This presentation can be used for basic information of Pharmacovigilance and ADR reporting

1. Basic Concepts Of Pharmacovigilance
&
ADR Reporting Tools
Dr. Prabhakar Patil
Professor Department of Pharmacology
Navodaya Medical College Raichur Karnataka

5. This topic will be covered in following headings:-
• Introduction
• Types of ADRs
• Why pharmacovigilance is needed ?
• Scope of Pharmacovigilance?
• Detection of Adverse drug reaction & Reporting
• Signal detection
• General Management of Adverse drug reaction
• What will be the impact of my reporting?
• Strengths and weakness of Pharmacovigilance in India
• How to Fill the ADR form (version 1.3)
• Activity

6. Introduction

7. World Health Organization (WHO) definition :-
“Pharmacovigilance is the science and activities related to
the detection, assessment, understanding and
prevention of adverse effects or any other drug related
problem”
Derived from the Greek “Pharmakon” meaning a drug or
medicine and from the Latin “Vigilans” meaning watchful
or careful

8. Classification of ADRs:-
Depending on :
1)Onset of action :- Acute (< 60 minutes), Subacute (1-24
hours), Latent (> 2 days)
2) Predictable/Nonpredictable, Immunological reaction,
Genetic abnormality, Continous use and withdrawl
a)Type A:- Predictable, Dose related e.g. :- Hypotension
with vasodialators/ Alpha blockers
b) Type B :- Nonpredictable, Not dose related :-
e.g. Immunological reaction :- Drug allergy
Genetic abnormality :- G6PD, Psuedocholinesterase

9. c) Type C :- Occurs on continuous use :- e.g. Drug
dependence like Physical dependence on opioids
d)Type D :- Delayed effect:- Mutagenicity and
Carcinogenicity
e) Type E :- End of Use/ Withdrawal : Clonidine or
Atenolol withdrawal- rebound hypertension
f) Type F :- Failure of therapy :- Failure of OCP or Vaccines

10. 3)Severity classification
Mild/Minor: No antidote therapy or prolongation of
hospitalization is required
Moderate: It requires a change in drug therapy, specific
treatment or an increase in hospitalization by at least 1
day
Severe: Potentially life threatening causing permanent
damage or requiring intensive medical care

11. 4) According to frequency they occur:-
Very common ≥ 1 in 10
Common < 1 in 10 but ≥ 1 in 100
Uncommon < 1 in 100 but ≥ 1 in 1000
Rare < 1 in 1000 but ≥ 1 in 10,000
Very rare < 1 in 10,000

12. Why pharmacovigilance is needed ?
Preclinical Trials:-
Tests in animals are insufficiently predictive of human
safety

13. In clinical trials :-
Patients are selected and limited in number— may miss
rare ADRs
Conditions of use in trials differ from those in clinical
practice—may miss drug interactions
Duration of trials is limited—may miss ADRs that
develop after years
Special groups (such as children, the elderly or pregnant
women)—not involved in clinical trials.

14. Other factors which make Pharmacovigilance important
are:-
1) Changing pharmaceutical marketing strategies
• Aggressive marketing
• Direct advertising to consumer
2) Changing patient’s preferences
• Increasing use of newer drugs
• Increasing use of drugs to improve quality of life

15. 3) Easy accessibility
• Increasing conversion of prescription drugs to over
the counter drugs
• Easy access to drug information on the Internet
• Easy availability of alternative medicines
• Easy availability of substandard drugs
4) Medication errors
5) Off Label :- Use of medicines for indications that are
not approved and for which there is inadequate scientific
basis
6) Polypharmacy

16. Scope of Pharmacovigilance has widened:
Pharmacovigilance
Detection of adverse
drug events
Herbal preparations
Complimentary medicines
Blood
products
Biologicals
Medical devices
Vaccines

17. Detection of Adverse drug reaction
&
Reporting

18. A male patient Chunni Lal (45 year old) working as Bank
Manager in SBI Raichur came with the complaints of severe pain
in epigastric region since 15 days. You saw his prescription.
He was on
1)Tab. Dilzem (Diltiazem) 30 mg TDS
2) Tab. Envas (Enalapril) 5 mg BD
3)Tab. Ecosprin (Aspirin ) 75 mg OD
4) Tablet Supradyn (Multivitamin Tablet) OD
5) Proteinex powder One teaspoon 2 times a day

20. Reporting of ADR
Who can report?
Health care professionals (doctors, dentists, pharmacists,
nurses) are the most preferred source of information for
collecting the data related to the ADR
Patient himself/herself can report ADR. (ADR reporting
forms are available in vernacular languages)
If patient is not competent to report he/she can contact
family physician in case of suspected ADR

21. Which things you should remember while Reporting?
1. Write legibly
2. Report immediately
3. Take decision to report whilst the patient is still with you
4. Think about any other factors which may contribute in causing the
event/ ADRs
5. If something happens to the patients that increases suspicion then
send a supplementary note immediately using ADRs reporting form
with the patient identifiers
6. All reports must have the following data elements: Patient
initials(1), age at onset of reaction(2), date of onset of reaction(5)
description of reaction problem(7), suspected medication(8) and
reporter information(16,17)

22. What to report ?
1)Report serious adverse drug reactions.
A reaction is serious when the patient outcome is:
Death
Life-threatening
Hospitalization (initial or prolonged)
Disability (significant, persistent or permanent)
Congenital anomaly
Required intervention to prevent permanent impairment
or damage

23. 2)Report non-serious, known or unknown, frequent or
rare adverse drug reactions due to Medicines, Vaccines
and Herbal products
3) All suspected ADRs associated with drug interactions,
medication errors, manufacturing defect and the use of
cosmetics should also be reported

24. How to report?
ADRs are reported by filling up the ADR form.
Reporting forms should be distributed to different
departments of hospital and institutions, general
practitioners etc. in order to collect the ADR data

26. Vernacular language ADR forms(10 Indian languages)
HINDI KANNADA

29. From Where to download these forms

30. Where to Report?
• Duly filled and signed form can be submitted to
nearest ADR monitoring center (AMC) or directly to
National Coordinating center (NCC) for PvPI
• List of all AMC of India is available at
http://www.ipc.gov.in. The Email of NCC is
pvpi@ipcindia.net
Or
pvpi.ipcindia@gmail.com
Toll Free number:-
18001803024

31. Pharmacovigilance program of India(PvPI)
The Central Drugs Standard Control Organisation
(CDSCO), New Delhi, under the aegis of Ministry of
Health & Family Welfare, Government of India has
initiated a nation-wide pharmacovigilance programme
in July, 2010.
Indian Pharmacopoeia commission(IPC),Ghaziabad, U.P.
became the National Coordinating Centre in April 2011.

32. What happens to submitted information?:-
The AMC reports ICSRs to NCC via a VigiFlow
These ICSRs are then assessed at NCC for quality of
data and if found valid
“Uppsala Monitoring Centre” in Sweden.
But if the data is not complete or valid, then the
ICSRs are reverted back to their concerned AMC with
the query or necessary comments

33. AMC can correct or complete ICSR and send to it again to
NCC again for evaluation.
The data from NCC is also sent to CDSCO, as and when
required.

34. Data Entry & Data Management related to ADRs
WEB BASED INDIVIDUAL CASE SAFETY REPORT (ICSR)
MANAGEMENT SYSTEM
Vigiflow: is available for use by national pharmacovigilance
centers.
VigiBase: is used by UMC . It is the largest database with over
25 million reports of suspected adverse effects of medicines,
submitted since 1968 from the national centers all over the
world

35. Signal detection

36. Signal
• Signal is the first alert about the averse drug effect
• It is the information obtained on a possible causal
relationship between an adverse drug reaction and
a drug
• The relationship might be unknown or known but
incompletely documented in the past
• Process of signal detection may spread through the life
cycle of drug (Very long process)
• Usually more than one report is required to generate
a signal

37. Methods of detecting Signals :-
Hypothesis generating methods
• Spontaneous ADR reporting
• Prescription event monitoring
Hypothesis testing methods
• Case-control study
• Cohort studies
• Randomized controlled trials.
The most commonly
adopted method is
spontaneous reporting
(Upto 70% ADRs are
reported by this
method)

38. Reaction of Interest
(Pancreatitis)
Case
All other reactions
Control
Total
Drug of Interest
(EXPOSED)
2050(a) 22821(b) 24871(a+b)
All other reactions due to
Other drugs
(NON-EXPOSED)
38665(c) 163748(d) 202413(c+d)
Total (a+b+c+d)
227284
We want to know that whether sitagliptin causes pancreatitis because we got few
ADR reports of pancreatitis with sitagliptin use.
So we generated hypothesis that there is casual relationship between pancreatitis
and sitagliptin.
Now we want to test the hypothesis for that we chose the method:- Case control
study.

39. To know the casual relationship in case control study we
use Odds Ratio
OR=odds that case was exposed/odds that control was
exposed
OR= ad/bc
OR= 2050 X 163748 / 38665 X 22821
= 335683400 / 88237395
= 3.8

40. Inference:-
OR = 1 :- odds of exposure among cases and controls is same. That
means exposure(Sitagliptin administration) is not associated
with pancreatitis
OR > 1 :- odds of exposure among cases is higher than control. That
means exposure (Sitagliptin administration) is associated with
pancreatitis
Here we got value odds ratio is 3.8
So we are now sure that there is casual relationship between sitagliptin
use and pancreatitis(This strengthens the evidence that we got a
confirmed signal )

41. WEB BASED MANAGEMENT SYSTEM FOR SIGNAL
VigiLyze: is a signal detection and management system that can
use national, regional or global data as the starting point for
quantitative signal detection. It provides support for the entire
signal management process, including the qualitative
assessments.

42. General Management of Adverse drug reaction:-
Two ways :-
a) Treat ADR
b) Prevent ADR

43. How to treat ADR
1) Taking proper history from the patient:-
Ask about how patient is taking the medicine?
Whether it is according to prescription i.e. right dose,
right frequency and right duration
Ask the patient about intake of drug from
complementary medicines?
At the same time see the prescription/ case sheet :-
This will give you idea about Medication Errors
This will also tell us about Drug interaction

44. 2) Was the ADR previously reported?
- Check whether the given drug/drugs are able to
cause ADR under investigation (Package inserts
which comes with the drugs, National Coordinating
Centre, Drug safety alerts)
3) Withdrawing:-
-Withdraw (dechallenge) the suspected drug and
observe whether ADR has subsided
- If multiple drugs are given withdraw the drug one
by one. This will help to catch the right culprit

45. 4) Re-administer:-
If the reaction subsides and it was not life
threatening you can restart (rechallenge) then
monitor for recurrence of the ADR
5) Reduce the dose:-
If overdose of the drug is suspected reduce the
dose and observe whether ADR has subsided
6) Give an alternative drug:- When all these measures
fails. Totally stop the suspected drug responsible for
ADR. Start with better alternative which is devoid
potential to cause ADR under investigation

46. 7) While treating the patient:-
Always have a clear therapeutic objective in mind, do
not treat for longer than is necessary
Review the patient regularly this will help you to
know any recurrence of ADR is there or any new ADR
has arised
Try to simplify the treatment(Give symptomatic and
specific )

47. How to prevent ADR?
1) Educate the patient about:
Avoiding polypharmacy
Avoiding unnecessary use of OTC drugs
The proper drug utilization(storage of drugs,
adherence to the treatment, not using drugs
prescribed for others, importance of expiry date)
The uses of the prescribed drugs and their possible
ADRs
Importance of ADR reporting by the consumer

48. 2) Repeated training of all health care provider about
• Rational use of drugs
- Avoid unnecessary drugs
• The signs of overdose of drugs
• The drug interactions(Drug-Drug, Drug-Food,Drug-
Disease)
• When to use TDM (e.g. Lithium, Phenytoin)
• When to use Lab investigation(PT for warfarin therapy,
LFT for Hepatoxic drugs ,KFT Nephrotoxic drugs)
• How to avoid Medication Errors

49. What will be impact of my reporting?
Patient will receive specific warning in the product
information
The status of medicine will change e.g. Over the counter
to prescription only
Helps in Signal detection

50. Product recall(Drug Withdrawal) :-In rare cases, removal
of medicine from market are found to outweigh the
benefit
e.g.
COX 2 Inhibitors
RAFECOXIB VALDECOXIB
They claim to relief the pain without causing stomach
ulcers unlike the aspirin
But they increased the incidence heart attack and stroke

51. Drug safety alerts can be provided so that doctors,
pharmacists and nurses know about adverse drug effects
and this will lead to prevention of risks due to ADRs
Incidence rate of ADRs can be estimated
Many patients will receive safe and efficacious
Deaths due ADR can be prevented

52. Strengths of Pharmacovigilance Program in India
1) Largest network of ADR Monitoring Centers(AMC):-
which provides larger size of evidence.
e.g During COVID time we were able to give sufficient
evidences for safety and efficacy of drugs like
COVID vaccines
Steroids
Amphotericin B
Hydroxychloroquine

53. 2) We know how to use ICT
We have apps developed by IPC like ADR PvPI readily
available on Google play store. This can be downloaded
by anyone
This makes easy reporting of ADR and detection of
preventable causes of ADR

54. 3) We are keeping pace with the changes occurring in
the area of PV:-
- Increasing the numbers of AMC, Materiovigilance and
Hemovigilance centers
- Making required changes in ADR forms
- New Apps are being developed for avoiding preventable
causes of ADRs e.g. Medication errors

55. Weakness of Pharmacovigilance Program in India:-
1) Under-reporting:-
The reasons for under-reporting are:
• Non-availability of ADR forms
• Ignorance
• Fear of legal action
• Fear of negative reflection of one’s competence
• Doubts regarding the causal role of the drug

56. 2) Non Functional AMC:-rate is recorded to be 40 %
3) Involvement of Physicians:-
Most adverse drug reactions are reported by
pharmacists and nurses, with physicians reporting the
fewest
4) Private sector involvement is less :-
Departments in private Medical Colleges and hospitals w
failed to contribute in ADR reporting

57. 5) Insufficient use of lab Investigation :-
Many Adverse drug reactions often go unnoticed due to
failure of medical teams to correlate adverse drug
reactions with biochemical, pathological or radiological
investigations
6) Budding health care professionals not properly
involved(PGs, UGs and Interns)
lack of knowledge and awareness about PvPI, lethargy,
insecurity, workload and lack of proper training in PV

58. 7) The amount of time dedicated to teaching of PV:- in
undergraduate and postgraduate courses in health care
professionals is low
What is the solution?:-
• More active involvement of HCP in reporting ADRs
• Intensive monitoring approach in PV can improve
the detection of ADRs
• Clinicians need to be reassured that reporting ADRs has
no legal implications
• More funding to run the program across the country
• Repeated training of HCP and Patients

59. Health Care System
Few Efforts by
dedicated people
Just Eyes are opened
Long way to go

60. Why I should take interest when most of the people are not interested in ADR
reporting?
Ethical Concern
“You know that something is Harmful to another person who doesn’t know ,and not
telling is unethical”
Unacceptable Act
“Dying from a disease is sometimes unavoidable; dying from
a medicine is unacceptable”
Thinking of My future
“ You know that one day you will become patient and at that time you will become
impatient to know whether therapy given to you is not harmful”

61. How to Fill the ADR form (version 1.3)

64. •
Note: Tab Chlorpromazine
Brand Name: LARGACTIL,
Manufacturer: Wedley labs
Batch No: LGL0881
Expiry Date : Dec 2018
Case Report
Madan Lal, a 65-years old male patient admitted to hospital on 12.01.2016 with chief complaints of pain in upper
abdomen and nausea since last 5 days. On physical examination, he had yellowish discoloration of palm, conjunctiva
and nail bed. His weight was 72 kg. He had few episodes of psychotic attacks, for which he was on Chlorpromazine
therapy since last 4 weeks(Since 12/12/2015 ). On enquiry, he told that he was taking Tab. Largactil
(Chlorpromazine) 100 mg, 4 tablets at bed time. He was also taking Tab. Diclofenac 50 mg twice-a-day (self-
medication) for abdominal pain for three days before admitting to hospital. He was investigated on the day of
admission for laboratory parameters which are as follows:
– Alkaline Phosphatase = 180 U/L (Normal range: 25 – 100 U/L)
– ALT = 205 U/L (Normal range: 10 – 40 Units/L)
– Total Bilirubin = 5.0 mg/dL (Normal range: 0.8 – 1.2 mg/dL)
On admission, Chlorpromazine and Diclofenac therapy was stopped. After 7 days of stopping the medications, the
intensity of pain decreased. Also, he was reinvestigated for above parameters which are as follows:
– Alkaline Phosphatase = 110 IU/L
– ALT = 98 Units/L
– Total Bilirubin = 1.8 mg/dL

65. Madan Lal, a 65-years
old male patient
admitted to hospital
on 12.01.2016 with
chief complaints of
pain in upper
abdomen and nausea
since last 5 days. On
physical examination,
he had yellowish
discoloration of palm,
conjunctiva and nail
bed. His weight was 72
kg

66. patient admitted to hospital
on 12.01.2016 with chief
complaints of pain in upper
abdomen and nausea since last
5 days. On physical
examination, he had yellowish
discoloration of palm,
conjunctiva and nail bed.. He
had few episodes of psychotic
attacks, for which he was on
Chlorpromazine therapy since
last 4 weeks(12/12/2015). On
enquiry, he told that he was
takingTab. Largactil
(Chlorpromazine) 100 mg, 4
tablets at bed time

68. On admission, Chlorpromazine therapy was
stopped(Dechallenge)

69. No Rechallenge

70. He was also taking Tab. Diclofenac 50 mg twice-a-day (self-medication) for
abdominal pain for three days before admitting to hospital

71. . He was investigated on the day of admission for laboratory parameters which are as follows:
– Alkaline Phosphatase = 180 U/L (Normal range: 25 – 100 U/L)
– ALT = 205 U/L (Normal range: 10 – 40 Units/L)
– Total Bilirubin = 5.0 mg/dL (Normal range: 0.8 – 1.2 mg/dL)
After 7 days of stopping the medications, the intensity of pain decreased. Also, he was reinvestigated for above
parameters which are as follows:
– Alkaline Phosphatase = 110 IU/L
– ALT = 98 Units/L
– Total Bilirubin = 1.8 mg/dL

75. Activity

76. Fill the ADR form for the given case :-
An adult female patient (Prem Lata) aged 48 years (weight 60 kg) was diagnosed to be suffering from deep vein
thrombosis (DVT) in right lower limb. She was hospitalized and prescribed warfarin (5 mg once a day) and
Enoxaparin (40 mg twice a day for 5 days) on 6/10/2020. On 4th day (10/10/2020) of she complaints of severe pain in
right foot which was cold and purple. Examination showed small punctate areas of necrosis and there was petechiae
in the area of skin before purple discolouration. The INR of the patient was 9.6 and provisional diagnosis of warfarin
induced skin necrosis was made. Both the enoxaparin and warfarin have been discontinued on 10/10/2020 and
patient was given intravenous vitamin K and fresh frozen plasma immediately.
The necrotic foot showed improvement on 13/10/2020 and patients INR value reached near therapeutic value
(INR- 3.4). Enoxaparin was restarted for treatment of DVT with revaroxaban and patient was discharged with proper
advise.
On the first follow up (after one week), she was still recovering from necrosis of foot
Details of drugs:-
1) Enoxaparin:-Manufacturer: Sanofi Aventis; Batch No.: Y-54; Expiry Date:June 2022
2) Warfarin: Manufacturer: Cipla; Batch: X-23; Expiry date: November 2022