1. Iran ADR Center

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

3. 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.

4. 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

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

6. percentage of hospital admissions due to adverse drug reactions: USA 28% UK 15.6% France 12.6% Norway 11.5%

7. Costs Associated with ADRs  $ 136 BILLION yearly (related to morbidity and mortality)  Greater than total costs of cardiovascular or diabetic care.  Mean length of stay, cost and mortality ADR patients are DOUBLE that for control group of patients without ADR.  ADRs cause 1 out of 5 injuries or deaths per year to hospitalized patients. Ref: U.S. Food and Drug Administration. Center for Drug Evaluation and Research

8. Since 1995 the costs associated with drug-related problems (DRPs) have more than doubled. The total cost of drug-related morbidity and mortality exceeds the cost of the medications themselves. Ref: Ernst Frank R, Grizzle Amy J. J Am Pharm Assoc. 2001; 41: 192-9

9. 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

10. 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

12. So many prescriptions!

13.  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

14. 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

15.  Assessment the quality of medications  Assessment of drug safety  Detection of occurrence rate of ADR  Decreasing the risk of occurrence of adverse events

16. How Knowledge About ADRs Is Created? 1-Animal experiments 2- Clinical trials 3- Epidemiological methods  Spontaneous reporting  Cohort studies  Case-control studies

17. Limitations of Clinical Trials  Limited size  Narrow population  Narrow indications  Short duration Ref: J. Russell May. Adverse drug Reactions and interaction, In: Pharmacotherapy, A pathophysiologic Approach. 1997, Appleton & Lange.

18. مركز ثبت و بررسي عوارض ناخواسته داروها، دفتر تحقيق و توسعه - معاونت غذا و دارو،وزارت بهداشت درمان و آموزش پزشكي Incidence of ADRs to be detected Spontaneous background incidence Minimum number of patients to be exposed 1 in1000360 1 in 10000520 1 in 1000730 1 in 1002000 1 in 100003600 1 in 100007300 1 in 100020300 1 in 100136400 1 in 5000018200 1 in 1000067400 1 in 1000363000 1 in 1003255000

19. How many patients one needs to treat to see with high probability the reaction?  Pre-marketing studies are carried out in limited number of patients: “The law of three” –In order to detect for sure SAE that occurs as 1 event per 2000 patients treated we need to treat 6000 patientsfor 1 case 9600 patientsfor 2 cases 13000 patientsfor 3 cases The number of patients involved in pre-marketing studies has been increasing but is still limited in comparison with the exposure to the drug in post-marketing phase

20. 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

21. Adverse reaction Drug Time lag(yr)  Pulmonary embolism Oral contraceptive 3  Myocardial infarction Oral contraceptive 5  Death fro asthma Sympathomimetic 4  Jaundice Halothane 7  Colitis Lincomycin 6  Colitis Clindamycin 5  Aplastic anemia Phenylbutazone 6 Ref: J.Russel May.Adverse Drug Reactions and interactions,In:Pharmacotherapy, a pathophysiologic approach.1997, Appleton & Lange.

22. “yellow cards”

23. Spontaneous Reporting Large population All medicines Hospital and out-patient care Long perspective Patient analysis possible Non-interventional Cheap

24. Recent trends: enlarging the scope of pharmacovigilance  Pharmacovigilance concerns have been widened to include: –herbal medicines –traditional and complementary medicines –blood products –biologicals –vaccines –medical devices

25. Pharmacovigilance Major Aims Early detection of unknown reactions and interactions Detection of increase in frequency Identification of risk factors Quantifying risks Preventing patients from being affected unnecessarily RATIONAL AND SAFE USE OF DRUGS Ref: World Health organization.

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

27. History of drug safety (1)  2003 - 155 years of pharmacovigilance 29.01.1848 15 year old Hannah Greener died in course of routine anaesthesia with chloroform (problem: ingrown nail of toe; fibrillation of ventricles?). Lancet’i initiated foundation of a (required, that the pharmaceuticals should be “pure” and “free of any contamination”, nothing was said about the efficacy)  1936 - USA-s 107 lethal cases (diethylenglycol was used to solubilize sulphanilamides); the law was amended in 1938

28. History of drug safety after thalidomide eradication  1961 : Dr William McBride (Australia)( thalidomide 4000 cases)  1964 : UK started “yellow cards” system  1968 : start of WHO Programme for International Drug Monitoring

29. 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.

30. 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.

31. Preventing ADR Over 75% of all ADR are dose-dependent Many ADR arise from failure to tailor the dosage of drugs to widely different individual needs. Ref:World Health Organization

32. Patient’s specification Patient’s drug history Pharmacology of prescribed drugs Prescription of minimum effective dosage

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

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

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

36. 1936 USA : 107 lethal cases diethylenglycol was used to solubilize sulphanilamides

37. Drugs cause hospitalization Digoxin 41 Aspirin 25 Aspirin 24 Digoxin 24 Prednisone 15 Warfarin 12 Warfarin n 9 HCTZ 11 Guanethidine 5 Prednisone 8

38. Type of Alerting Order One time stat dose PRN orders Short course therapy Abrupt decrease in dose Followed by a stat Serum level State laboratory tests Example Sub-cutaneous epinephrine, corticosteroids, dextrose 50%, sodium polystyrene sulfate Antihistamins, topical corticosteroids Oral corticosteroids (eg.20 mg prednisone p.o 7 days) aminoglycosides, antiarrhythmic agents, anticonvulsants Theophylline, phenytoin, aminoglycosides, Drug interactions (eg. Digoxin-verapamil, cimetidine-theophylline) Stool guiac, prothrombin time

39. در بيمارستان ADR فوايد 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

40. دلايلي كه باعث كاهش گزارشات ADR 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 فرم مربوطه 6 - اجتناب از درگيري در كارهاي اداري 7 - ترس از شكايات حقوقي, كيفري توسط دارو ADR 8- عدم اطمينان از بوجود آمدن

41. Misconceptions about ADR Reporting  All serious ADRs are documented by the time a drug is marketed  About patient receiving multiple medications,it is difficult to determine if a drug is responsible for the ADR  ADRs should only be reported if absolutely certain  One reported case can’t make a different  Ref: U.S. Food and Drug Administration. Center for Drug Evaluation and Research

43. Report of Iranian ADR monitoring center

44. 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

45. Pharmacovigilance Activities in Iran Accepted as a full member of WHO International Drug Monitoring Program in July 1998. Implemented Spontaneous Reporting System in Iran. Collected more than 6000 ADR reports from different parts of the country. Issued 38 Alert Letters on drug safety sending to the health professionals.

46. Pharmacovigilance Activities in Iran Has published 24 monthly reports in Razi journal. Has published 9 issues of national ADR Bulletin. Has over 150 workshops and seminars all over the country. Has trained over 8000 health professionals on ADRs.

47. Reporters

48. 58 countries have joined the programme

49. - 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.

50. 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.

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

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

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

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

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

56. 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

57.  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 Age groups (Reaction of Tramadol):

58. Rout of administration (In patients with Tramadol adverse effects)

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

60. Adverse effects of Tramadol from 04.81 to 03.83 ReactionNumberReactionNumber Sweating24Myalgia7 Headache21Pale7 Agitation20Ataxia6 Somnolence17Vision disorders6 Pruritus16Paraesthesia6 Rigors15Injection site reaction6 Flushing11Delusion6 Urticaria11Tachycardia6 Bronchospasm10Respiratory depression6 Hallucination9Palpitation5 Convulsion9Rash4 Hypertension8Cold extremity4 Confusion8Apnoea3 Abdominal pain8Anxiety3 Dry mouth7Stupor3

61. ReactionNumberReactionNumber Cardiac arrest3Back pain1 Anorexia3Arrhythmia1 Shock3Bradycardia1 Allergic reaction2Lacrimation abnormal1 Cyanosis2Myocardial Ischemia1 Constipation2Diarrhea1 GI disorders2Depression1 Leg pain2Erythem1 Dysphagia2Coma1 Speech disorders2Edema1 Urinary retention2Hearing decrease1 Chest pain2Facial pain1 Fever2Withdrawal syndrome1 Syncope2Foot drop1 Insomnia2Tremor1 Adverse effects of Tramadol from 04.81 to 03.83

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

63. 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)

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

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

66. 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.

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

68. 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 FDA alert (2003)

69. 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.

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

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

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

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

74. مرگ ناشی از تزریق سرم حیوانی به جای سرم انسانی درود- آبان 1381

75. Salmeterol 3 cases of Asthma attack تهران- بهمن ماه 1382

76. 3 مورد مرگ ناشی از تزریق اشتباه ÷تاسیم کلراید به جای مترونیدازول تیر ماه 1384

77. One case of Death Promethazin + Hyoscin+Dicyclomin اردیبهشت 1385

78. محلولهای دیالیز صفاقی ساخت شرکت ثامن 250 مورد ÷ریتونیت شیمیایی اردیبهشت 1385

79. Contribution of Drug Interactions to the Overall Burden of preventable ADRs Drug interactions represent 3-5% of preventable in- hospital ADRs. Drug interactions are an important contributor to number of emergency departments visits and hospital admissions. Ref: U.S. Food and Drug Administration. Center for Drug Evaluation and Research

80. Comparison Type A and Type B

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

82. www.fdo.ir معاونت غذا و دارو

83. 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

84. 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

85. Case II خانم 35 ساله اي با سابقه افسردگي و فشار خون تحت درمان با ترانيل سيپرومين، انالاپريل و هيدروكلرتيازيد مي باشد. ايشان به دليل جراحي اورژانس، تحت بيهوشي با هالوتان و پتيدين قرارمي گيرد. پس از جراحي براي بيمار در اطاق Recovery فشار خون 210/120 و انقباضات ميوكلونيك ثبت مي شود. بيمار به دليل عدم هوشياري كامل و به دليل فشار خون اورژانس به ICU منتقل و تحت درمان با نيترو پروسايد قرار مي گيرد.پس از اقدام به كاهش ويا قطع نيتروپروسايد، فشار خون بيمارمجددا افزايش مي يابد. كليه آزمايشات پاراكلينيك بيمار طبيعي مي باشد. سوال : به نظر شما علت افزايش فشار خون بيمار چيست؟

86. Ccase III بيمار پسر بچه 4 ساله اي است كه با تشخيص اوتيت مدياي حاد تحت درمان با آموكسي سيلين قرار گرفته است. شكايت اوليه بيمار تب – بي قراري و درد گوش بوده است. 2 روز بعد از شروع دارو تب بيمار قطع شده و حال عمومي بهتر شده است. 4 روز بعد از شروع درمان، كودك دوباره تب كرده است ولي حال عمومي خوب بوده و Toxic نمي باشد. مادر بيمار ذكر مي نمايد كه آموكسي سيلين را به موقع داده است و هنوز درمان ادامه دارد. پزشك در منطقه اي كه طبابت مي كند تجربه اوتيت مقاوم به آموكسي سيلين را نداشته و بيمار نيز سابقه مصرف آنتي بيوتيك در يك ماه اخير و اوتيت مكرر را نمي دهد. در معاينه اخير راشهاي ماكولوپاپولار بر روي تنه مشاهده مي شود. در CBC اخير بيمار : WBC = 9000 PMN = 57% L= 30% E=10% M=2% B= 1% پزشك تصميم به قطع داروي آموكسي سيلين و ادامه درمان با اريترومايسين مي گيرد. 48 ساعت بعد از قطع آموكسي سيلين تب بيمار قطع شده و راشهاي جلدي محو مي شود. لطفا در مورد اين بيمار به سوالات زير پاسخ دهيد : 1- تشخيص شما در مورد مشكل بيمار چيست؟ 2- چه نكات مثبتي به تشخيص شما كمك مي كند؟ 3- تشخيص هاي افتراقي در اين بيمار كدامند؟ 4- درمان مشكل اخير بيمار چيست؟