گروه فارماكولوژي دانشكده پزشكي Adverse Drug Reaction & Pharmacovigilance Iran ADR Center دكتر پارسائي گروه فارماكولوژي دانشكده پزشكي

ADR (Adverse Drug Reaction) WHO definition: Any response to a drug which is Noxious and Unintended and which occurs at doses used in man for prophylaxis, diagnosis or treatment. هر گونه پاسخ داروئي مضر و نامطلوبي كه با دوز معمولي دارو در انسان جهت پيشگيري، تشخيص و يا درمان ايجاد شده باشد

Side Effects عوارض كم اهميت و مختصر اصطلاحات رايج: Side Effects عوارض كم اهميت و مختصر Adverse Reaction عوارض مهم و كاملا نا خوشايند Toxicity ( اثرات سمي مستقيم دارو (غالبا دوز بالا Secondary Effects آثار ثانوي غير مستقيم Intolerance عدم تحمل بدليل آستانه پايين پاسخ دهي Idiosyncrasy پاسخ غير نرمال بدليل اختلال ژنتيكي

Why Should We Learn about Adverse Drug Reactions (ADR)? Over 2 MILLION serious ADRs yearly 100,000 DEATHS yearly 6.7% of hospitalized patients have an ADR with a fatality of 0.32 Ref: U.S. Food and Drug Administration . Center for Drug Evaluation and Research

Annual death rates in USA AIDS 16,516 Breast cancer 42,297 Highway accidents 43,458 ADR 100,000

percentage of hospital admissions due to ADR: USA 28% UK 15.6% France 12.6% Norway 11.5%

Costs Associated with ADRs $ 136 BILLION yearly (related to morbidity and mortality) Greater than total costs of cardiovascular or diabetic care. The total cost of drug-related morbidity and mortality exceeds the cost of the medications themselves. Ref: U.S. Food and Drug Administration . Center for Drug Evaluation and Research

Country Serious ADRs Lost Activity Days The cost of adverse drug events: estimated lost patient activity days per year in hospitalised patients Country Serious ADRs Lost Activity Days US 700,000 1,218,000 Germany 206,000 358,440 UK 148,000 257,520 Australia 48,000 83,520 Sweden 22,000 38,280

ADR has financial and social effects: 1- Unreliability on manufacturer 2- Unreliability on health system (Physician, Pharmacist & Nurse) 3- Unreliability on governments in saving the social safety 4- Causing mortality & morbidity

Why Are There So Many ADRs? Tow-thirds of patients visits result in a prescription 2.8 BILLION outpatients prescriptions were filled in the year 2000 (about 10 prescriptions per person in the U.S.) ADRs increase exponentially with 4 or more medications Ref: U.S. Food and Drug Administration . Center for Drug Evaluation and Research

Why Are There So Many ADRs? So many prescriptions!

Even more, dramatic situation with drug safety is in developing countries (IRAN) They often have older, cheaper drugs which may be more toxic. Health professional have less opportunity for post-graduate education on clinical pharmacology. Useful,easily available, balanced information on adverse effects and their management is absent or not enough. Ref:World Health Organization

طبقه بندي عوارض جانبي (A-E) انواع فرعي: نوع Continuos) C) نوع Delayed) D ) نوع Ending of use) E ) انواع اصلي: نوع Augmented) A) نوع Bizarre) B)

مقايسه عوارض جانبي نوع A و B قابل پيش بيني + - وابستگي به دوز + - ميزان شيوع زياد كم مرگ و مير كم زياد درمان تنظيم دوز قطع مصرف

Some drugs cause serious ADRs at very low frequencies bromfenac hepatotoxicity 1 in 20,000 patients, removed from the market in 1998, less than 1 year after it was introduced). Ref: U.S. Food and Drug Administration . Center for Drug Evaluation and Research

چگونه يك عارضه جانبي به دارو نسبت داده ميشود؟

شرايط ارزيابي ارتباط عارضه جانبي با دارو 1- ارتباط منطقي بروز عارضه با زمان مصرف دارو 2- ارتباط عارضه با خصوصيات شناخته شده دارو 3- رفع عارضه با قطع مصرف دارو 4- عود عارضه با شروع مصرف مجدد دارو 5- توجيه منطقي ارتباط عارضه با بيماري مريض يا ...

بررسي ارتباط عارضه جانبي با دارو 5 4 3 2 1 ارزيابي ارتباط + قطعي Definit _ احتمالي ‍ Probable ممكن Possible مشروط Conditional غير قابل بررسي Unassessable غیر محتمل Unlikely

Detection, Assessment, Prevention of ADRs in Human. Pharmacovigilance Detection, Assessment, Prevention of ADRs in Human. Ref: World Health Organization.

اهداف اصلي فارماكوويژيلانس شناسائي زودهنگام واكنشهاي ناشناخته داروئي تعيين ميزان افزايش در بروز عوارض شناسائي فاكتورهاي خطر ارزيابي كيفي مخاطرات پيشگيري از بروز مخاطره غير ضروري در بيمار مصرف منطقي و سالم داروها

The ultimate goal of pharmacovigilance is improving pharmacotherapy Ref:World Health Organization

تاريخچه فارماکوويژيلانس حدود 160 سال قبل (1848): فوت جوان 15 ساله در بيهوشي با کلروفرم بعلت فيبريلاسيون بطني (جراحي ناخن پا) بيانيه: ”فراورده هاي داروئي بايد خالص و عاري از هر گونه آلودگي باشند“ سال 1936: 107 مورد مرگ ناشي از دي اتيلن گليکول بعنوان حلال سولفوناميد سال 1961 : گزارش 4000 مورد نقص عضو ناشي از تاليدوميد از استراليا سال 1964: شروع استفاده از سيستم کارت زرد در انگليس سال 1968: شروع برنامه Drug Monitoring توسط سازمان ملل

Drug Classes Responsible for ADRs Drug Class Frequency Antibiotics Most frequent Antitumor agents Anticoagulants Cardiovascular agents Anticonvulsant agents Antihypertensives Analgesics Antiasthmatics Sedative/hypnotics Antidepressants Antipsychotics Peptic ulcer therapy Least frequent Ref: J. Russell May. Adverse Drug Reactions and Interactions, In: Pharmacotherapy, A pathophysiologic Approach. 1997, Appleton & Lange.

Types of Drug-Related Effects by Frequency Type of adverse event Frequency Marrow suppression Most frequent Bleeding Central nervous system Allergic/cutaneous Metabolic Cardiac Gastrointestinal Renal Respiratory Least frequent Ref: J. Russell May. Adverse Drug Reactions and Interactions, In: Pharmacotherapy, A pathophysiologic Approach. 1997, Appleton & Lange.

Important factors to decrease ADRs Patient’s specification Patient’s drug history Pharmacology of prescribed drugs Prescription of minimum effective dosage

Preventing ADR Over 75% of all ADR are dose-dependent Dosage of many drugs widely different to individual needs. Ref:World Health Organization

Essential factors causing ADRs: Factors related to drug: Route of administration Dosage Duration of treatment Problems with drug: 1-Formulation 2-Problems with preparing of drug

Essential factors causing ADRs: Factors related to patient: Sex Age (weight) Genetic (PHARMACOGENOMICS) Drug allergy Lack of knowledge in patients Concomitant drugs

Factors related to patient (Cont): Non-compliance - underestimated Route of Administration - bioavailability Food - protein malnutrition Pollutants - smoking/herbicide residues Timing - chronopharmacology

در بيمارستان ADRفوايد وجود برنامه 1- افزايش كيفيت درمان 2- جلوگيري از شكايات حقوقي 3- ارزيابي مشكلات دارويي 4- ارزيابي مشاهدات پزشكان و ديگر حرف پزشكي 5- ارتقاء دانش دارويي دست اندركاران درمان

دلايلي كه باعث كاهش گزارشاتADR ميگردد: 1- عدم اطلاع از مكانيزم موجود براي ارسال گزارش 2- عدم دسترسي به فرم مربوطه 3- عدم اهميت عارضه از نظر گزارشگر 4- نداشتن وقت 5- در رابطه با تكميل فرم مربوطه 6- اجتناب از درگيري در كارهاي اداري 7- ترس از شكايات حقوقي, كيفري 8- عدم اطمينان از بوجود آمدنADR توسط دارو

Drugs cause hospitalization Digoxin 41 Aspirin 25 Aspirin 24 Digoxin 24 Prednisone 15 Warfarin 12 Warfarin 9 Prednisone 8 Guanethidine 5

The numbers of reports, registered in ADR center of Iran From the year 1377 to Mordad 83 , 5861 cases of Adverse Drug Reaction have been sent to Iranian ADR Center

Reporters

Diclofenac Na Above 100 Cases of Foot drop Withdrawal from Iranian Pharmacopoeia Streptokinase

Tramadol? From 04.81 to 05.83, 289 cases of adverse effects of Tramadol have reported to ADR center Among them : 81 cases have been in Male & 208 cases have been in Female

Adverse Reaction of Tramadol from 04.81 to 03.83 6 Major Adverse Effects of Tramadol: Nausea 125 Vomiting 116 Vertigo 109 Asthenia 57 Dyspnea 42 Hypotension 41

Rout of administration (In patients with Tramadol adverse effects)

4 Cases of Para-plegia following IT injection 2 of them led to Death Bupivacaine 4 Cases of Para-plegia following IT injection 2 of them led to Death

Sildenafil has cardiac related side effect. Some cases of myocardial infarction were reported to ADR center due to this drug.

معاونت غذا و دارو www.fdo.ir

دبيرخانه تحقيقات كاربردی مركز ثبت و بررسی عوارض ناخواسته دارويی Iranian Adverse Drug Reaction Monitoring Center   • معرفي مركزADR • فرم ADR • عضويت • اطلاعيه ها • خبرنامه •گزارشات مركزADR •لينكهای مفيد

E-mail: iadrmc@yahoo.com مركز ثبت و بررسي عوارض ناخواسته داروها دفتر تحقيق و توسعه-معاونت غذا و دارو وزارت بهداشت درمان و آموزش پزشكي تلفن:6405569 نمابر:6417252 E-mail: iadrmc@yahoo.com

Report of Iranian ADR monitoring center

58 countries have joined the programme

International Vigilance Every healthcare professional in the world should be constantly alert for adverse effects or potentional new hazards and reporting them to their National Centers. -

Countries with the best reporting rates generate: Over 200 reports per 1,000,000 inhibitants per year. Over 150 reports per 1000 physicians per year.

Adverse Drug Reaction vs Drug classes From: 1377 To Mordad 83

Site of Reaction (CNS agents ) From: 77 To Mordad 83 Site of Reaction (CNS agents )

Site of Reaction (Antibiotics) From: 77 To Mordad 83 Site of Reaction (Antibiotics)

Age groups (Reaction of Tramadol): 0-10 3 11-20 7 21-30 86 31-40 61 41-50 51 51-60 29 61-70 18 71-80 11 >80 3 Unknown 20

Adverse effects of Tramadol from 04.81 to 03.83 Reaction Number Sweating 24 Myalgia 7 Headache 21 Pale Agitation 20 Ataxia 6 Somnolence 17 Vision disorders Pruritus 16 Paraesthesia Rigors 15 Injection site reaction Flushing 11 Delusion Urticaria Tachycardia Bronchospasm 10 Respiratory depression Hallucination 9 Palpitation 5 Convulsion Rash 4 Hypertension 8 Cold extremity Confusion Apnoea 3 Abdominal pain Anxiety Dry mouth Stupor

Adverse effects of Tramadol from 04.81 to 03.83 Reaction Number Cardiac arrest 3 Back pain 1 Anorexia Arrhythmia Shock Bradycardia Allergic reaction 2 Lacrimation abnormal Cyanosis Myocardial Ischemia Constipation Diarrhea GI disorders Depression Leg pain Erythem Dysphagia Coma Speech disorders Edema Urinary retention Hearing decrease Chest pain Facial pain Fever Withdrawal syndrome Syncope Foot drop Insomnia Tremor

The following tips must be reminded when using Sildenafil: Cardiovascular adverse effects such as atrial fibrillation, cardiomyopathy, flushing, hypotension, myocardial infarction, thrombosis, ventricular tachycardia have been reported with Sildenafil. Concomitant use of Sildenafi with following drugs are forbidden: Organic nitrates (eg. Nitroglycerin) Nitrates & Nitric donors (eg. Nitroproside)

Lamotrigine Common adverse effects: Skin reaction: rash ,Steven's Johnson syndrome, TEN Women more than men Onset Caution Adverse events causing hospitalization Weight limitation

Age Limitation Not effective & safe in children under 16 years old Person younger than 16 years old: Risk factor for severe skin reactions

Lindane *This drug has entered to the world drug market since 1901. *Since the year 1990 Lindane has been introduced as a second line treatment.

Suggestion: Single dose of use Second line of treatment Labeling Contraindication Precaution

FDA alert (2003) Systemic adverse effects of Lindane 70% of adverse effects have been the CNS adverse events,including: Seizure,Vertigo,Headache,Parasthesia 17 cases of death have been reported to FDA, IN 3 cases an established relationship between the events and using of drug were found

Celecoxib Labelling Changes Celecoxib Long-term Arthritis Safety Study (Class) did not show a safety advantage of upper GI events for celecoxib compared with diclofenac or ibuprofen.

Hypiran Drug Interaction with: Indinavir OCPs Antidepressants Digoxin, Warfarin, Theophylline, Cyclosporin

Risperidone Rabbit Syndrome Extrapyramidal Reactions: 1 Case in the USA 2 Cases in the English- Language Literature 4 Cases reported to IADRMC

following Administration of Vials with Unusual Color IV IG . 2 Cases of Death following Administration of Vials with Unusual Color

Benzyl benzoate . 5 Cases of Sever Systemic Side Effects following Topical Administration 3 of them led to Death

The FDA Safety Information and Adverse Event Reporting Program: MedWatch The FDA Safety Information and Adverse Event Reporting Program: www.fda.gov/medwatch/ Safety alerts Recalls Withdrawals Important labeling changes Biologicals, Drugs, Dietary supplements