adverse drug reaction

1. DETECTION, REPORTING AND
MONITORING OF ADRs
DR SABEENA K CHOUDHARY

2. Overview
• ADRs ( types and importance)
• ADR Reporting (Pharmacovigilance): what
when and how to report these ADRs

6. History

7. • Everytime we give a drug we take a risk
• Public and professional concern about
these matters first arose in the late 19th
century.
• In 1922, there was an enquiry into the
JAUNDICE associated with the use of
SALVARSAN, an organic arsenical used in
the treatment of Syphillis.

8. • In 1937 in USA,
107 people died from taking
an Elixir Of Sulfalinamide
that contained the Solvent
Di-ethylene Glycol
This led to establishment of FOOD AND DRUG
ADMINISTRATION (FDA), which was given the task
of enquiring into the safety of new drugs before
allowing them to be marketed

10. • In 1961, it was reported in West Germany that
there was an outbreak of PHOCOMELIA
(hypoplastic and aplastic limb deformities) in
the new born babies.

11. • The Thalidomide Incident led to
development of a much more
sophisticated approach to preclinical
testing & clinical evaluation of drugs
before marketing, & greatly increased
awareness of adverse effect of drugs and
methods of detecting them.

12. Importance of ADR’S in
Therapeutics

13. Adverse event
• Any untoward medical occurrence that may
present during treatment with a
pharmaceutical product
• But doesn’t have a causal relation with this Rx

14. Adverse drug reaction
• Response which is noxious and unintended ,
which occurs at doses normally used in
humans for the Px, Dx or therapy of the
disease or for modification of physiological
function
• All ADR are AE but not vice versa

15. Side effect
• Any unintended effect (unwanted but unavoidable of a product
occurring at normal dose which is related to the pharmacological
properties of the drug )
Unwanted but often unavoidable pharmacodynamic effects of a drug at
therapeutic doses”
As Extension of therapeutic effect
Atropine - dry mouth
As distinctly different effect
Promethazine – Sedation.
Side effect exploited for therapeutic use
Codeine – Diarrhoea

16. ADR vs side effect

19. Serious ADR
• Death
• Life threatening condition
• Requires inpatient hospitalization/ prolongation
• Persistent disability/incapacity
• Congenital abnormality

20. Incidence
Hospital in-patients:10-20%
Deaths in hospital in-patients: 0.3-3%
Hospital admissions: 0.3-5%

21. Why incidence is more ?

22. • Ever-increasing number of new drugs in
the market
• Number of drugs prescribed are high
• Medication errors
• Lack of awareness of a system for
reporting ADR’S

23. Common causes
 Failing to take the correct dose at the correct times
Overdosing
 Allergies to chemical components of the medicine
 Combining the medicine with alcohol
 Taking other drugs or preparations that interact with
the medicine

24. Factors affecting Adverse Drug
Reactions

25.  Age
 Genetic influences
 Concurrent diseases (Renal, Liver, Cardiac)
 Previous allergies or adverse drug reactions
 Compliance with dosing regimen
 Total number of medications
 Misc. (diet, smoking, environmental
exposure)

26. Idiosyncracy

27. Idiosyncracy
• Genetically determined abnormal reaction to
the agent
• Interaction of the drug with the unique
feature of the individual
• Produces uncharacteristic reaction

28. Types of ADR’s

29. Rawlins and Thompson classification -1991
Type A Predictable
-More Common(80%)
-Augmented normal
response
-Dose dependent
-Hypo/Hyper response
Type B Unpredictable
-Less common (6-10%)
-Abnormal/bizarre
response
-Dose Independent
-Genetic/Immunological

30. Type A Predictable
-Low Mortality
-d/t Pharmacological activity
of drug
-Rx : Dose Adjustment
Eg., S/E, Toxic effect,
Withdrawal effect
Diarrhea due to antibiotics
Type B Unpredictable
-High Mortality
-d/t Patient peculiarities
-Rx : Withdrawal of drug
Eg., Allergy, Idiosyncrasy
Hypersensitivity to
penicillin
Types of ADR’s – Contd…

31. Type C (Chronic)
- Reactions due to prolonged use of the
Drug.
e.g. HPA axis suppression by corticosteroids

32. Type D (Delayed)
• Occuring years after the treatment
• Can be due to accumulation
E.g : Teratogenisis

33. Type E (End of use)
• Occur on withdrawal especially when drug
is stopped abruptly
E.g.
• Steroid withdrwal

34. Type F (Failure of drug)
• Underdosing of medications
• Drug interactions
Eg: OCP failure

35. Type Mnemonic Example
A Augmented Diarrohea due to antibiotics
B Bizzare Hypersensitivity due to
penicillin
C Chronic Steroid decrease HPA axis
D Delayed Teratogenicity, carcinogenesis
E End of use Precipitation of MI by β
blocker withdrawal
F Failure OCP failure
Types of ADR’s in Brief:

36. Mild No need of Rx, antidote or Hospitalization
Moderate Requires drug change specific
Rx, hospitalization
Severe Potentially life threatening; permanent
damage, and prolonged hospitalization.
Lethal Directly or indirectly leads to
death
ADR GRADING

37. How to recognize an ADR

38. Who can get an ADR?
Anyone who takes medicine
Differential diagnosis should include
the possibility of an ADR if the
patient is taking any form of
medication

39. If symptoms,
Appears soon after a new drug is
started
Appears after an increase in dose
Disappears when the drug is stopped
Reappears when a drug is restarted
When To Report :

40. ADR Reporting System

41. • WHO international system(Uppsala
monitoring centre, Sweden)
• US FDA "Med watch"
• UK "Yellow card system"
• PvPI under CDSCO, India

42. • ACTIVE SURVEILLANCE
• PASSIVE SURVEILLANCE

43. • SPONTANEOUS REPORTING SYSTEM :
• Communication by HCP/ consumers/ pharma
company to NCC/CDSCO/AMC

44. Why is ADR Monitoring Needed?
• Unreliability of pre-clinical studies
• Limitations of pre-marketing phases of clinical trial
• Aggressive marketing strategies of pharmaceutical companies

45. Limitations of pre-marketing phases of clinical
trial
• Conducted in strictly controlled conditions, in highly
selected and limited number of patients
• Fails to detect rare and delayed ADRs
• Do not provide data –
- In children, elderly patients, pregnant/lactating
women
- In patient suffering from other disease
- In patient receiving other drugs
- On interpopulation difference

46. What to report
• All types of suspected ADRs irrespective of
whether they r known / uk, serious or non
serious , frequent or rare, and regardless of an
established causal relationship
• Pharma meds and vaccines, drugs used in
traditional meds , medical devices, contrast
media
• Any AE

47. • Doctors
• Dentists
• Nurses
• Pharmacists
Health care
professionals
• Patients
• Consumers
• Relatives
Others
Who can report ??

48. Problems in ADR reporting
Patient Related
(i) Cannot recognize ADR
(ii) Recognize but do not
report
(iii) Illiteracy
Health professional
Related
(i) Cannot recognize ADR
(ii) Recognize but do not report due
to
- Lack of time
- Hesitancy
- Ignorance
- Fear of litigation
- Guilt
•

49. HOW TO REPORT??

52. Patient related information

53. Suspected adr

54. Suspected medications

55. Causality Assessment
• Routine procedure in Pharmacovigilance
• Relationship of cause & effect
• Most outcomes : multiple interacting causes
• Aim : to define contribution due to drugs
• Problems:
ADRs rarely specific
Diagnostic tests usually absent
Re challenge rarely ethically justified

56. Causality Assessment Methods
Algorithmic:
Series of questions
Answers are weighted
Overall score determines causality category
e.g. Naranjo’s scale
Probalistic:
Set of explicitly defined causality categories
e.g. WHO UMC method

57. Questions Yes No Don’t
Know
1) Are there previous conclusive reports on this reaction? +1 0 0
2) Did the ADR appear after the suspected drug was
administered?
+2 -1 0
3) Did the ADR improve when the drug was discontinued? +1 0 0
4) Did the ADR appear with re-challenge? +2 -1 0
5) Are there alternative causes for the ADR? -1 +2 0
6) Did the reaction appear when placebo was given? -1 +1 0
7) Was the drug detected in blood at toxic levels? +1 0 0
8) Was the reaction more severe when the dose was
increased, or less severe when the dose was decreased?
+1 0 0
9) Did the patient have a similar reaction to the same or
similar drug in any previous exposure?
+1 0 0
10) Was the ADR confirmed by any objective evidence? +1 0 0

58. The Naranjo Probability Scale
The score :-
≥ 9 = Definite
5-8 = Probable
1-4 = Possible
0 = Doubtful

60. Actions taken

66. Drugs restricted due to adverse
reactions

67. Drug Year Adverse Reaction Outcome
Sulfanilamide 1937 Liver damage due to
diethylene glycol
Solvent changed;
FDA established
Thalidomide 1961 Congenital
Malformations
Withdrawn
Chloramphenicol 1966 Blood Dyscrasias Uses restricted
Benoxaprofan 1982 Liver damage Withdrawn
Aspirin 1986 Reye’s syndrome Uses restricted
Flecainide 1989 Cardiac Arrhythmias Uses restricted
Noscapine 1991 Gene toxicity Withdrawn
Triazolam 1991 Psychiatric disorders Withdrawn

68. Drug Year Adverse reaction Outcome
Temafloxacin 1992 Various serious
adverse effects
Withdrawn
Co-trimoxazole 1995 Serious allergic
reactions
Uses restricted
Terfenadine 1997 Interactions
(e.g. with
grapefruit juice)
Withdrawn
from OTC sale
Sotalol 1997 Cardiac
arrhythmias
Uses restricted
Astemizole 1998 Interactions Withdrawn
Cisapride 2000 Cardiac
arrhythmias
Withdrawn
Cerivastatin 2001 Rhabdomylosis Withdrawn

69. Drug Event Outcome
Fenfluramine,
Dexfenfluramine
Heart valve disease, Pulmonary
hypertension, Cardiac fibrosis
Banned
Sibutramine Heart attack , Stroke Banned
Astemizole ,Terfinadine Arrhythmias Banned
Rofecoxib ,Valdecoxib Myocardial infarction Banned
Rosiglitazone MI, stroke,CHF,death Banned
Cisapride QT interval prolongation- ventricular
arrhythmias
Banned
Gatifloxacin Arrhythmias, Phototoxicity,
Unpredictable hypoglycemia
Banned
Nimesulide (Paediatric) Fulminant hepatic failure Paediatric use -banned
Phenylpropanolamine Hemorrhagic stroke
Psychiatric disturbances
Banned( Banned order under
court stay)

70. Take home message…
• Every drug which has an effect has an adverse effect every
time a drug is given risk is involved
• For rational use of drug not only its clinical indications are
important but the knowledge of adverse effects as well
• Early detection of adverse effects and its proper
management can be life saving in many situations
• ADR Reporting (Pharmacovigilance) plays a important
role in the evolution and life history of a drug