347(2.5) 70(1.8) J 564(13.3) 1,611(11.5) 672(17.2) L 165(3.9) 718(5.1) 134(3.4) M 261(6.2) 1043(7.5) 312(8.0) N 994(23.5) 3,003(21.5) 682(17.4) P 21(0.5) 154(1.1) 16(0.4) R 142(3.4) 553(4.0) 130(3.3) S 313(7.4) 1,032(7.4) 453(11.6) V 17(0.4) 23(0.2) 11(0.3) Total 4,228 13,952 3,913 ATC Not Assigned 78 1, š ü t w y x w wš ü t ( xƒ w) w. ü t sw 1, % w w ƒ ( moderate ) y x š, ü t 176 y ü t (xƒ w) w š x. y (9,028 ) 55.2%ƒ ü t (xƒ w)» š, ü t (xƒ w)» ù DIF y 2,543 ( 28.2%) ü t (xƒ w) x e ƒ û. ü t (xƒ w) y ƒw œw w. s t( x t) w» t sw. w w t ü t sw. w minor w ƒ ƒ y w. DIF x (210), (110), w (610), ATC Nervous System (N), Cardiovascular System (C), Antiinfectives For Systemic Use (J) y w. ƒ t l ATC Nervous System (N) w (110) w m (114) swwš, ƒ» w (130) ATC ƒ» (Sensory Organs, S) w. ƒ» y, v y w w» n (systemic administration) n w y y x. y ƒ r y contraindicated y (110), yw (620), y (210). ATC Nervous System (N) Antiinfectives For Systemic Use (J) ƒw Table 23. Comparison of Drug Interaction Severity in and Drug Interaction Facts DIF Contraindicated Major Moderate Total Major 99(6.1) 187(11.5) 104(6.4) 390(24.0) Moderate 39(2.4) 177(10.9) 1,019(62.7) 1,235(76.0) Total 138(8.5) 364(22.4) 1,123(69.1) 1,625 Table 24. Comparison of Drug Interaction Onset in and Drug Interaction Facts DIF Rapid Delayed Unspecified Total Rapid 257(15.8) 114(7.0) 21(1.3) 392(24.1) Delayed 151(9.3) 761(46.8) 321(19.8) 1,233(75.9) Total 408(25.1) 875(53.8) 342(21.0) 1,625

16 16 Kor. J. Clin. Pharm., Vol. 19, No. 1, 2009 Table 25. Comparison of Drug Interaction Information in KFDA Drug Label,, and Drug Interaction Facts Total Drug Label Information Contraindication Caution Not Available in Drug Label DIF Total Contra-indicated Major Moderate Total Major Moderate 7,582 4,365 (57.6) 831 (11.0) 3,534 (46.6) 3,217 (42.4) (71.3) 221 (46.6) 117 (24.7) 136 (28.7) 2,864 1,373 (47.9) 365 (12.7) 1,008 (35.2) 1,491 (52.1) 4,244 2,656 (62.6) 243 (5.7) 2413 (56.9) 1,588 (37.4) 3,071 1,796 (58.5) 338 (11.0) 1,458 (47.5) 1,275 (41.5) (70.1) 150 (27.2) 236 (42.8) 165 (29.9) 2,520 1,410 (56.0) 188 (7.5) 1,222 (48.5) 1,110 (44.0) KFDA Only 2,543 2, (14.1) 2,185 (85.9) y. contraindicated y», ƒw (QT ) j, ü catecholamine w e. x ƒw y ú ƒ ƒ w vw «šwš, n ƒ v w ù e z w l w ù, w š n w ƒw y w «šw. y vw» w n w 30 5 ¾ w., dinoprostone z oxytocin methylergometrine (methylergonovine) w 30 «w, MAOI SSRI n w 14 «w. SSRI»ƒ ¼ fluoxetine, escitalopram MAOI n 5 n w «šwš. DIF y w ƒ ƒ moderate y 715, DIF 488 ƒ DIF w 1.5 w y œwš. w y s³ 21.2, DIF s³ 12.6 ƒ w w y œw DIFƒ w œw œ ƒ w» ƒ. 465 x y ƒ œ. ù y w ü x e 1, %, DIF 52.9% w w. œm y ƒ 80.3%ƒ ewš, ƒ e w 49.9% w. Fulda ww w 5 w US Pharmacopoeia Drug Information, AHFS Drug Information, Hansten's Drug Interactions Analysis and Management, Drug Interaction Facts, DRUG-REAX 5 w y w, w y 2 x» 19.0% ü 24.8% š, (significance) w e 43.3% ü 56.4% w 6. mw x y w x ü ƒ j, ü t t (x ƒ w) x ƒ. w y w, x w, wš, w w», w ƒ» ƒ. y w»,, wš, x ü ew x y w ƒ w wwš x w w y w w. (D06002) w. š x 1. y,. y w

17 ü t y y. z. 1998; 15(2): x,. y» w Carter BL, Lund BC, Hayase N, Chrischilles E. A longitudinal analysis of antihypertensive drug interactions in a Medicaid population. Am J Hypertens. 2004; 17: x sƒ /4» sƒ ( 6. FULDA TR, Valuck RJ, Zanden JV, ParkerS, Byrns PJ. Disagreement Among Drug Compendia on Inclusion and Ratings of Drug-Drug Interactions. Curr Ther Res. 2000; 61: