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1 대한내과학회지 : 제 86 권제 6 호 약물유해사례자발보고자료를통한국내중증피부유해반응원인약물분석 1 서울대학교의학연구원알레르기및임상면역연구소, 2 인제대학교의과대학부산백병원내과, 3 서울특별시보라매병원내과, 4 서울대학교의과대학서울대학교병원내과 김미영 1,2 양민석 1,3 강혜련 1,4 조상헌 1,4 민경업 1,4 Analysis of Drugs Causing Severe Cutaneous Adverse Reactions, Based on the Korean Database of Spontaneously Reported Adverse Drug Reactions Mi-Yeong Kim 1,2, Min-Suk Yang 1,3, Hye-Ryun Kang 1,4, Sang-Heon Cho 1,4, and Kyung-Up Min 1,4 1 Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul; 2 Department of Internal Medicine, Busan Paik Hospital, Inje University College of Medicine, Busan; 3 Department of Internal Medicine, SMG-SNU Boramae Medical Center, Seoul; 4 Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea Background/Aims: Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) are severe cutaneous adverse reactions (SCARs) that also affect the internal organs with high mortality. However, there has been no previous nationwide study of SCARs in Korea. Methods: Cases of SCARs were recruited from the nationwide Korean Pharmacovigilance Research Network database, collected from June 2009 to December 2010, by a spontaneous reporting system. We analyzed age, gender, route of administration and the causative agents. We also reviewed previously published cases of SCARs in Korea. Results: In total, 100 cases of SJS (66 cases), TEN (7 cases), and DRESS (27 cases) were reported. The mean age of the patients was 54.1 ± 19.8 years and the proportion of males to females was 1:0.88. In total, 81 drugs were reported as causative agents: SJS (61 drugs), TEN (15 drugs), and DRESS (29 drugs). The most commonly reported causative drug was allopurinol (12 cases). Allopurinol (8 cases) and levofloxacin (2 cases) were the most commonly reported causative drugs for SJS and TEN, respectively. In DRESS, allopurinol (4 cases) and vancomycin (4 cases) were the two most common causative drugs. Anti-infective drugs were the most common drug category (75 cases). Carbamazepine was the most commonly reported causative drug according to published cases in Korea. Conclusions: Allopurinol in the spontaneous reporting system and carbamazepine in the published cases were the most common single causative drugs in SCARs in Korea. Anti-infectives were the most common drug category in the spontaneous reporting system. (Korean J Med 2014;86: ) Keywords: Stevens-Johnson syndrome; Pharmacovigilance; Drug hypersensitivity; Eosinophilia Received: Revised: Accepted: Correspondence to Kyung-Up Min, M.D., Ph.D. Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, 103 Daehak-ro, Seoul , Korea Tel: , Fax: , drmin@snu.ac.kr * This research was supported by a grant from Ministry of Food and Drug Safety to operation of the regional pharmacovigilance center in Copyright c 2014 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

2 - Mi-Yeong Kim, et al. Causative agents of SCARs - 서론약물유해반응은의약품등을정상적으로투여및사용하였을때에발생한해롭고의도하지않은반응으로서해당의약품과의인과관계를배제할수없는경우로정의한다 [1]. 외국에서는 1960년대에이미자발적부작용신고시스템이구축되었고이를통해다양한정보를제공하고있다 [2]. 국내에서는 1985년의약품의부작용으로인한약물유해반응을감시하기위해 의약품등안전성정보처리규정 을제정하였고 1988년부터약물부작용모니터링기관을지정하여자발적으로신고할수있도록하였다. 이어 2000년 10월부터전국 15개대학병원과종합병원을대상으로원내부작용모니터링체계를구축한후 2001년부터유해사례신고건수가증가하기시작하였다 [1]. 스티븐스-존슨증후군 (Stevens-Johnson syndrome, SJS), 독성표피괴사용해 (toxic epidermal necrolysis, TEN) 그리고호산구증가증및전신증상을동반한약물반응 (drug reaction with eosinophilia and systemic symptoms, DRESS) 은중증피부유해반응 (severe cutaneous adverse reactions, SCARs) 에속하는대표적인질환들로발병률은높지않지만심한경우사망에이르는중대한질환이다 [3,4]. SCARs 의발생은유전적, 인종적차이를보이므로각나라마다원인약제의종류와빈도는다를수있다. 그러나이들반응은매우드물게발생하기때문에잘정리된역학적자료를얻는것이매우어려우며한국인에서발생한 SCARs 에대한대규모역학조사는아직까지이루어지지않은상태이다. 본연구자들은국내약물유해반응자발보고데이터베이스를이용하여한국인에서 SCARs 을일으킨원인약제를파악하고지금까지국내연구자들에의해증례로보고된 SCARs 의사례를수집하여한국인에서보고된 SCARs 의원인약물을확인하고자하였다. 대상및방법약물유해사례자발보고체계를통한수집본연구는식품의약품안전청 ( 현식품의약품안전처 ) 이지원한약물감시사업단이발족된 2009년 6월 24일부터 2010년 12월 31일까지자발적으로보고된부작용사례들을바탕으로하였다. 자료수집당시전국에총 15개의지역약물감시 센터가운영되었다. 약물유해사례는약물감시사업단홈페이지 ( 를통해보고서양식 (Supplement 1) 을다운로드받거나전산을통해각지역약물감시센터로직접신고할수있었다. 각지역약물감시센터에서는신고받은사례들을약물감시사업단에보고하였다. 보고서는작성일자, 보고자정보, 환자정보, 투여의약품정보 ( 의심의약품및병용의약품 ), 약물유해사례정보, 약물유해반응경과및조치에대한내용을포함하고있다. 수집된자료는고유의식약청관리번호를부여받았다. 하나의관리번호에등록된사건은의심약물과병용약물, 그리고유해사례의조합에따라독립적인조합단위로등록된다. 예를들어 1번식약청관리번호사건에의심약물 2개, 병용약물 3개, 유해사례 1개라면, 자료는의심약물수 (2) 병용약물수 (3) 유해사례수 (1) 로총 6개의조합단위로등록된다. 보고된자료는의약품명의경우영문성분명, Anatomical Therapeutic Chemical (ATC) 분류체계코드로, 유해사례의경우 World Health Organization Adverse Reactions Terminology (WHO-ART) 092 버전으로입력되었다 [5,6]. 또한보고된사례들은 WHO The Uppsala Monitoring Centre (WHO- UMC) 인과관계평가기준에따라분류되었다 [7]. 이렇게수집된사례는기본정보 ( 센터명, 식약청관리번호, 발생인지일, 보고서작성일, 등록일 ), 제조 / 수입회사 ( 회사명, 전화번호, 전자메일주소, 보고원, 동일사례보고여부 ), 추적보고 ( 최초보고여부, 추적보고횟수, 최초보고일, 최초관리번호 ), 보고자 ( 보고자구분, 보고기관명, 식약청이외동일사례를보고한기관 ), 환자정보 ( 나이, 생년월일, 성별, 체중, 합병증병력코드, 합병증명, 합병증상세내역, 과거병력코드, 과거병력명, 과거병력상세내역 ), 의약품정보 ( 품목코드, 제품명, 성분코드, ATC코드, 영문성분명, 복지부코드, 1일투여량, 투여경로, 투여시작일, 투여종료일, 투여기간, 투여목적, 투여중지시유해사례여부, 재투여시유해사례여부, 병용의약품구분 ), 유해사례정보 ( 증상발현일, 증상종료일, 현재진행여부, 유해사례코드, 유해사례영문명, 유해사례내용, 검사치 ), 중대한유해사례 ( 결과의중대성, 부검여부, 사망당시보고된원인, 부검시입증된사망원인 ), 전문가소견 ( 전문가소견유무, 전문가소견코드, 의약전문가소견내용 ) 이각각변수화되어데이터자료로구성되었다. 기본적으로수집된자료중 WHO-UMC 인과관계평가기

3 - 대한내과학회지 : 제 86 권제 6 호통권제 646 호 준에따라확실함 (certain), 거의확실함 (probable/likely), 가능함 (possible) 인경우분석에포함시켰으며평가가누락된경우라도알레르기내과의사의판단에의해기준에합당하다고평가되는경우도함께분석하였다. 데이터화된약물유해반응사례조합자료에서 WHO-ART 092 버전에따른유해사례에따라 SJS, TEN로검색하여선택하였다. WHO-ART 092 버전에는 DRESS가코딩되어있지않아 eosinophilia ( 호산구증가증 ) 의유해사례명을가지면서 RegiSCAR scoring system에따라 2점이상만족하는경우를 DRESS 라고정의하였다 [8]. 유해사례명은있으나구체적인호산구수치가제시되지않은경우는기타항목에서 2점이상획득하는경우만 DRESS 로정의하였고정보의부족으로점수를만족하지못하더라도전문가평가항목에 DRESS 로명기되어있는경우는분석에포함하였다. 보고된이상반응이허가사항에반영되어있는지혹은그렇지않은지를확인하기위해대한약사회홈페이지 ( kpanet.or.kr) 에서제공하는의약품검색이상반응을참고하였다. 대상사례들에대해보고자유형, 증상발생당시환자의나이및성별분포를조사하였다. 의심약물성분명및 ATC 상위코드에따른보고빈도와투약경로가함께조사되었다. 보고빈도가가장높았던 ATC 상위코드약물에대하여하위코드에따른빈도를추가로조사하였다. 문헌검색을통한국내사례수집 SCAR 을일으킨의심약물로빈번하게보고된약물과현재까지국내에서보고된약물의빈도가차이가있는지를알아보기위해 KoreaMed 및 Pubmed에서 "Stevens-Johnson syndrome", "toxic epidermal necrolysis" 그리고 "severe cutaneous adverse reactions" 를검색하여한국인연구자에의해보고된사례를수집하였다. DRESS 보고사례는 "drug reaction with eosinophilia and systemic symptoms" 와 "eosinophilia and rash" 또는 "hypersensitivity syndrome" 으로검색된사례중 DRESS의표현형에합당한증례를종합하였다. 통계분석방법질환별평균나이비교를위해일원배치분산분석 (one-way ANOVA) 법을사용하여분석하였고질환별성별분포, 투약경로에있어유의한차이가있는지를비교하기위해 Pearson 카이제곱 (chi-square) 검정을사용하여분석하였다. 통계프로그램은 SPSS 18.0판을이용하였다. 연구결과총자발보고건수및보고유형자료수집기간동안총 48,261건의유해사례가보고되었고의심약물과유해사례유형에따라총 153,557개의조합이생성되었다. SJS, TEN 그리고 DRESS 는총 100건이었고하나의유해사례에보고된평균의심약물수는 1.6개였다. SJS 은유해사례 66건, 101개의유해사례- 의심약물조합이보고되었고 TEN은유해사례 7건, 17개의유해사례- 의심약물조합이보고되었다. DRESS 는유해사례 27건, 43개의유해사례- 의심약물조합이보고되었다 (Table 1). 자발적으로보고된유해반응사례에있어환자군의평균나이는 54.1 ± 19.8세였고, 남녀각각 50명, 44명이었다. 6건은성별이누락되어있었다. 질환별평균연령 (p = 0.298) 및성별분포 (p = 0.101) 의 Table 1. Baseline characteristics of the study population SCARs SJS TEN DRESS p-value Age (Mean ± SD, yr) 54.1 ± ± ± ± Male/Female 50/44 28/35 5/2 17/ Total number of drug adverse reactions Mean number of causative drugs per case (range) (1-7) 2.4 (1-5) 1.6 (1-5) Route of administration Oral 108 (67.1) 74 (73.3) 12 (70.6) 22 (51.2) Injection 36 (22.4) 17 (16.8) 4 (23.5) 15 (34.9) NA 17 (10.6) 10 (9.9) 1 (5.9) 6 (14.0) Data are presented as number or n (%) unless otherwise indicated. SCARs, severe cutaneous adverse reactions; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis; DRESS, drug reaction with eosinophilia and systemic symptoms; NA, not available

4 - 김미영외 4 인. 중증피부유해반응의원인약물분석 - Table 2. Numbers of cases according to the causative drugs of SCAR SCARs N SJS N TEN N DRESS N Allopurinol 12 Allopurinol 8 Levofloxacin 2 Allopurinol 4 Amoxicillin/augmentin 6 Carbamazepine 5 Cefotaxime 1 Vancomycin 4 Carbamazepine 6 Amoxicillin/augmentin 4 Cephradine 1 Ethambutol 3 Propionic acid derivatives 6 Lamotrigine 4 Ceftriaxone 1 Isoniazid 2 Vancomycin 6 Paracetamol 4 Dexibuprofen 1 Mefenamic acid 2 Ethambutol 5 Propionic acid derivatives 4 Diclofenac 1 Meropenem 2 Isoniazid 5 Doxycycline 3 Ethambutol 1 Moxifloxacin 2 Metronidazole 5 Metronidazole 3 Isoniazid 1 Piperacillin and 2 Lamotrigine 4 TMP-SMZ 3 Metronidazole 1 enzyme inhibitor Mefenamic acid 4 Acetylsalicylic acid 2 Oseltamivir 1 Pyrazinamide 2 Paracetamol 4 Almagate 2 Propionic acid derivatives 1 Carbamazepine 1 Ceftriaxone 3 Cefpiramide 2 Pyridoxine 1 Cefepime 1 Ciprofloxacin 3 Ciprofloxacin 2 Rifampicin 1 Cefotaxime 1 Diclofenac 3 Clarithromycin 2 Teicoplanin 1 Ceftriaxone 1 Doxycycline 3 Diclofenac 2 Vancomycin 1 Cefuroxime 1 Levofloxacin 3 Enzymes 2 Cimetidine 1 Rifampicin 3 Isoniazid 2 Ciprofloxacin 1 TMP-SMZ 3 Mefenamic acid 2 Imatinib 1 Others a (One or two cases 77 Phenytoin 2 Levofloxacin 1 for each) Piroxicam 2 Metronidazole 1 Prednisolone 2 Rifampicin 1 Others a (one case for each) 39 Tamsulosin 1 Teicoplanin 1 Others a (one case for each) 7 Total 161 Total 101 Total 16 Total 43 SCARs, severe cutaneous adverse reactions; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis; DRESS, drug reaction with eosinophilia and systemic symptoms; TMP-SMZ, trimethoprim and sulfamethoxazole. a Others (SJS: amikacin, ampicillin and enzyme inhibitor, candesartan, cefaclor, cefazolin, cefdinir, ceftizoxime, ceftriaxone, cefuroxime, celecoxib, cilostazol, clindamycin, deflazacort, dexibuprofen, enalapril, ethambutol, furosemide, gallamine, ibuprofen, iopromide, levetiracetam, linezolid, methotrexate, naproxen, ofloxacin, oseltamivir, pantoprazole, potassium chloride, propacetamol, propyphenazone, pseudoephedrine, ranitidine, rifampicin, rosuvastatin, spironolactone, topiramate, triflusal, valproic acid and vancomycin; DRESS: other anti-inflammatory and antirheumatic agents, non-steroids (talniflumate), other drugs for peptic ulcer and gastro-oesophageal reflux disease (rebamipide), propionic acid derivatives, temozolomide, ticlopidine, tigecycline and valproic acid). 유의한통계적차이는보이지않았다. 보고자는의사가 47.0% 로가장많았고, 약사가 44.0%, 간호사가 9.0% 를차지하였다. SJS 또는 TEN의경우의사, 약사, 간호사가각각 53.4%, 39.7%, 6.8% 를차지하였고, DRESS 의경우는의사, 약사, 간호사가각각 29.6%, 55.6%, 14.8% 를차지하였다. 투약경로는경구투여가 108건 (67.1%) 으로가장빈번하였 고주사제로주입된경우가 36건 (22.4%) 이었으며나머지는기록이누락되었다 (Table 1). 성분명으로분류한 SCAR 원인약물건수원인약물로보고된약물수는성분명기준으로총 81개였다. SJS 의심약물은 61개, TEN은 15개그리고 DRESS 는 29개였다 (Table 2). SCAR 보고사례중에서가장빈번하게보

5 - The Korean Journal of Medicine: Vol. 86, No. 6, Table 3. Types of anti-infectives as causative drugs in SCARs SCARs SJS TEN DRESS β-lactam antibacterials, penicillins 24 (32.0) 13 (35.1) 3 (25.0) 8 (30.8) Drugs for treatment of tuberculosis 15 (20.0) 4 (10.8) 3 (25.0) 8 (30.8) Quinolone antibacterials 8 (10.7) 3 (8.1) 2 (16.7) 3 (11.5) Tetracyclines 4 (5.3) 3 (8.1) 0 (0.0) 1 (3.8) Sulfonamides and trimethoprim 3 (4.0) 3 (8.1) 0 (0.0) 0 (0.0) Macrolides, lincosamides, and streptogramins 3 (4.0) 3 (8.1) 0 (0.0) 0 (0.0) Direct-acting antivirals 2 (2.7) 1 (2.7) 1 (8.3) 0 (0.0) Aminoglycoside antibacterials 1 (1.3) 1 (2.7) 0 (0.0) 0 (0.0) Other antibacterials 15 (20.0) 6 (16.2) 3 (25.0) 6 (23.1) Data are presented as n (%). SCARs, severe cutaneous adverse reactions; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis; DRESS, drug reaction with eosinophilia and systemic symptoms. SCARS SJS TEN DRESS Figure 1. Percentage of cases according to causative drug categorized by ATC code. A, Alimentary tract and metabolism; B, Blood and blood-forming organs; C, Cardiovascular system; G, Genitourinary system and sex hormones; H, Systemic hormonal preparations, excluding sex hormones and insulins; J, Anti-infectives for systemic use; L, Antineoplastic and immunomodulating agents; M, Musculoskeletal system; N, Nervous system; R, Respiratory system; S, Sensory organs; V, Various. 고된원인약물은 allopurinol (12건) 이었고, amoxicillin/augmentin, carbamazepine, propionic acid derivatives, vancomycin 이각각 6건, ethambutol, isoniazid, metronidazole이각각 5건씩보고되었다. SJS의원인약물로는역시 allopurinol이 8건으로가장많았으며, carbamazepine이 5건으로그뒤를따랐다. TEN 은사례수가많지않았는데 levofloxacin 2건이보고되었고기타약물은 1건씩만보고되었다. DRESS 또한 SJS와마찬가지로 allopurinol이 4건으로원인약물중가장빈도가높았다. ATC 코드로분류한카테고리별 SCAR 의심약물건수 ATC 코드별신고약물분포를그림 1에기술하였다. 대분 류로보았을때가장빈번한빈도를보인카테고리는전신적항감염제 (antiinfectives for systemic use) 로총 75건 (46%) 이었다. 다음으로근골격계약물이 34건 (21%) 이었고이중항염증및항류마티즘제 (anti-inflammatory and anti-rheumatic products) 가 21건, 항통풍제 (anti-gout preparations) 가 12건, 근이완제가 1건이었다. 세번째순위를차지한카테고리는신경계약물로 22건 (13%) 이보고되었고이중항경련제 (antiepileptics) 가 16건, 진통제가 6건이었다. 질환별로보았을때 SJS 의심약물로보고된카테고리는전신적항감염제 37건 (36%), 근골격계약물 ( 항염증및항류마티즘제 14건, 항통풍제 8건, 근이완제 1건 ) 23건 (22%), 신

6 - Mi-Yeong Kim, et al. Causative agents of SCARs - Table 4. Summary of domestic published reports of SJS, TEN, and DRESS in Korea identified by searching KoreaMed and PubMed ( SJS (145 cases) SJS/TEN Overlap (23 cases) SJS-TEN NOS (57 cases) TEN (62 cases) DRESS (197 cases) Drug N Drug N Drug N Drug N Drug N Anticonvulsant 40 Aspirin, NSAID 8 Anticonvulsant 19 NSAID 18 Anticonvulsant 78 Carbamazepine/Oxcarbazepine 20 Aspirin 1 Carbamazepine 9 Mefenamic acid 3 Carbamazepine 59 Lamotrigine 13 Ibuprofen 1 Phenytoin 5 Loxoprofen 1 Phenytoin 7 Valproic acid 2 Tenoxicam 1 Valproic acid 2 Diclofenac 1 Lamotrigine 6 NOS 5 NOS 5 Phenobarbital 2 Piroxicam 1 Phenobarbital 3 Anti-infectives 28 Anticonvulsant 4 Lamotrigine 1 NOS 12 Valproic acid 2 Ceftriaxone/cefradine 6 Lamotrigine 2 Anti-infectives 19 Anti-infectives 17 Zonisamide 1 Ciprofloxacin 6 Carbamazepine 1 Cephalosporin 6 Ofloxacin/tosufloxacin 3 Anti-infectives 50 Vancomycin 5 Phenobarbital 1 Vancomycin 3 Amoxicillin/augmentin 2 Antituberculosis 15 TMP-SMZ 3 CAI 3 Penicillin 2 Ceftriaxone 2 Cephalosporin 8 Dapsone 2 Methazolamide 3 Levofloxacin 2 Sulfamethoxine 1 Vancomycin 6 Rifampicin 2 Anti-infectives 1 TMP-SMZ 2 Thioacetazone 1 Dapsone 4 Amoxicillin 1 Ceftriaxone 1 Rifampicin 2 Vancomycin 1 Ethambutol 4 NOS 4 Others 4 Doxycyline 1 NOS 7 Ciprofloxacin/ 3 CAI 20 Allopurinol 1 Hydrochloroquine 1 Anticonvulsant 10 Ofloxacin Methazolamide 16 Chlormezanone 1 NSAID 10 Carbamazepine 3 Rifampin 3 Acetazolamide 3 Isopropylantipyrine 1 Other NSAID 5 Valproic acid 2 Isoniazid 2 Dorzolamide 1 Sulfasalazine 1 Ibuprofen 1 Lamotrigine 1 Pyrazinamide 2 Allopurinol 23 Unknown 3 Indomethacin 1 Phenytoin 1 Nafcillin 1 NSAID 7 Meloxicam 1 NOS 3 Teicoplanin 1 Ibuprofen 1 Naproxen 1 CAI 9 Tazobactam 1 NOS 6 Nimesulide 1 Dorzolamide 6 Allopurinol 46 Others 30 Allopurinol 2 Methazolamide 2 NSAID 12 Lithium 6 Others 15 Brinzolamide 1 Ibuprofen 7 Herbs 4 Herbs 6 Steroid 5 Diclofenac 4 Trichloroethylene 3 Antipsychotic 1 Prednisolone 4 Celecoxib 1 Clopidogrel 2 Dantrolene 1 Deflazacort 1 Others 14 Sulfonamide 2 Diazepam 1 Allopurinol 4 Lithium 3 Betamethasone 1 Famciclovir 1 Others 9 Carvedilol 2 Bosentan 1 Hair dye 1 Sorafenib 2 Propylthiouracil 2 Carbamate 1 Hydantoin 1 Health supportives 1 Captopril 1 Cytosine arabinoside 1 Lansoprazole 1 Enalapril 1 Cilostazole 1 Deflazacort 1 L-cysteine 1 Fluoxetine 1 Mexiletine 1 Diphenylcyclopropenone 1 Sulfasalazine 1 Hantavax 1 Oseltamivir 1 Furosemide 1 Paraquat 1 Rebamipide 1 Gabapentin 1 Thalidomide 1 Risperidone 1 Minocycline 1 Sulfasalazine 1 Prednisolone 1 Sunitinib 1 Vandetanib 1 Total NOS, not otherwise specified; CAI, carbonic anhydrase inhibitors; TMP-SMZ, trimethoprim and sulfamethoxazole

7 - 대한내과학회지 : 제 86 권제 6 호통권제 646 호 경계약물 ( 항경련제 14건, 진통제 6건 ) 20건 (19%) 이었다. TEN 의심약물도전신적항감염제가 12건 (70%) 으로가장빈번하게신고되었고항염증및항류마티즘제가 3건, 소화관및대사약물 (alimentary tract and metabolism) 이 2건 ( 소화기능장애약물 1건, 비타민 1건 ) 으로신고되었다. DRESS 의심약물또한전신적항감염제가 26건 (60%) 으로가장많았고근골격계약물이 8건 ( 항염증및항류마티즘제 4건, 항통풍제 4 건 ) 으로보고되었다. 전신적항감염제하위분류별의심약물건수전체 SCAR 에서보고빈도가가장높았던카테고리인전신적항감염제중에서베타락탐계항생제 (β-lactam antibacterials, penicillins) 의보고빈도가 24건 (32.0%) 으로가장많았다 (Table 3). 항결핵제 (drugs for treatment of tuberculosis) 는 15 건 (20.0%) 이보고되었고 SJS에서 4건, TEN에서 3건, DRESS 에서 8건이보고되었다. 그외 quinolone계 8건 (10.7%), tetracycline계 4건 (5.3%), sulfonamide and trimethoprim (ATC code; J01E) 3건 (4.0%), macrolide, lincosamide and streptogramine (ATC code; J01F) 3건 (4.0%), 항바이러스제 (direct acting antivirals) 2건, aminoglycoside계 1건의순으로신고되었다. SJS에서는베타락탐계항생제 13건 (35.1%), 항결핵제 4건 (10.8%), quinolone계, tetracycline계, sulfonamide and trimethoprim (ATC code; J01E) 그리고 macrolide, lincosamide and streptogramine (ATC code; J01F) 이각각 3건 (8.1%), 항바이러스제, aminoglycoside계가각각 1건의순으로보고되었다. TEN 에서는베타락탐계항생제, 항결핵제가각각 3건 (25%), quinolone 계 2건, 항바이러스제 1건순이었고 DRESS 에서는베타락탐계항생제, 항결핵제가각각 8건 (30.8%), quinolone계 3건 (11.5%), tetracycline계 1건의순으로보고되었다. 허가사항반영여부보고된약물들의허가사항여부를살펴보면, SJS의의심약물 61가지중 37가지 (60.6%) 는허가사항에 SJS이반영되어있었고, TEN 의경우 15가지중 13가지 (86.7%) 에서반영되어있었다. DRESS 는 29가지약물중에서는 carbamazepine 의경우에만 지연성다기관과민성장애 라고표기되어있었다. 발열, 림프절종대, 간효소수치상승, 신기능저하, 발진그리고호산구증가와같이 DRESS 에서나타날수있는임상증상에관한설명은있었으나약물로인한과민성증후군과같이 DRESS 에상응하는유해사례명을포함하는경우는없었다. 국내에서보고된 SJS, TEN 그리고 DRESS 증례 KoreaMed와 Pubmed 에서 2013년 7월까지검색가능한전기간에서한국에서보고된 SCAR 증례를분석한결과최초보고는 1991년이었으며전체 484예의사례가확인되었다 (Table 4). 표현형별로는 SJS, TEN, SJS/TEN overlap 이각각 145예, 62예, 23예였고 SJS 또는 TEN으로구분하지않고 SJS/TEN으로표기한증례가 57예에달하여 SJS 및 TEN 증례는총 287예였다. DRESS 는 197예의보고가확인되었다. 원인약물중단일약제로는 carbamazepine 이 92건으로가장많았다. 질환별로는 SJS는 carbamazepine 20건, SJS/TEN overlap은 methazolamide 가 3건, TEN 은 dorzolamide가 6건으로표현형별로가장많은원인약제였다. 같은질환군으로생각되는 SJS, TEN, SJS/TEN overlap, SJS/TEN NOS 을합칠경우 carbamazepine 이 33건에달하였다. DRESS 도 carbamazepine 이 59건으로가장많았다. 항경련제는 SJS 및 TEN 사례들중 73건 (24.3%), DRESS 사례들중 78건 (39.0%) 으로가장높은비율을차지하였다. 고찰이번연구의목적은한국인에서발생한 SCARs 신고수및의심약물종류와빈도를확인하기위함이다. 약물감시사업단발족이후 18개월동안신고된전체약물유해사례수는 48,261건으로, 2005년, 2006년에각각 1,841건, 2,467건이신고되었던것과비교하여최근빠른신장을보였다 [2]. SCARs 는유병률이낮아증례위주의보고가대부분이기때문에발생빈도및원인약물현황을확인하기가어렵다. 국외에서는 2007년 Euro SCAR-study 를바탕으로 SJS과 TEN의고위험 (high risk) 약물로 nevirapine, lamotrigine, carbamazepine, phenytoin, phenobarbital, cotrimoxazole, sulfasalazine, allopurinol 그리고 oxicam-non steroidal antiinflammatory drug (NSAID) 을보고하였다 [9]. 2011년발표된리뷰논문에서는 Pubmed 와 Medline 검색을통해 DRESS 의원인약물을보고하였으며 carbamazepine, allopurinol, lamotrigine, phenobarbital 그리고 sulfasalazine 등이있었다 [8]. 그러나지금까지 SCARs 에대한대규모국내사례분석자료가없어한국인에서 SCARs 를일으키는주요약물에대한정보는명확하게알려진바가

8 - 김미영외 4 인. 중증피부유해반응의원인약물분석 - 없었다. 본연구에서자발보고자료분석에서가장빈번하게보고된약물은 allopurinol (SJS 8건, DRESS 4건 ) 이었다. HLA-B* 58:01은 allopurinol에의한 SCARs 발생과강한연관성을보인다 [10]. 우리나라의경우일반인구의 12.16% 가 HLA-B*58:01 를보유하고있어 allopurinol을복용할경우 SCARs 발생위험이다른국가에비해높을것으로예상된다 [11]. 두번째로흔한보고빈도를보였던 carbamazepine의경우한족을대상으로한연구에서 SJS과 HLA-B*15:02 의강한관련성이보고된바있다 (odds ratio [OR], 2,504; 95% confidence interval [CI], ,522). 그러나한국인환자를대상으로 HLA형과의관련성에관한연구를진행한결과한국인에서는 carbamazepine에의한 SCARs 발생에 HLA-B*15:02가관련성이없었는데 [12], 이는한국인에서 HLA-B*15:02의빈도가 0.41% 에불과하기때문인것으로보인다. Carbamazepine 에의한 SCARs 사례가한국인에서빈번하게관찰되는것에대해서는 B*15:02 외에다른유전적소인에대한추가연구가필요하겠다. 본연구에서한국인에서 allopurinol 및 carbamazepine에의한 SCAR 보고가다른약제에비해상대적으로빈번함을확인함에따라향후한국인에서이들약제에 SCAR 발생위험성에대해보다적극적으로알려조기발견및예방에힘써야하겠다. 2011년인도에서발표된한논문에서는 SJS과 TEN 총 32 증례의원인의심약물 58개를약물계통별로조사하였는데 antimicrobials 가 29건으로가장많았고, NSAID가 13건, 항경련제가 11건, 그리고기타 5건이었다. 단독제제로는항감염제분류에속하는 nevirapine이 9건으로가장많았고 phenytoin 이 7건으로그다음을차지하였다 [13]. 본연구에서도 ATC 코드에따른분류를통해사례를분류해본결과항감염제가가장빈번하게보고되었고그중에서도베타락탐 (β-lactam) 계열의항생제가 24건으로가장흔하게보고되었다. 베타락탐계열항생제의구조적인유사성이세포성면역 (cellular immunity) 과관련한발병기전에주요한부분을담당하는것으로추측해볼수있겠다 [14]. 다빈도로보고된약물의종류와빈도가국가별로차이를보인다는것은약물의종류, 인종및실제처방되는빈도에따라 SCAR 의발생위험도가다를수있다는점을나타내며, 이는본국내에서도보다활발한수집을통한대규모유해반응자료의분석이반드시필요하다는것을시사한다. 의심약물로보고된약물중 DRESS 의경우허가사항에 반영된비율이저조하였는데, 이는 DRESS 가비교적최근에정의되어허가사항에미쳐반영되지못했기때문으로추정된다. 그러나 SCAR를일으킬가능성이있는약물에대해허가사항에미리제시하지못한경우가많다는것은 SCARs 의중증도를고려하였을때반드시빠른시일내에보완되어야할사항이다. 현재보고자료들은각각의사례별로여러개의의심약물이동시에신고되어있어추후사례의재평가를통하여상기약물들이원인약물로서의위험도가얼마나되는지확인하는작업이허가사항반영이전에선행되어야하겠다. 본연구에사용된약물유해사례자료에누락된내용이다수있었는데, 이는약물투약일자, 증상의발현기간등이없는경우가많았다. 약물의투약일자나증상의발현일시, 과거동일약물투약병력등은신고자가발병즉시평가하여신고하는것이가장효율적이고추후사례의인과관계평가를위해서도중요한항목들이다. 따라서보고당시이러한내용들이누락되지않도록개선하는것이시급하며증상발생당시약물유해반응에경험이많은의사에의해인과관계평가가최대한정확하게이루어지도록제도적인뒷받침이되어야향후보다양질의유해사례를축적할수있겠다. 본연구에서현재까지국내사례보고를종합한결과와비교해보면질환별로빈번하게보고되는의심약물및약물군에있어자발적보고분석과다소차이를보인다. 자발적보고에서 allopurinol과항감염제가가장많았다. 국내사례보고문헌분석에서도 allopurinol은 39건, 항감염제는 115건 Figure 2. Annual number of case reports of severe cutaneous adverse reactions caused by allopurinol or carbamazepine in Korea

9 - The Korean Journal of Medicine: Vol. 86, No. 6, 으로많은비중을차지했지만자발보고와는다르게 carbamazepine 을포함한항전간제가 127건으로가장많은수를차지했다. Carbamazepine 에의한 SCAR 는국내에서는 1993년에처음증례가보고된 [15] 이래최근까지도증례들이보고되고있다 [12,16-26] (Fig. 2). Allopurinol에의한 SCAR 증례는 2003년에첫국내사례가문헌으로보고되었으며 [27] 이후 20011년까지여러증례들이연이어보고되었다 [28-33] (Fig. 2). 자발보고된자료와증례보고된사례중에는일부중복된사례가있을가능성을배제할수는없으나수집시기와출판시기를감안할때중복사례는많지않을것으로추정된다. 일부중복의가능성을감안하더라도자발적보고와실제보고사례의결과를비교해보았을때, 드문사례들의자발보고가누락되고있을가능성이있어향후보다적극적인보고및감시체계가필요하겠다. 본연구의제한점은첫째, 자발적인보고자료를기반으로하였기때문에전체약물사용량을알수없어정확한발생률을구할수없다는점이다. 그러나이러한드문질환에서전향적인역학조사가현실적으로불가능한점을감안할때본연구와같은자발적약물유해사례데이터의분석은매우유용하다. 둘째, 원인약물이확진되지않아도신고가가능하며보고할때의심되는약물을복수로입력한사례들이포함되어있어원인약물이아닌약제들도분석에일부포함되었을가능성이있어향후원인약제로의심되어보고된약제들에대해면밀한평가가필요하다. 셋째, 자발적보고의단점이라고할수있는자료의질적문제다. 추정진단상태에서보고하였거나경과관찰중최종진단명이변경되었을경우이후확진된진단명으로수정되지않았을가능성이있다. 하지만대부분의사례가대학병원에서보고된점을감안하면보고된진단은상당히정확하였을것으로보인다. 다만전수가보고되지않았을가능성은있어보다정확한정보를위해서는향후전국적인등록사업이필요할것으로사료된다. 본연구는증례보고위주였던약물유해보고사례에대하여범국가적감시센터를통해보고된대규모자료를분석하여본첫사례로서의의가있다. 본연구를통해국내에자발적약물유해반응신고사례를통해 SCAR 의원인약물로빈번하게보고되는약물을분석해보았고단독약물로서 allopurinol이, 약물군으로서전신적항감염제, 그중에서도베타락탐계항생제가빈번한것으로조사되었다. 신고된사 례중허가사항에반영되지않은경우도다수있어추후추가적인자료의수집과적절한평가를통해인과관계를확인하여허가사항에반영할수있도록해야할것이다. 요약목적 : 스티븐스-존슨증후군 (Stevens-Johnson syndrome, SJS), 독성표피괴사용해 (toxic epidermal necrolysis, TEN) 그리고호산구증가증및전신증상을동반한약물반응 (drug reaction with eosinophilia and systemic symptoms, DRESS) 은중증피부유해반응 (severe cutaneous adverse reactions, SCARs) 에속하는질환으로내부장기를침범하고사망률이높다. 국내에는지금까지 SCARs 에대한범국가적인연구가없었다. 방법 : 2009년 6월부터 2010년 12월까지약물감시사업단을통해수집된의약품유해사례보고자료중 SCARs 에해당되는사례들을분석하였다. 보고자나이, 성별, 투약경로, 의심약물의종류에대하여분석하였다. 아울러기존에국내에서발표된 SCARs 사례를분석하였다. 결과 : SJS은 66건, TEN은 7건그리고 DRESS 는 27건으로총 100건의 SCAR 가보고되었다. 환자군의평균연령은 54.1 ± 19.8였고, 남녀비율은 1:0.88이었다. SJS 61가지, TEN 15가지, DRESS 29가지로총 81가지의약물이보고되었다. 가장빈번하게보고된의심약물은 allopurinol (12건 ) 이었다. SJS의의심약물로 allopurinol (8건) 이가장빈번하였고 carbamazepine 이 5건으로그뒤를따랐다. TEN에서는 levofloxacin이 2건으로가장많았다. DRESS 에서가장빈번하게보고된의심약물은 allopurinol (4건) 과 vancomycin (4건) 이었다. 가장흔한약물군은전신적항감염제 (antiinfectives for systemic use, 75건, 46.6%) 였다. 국내에서보고된증례에서가장빈번한의심약물은 carbamazepine 이었다. 결론 : 자발적보고에서가장흔한 SCARs 원인은개별약제로는 allopurinol, 약물군으로는전신적항감염제가원인약물이었다. 지금까지국내에서보고된 SCARs 증례를분석한결과 carbamazepine 이가장높은빈도를차지하였다. 중심단어 : 부작용모니터링 ; 스티븐스-존슨증후군 ; 약물과민반응 ; 호산구증가증

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12 - 김미영외 4 인. 중증피부유해반응의원인약물분석 - Supplement 1. Report form for drug adverse reactions provided by the Pharmacovigilance Research Network