1. Iranian Pharmacovigilance Center
4/6/2019
Iranian Pharmacovigilance Center
Research & Development Office
Undersecretary for Food & Drug
Ministry of Health & Medical Education

4. Adverse drug reaction (ADR) =
any harmful effect caused by administration of a drug at a normal dosage during normal use

5. Adverse Drug Reaction WHO definition:
Any response to a drug which is Noxious and Unintended, and which occurs at doses used in men of prophylaxis, diagnosis or treatment.

6. Types of Adverse Drug Reactions (A-B-C-D-E):
Type A:
Augmented pharmacologic effects
Dose dependent and predictable (e.g. hypoglycaemia with insulin, bleeding after anticoagulants, drowsiness after opioids)
Common but often not severe
Usually caused by too high dosage or alered pharmacokinetics (genetic factors, age, reduced renal or hepatal elimination)
Most often with drugs that have a steep dose-response curve and/or a low therapeutic index
Steep means saturable

7. Types of Adverse Drug Reactions (A-B-C-D-E):
Type B:
Bizarre effects (or idiosyncratic)
dose independent and unpredictable
are relatively rare and may occur with very low doses (e.g. drug allergy – skin rashes – anaphylaxis, blood dyscrasias)
Bizarre means very strange or unusual

8. Types of Adverse Drug Reactions (A-B-C-D-E):
Type C:
Chronic effects after chronic administration
analgesic nephropathy after some analgesics
tardive dyskinesia after antipsychotics
Type D:
Delayed effects
teratogenic effects – thalidomide
cancerogenic effects – stilbestrol during pregnancy (vaginal carcinoma in daughters 20+years later)
Type E:
End-of-treatment effects (withdrawal effects)
opioids, antiepileptics, anxiolytics, rebound phenomenon- hypnotics

9. Examples of adverse effects associated with specific medications
Bleeding in GIT
NSAIDs
Thrombosis
hormonal contraceptives
Ototoxicity, nephrotoxicity
aminoglycoside antibiotics
Parkinsonism
1st generation (typical) antipsychotics
Aplastic anaemia
chloramphenicol
Agranulocytosis
clozapine (atypical antipsychotic)
Hair loss
anticancer drugs

10. 4/6/2019

11. Specific ADR Cases

12. Troglitazone (Rezulin™)
Indication: Antidiabetic agent used in combination with insulin or sulfonylurea for Type II diabetes
ADR Problem: Hepatotoxicity
Indicated by increased liver transaminase levels
Some cases of liver transplantation, and a few deaths reported
Withdrawn: Rezulin™ recalled from market in 2000
References:
Ahmad S.R., J Gen Intern Med, 2003; 18:57-60

13. Grepafloxacin (Raxar™)
Indication: Oral fluoroquinolone antibiotic
ADR Problem: Linked to prolongation of the heart’s QT interval, leading to ventricular arrhythmia
Withdrawn: Raxar™ removed from the market in 1999
References:
Ahmad S.R., J Gen Intern Med, 2003; 18:57-60

14. Cerivastatin (Baycol™)
Indication: Oral statin to lower cholesterol
ADR Problem: Rhabdomyolysis (injury to skeletal muscle)
Muscle weakness and myalgia very common
Many cases seen in combination with gemfibrazil
Deaths reported with cerivastatin, although no definitive link
Withdrawn: Baycol™ removed from the market in 2001
References: Psaty BM, et al, JAMA, 2004 Dec 1; 292 (21),
Ahmad S.R., J Gen Intern Med, 2003; 18:57-60

15. Incidence of adverse drug reactions
HOSPITAL IN-PATIENTS:10-20% suffer an adverse drug reaction
DEATHS IN HOSPITAL IN-PATIENTS: % are due to adverse drug reactions.
HOSPITAL ADMISSIONS: 0.3-5% of hospital admissions are due to adverse drug reactions.

16. quality of life while Minimizing patient risk
4/6/2019
The goal of drug therapy is the achievement of defined therapeutic outcomes that improve a patient’s
quality of life while Minimizing patient risk
SAFETY
EFFICACY

17. Limitations of Clinical Trials

18. 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

19. Adverse Drug Reaction
Adverse Drug Reaction
Pharmacovigilance

20. Pharmacovigilance in EU:
European Medicines Agency (EMA)
EudraVigilance -
the system of collecting all suspected serious ADRs

21. Pharmacovigilance in USA:
Postmarketing surveillance is overseen by the
Food and Drug Administration (FDA),
which operates a system called MedWatch,
to which doctors or the general public can voluntarily report adverse reactions to drugs

22. Frequency of adverse drug reactions
• Very common (>10%) >= 1/10
• Common (frequent) (1-10%) > = 1/100 and < 1/10
• Uncommon (infrequent) (0,1 - 1 %) >= 1/1000 and < 1/100
• Rare (0,001-0,1%) >= 1/10000 and < 1/1000
• Very rare (< 0,001 %) < 1/10000

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

24. percentage of hospital admissions due to adverse drug reactions:
USA %
UK %
France %
Norway %

25. exceeds the cost of the medications themselves
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

26. 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

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

29. Why Should We Report ADRs?!
Assessment the quality of medications
Assessment of drug safety
Detection of occurrence rate of ADR
Decreasing the risk of occurrence of adverse events

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

31. 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.

32. Incidence of ADRs to be detected Spontaneous background incidence
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 in100
360
1 in 10000
520
1 in 1000
730
1 in 100
2000
3600
7300
20300
136400
1 in 5000
18200
67400
363000

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

34. “yellow cards”

35. Spontaneous Reporting
Large population
All medicines
Hospital and out-patient care
Long perspective
Patient analysis possible
Non-interventional
Not Expensive

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

37. Pharmacovigilance concerns have been
widened to include:
Drugs
Vaccines
Blood products
Traditional and complementary medicines
herbals
Food additives
Medical devices
Biologicals
Biotechnology products
cosmetics

38. 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.

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

40. The sort of ADRs that should be reported are:
The American Food and Drug Administration :
Death
Life-threatening
Hospitalization (initial or prolonged)
Disability - significant, persistent, or permanent change, impairment, damage or disruption in the patient's body function/structure, physical activities or quality of life.
Congenital anomaly
Requires intervention to prevent permanent impairment or damage

41. ADR Effects (Erythema Multiforme)
Used with permission from Michelle Ehrlich, MD and eMedicine.com, Inc., 2005

42. ADR Effects (Gingival Enlargement due to Ca2+-Channel Blockers)
Used with permission from Carl Allen, DDS and eMedicine.com, Inc., 2005

43. ADR Effects (Coumadin Necrosis of the Leg)
Used with permission from Michelle Ehrlich, MD and eMedicine.com, Inc., 2005

44. Frequency of ADRs reported during 2004-2010
Year
Frequency
Percentage
P-value
2004 16 2
0.001
2005 10
1.3
2006 12
1.5
2007
162
20.4
2008 82
10.3
2009
229
28.9
2010
237
29.9
Year Unknown 45
5.7
Total
793
100

45. ADR reporters

46. Frequency of ADRs with different rout of administration
Route of administration
Frequency
Percentage
P-value
INJECTION
586
73.9
0.001
ORAL
172
21.7
ORAL& INJECTION 12
1.5
TOPICAL 11
1.4
RESPIRATORY 4
0.5
INTRASPINAL 3
0.4
RECTAL
OPHTHALMIC 2
0.3
Total
793
100