The document discusses pharmacovigilance and adverse drug reactions (ADRs). It provides historical context on important events that increased focus on pharmacovigilance like the Thalidomide disaster. It describes the need for pharmacovigilance due to limitations of preclinical and clinical trials. It outlines the aims, methods like spontaneous reporting and causality assessment, and programs in India and by the WHO. It defines ADRs and provides classifications. In summary, the document overviews the importance and process of pharmacovigilance in monitoring drug safety post marketing.

1. Pharmacovigilance &
ADR
Dr. Nilesh Siddhawar,
JR1, Dept. of Pharmacology,
VNGMC, Yavatmal

2. 1.Introduction
2. Historical Perspective
3.Need of pharmacovigilance
4.Aims
5.Methods of pharmacovigilance
6.Causality Assessment
7. Pharmacovigilance program of India
8.WHO Pharmacovigilance Program
9.Summary

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

4. Historical Perspective
 English Physician William Withering publish his work on
Foxglove in 1785.
 In 1789, Wouter van Doeveren, in his lecture named
Remedio Morbi discussed ocurance of ailments d/t
administration of remedies for therapeutic purposes
 Sulfanilamide Disaster(1938).

5. 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.

7. 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

8. 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

9. 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

10. 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

11. 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

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

13. 1. 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

15. 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.

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

17. 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.

18. Cohort Study

19. Case control Study

20. 6.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.

21. 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

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

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

24. 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

25. 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

26. 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)

27. 90 PVPI AMCs
National Coordinating Center,
IPC, Ghaziabad
Ghaziabad Mumbai Kolkata Chennai
PVPI Headquarters, CDSCO
Pharmacovigilance Program of India (PVPI)

28. PERFORMANCE & EFFECTIVENESS OF THE
PHARMACOVIGILANCE SYSTEM
Who can Report What to Report Whom to Report
Healthcare professionals
(clinician, dentist
pharmacist ,nurses and
others) can report
suspected adverse drug
reaction. Pharmaceutical
companies can also send
ADR specific for their
product to NCC.
All types of suspected ADRs-
irrespective of whether they are
known or unknown, serious
and non-serious, frequent or
rare. Although
pharmacovigilance is primarily
concerned with pharmaceutical
medicines, adverse reactions
associated with drugs used in
traditional medicine (e.g.
herbal remedies) should also be
considered.
Use the ‘Suspected Adverse
Drug Reaction Reporting
Form’ which is available on
the official website of IPC
(www.ipc.gov.in) as well as
CDSCO (www.cdsco.nic.in)
to report any ADR.

29. 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

30. 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.

31. 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

32. 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

33. ADVERSE DRUG REACTIONS

34. • 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.

35. 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)

36.  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)
Pharmacological Classification-

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

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

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

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

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

42. 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.
Side effects

43. 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
Secondary effects

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

45. 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
Intolerance

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

47. -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
Drug Reaction-

48. 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

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

50. 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)
Teratogenicity

51. -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.
Mutagenicity and Carcinogenicity-

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

53. 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.