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

3. 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

4. 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

5. 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

6. Annual death rates in USA
AIDS ,516
Breast cancer ,297
Highway accidents ,458
ADR ,000

7. percentage of hospital admissions due to ADR:
USA %
UK %
France %
Norway %

8. 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

9. 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 , ,218,000
Germany , ,440
UK , ,520
Australia , ,520
Sweden , ,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. 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

13. Why Are There So Many ADRs?
So many prescriptions!

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. 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)

16. 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

17. 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

18. چگونه يك عارضه جانبي به
دارو نسبت داده ميشود؟

19. 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 ...

20. بررسي ارتباط عارضه جانبي با دارو5 4 3 2 1
ارزيابي ارتباط +
قطعي Definit _
احتمالي ‍ Probable
ممكن Possible
مشروط Conditional
غير قابل بررسي Unassessable
غیر محتمل Unlikely

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

22. 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

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

24. 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

25. 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.

26. 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.

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

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

29. 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

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

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

32. 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

33. 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

35. Drugs cause hospitalization
Digoxin Aspirin
Aspirin Digoxin
Prednisone Warfarin
Warfarin Prednisone
Guanethidine

36. 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

37. Reporters

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

39. Tramadol?
From 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

40. Adverse Reaction of Tramadol from 04.81 to 03.83
6 Major Adverse Effects of Tramadol:
Nausea
Vomiting
Vertigo
Asthenia
Dyspnea
Hypotension 41

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

42. 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

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

44. معاونت غذا و دارو

45. 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

46. 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:
نمابر:

47. Report of Iranian ADR monitoring center

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
Site of Reaction (CNS agents )

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

54. Age groups (Reaction of Tramadol):
>
Unknown 20

55. 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

56. 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

57. 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)

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

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

60. 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.

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

62. 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

63. 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.

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

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

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

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

68. The FDA Safety Information and Adverse Event Reporting Program:
MedWatch
The FDA Safety Information and Adverse Event Reporting Program:
Safety alerts
Recalls
Withdrawals
Important labeling changes
Biologicals, Drugs, Dietary supplements