This document discusses pharmacovigilance and adverse drug reactions (ADRs). It begins by defining pharmacovigilance as the monitoring of drug safety, and describes how the thalidomide disaster in the 1960s prompted significant changes to drug safety systems worldwide. It then discusses various reasons for the need of pharmacovigilance like limited preclinical safety data and changing drug use patterns. The aims and methods of pharmacovigilance including spontaneous reporting, case studies, and periodic safety reports are summarized. It also provides an overview of the Pharmacovigilance Program of India and its goals of monitoring ADRs and ensuring drug benefits outweigh risks. Finally, it defines different types of ADRs and their

1. Pharmacovigilance & ADR
By-Dr. Rahul Kumar Bhati

2. • Pharmacovigilance(PV) also called as drug
safety
-Pharmakon( greek)- drug
-Vigilare (latin)- to keep watch

3. Thalidomide Disaster
• This has brought significant changes in
pharmacovigilance system world over.
• Dr. McBride published letter in The Lancet (1961)
noting large no. of birth defects in children of pt.
prescribed Thalidomide.
• Dr. Lenz from Germany discussed the association
of congenital malformation with maternal use of
thalidomide.
• 6000-12000 children had congenital anomalies
d/t maternal use of Thalidomide.

4. NEED OF PHARMACOVIGILANCE
1.Unavailability of preclinical safety data
-Animal studies are often not a good predictor
for human effects .
-Evidence of safety from clinical trials is
insufficient due to 1) limited size , 2) narrow
population (age &sex specific), 3) narrow
indications (only specific disease), 4) short
duration

5. 2)Changing Pharmaceutical Marketing Strategy
• Direct to consumer advertising
• Launch in many countries at a same time.
3)Changing Physicians and patients preferences
• Increasing use of newer drugs
• Shift of supervised to self administered therapy
4)Easy accessibility
• Easy access by internet
• Increasing conversion of prescription drugs to OTC
Drugs
• Easily available substandard drugs

6. AIMS
• To improve patient care and safety
• To contribute to the assessment of benefit,
harm ,effectiveness and risk of medicines
• To promote education and clinical training
• To promote rational and safe use of medicines

7. Short Term Goals
• To develop and implement pharmacovigilance
system in India
• To enroll all MCI approved medical colleges in the
program covering north, south, east and west of
India
• To encourage healthcare professionals in
reporting of adverse reaction to drugs, vaccines,
medical devices and biological products
• Collection of case reports and data

8. Long Term Goal
• To expand the pharmacovigilance program.
• To develop and implement electronic
reporting system (e-reporting)
• To develop reporting culture amongst
healthcare professionals
• To make ADR reporting mandatory for
healthcare professionals

9. METHODS 0F PHARMACOVIGILANCE
1. Spontaneous Case Reporting
2. Case Series
3. Active Surveillance
4. Comparative Observational Studies
5. Periodic Safety Update Reports (PSUR)

10. Spontaneous Case Reporting
• Unsolicited communication by Health care
professionals/ Consumers to Company ,
Regulatory Authority or other organisation
• It is Voluntary Reporting
• In India form used for reporting is known as”
Suspected Adverse Drug Reaction Reporting
Form”.
• In UK “Yellow Cards” and in USA “Med Watch
forms” are used

12. Case Series
• Useful for generating hypothesis about effects
of drug
• Can provide association between drug and
adverse event.
• Adverse events associated more frequently
with drug therapy such as Anaphylaxis,
Aplastic anaemia, Toxic epidermal necrolysis
and Steven-Johnson syndrome can be
assessed with case series.

13. Active Surveillance
1)Sentinel Sites
2)Drug Event Monitoring
3)Registries

14. Comparative Observational Studies
• Traditional methods are key component in evaluation
of adverse events. Major types
1)Cross Sectional Study(Survey)
• Data collected on patients population at a single point
in a time
• Used to gather data for Survey
• Major Drawback is that temporal relation between
exposure and outcome can not be directly addressed.
• Best used to examine prevalence of a Disease at one
point.

15. Cohort Study

16. Case control Study

17. PERIODIC SAFETY UPDATE
REPORTS(PSUR):
• Medically advanced countries impose the “post
marketing drug safety monitoring period ” on
new drugs
• license holders collect post marketing safety
data, prepare PSUR and submit them to the
health authority.
• If pharmaceutical companies fail to submit PSUR
as required , then the health authority may
reassess the safety of the concerned product.
• The last PSUR should be submitted before the
expiration of the drug safety monitoring period.

18. Causality assessment
• Major component of evaluation of ADR is how much
adverse event is causally related to suspected drug.
• Factors to be considered
1) Temporal relationship between drug administration
and onset of adverse reaction
2) Clinical and pathological characteristics of the event
3) Response to Dechallenge and Rechallenge
4) Patients characterastics and previous medical history.
5) Drug Interaction

19. Methods
A) Global Introspection
1) Certain
2) Probable/Likely
3) Possible
4)Unlikely
5)Unclassified

20. B)Structured Algorithm- e.g. Naranjo`algorithm

21. Pharmacovigilance Program of India
(PVPI) Introduction –
-officially started on 23 November 2004 at new
Delhi
-India is now being recognized as the “global
pharmacy of generic drugs”
-India is also emerging rapidly as a hub of global
clinical trials & destination for drug discovery
and development

22. Background
• 1989 -ADR monitoring system for India
proposed (12 regional centers)
• 1997 - India joined WHO-ADR monitoring
program (3 centers: AIIMS, KEM, JLN)
• 2004 – 2008 - National Pharmacovigilance
Program.
• 2010 – Pharmacovigilance Program of India

23. PVPI is under control of
1.CDSCO(Central Drugs Standard Control
Organization)
2.Directorate General of Health Services
3.Indian Pharmacopeia Commission (Ghaziabad)
-The programme is conducted by NCC (National
Coordinating Centre)

24. Pharmacovigilance Program of India
(PVPI)

25. PERFORMANCE & EFFECTIVENESS OF
THE PHARMACOVIGILANCE SYSTEM

26. Goals & objectives
• Goal- to ensure that the benefits of use of medicine
outweighs the risks
• Objectives
1. To monitor ADR
2. To create awareness among health care professionals
about ADR
3. To monitor benefit –risk profile of medicines
4. Generate independent ,evidence based recommendations
5. Support the CDSCO
6. Communicate findings with all stake holders
7. Create a national center

27. WHO PHARMACOVIGILANCE
PROGRAM
• Introduction :
-started in 1978 known as WHO Program for international
drug monitoring, which is located in Uppsala, Sweden.
-Till now there are 127 full members and 29 associate
members of UMC
Functions –
1. Identification and analysis of new ADR signals from national
centers & sent to the WHO ICSR database
2. Provision of the WHO database as a reference source.
3. Information exchange between WHO UMC , national
centers.

28. 4. Publications, news letters, guidelines and
books in the pharmacovigilance
5. Supplying tools like WHO drug dictionary and
WHO adverse reaction terminology
6. Training to national centers
7. Maintaining of computer software
8. Annual meetings
9. Research on pharmacovigilance

29. Summary
• The world has witnessed horrific disasters following
use of drugs
• Currently WHO collaborating center for international
drug monitoring Uppasala is playing central role in
collecting, compiling, and disseminating information
relating to drug safety monitoring
• National center at CDSCO ,New Delhi monitors ADR
and create awareness among people
• Today there is need of efficient and more integrated
pharmacovigilance system to ensure safe use of drugs

30. ADVERSE DRUG REACTIONS

31. • Adverse Event (AE): Any untoward medical
occurrence that may present during treatment
with a pharmaceutical product but which does
not necessarily have a causal relationship with
this treatment.
• Adverse Drug Reaction (ADR): Any noxious
change which is suspected to be due to a drug,
occurs at doses normally used in man, requires
treatment or decrease in dose or indicates
caution in future use of the same drug.

32. Classification of ADRs
1)Onset Of Event: Acute (<60 Minutes), Sub-acute (1-24 Hrs)
And Latent (>2 Days)
2)Frequency: Very common, common, uncommon, rare, very
rare.
3)Severity: Mild, Moderate, severe.
4)Mechanism: Intolerance, Idiosyncrasy, Drug Allergy, Drug
interaction
5)Severity: Minor, Moderate, Severe, Lethal Adrs
6)Pharmacological Classification.
7)Others: Side Effects, Secondary Effects ,toxic effects,
Photosensitivity, Drug Dependence, Drug Withdrawal
Reactions, Teratogenicity, Mutagenicity, Carcinogenicity,
Drug Induced Disease (Iatrogenic)

33. Pharmacological Classification
• Type A (Augmented)
• Type B (Bizarre)
• Type C (Continuous Drug Use)
• Type D (Delayed)
• Type E (End Of Dose)
• Type F (Familial)
• Type G (Genotoxicity)
• Type H (Hypersensitivity)
• Type U (Unclassified)

34. Type A (Augmented) reactions
• Reactions which can be predicted from the
known pharmacology of the drug
• Dose dependent,
• Can be alleviated by a dose reduction
• E.g.
1. Anticoagulants - Bleeding,
2. Beta blockers - Bradycardia,
3. Nitrates - Headache,
4. Prazosin - Postural hypotension.

35. Type B (Bizarre) reactions
• Cannot be predicted from the pharmacology
of the drug
• Not dose dependent,
• Host dependent factors important in
predisposition
• E.g.
1. Penicillin -Anaphylaxis,
2. Anticonvulsant - Hypersensitivity

36. Type C(Continuous Drug Use)
-May be irreversible, unexpected or
unpredictable.
• E.G.
1)Tardive Dyskinesias by Antipsychotics
2)Dementia by Anticholinergics.

37. Type D (Delayed) reactions
• Occur after many years of treatment.
• Can be due to accumulation.
• E.g.
1. Chemotherapy - Secondary tumours
2. Analgesics - Nephropathy
3. Corneal opacities after thioridazine

38. Type E (End of Dose) reactions
• Occur on withdrawal especially when drug is
stopped abruptly
• E.g.
1. Phenytoin withdrawal - Seizures,
2. Steroid withdrawal -Adrenocortical
insufficiency.

39. Side effects
• Unwanted but often Unavoidable,
pharmacodynamic effects that occur at
therapeutic doses
• e.g.
1) Atropine (Pre-anaesthetic) :dryness of mouth
2) Acetazolamide (diuretic-bicarbonate excretion)
:acidosis
3) Promethazine (anti-allergic) :sedation
4) Estrogen (anti ovulatory) :nausea.

40. Secondary effects
• Indirect consequences of a primary action of
the drug
• e.g. Tetracyclines__suppression of bacterial
flora__superinfections
• Corticosteroids__weaken host
defense__activation of latent tuberculosis

41. Toxic Effects
• Excessive pharmacological action of the drug
due to over dosage or prolonged use
• e.g.
1. Barbiturates - Coma,
2. Digoxin - Complete A-V Block,
3. Heparin - Bleeding
4. Atropine -Delirium
5. Paracetamol - Hepatic Necrosis

42. Intolerance
• Appearance of characteristic toxic effects of a
drug in an individual at therapeutic dose.
• e.g.
1)Carbamazepine -ataxia in some individuals
2)Chloroquine - vomiting and abdominal pain in
some individuals

43. Idiosyncrasy
• Genetically determined abnormal reactivity to a
chemical
• Restricted to individuals with particular genotype.
• e.g.
1. Barbiturates -excitement and mental confusion
in some individuals
2. Quinine - cramps, diarrhea, asthma, vascular
collapse in some individuals
3. Chloramphenicol - Rarely causes aplastic anemia
in some individuals

44. Drug Reaction
-Immunologically mediated reaction producing
stereotype symptoms, unrelated to the
pharmacodynamic profile of the drug.
-occur even with much smaller doses
•Type I: Immediate, Anaphylactic e.g: penicillins -
anaphylaxis
•Type II: Cytolytic Reaction e.g: methyldopa - hemolytic
anemia
•Type III: Arthus Reaction e.g: serum sickness
•Type IV: Delayed Hypersensitivity e.g: contact dermatitis

45. Photosensitivity
• Cutaneous reaction resulting from drug induced
sensitization of the skin to UV radiation. the
reactions are of two types
1)Phototoxic: sunburn-like, i.e., erythema, edema,
blistering, hyperpigmentation
e.g. demeclocycline, and tar products, nalidixic acid,
fluoroquinolones, sulfones etc
2)Photo allergic:
e.g. sulfonamides, sulfonylureas, griseofulvin,
chloroquine, chlorpromazine

46. Drug Dependance
1)Psychological dependence
2)Physical dependence
3)Drug Abuse
4)Drug addiction
5)Drug Habituation

47. Teratogenicity
• Capacity of a drug to cause foetal
abnormalities when administered to the
pregnant mother.
• E.g:
• Thalidomide__Phocomelia, multiple defects
• Anticancer drugs__Cleft palate,
hydrocephalus, multiple defects
• ACE inhibitors__Hypoplasia of organs (lungs,
kidney)

48. Mutagenicity and Carcinogenicity
-Capacity of a drug to cause genetic defects and
cancer respectively.
-Chemical carcinogenesis generally takes several
(10-40) years to develop.
• e.g. anticancer drugs,
• radio-isotypes,
• estrogens,
• tobacco.

49. Drug induced disease
• Also known as iatrogenic(physician induced)
diseases.
• e.g.
1. Salicylates, Corticosteroids -peptic ulcer
2. Phenothiazines, other antipsychotics -
Parkinsonism
3. Isoniazid -Hepatitis
4. Hydralazine - DLE

50. Summary
• Adverse drug reactions are major clinical
problem.
• ADR also responsible for longer stay in
hospital leading to increased cost
• ADR may mimic diseases and result in
unnecessary investigation or delay in
treatment
• ADR may lead to Disability, Congenital
anomalies and even death.