emr의 자발적 약물부작용보고 시스템을 이용한 한약약물유해반응 분석 ·...

http://dx.doi.org/10.13048/jkm.15005 45

EMR

1, 1,2

1 , 2

Original Article

Analysis of Herbal-drug-associated Adverse Drug Reactions Using Data from Spontaneous Reporting System in Electronic Medical Records

Mikyung Kim1, Chang-ho Han1,21Research Institute of Oriental Medicine, Dongguk University

2Dept. of Internal Medicine, College of Korean Medicine, Dongguk University

Objectives: The purpose of this study was to understand the status of reporting and characteristics of adverse drug reactions (ADRs) induced by herbal drugs and to make a suggestion for the domestic pharmacovigilance system on herbal medicine.Methods: We carried out a hospital-based observational study at Dongguk University Ilsan Oriental Hospital from April 2012 to December 2014. We reviewed all the herbal-drug-associated ADRs reports registered to the spontaneous ADR reporting system in electronic medical records of the hospital in the period.Results: We found out 101 reports including 163 herbal-drug-associated ADRs from 97 patients. Females (69.3%) outnumbered males and the most frequent age group was the 50s (44, 27.0%). No serious adverse event was observed. The most commonly reported ADR was gastro-intestinal system disorders (68, 41.5%) followed by skin-related disorders (42, 25.8%). Diarrhea (29, 17.8%) was the most frequently referred clinical manifestation. Most ADRs were induced by internal medicines (160, 98.2%) including manufactured (36, 22.1%) and self-prepared decoction (160, 76.1%). The pairs of Igi-hwan-diarrhea, gamiboa-tang-vomiting, and Magnoliae Flos-gastro-intestinal-system-related ADRs were observed twice each and the others appeared only once.Conclusions: We propose Korean government to take an initiative in national pharmacovigilance system for herbal medicine. To perform the surveillance on herbal drugs, the Association of Korean Medicine (AKOM) should set up a nationwide network by designating centers connecting the Korean medical hospitals, local Korean medicine clinics, and the public health centers. The government and AKOM should also educate and encourage them to understand the pharmacovigilance system and report the ADRs actively.

Key Words : side effects, adverse drug reaction, ADR reporting system, herbal-drug-associated ADR, pharmacovigilance, herbal medicine, Korean medicine

Received19 March 2015 Revised25 March 2015 Accepted25 March 2015Correspondence to(Chang-ho Han)780-714 123

Tel+82-54-770-1257, FAX+82-54-770-1500, [email protected]

1, 2). () aristolochic acid

36 1(2015 3)J Korean Med. 2015;36(1):45-60

http://dx.doi.org/10.13048/jkm.15005pISSN 1010-0695 eISSN 2288-3339

(46) 36 1 (2015 3)

http://dx.doi.org/10.13048/jkm.1500546

3),

ephedra alkaloid 4). 5) 371 , 27.5% 6).

, , 7,8).

.(Pharmacovigilance) (Adverse

Drug Reaction, ADR)

9),

10). , 1988 ,

. ,

9, 10). 2008

. ( ) , 25 , 2 .

, (WHO)

(Uppsala Monitoring Center, WHO-UMC) 9).

2008

(Electronic Medical Records, EMR) EMR

. 4 11) , ,

.

.

,

, .

(Institute Review Board, IRB) .

1.

2012 4 2014 12 33 EMR

(, , ) .

(47) 1 : EMR


1. (certain) , , ,

2. (probable/likely) , ( )

3. (possible) ,

4. (unlikely) ,

5. (conditional/unclassified)

6. (unassessible/unclassifiable)

Appendix I. WHO-UMC Causality Categories.2)2.

1)

( ) EMR .

, EMR , .

2) -

. ,

. 1 A B , C D , A-C/ A-D/ B-C/ B-D .

3)

1 WHO-UMC ( UMC ) (Appendix I). UMC , ,

, (certain), (probable/ likely), (possible), (unlikely), (conditional/unclassified), (unassessible/unclassifiable) 12). UMC

, . 2

2.0( KA) (Appendix II). KA , , , , , ( ), , 8

. , 1 3, -1 -3 , 0 , 12 (certain), 6-11 (probable), 2-5 (possible), 1 (unlikely) 12). ( )

(48) 36 1 (2015 3)


? (+3) (-3)(0)

? (+3) (-2) (0)(0)

?(+1) (-1)(0)

? (+2) (-3) (+2) (0)(0)

? (+1) (-1)(0)

(label, insert ) (+3) (+2) (0)

? (+3) (-2) (0)(0)

, ?(+3) (-1) (0) (0)

: 19, : -13. 12 (certain), 6-11 (probable), 2-5 (possible), 1 (unlikely) .

Appendix II. Korean Algorithm for ADR Causality Assessment (version 2.0).12)

(http://www.druginfo.co.kr),

(http://oasis.kiom.re.kr/pres/prbaseSearch. jsp), 13), WHO Monographs on Selected Medicinal Plants14), ( 2013-7, 2 7 1. 21 ) .

3.

1)

UMC possible, probable/likely, certain

.

2)

,

(49) 1 : EMR


1. (severe) , . .

2. (moderate) . , .

3. (mild) , . .

Appendix III. Severity of Adverse Drug Reactions.12)

Question Yes No UnknownDid the adverse drug reaction impair the patient's quality of life? 1 -1 0Was the (immediate) discontinuation of the drug necessary or recommended? 1 0 0Was the use of a different drug or other therapy necessary or recommended? 1 0 0Did the adverse drug reaction prolong treatment or lead to hospitalization? 1 0 0Did the adverse drug reaction cause temporary malfunctioning of an organ (system)? 1 0 0Did the adverse drug reaction cause permanent malfunctioning of an organ (system)? 2 0 0Did the adverse drug reaction lead to permanent inability to work? 1 0 0Was the adverse drug reaction potentially dangerous? 1 0 0Was the adverse drug reaction (potentially) life-threatening? 2 0 0Was the adverse drug reaction fatal? 3 0 0

The severity of the ADRs is classified according to the total score. A score of 14 indicates a mild reaction, a score of 58 a moderate reaction, and a score of 9 a severe adverse drug reaction

Appendix IV. LDS Scale Categories.15, 16)

.

3)

LDS scale .

(mild), (moderate), (severe) (Appendix III)12).

LDS scale , , , , , , 10 3

-1 9 (severe), 5-8 (moderate), 4 (mild) (Appendix IV)15, 16).

4)

WHO-UMC WHO-Adverse Reaction Terminology (WHO-ART) 092 . WHO-ART (System-Organ Classes, SOC), (High Level Terms, HLT), (Preferred Terms, PT), (Included Terms, IT) 4 17). WHO-ART PT , PT SOC .

5)

EMR

.

, , , + .

(50) 36 1 (2015 3)


6)

. , . , . , . A B ,

. .

. , . , , , ,

.

.

1, 2 .

1 . 2

.

1.

33

7,541 101. 97 4 2 2 , 1 . 79(78.2%) , 22(21.8%), . 54(53.5%) , 42(41.6%) , 4(4.0%) 1(1.0%).

2.

1)

101 16 . 13, 2, 1 . 3 .

7 ,

6, 1 . 3 2 , 1 .

2) -

1 1 177 .

3)

(1) (UMC )

(51) 1 : EMR


Rater Group Certain Probable Possible Unlikely Unclassified Not doneRPVC* 0 (0.0) 6 (3.4) 97 (54.8) 1 (0.6) 2 (1.1) 71 (40.1)

Authors 0 (0.0) 17 (9.6) 146 (82.5) 14 (7.9) 0 (0.0) 0 (0.0)* Raters of Regional Pharmacovigilance Center in Dongguk University Ilsan Hospital, Authors who are Korean Medical doctors

Table 1. Between-group Comparison of the WHO-UMC Causality Assessment.

Categories Number (%)Chronologic relationship 2 ( 1.1)Dose reduction or stop 129 ( 72.9)Past history of ADR 169 ( 95.5)

Combined medication 173( 97.7)Drug-unrelated cause 118( 66.7)

Any unveiled information of drugs 173( 97.7)Re-challenge 166( 93.8)Specific Tests 177(100.0)

Table 2. Number of the Cases with No Available Information to Score Each Category of Korean Algorithm for ADR Causality Assessment version 2.0.

(unclassified )

UMC , 177 probable, possible, unlikely (Table 1). 73 104 88(84.6%), 16(15.4%), probable possible 2, possible unlikely 8, possible probable 6.

(2) (KA) 177 KA

, UMC . KA

2 ,

129 , 118 (Table 2).

48(27.1%), 11(6.2%), ( ) 4(2.3%) , 98(55.4%).(Table 2)

3.

1)

UMC 163.

2)

(69.3%) (Table 3). 1 89 , 50 , (Table 3).

3)

, 163 159(97.5%) (mild), 4(2.5%) (moderate), . LDS scale .

4) ( )

(29, 17.8%), (20, 12.3%), (17, 10.4%), (12, 7.4%), (10, 6.1%)

(52) 36 1 (2015 3)


Total (%) Male (%) Female (%)Number 163 (100.0) 50 (30.7) 113 (69.3)

Age 4920.8 4124.0 5218.30-9 10 ( 6.1) 8 (4.9) 2 (1.2)

10-19 10 ( 6.1) 6 (3.7) 4 (2.5)20-29 8 ( 4.9) 3 (1.8) 5 (3.1)30-39 20 (12.3) 2 (1.2) 18 (11.0)40-49 20 (12.3) 8 (4.9) 12 (7.4)50-59 44 (27.0) 12 (7.4) 32 (19.6)60-69 30 (18.4) 7 (4.3) 23 (14.1)70-79 11 ( 6.75) 4 (2.5) 7 (4.3)80+ 10 ( 6.1) 0 (0.0) 10 (6.1)

Table 4. Types of Clinical Manifestations of Adverse Drug Reactions.

Clinical Manifestations Number SOC* Number (%)PRURITUS

RASHURTICARIA

SWEATING INCREASEDRASH FOLLICULAR

ACNE

1712 8 2 2 1

Skin and appendages disorders 42 (25.8)

MYALGIA 1 Musculo-skeletal system disorders 1 ( 0.6)DIZZINESS

HYPERTONIA 5 1

Central & peripheral nervous system disorders 6 ( 3.7)

PALPITATION 6 Autonomic nervous system disorders 6 ( 3.7)INSOMNIA 3 Psychiatric disorders 3 ( 1.8)VOMITINGDIARRHEADYSPEPSIA

ABDOMINAL PAINNAUSEA

FLATULENCE

5292010 2 2

Gastro-intestinal system disorders 68 (41.5)

HEPATIC ENZYMES INCREASED 7 Liver and biliary system disorders- 7 ( 4.2)HYPERGLYCAEMIA

OEDEMA DEPENDENTWEIGHT INCREASE

1 1 1

Metabolic and nutritional disorders 3 ( 1.8)

ARRHYTHMIA 1 Heart rate and rhythm disorders 1 ( 0.6)DYSPNEA 2 Respiratory system disorders 2 ( 1.2)DYSURIA 1 Urinary system disorders 1 ( 0.6)

HEADACHETEMPERATURE CHANGED

SENSATIONCHEST PAIN

FEVERASTHENIA

OEDEMA PERIORBITAL

10 4 2 2 1 1

Body as a whole - general disorders 20 (12.3)

APPLICATION SITE REACTION 3 Application site disorders 3 ( 1.8)* System-Organ Classes

Table 3. Destribution of Adverse Drug Reactions by Gender and Age groups.

(53) 1 : EMR


Single administration (%) Concomitant administration (%)

84 (51.5)79 (48.5)

HD* WD HD+WD15 (9.2) 44 (27.0) 20 (12.3)

* Herbal drug, Western drug

Table 6. Demographic Data from the ADR*s associated with Manufactured Herbal Drug.


Age 45 19.8 4425.1 4717.3* Adverse drug reactions

Table 7. Numbers of Clinical Manifestations of ADR*s Due to Manufactured Herbal Drug.

Clinical Manifestations Number SOC Number (%)PRURITUS

SWEATING INCREASEDRASH FOLLICULAR

312


DIZZINESSHEADACHE

32

Central & peripheral nervous system disorders 5 (13.9)

PALPITATION 3 Autonomic nervous system disorders 3 (8.3)VOMITINGDIARRHEADYSPEPSIA

ABDOMINAL PAINNAUSEA

26441


HEPATIC ENZYMES INCREASED 2 Liver and biliary system disorders- 2 (5.6)TEMPERATURE CHANGED SENSATION

CHEST PAINOEDEMA PERIORBITAL

111


* Adverse drug reactions , System-Organ Classes

Table 5. Status of Concomitant Drug Administration.

(10, 6.1%) . SOC , 68(41.5%) , 42(25.8%) SOC 110 67.5% (Table 4).

5)

51.5%, 48.5%. 27%,

12.3%, 9.2%(Table 5).

6)

(1) 1,

2 3(1.8%) . 30

.

(2)

(54) 36 1 (2015 3)


36(22.1%) 17 . (30.6%) (69.4%) , 13 79 4519.8(Table 6). 17(47.2%), 19(52.8%). 2 . 2 1 (50 ) 1 , 2 ( 4g bid pc, 5g tid pc) 2 . 6 , 34, 3 , (Table7). SOC , SOC (17, 47.2%), 6(16.7%) 5(13.9%)(Table 7). SOC 2 , , , , , (Table 8).

-(2) 1 .

(3) 163 124(76.1%)

, 66 . (68.5%) , (5418.5) (4023.8) (Table 9). 65(52.4%), 59(47.6%) . 122

. (23), (16) (14), (12) (8) (8) (Table 10). SOC 51(41.1%) , 36(29.0%). SOC 2 , , , , , , , , , , , , , , , , , , , , (Table 8), 2 -(2) 1 .

(4)

6 . 9, 15 - -, -, -, -, -, -, -, -, -, -, -, -, -, -, -. SOC SOC 2 (, Magnoliae Flos) -, - 1 .

, , , ,

18).

(55) 1 : EMR


Drug Type Drug Clinical Manifestation SOC

HD Gamiboa-tang4 (4) PRURITUS, RASH

Skin and appendages disorders

HD Gamisamhwang-tang1 (1) PRURITUS, URTICARIA, RASHHD Gamiwon-tang2 (2) PRURITUS, URTICARIAHD Gamicheongyeol-tang1 (1) PRURITUS, RASHHD Gosamhoma-san1 (1) PRURITUS, URTICARIAHD Gwibi-tang1 (1) PRURITUS, RASHHD Gwibi-tang3 (3) PRURITUS, RASHHD Danggwisu-san1 (1) PRURITUS, RASHHD Saenghwa-tang2 (2) PRURITUS, URTICARIA, RASHHD Untitled decoction2 (2) PRURITUS, RASHHD Jagamcho-tang1 (1) PRURITUS, URTICARIA, RASHHD Cheongsimyeonja-tang2 (2) URTICARIA, RASHHD Hyangsayuggunja-tang1 (1) PRURITUS, URTICARIA

MHD Socheonglyong-tang () PRURITUS, RASH FOLLICULARMHD Samchulgeonbi-tang () DIARRHEA, DYSPEPSIA

Gastro-intestinal system disorders

MHD Gamiseogyeong-hwan () ABDOMINAL PAIN, DYSPEPSIA

MHD Sodo-hwan () ABDOMINAL PAIN, DIARRHEA, DYSPEPSIAMHD Bangpungtongseong-san () ABDOMINAL PAIN, DIARRHEA

MHD Igi-hwan () ABDOMINAL PAIN, DIARRHEA, DIARRHEA

HD Gamiwon-tang1 (1) ABDOMINAL PAIN, DIARRHEAHD Gamiboa-tang2 (2) DYSPEPSIA, FLATULENCEHD Gamiboa-tang5 (5) VOMITING, VOMITING

HD Gamiwon-tang2 (2) DIARRHEA, DYSPEPSIAHD Bangpungtongseong-san2 (2) DIARRHEA, DYSPEPSIAHD Boyanghwano-tang1 (1) ABDOMINAL PAIN, DIARRHEAHD Bojungiggi-tang3 (3) DIARRHEA, DYSPEPSIAHD Sihosogan-tang1 (1) VOMITING, DYSPEPSIAHD Eoms tonggyu-bang1 (1) DIARRHEA, DYSPEPSIAHD Untitled decoction6 (6) DIARRHEA, DYSPEPSIAHD Cheongsimyeonja-tang (1) DIARRHEA, FLATULENCE

HD Taeeumincheonghyeolganggi-tang1(1) ABDOMINAL PAIN, DYSPEPSIA

* Adverse Drug Reactions, System-Organ Classes, Herbal Decoction, Manufactured Herbal Drug, bold letters the same drug-clinical manifestation pairs

Table 8. Repeated Occurrence of the ADR*s with the Same Drug SOC Pairs.

19). 10).

,

18). . 2012 4

(56) 36 1 (2015 3)



Age 50 21.3 4023.8 5418.5*Adverse drug reactions

Table 10. Numbers of Clinical Manifestations of ADR*s Due to Herbal Decoction.

Clinical Manifestations Number SOC Number (%)PRURITUS

RASHURTICARIA

SWEATING INCREASEDACNE

1412 8 1 1


MYALGIA 1 Musculo-skeletal system disorders 1 ( 0.8)DIZZINESS

HYPERTONIA 2 1

Central & peripheral nervous system disorders 3 ( 2.4)

PALPITATION 3 Autonomic nervous system disorders 3 ( 2.4)INSOMNIA 3 Psychiatric disorders 3 ( 2.4)DIARRHEADYSPEPSIA

ABDOMINAL PAINVOMITING

FLATULENCENAUSEA

2316 6 3 2 1


HEPATIC ENZYMES INCREASED 5 Liver and biliary system disorders- 5 ( 4.0)HYPERGLYCAEMIA

OEDEMA DEPENDENTWEIGHT INCREASE

1 1 1

Metabolic and nutritional disorders 3 ( 2.4)

ARRHYTHMIA 1 Heart rate and rhythm disorders 1 ( 0.8)DYSPNEA 2 Respiratory system disorders 2 ( 1.6)DYSURIA 1 Urinary system disorders 1 ( 0.8)

HEADACHETEMPERATURE CHANGED SENSATION

FEVERASTHENIA

CHEST PAIN

8 3 2 1 1


* Adverse drug reactions , , System-Organ Classes

Table 9. Demographic Data from the ADR*s associated with Herbal Decoction.

(KAERS)

,

20).2008 2012 2

EMR

11)

. 28 39 .

,

. 2012 4 2014 12

(57) 1 : EMR


101 163 .

. 92% 21).

15 , 5 . ,

.

, ,

, .

, .

. KA

8 , 8

.

. , ,

.

. KA 177 2 1( ), 1() . ,

,

DB . 163

, , , 67.5% . , 22)

,

.

, 50 ,

21, 22).

, 40-50

23).

159(97.5%) (mild), (moderate) 4(2.5%) ,

possible . (severe) . 11) , 10%

(58) 36 1 (2015 3)


.

(under-reporting) 18). ,

. (2, 1 - ),

. ,

.

. WHO-UMC

, ,

,

18). .

, 2 . 2, 2 . ,

, () , .

, ()

,

. 2 ,

, possible .

, ,

11)

.

, ,

.

.

. ,

.

,

.

, . ,

.

.

(59) 1 : EMR


. 25 , _ .

, , .

,

. , .

.

. . EMR

. ,

, .

(HI13C0656) .

1. Cheon C, Park JS, Park S, Kweon KT, Shin Y, Ko SG. Necessity of Adverse Event Reporting System through the Trend of Internet News about Safety of Herbal Medicine. Kor. J. Oriental Preventive Medical Society. 2011;15(2):131-43.

2. Jang IS, Yang CS, Lee SD, Han CH. A Review of Herbal Medicinal Products Associated with Toxic Events in Korea. J Korean Oriental Med. 2007;28(1):1-10.

3. Heinrich M, Chan J, Wanke S, Neinhuis C, Simmonds MS. Local uses of Aristolochia species and content of nephrotoxic aristolochic acid 1 and 2--a global assessment based on bibliographic sources. Journal of ethnopharmacology, 2009;125(1):108-44.

4. Haller CA, Benowitz NL. Adverse Cardiovascular and Central Nervous System Events Associated with Dietary Supplements Containing Ephedra Alkaloids. New England Journal of Medicine. 2000;343(25):1833-8.

5. Sato A, Toyoshima M, Kondo A, Ohta K, Sato H, Ohsumi A. [Pneumonitis induced by the herbal medicine Sho-saiko-to in Japan]. Nihon Kyobu Shikkan Gakkai zasshi. 1997;35(4):391-5.

6. Suk KT, Kim DJ, Kim CH, Park SH, Yoon JH, Kim YS, et al. A Prospective Nationwide Study of Drug-Induced Liver Injury in Korea. Am J Gastroenterol. 2012;107(9):1380-7.

7. Lee J, Son C, Lee JA, Choi J, Lee MS. Do herbal medicines negatively affect liver tests? A systematic review of Korean clinical studies on safety. European Journal of Integrative Medicine. 2014;6(4):441-50.

8. Shin HK, Jeong SJ, Lee MS, Ernst E. Adverse events attributed to traditional Korean medical practices: 19992010. Bull World Health Organ. 2013;91(8):569-75.

9. Korea Institute of Drug Safety & Risk Management.

(60) 36 1 (2015 3)


Pharmacovigilance. 2014. Available at: URL:https: //www.drugsafe.or.kr/iwt/ds/ko/information/ EgovDrugWatchTerm.do. Accessed February 21, 2014.

10. Korean Society for Pharmacoepidemiology & Risk Management. Pharmacoepidemiology. 2 ed. SNU Book. 2012:1-9, 33, 74-82, 108-121.

11. Kwon YJ, Cho WK, Han CH. Status of Herbal-drug-associated Adverse Drug Reactions Voluntarily Reported by EMR. J. Int. Korean Med. 2012;33(4):485-97.

12. Korea Institute of Drug Safety & Risk Management. Adverse Drug Reaction Assessment Report. 1 ed. Korea Institute of Drug Safety & Risk Management. 2013:60-63.

13. Herbology Textbook Compilation Commitee for College of Korean Medicine, Herbology. Yeonglim. 2011.

14. WHO. WHO Monographs on Selected Medicinal Plants. WHO 2009.

15. Ryu JH. Analysis of Spontaneously Reported Adverse Drug Reactions(ADRs) and a Survey Regarding ADR from a Single Hospital. Chungnam National University. 2013.

16. Kyung EJ, Ryu JH, Kim EY. Evaluation of adverse reactions to contrast media in the hospital. 2013;86(1032):20130418.

17. Korea Institute of Drug Safety & Risk

Management. Terminology Guide for Reporting Adverse Drug Reactions. Korea Institute of Drug Safety & Risk Management. 2014:1-6.

18. Shaw D, Graeme L, Pierre D, Elizabeth W, Kelvin C. Pharmacovigilance of herbal medicine. Journal of ethnopharmacology. 2012;140(3): 513-8.

19. Park JW. Spontaneous Adverse Drug Reaction Reporting Program in Korea JPERM. 2008; 1:20-4.

20. Woo YJ, Chung SY, Park BJ. Current Status of Spontaneous Adverse Reactions Reporting System on Herbal Medicine in China, Japan, Korea and WHO. J. Int. Korean Med. 2014; 35(2):111-8.

21. Kim MG, Kang HR, Kim JH, Ju YS, Park SH, Hwang YI, et al. Analysis of adverse drug reactions collected by an electronic reporting system in a single hospital. The Korean Journal of Medicine. 2009;77(5):601-9.

22. Rhew KY, Lee S. Analysis of the Korea Food and Drug Administration Adverse Drug Reaction Reports. Kor. J. Clin. Pharm. 2011;21(2):138-44.

23. Korean Institute for Health & Social Affairs. The Domestic Survey on the Usage and Awareness Level of Korean Medicine. Health & Welfare Issue & Focus. 2012;140(2012-21):1-8.

emr의 자발적 약물부작용보고 시스템을 이용한 한약약물유해반응 분석 ·...

Documents