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MedDRA R 3.5 MedDRA Version 8.1 MedDRA / 2005 11 7

MedDRA TERM SELECTION: POINTS TO CONSIDER Release 3. Based on MedDRA version.1 ICH-Endorsed Guide for MedDRA Users Application to Adverse Drug Reactions / Adverse Events & Medical and Social History & Indications 7 November 2005

Copyright ICH Secretariat (c/o IFPMA) Copying is permitted, with reference to source, but material in this publication may not be used in any documentation or electronic media which is offered for sale, without the prior permission of the copyright owner. IFPMA Chemin Louis-Dunant, 15 P.O. Box 195 1211 Geneva 20 Switzerland Tel: +41 (22) 338 32 00 Fax: +41 (22) 338 32 99 JMO

1.0... 1 1.1...1 1.2 MedDRA...2 1.3...2 1.4...2 2.0... 2 2.1...2 2.2...3 2.3 LLT...3 2.4...3 2.5...4 2.5.1... 4 2.5.2... 4 2.5.3... 5 2.6...5 3.1...6 3.2...7 3.3...8 3.3.1... 8 3.3.2... 8 3.3.3... 8 3.4...9 3.5...10 3.6...10 3.7...10 3.8...12 3.9...12 3.10...13 3.11...15 3.12...16 3.13...16 3.14...17 3.15...18 3.16...18

3.17...19 3.18...20 3.19...20 4.1 ICH Points to Consider :...23 Tetsuya Kusakabe...23 4.2 ICH Points to Consider...24

1.0 ICH MedDRA) 1) MedDRA MedDRA Term Selection:Points to Consider(PTC) ICH MedDRA ICH MedDRA MedDRA EU USA MSSO JMO 4.0 MedDRA V.8.1 1.1 Points to Consider MedDRA Points to Consider MedDRA MedDRA

1.2 MedDRA (safety signals) / ADR/AE 2 ADR/AE ADR/AE 1.3 MedDRA Points to Consider MedDRA MedDRA MedDRA PTC MedDRA MedDRA MedDRA MedDRA (MedDRA) MedDRA Introductory Guide 1.4 ADR/AE 2.0 2.1 2) ADR/AE ICH CIOMS

3.3 2.2 (LLT) 2.3 LLT ( )LLT ( ) 2.4 2.4.1 2.4.2 MedDRA MedDRA MSSO (change request) HIV viral load increased MedDRA

2.4.3 MedDRA brittle hair Hair texture abnormal Hair disorder 2.4.4 MedDRA MSSO (metastatic gallbladder cancer) MedDRA (Gallbladder cancer) 2.5 2.5.1 ADR/AE, 2.5.2 ( abdominal pain) ( increased serum amylase) (increased serum lipase) (Pancreatitis)

2.5.3 (anaphylactic reaction) (rash) (dyspnea) (hypotension) (laryngospasm) (Anaphylactic reaction) (myocardial infarction) (chest pain) (dyspnea), (diaphoresis) ECG (ECG changes) (jaundice) (Myocardial infarction) (Jaundice) 2.6 Points to Consider MedDRA MedDRA MedDRA MedDRA SOC MedDRA MSSO MedDRA VIII (Factor deficiency) SOC SOC SOC

3.0 3.1 3.1.1 possible myocardial infarction Myocardial infarction 3.1.2 (chest pain) (dyspnea) (diaphoresis) (jaundice) (possible myocardial infarction) (myocardial infarction) (jaundice) (chest pain) (dyspnea) (diaphoresis) (jaundice) (possible myocardial infarction) (chest pain) (dyspnea) (diaphoresis) (jaundice) 3.1.3 pulmonary embolism (myocardial infarction) (congestive heart failure) Pulmonary embolism (Myocardial infarction) (Congestive heart failure)

3.1.4 : (chest pain) (cyanosis) (shortness of breath) (blood pressure decreased) (pulmonary embolism) (myocardial infarction) (congestive heart failure) (Chest pain) (Cyanosis) (Shortness of breath) (Blood pressure decreased) : (pulmonary embolism) (myocardial infarction) (congestive heart failure) (chest pain) (cyanosis) (shortness of breath) (blood pressure decreased) (Chest pain) (Cyanosis) (Shortness of breath) (Blood pressure decreased) (Pulmonary embolism) (Myocardial infarction) (Congestive heart failure) 3.2 ADR/AE ADR/AE 3.2.1 3.2.1.1 ADR/AE (death due to myocardial infarction) (Myocardial infarction) 3.2.1.2 ADR/AE MedDRA : (constipation) (ruptured bowel) (peritonitis) (sepsis) (patient died) (Constipation) (Perforated bowel) (Peritonitis) (Sepsis) 3.2.1.3 : (a patient was found dead) (Found dead) 3.2.2 ADR/AE ADR/AE : (hospitalization due to congestive heartfailure) ADR/AE (Congestive heartfailure) (Hospitalization) 3.2.2.1 : (a patient was hospitalized) Hospitalisation

3.3 2.1 3.3.1 : 1.6mEq/L (hyperkalemia with a serum potassium of 1.6 meq/l) (Serum potassium abnormal) 1.6mEq/L 3.3.2 : GU (GU pain) GU (genito-urinary) (gastric ulcer) (pain) (Pain) 3.3.3 (patient experienced every listed adverse event) (Unevaluable event)

3.4 3.4.1 2.5.3 3.4.2 (arrhythmia due to atrial fibrillation) (Atrial fibrillation) (hepatic function disorder (acute hepatitis) ) (Hepatitis acute) 3.4.3 MedDRA (retinopathy due to diabetes) (Diabetic retinopathy) (rash with itching) (Itchy rash) 3.4.4 (diarrhea and vomiting) (Diarrhea) (Vomiting) DIC(DIC due to sepsis) DIC (Sepsis) (wrist fracture due to fall) (Wrist fracture) (Fall) 3.4.5 MedDRA ; pain due to cancer Cancer pain JMO 3.4.3 ; shortness of breath due to cancer (Shortness of breath)

3.5 3.5.1 MedDRA (skin rash on face) (Rash on face) 3.5.2 MedDRA MedDRA (skin rash on chest) (Rash) 3.5.3 PT (skin rash on face and neck) (Skin rash) 3.6 3.6.1 MedDRA (pneumococcal pneumonia) (Pneumococcal pneumonia) 3.6.2 MedDRA MedDRA (respiratory chlamydial infection) (Chlamydial infection) (respiratory chlamydial infection) (Respiratory infection) (respiratory chlamydial infection) (Chlamydial infection) (Respiratory infection) 3.7 3.18 ADR/AE 3.7.1 MedDRA (exacerbation of myasthenia gravis) (Myasthenia gravis aggravated)

3.7.2 3.7.2.1 MedDRA (halitosis worsened) (Halitosis) 3.7.2.2 (Condition aggravated) (Disease progression (progression of Alzheimer s disease) (Alzheimer s disease) (Disease progression ) (aggravation of jaundice) (Jaundice) (Condition aggravated) 3.7.2.3 MedDRA MSSO (MedDRA 8.1 )

3.8 MedDRA (congenital) MedDRA 8.1 3.8.1 SOC (congenital heart disease) (child born with heart disease) (Heart disease congenital ) 3.8.2 MedDRA (night blindness ) PT ( Night blindness ) (Night blindness) (cholangiectasis) (Cholangiectasis acquired) 3.9 SOC ADR/AE SOC 3.9.1 (patient had gallbladder surgery) (Gallbladder operation ) (patient had tonsillectomy in childhood) (Tonsillectomy)

3.9.2 ADR/AE (liver tranlplantation due to liver failure) (Liver failure) (Liver failure) (Liver transplantation) JMO LLT Liver transplantation N LLT/PT: Liver transplant (surgery for bleeding gastric ulcer) (Bleeding gastric ulcer) (Bleeding gastric ulcer) (Gastric surgery) 3.10 SOC (increased) (decreased) (abnormal) (normal) hyperhypo SOC SOC SOC 3.10.1 SOC E2b B.3.1c. bilirubin test Bilirubin (cardiac output) (Cardiac 3.10.2 ADR/AE 3.10.2.1 (hypoglycemia) (Hypoglycemia) (Hypoglycemia) SOC (decreased glucose) (Glucose decreased) (Glucose decreased) SOC 3.10.2.2 40mg/dl(glucose 40 mg/dl) (Glucose low) 3.10.2.3 40 (his glucose was 40) (Glucose abnormal)

3.10.3 K7.0mmol/L (elevated potassium, K7.0 mmol/l and hyperkalemia) (Hyperkalemia) 3.10.4 7.0mmol/L (alopecia, rash, and elevated potassium 7.0 mmol/l) (Alopecia) (Rash) (Potassium increased) 3.10.5 (abnormal liver function tests) (Abnormal liver function tests) SGPT SGOT LDH (increased alkaline phosphatase, increased SGPT, increased SGOT, and elevated LDH) 4 (Liver function tests abnormal) 1 4

3.11 MedDRA 8.0 HLGT HLT HLT ( Maladministrations ) HLT ( Medication monitoring errors ) HLT ( Overdoses ) HLT ( Medication errors due to accidental exposures ) HLT ( Medication errors NEC ) 3.11.1 JMO term(s) for the medication error and the clinical consequences should be selected hives due to medication error Hives ( Medication error) 3.11.2 ADR/AE (medication was given intravenously instead of intramuscularly) (Intramuscular formulation administered by other route) 2 3.11.3 (nurse splashed an injectable drug in her eye) (Inadvertent exposure to drug) (child exposed to drug during breast feeding) (Drug exposure via

breast milk) 3.11.4 ( No adverse effect) 3.14 (medication was given intravenously instead of intramuscularly without sequelae) (Intramuscular formulation administered by other route) (No adverse effect) 3.12 3.12.1 MedDRA Overdose Toxicity Poisoning HLT Overdoses HLT (Poisoning and toxicity) MedDRA Version 8.1 (overdose of pills) (Overdose) 3.12.2 (stomach upset from study drug overdose) (Stomach upset) (Overdose) 3.12.3 (Overdose) (No adverse effect) ( 3.13 3 MedDRA 3.13.1 (torsade de pointes with suspected drug interaction) (Torsade de pointes) (Drug interaction) 3.13.2 (patient was started on an anit-seizure and heart medication and developed syncope) (Syncope) (patient was already on anti-seizure medication and was started on a heart medication and anti-seuzure medicaiton levels increased) (Drug)

(Anticonvulsant level increased) 3.14 (No adverse effect) ADR/AE 3.11.4 3.12.3 MedDRA (Normal baby) (Normal electrocardiogram) (Sinus rhythm)

3.15 ADR/AE (a bold patient was pleased that he grew hair while using a product) (Unexpected therapeutic effect) (Hair growth increased) 3.16 ADR/AE MedDRA 3.16.1. (antibiotic didn t work) (Lack of drug effect) (patient took drug, her headache didn t go away, drug is ineffective) (Drug ineffective) 3.16.2 (an epilectic patient took an anti-convulsant, but the seizures continued unchanged) (Lack of drug effect) 3.16.3 HIV AIDS (AIDS patient taking anti-hiv drug died) (Lack of drug effect) 3.2 3.2

3.16.4 Increased Decreased Prolonged A (patient had increased effect from drug A) (Increased drug effect) A (patient had decreased effect from drug A) (Drug effect decreased) A (patient had prolonged effect from drug A) (Drug effect prolonged) 3.17 SOC SOC ADR/AE ADR/AE SOC (patient was abusing an analgesic) (Analgesic abuse) SOC MedDRA SOC (Disorder) SOC ADR/AE SOC Social Circumstances SOC SOC Disorder SOC (Alcoholic ) (Alcoholism) (Drug addict) (Drug addiction )

3.18 MedDRA (history of gastrointestinal bleed and hysterectomy) (Gastrointestinal bleed) (Hysterectomy) (patient is a cigarette smoker with coronary artery disease) (Cigarette smoker) (Coronary artery disease) 3.19 weight loss (Weight loss) immunosuppression (Immunosuppression )

3.19.1 3.19.1.1 hypertension (Hypertension) anti-hypertensive (Hypertension) chemotherapy for breast cancer (Breast cancer) (medication for gastrointestinal problem) ( Gastrointestinal disorder) 3.19.1.2 MedDRA a patient had received chemotherapy Chemotherapy 3.19.2 Prevention and Prophylaxis 3.19.2.1 MedDRA prevention prophylaxis (arrhythmia prophylaxis) (Arrhythmia prophylaxis) prevention of migraine (Migraine prophylaxis) 3.19.2.2 3.19.2.2.1 (prevention of hepatotoxicity) (Hepatotoxicity) 3.19.2.2.2 (prevention of hepatotoxicity) (Prevention) 3.19.2.2.3 (prevention of miscarriage) (Prevention) (Hepatotoxicity) 3.19.3 contrast agent for angiogram (Angiogram ) contrast agent for coronary angiogram ( Coronary angiogram) 3.19.4 (induction of anesthesia) (Induction of anesthesia)

3.19.5 SOC 3.9 testosterone replacement therapy (Androgen replacement therapy) thyroid replacement therapy (Thyroxine therapy) prenatal vitamin (Vitamin supplementation) 3.19.6 (Drug use for unknown indication) (aspirin was taken for an unknown indication) (Drug use for unknown indication)

4.0 4.1 ICH Points to Consider : Rapporteur: Reinhard Fescharek Japan: Ministry of Health, Labour and Welfare: Tatsuo Kishi Tetsuya Kusakabe Japan Pharmaceutical Manufacturers Association Takayoshi Ichikawa Yo Tanaka Japanese Maintenance Organization Reiji Tezuka Yasuo Sakurai European Union: Commission of the European Communities Dolores Montero Carmen Kreft-Jais European Federation of Pharmaceutical Industries Associations Reinhard Fescharek Christina Winter Canada: Health Canada Bill Wilson United States: US Food and Drug Administration John (Jake) Kelsey Toni Piazza-Hepp

Pharmaceutical Research and Manufacturers of America Susan M. Lorenski JoAnn Medbery MedDRA MSSO Patricia Mozzicato 4.2 ICH Points to Consider Japan: Ministry of Health, Labour and Welfare Tamaki Fushimi Kazuhiro Kemmotsu Chie Kojima Emiko Kondo Kemji Kuramochi Takashi Yasukawa Kaori Nomura Kenichi Tamiya Manabu Yamamoto Japan Pharmaceutical Manufacturers Association Akemi Ishikawa Satoru Mori Yasuo Sakurai Kunikazu Yokoi Japanese Maintenance Organization Yuki Tada Akemi Ishikawa Canada: Health Canada Heather Morrison

European Union: European Federation of Pharmaceutical Industries Associations Barry Hammond past Rapporteur United States: US Food and Drug Administration Miles Braun Brad Leissa Andrea Feight Pharmaceutical Research and Manufacturers of America David Goldsmith Sidney Kahn Margaret M. Westland past Rapporteur MedDRA MSSO: JoAnn Medbery