PRINCIPLES OF

PHARMACOVIGILANCE
For
All those interested in Drug Safety

Dr. S. B. Bhise
M. Pharm., Ph.D.
Ex. Principal, Govt. College of Pharmacy,
Karad / Aurangabad &
Managing Director, KLK Consultants, Pune

Price ` 240.00

N1619
PRINCIPLES OF PHARMACOVIGILANCE ISBN 978-93-86084-89-7
Second Edition : April 2018
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 Acknowledgement

I am extremely thankful to Dr. R. B. Navale, Associate Professor, GCOP Aurangabad for

editing the content. I am specially thankful to Manjiri, my better half in supporting me on all
fronts related to the book.

I am thankful to Dr. S. B. Bumrela for designing cover page for the book.

I am very thankful to Mrs Manasi Pingle, for improving critical details in the content.
Support from Prof. S. B. Gokhale and Mr. Jignesh Furia has been a source of inspiration for
me.

Dr. S. B. Bhise

■■■
 Preface

Pharmacovigilance is an emerging area for employment in recent years. Background of

drugs is an advantage for anybody who wants to make a career in pharmacovigilance.
Hence, pharmacists are well-suited to exploit the opportunity. The job potential is both local
as well as global. Opportunities are enormous; only one has to make commitment for the
career.

Hence, first book in the series on Principles of Pharmacovigilance is presented here. It

will be followed by another book on Regulatory Aspects of Pharmacovigilance. The future
books will depend on demand of stakeholders.

I have tried the contents of the book more informative and inclusive; however for an
everchanging field like Pharmacovigilance, updates are probably a daily affair. I have
attempted to make the content inclusive; however comments are welcome.

I appeal to all budding pharmacists, teachers and newcomers in the field to go through
the contents and communicate constructive criticism to develop the book in coming
editions.

September 2016 Dr. S. B. Bhise

■■■
 Curriculum

1. Introduction to Adverse Drug Reactions

1.1 Definitions and classification of ADRs
1.2 Detection and reporting
1.3 Causality assessment
1.4 Severity and seriousness assessment
1.5 Predictability and preventability assessment
1.6 Management of adverse drug reactions
2. Introduction to Pharmacovigilance
2.1 History and development of pharmacovigilance
2.2 Importance of safety monitoring / Why pharmacovigilance?
3. National and International Scenario
3.1 Pharmacovigilance in India
3.2 Pharmacovigilance: global perspective
3.3 WHO international drug monitoring programme
4. Basic Terminologies used in Pharmacovigilance
4.1 Terminologies of adverse medication related events
4.2 Regulatory terminologies
5. Information Resources in Pharmacovigilance
5.1 Basic drug information resources
5.2 Specialised resources for ADRs
5.3 Critical evaluation of medication safety literature
6. Establishing Pharmacovigilance Programme
6.1 Establishing in a hospital
6.2 Establishment and operation of drug safety department in industry
6.3 Establishing a national programme
6.4 SOPs – Types, designing, maintenance and training
6.5 Roles and responsibilities in pharmacovigilance
6.5.1 Licence Partners,
6.5.2 Contract Research Organisations (CROs) and
6.5.3 Market Authorisation Holders (MAH)
7. Pharmacovigilance Methods
7.1 Passive surveillance – Spontaneous reports and case series
7.2 Stimulated reporting
7.3 Active surveillance – Sentinel sites, drug event monitoring and registries
7.4 Comparative observational studies – Cross-sectional study, case control study
and cohort study
7.5 Targeted clinical investigations
7.6 Vaccine safety surveillance
8. Adverse Drug Reaction Reporting
8.1 Introduction to reporting systems
8.2 Spontaneous reporting system
8.3 Reporting to regulatory authorities
8.4 Guidelines for reporting ADRs in biomedical literature
9. Signal detection, Risk Assessment and Management
9.1 Identification of new adverse drug reactions
9.2 Signal detection in pre and post marketing period
9.3 Prioritization and risk assessment
9.4 Risk management
10. Drug and Disease Classification
10.1 Anatomical, therapeutic and chemical classification of drugs
10.2 International classification of diseases
10.3 Daily defined doses
10.4 International non-proprietary names for drugs
11. Drug Dictionaries and Coding in Pharmacovigilance
11.1 WHO adverse reaction terminologies
11.2 MedDRA and standardised MedDRA queries
11.3 WHO drug dictionary
11.4 Eudravigilance medicinal product dictionary
12. Communication in Pharmacovigilance
12.1 Effective communication in pharmacovigilance
12.2 Communication in drug safety crisis management
12.3 Communicating with regulatory agencies, business partners, healthcare facilities
and media
12.4 Dear doctor letters to healthcare professionals
13. Tools used in Pharmacovigilance
13.1 Introduction to Argus
13.2 Introduction to Arisg Pharmacovigilance and safety
14. Drug Informatics
14.1 Basic Prescribing Information (BPI) Labelling
14.2 EMEA labelling
14.3 Investigator’s Brochure (IB) Labelling
15. Seriousness Assessment Criteria
15.1 Event verbatim
15.2 CTCAE guidelines
16. Statistical methods for evaluating medication safety data
17. Pharmacogenomics of adverse drug reactions
18. Heamovigilance
19. Pharmcovigilance for Herbal Drugs
20. Job Opportunities and Responsibilities
■■■
 Contents

1. Introduction to Adverse Drug Reactions 1.1 - 1.8

2. Introduction to Pharmacovigilance 2.1 - 2.13
3. National and International Scenario 3.1 - 3.6
4. Basic Terminologies used in Pharmacovigilance 4.1 - 4.10
5. Information Resources in Pharmacovigilance 5.1 - 5.8
6. Establishing Pharmacovigilnce Programme 6.1 - 6.6
7. Pharmacovigilance Methods 7.1 - 7.6
8. Adverse Drug Reaction Reporting 8.1 - 8.8
9. Signal Detection, Risk Assessment and Management 9.1 - 9.6
10. Drug and Disease Classification 10.1 - 10.12
11. Drug Dictionaries and Coding in Pharmacovigilance 11.1 - 11.4
12. Communication in Pharmacovigilance 12.1 - 12.16
13. Tools used in Pharmacovigilance 13.1 - 13.6
14. Drug Informatics 14.1 - 14.14
15. Seriousness Assessment Criteria 15.1 - 15.4
16. Statistical Methods for Evaluating Medication Safety Data 16.1 - 16.4
17. Pharmacogenomics of Adverse Reactions 17.1 - 17.3
18. Hemovigilance 18.1 - 18.6
19. Pharmacovigilance of Herbal Drugs 19.1 - 19.5
20. Job Opportunities and Responsibilities in Pharmacovigilance 20.1 - 20.1
• Appendix 1 A.1 - A.14
• Appendix 2 A.15 - A.55
• Appendix 3 A.56 - A.57
• Appendix 4 A.58 - A.66
• Appendix 5 A.67 - A.68
• Appendix 6 A.69 - A.73
• Appendix 7 A.74 - A.78
• Appendix 8 A.79 - A.83
• Appendix 9 A.84 - A.89
• Appendix 10 A.90 - A.97
• Appendix 11 A.98 - A.99
• Appendix 12 A.100 - A.106
• Glossary G.1 - G.7
• References R.1 - R.10
■■■
Chapter 1
Introduction to
Adverse Drug Reactions
Contents 
1.1 Definitions and Classification of ADRs
1.1.1 Definitions
1.1.2 Classification of ADRs
1.2 Detection and Reporting
1.2.1 Detection of ADRs
1.2.2 Reporting of ADRs
1.3 Causality Assessment
1.4 Severity and Seriousness Assessment
1.5 Predictability and Preventability Assessment
1.6 Management of Adverse Drug Reactions

In the standard textbooks of pharmacology it is mentioned that consuming a drug is

equivalent to consuming a risk. It is only when the benefit(s) associated with drug(s) are
more than the risk(s), that the consumption of a drug is justified. Thus, it is the benefit vs
risk ratio of the drug which decides whether a drug is to be taken or not. The next question
is how to measure risks and how to measure the benefits. Due to individualization of drugs
to patients, it is the clinical judgment of the physician to identify what will benefit the
patient. At the same time, risk associated with the drug(s) can be ascertained by
observations related to pharmacovigilance. The studies related to pharmacovigilance
indicate what are possible risks associated with the drug. Every drug can be associated with
possible adverse reactions, intended or unintended. The only exception to this generality is
the case of drug(s) which are given in case of deficiency of specific components like
vitamins or minerals. It is the study of possible adverse reactions of drugs which
constitutes the essential content of Pharmacovigilance. This takes us to the definition of
Pharmacovigilance.
(1.1)
Principles of Pharmacovigilance 1.2 Introduction to Adverse Drug Reactions

Pharmacovigilance is a science which deals with adverse reactions to drugs.

Although this meaning of the term Pharmacovigilance offers broad understanding about it,
technical definition of few related terms are in place. Some important terms are defined
here. Glossary of all terms is included in the Appendix.
1.1 DEFINITIONS AND CLASSIFICATION OF ADVERSE DRUG
REACTIONS
1.1.1 Definitions
 Absolute Risk
Risk in a population of exposed persons is the probability of an event affecting
members of a particular population (e.g. 1 in 1,000). Absolute risk can be measured
over time (incidence) or at a given time (prevalence).
 Adverse Event (AE)
Any untoward medical occurrence that may occur during treatment with a
pharmaceutical product, but which does not necessarily have a causal relationship with
the treatment.
 Adverse Drug Reaction (ADR)
A response to a medical product, which is noxious and unintended, and which occurs
for doses normally used in Human beings for the prophylaxis, diagnosis, or therapy of
disease, or for the modification of a physiological function.
 Attributable Risk
Difference between the risk in an exposed population (absolute risk) and the risk in an
unexposed population (reference risk) is called attributable risk. Attributable risk is the
result of an absolute comparison between outcome frequency measurements, such as
incidence.
 Effectiveness Vs. Risk
The balance between the rates of effectiveness of a medicine versus the risk of harm is a
quantitative assessment of the merit of a medicine used in routine clinical practice.
Comparative information between therapies is most useful. This is more useful than the
efficacy and hazard predictions from pre-marketing information that is limited and
based on selected subjects.
 Pharmacovigilance
The science and activities related to the detection, assessment, understanding and
prevention of adverse effects or any other drug-related problem.
 Relative Risk
Relative risk is defined as, 'ratio of the risk in an exposed population (absolute risk) and
the risk in an unexposed population (reference risk)'. Relative risk is the result of a
relative comparison between outcome frequency measurements, e.g. incidences.
 Risk
The probability of harm being caused; the probability (chance, odds) of an occurrence.
Principles of Pharmacovigilance 1.3 Introduction to Adverse Drug Reactions

1.1.2 Classification of ADRs

The adverse reactions to drugs can be are classified on the basis of effects as given
below:
Type A Effects:
These are the effects which are due to (exaggerated) pharmacological effects. Type A
effects tend to be fairly common, dose related (i.e. more frequent or severe with higher
doses) and may often be avoided by using doses which are appropriate to the individual
patient. Such effects can usually be reproduced and studied experimentally and are often
already identified before marketing. e.g. dryness of mouth caused by Atropine.
Interactions between drugs, especially pharmacokinetic interactions, may often be
classified as Type A effects, although they are restricted to a defined sub-population of
patients (i.e. the users of the interacting drug).
Type B Effects:
These occur characteristically in only a minority of patients and display little or no dose
relationship. They are generally rare and unpredictable, and may be serious and are
notoriously difficult to study. Type B effects are either immunological or non-
immunological and occur only in patients, with - often unknown - predisposing conditions.
Immunological reactions may range from rashes, anaphylaxis, vasculitis, inflammatory
organ injury, to highly specific autoimmune syndromes. Also non-immunological type B
effects occur in a minority of predisposed, intolerant patients, because of an inborn error of
metabolism or acquired deficiency in a certain enzyme, resulting in an abnormal metabolic
pathway or accumulation of a toxic metabolite. e.g. chloramphenicol-induced aplastic
anaemia and isoniazid-induced hepatitis.
Type C Effects:
These effects refer to situations where the use of a drug, often for unknown reasons,
increases the frequency of a disease. Type C effects may be both serious and common (and
include malignant tumours) and may have pronounced effects on public health. Type C
effects may be coincidental and often concern long term effects; there is often no suggestive
time relationship and the connection may be very difficult to prove.
The adverse effects can also be classified on the basis of related cause. It is separately
dealt in the section 1.3 related to causality assessment.
1.2 DETECTION AND REPORTING
1.2.1 Detection of ADRs
Since ADRs may act through the same physiological and pathological pathways as
different diseases, they are difficult and sometimes impossible to distinguish. However, the
following step-wise approach may be helpful in assessing possible drug-related ADRs:
1. Ensure that the medicine received is the medicine ordered and actually taken by the
patient at the dose advised.
Principles of Pharmacovigilance 1.4 Introduction to Adverse Drug Reactions

2. Verify that the onset of the suspected ADR was after the drug was taken, not before
and discuss carefully the observation made by the patient.
3. Determine the time interval between the beginning of drug treatment and the onset
of the event.
4. Evaluate the suspected ADR after discontinuing the drugs or reducing the dose and
monitor the patient's status. If appropriate, restart the drug treatment and monitor
recurrence of any adverse events.
5. Analyse the alternative causes (other than the drug) that could on their own have
caused the reaction.
6. Use relevant up-to-date literature and personal experience as a health professional
on drugs and their ADRs and verify if there are previous conclusive reports on this
reaction. The National Pharmacovigilance Centre and Drug Information Centres are
very important resources for obtaining information on ADR. The manufacturer of
the drug can also be a resource to consult.
7. Report any suspected ADR to the person nominated for ADR reporting in the
hospital or directly to the National ADR Centre.
1.2.2 Reporting of ADRs
Within India, regulatory authorities have designed a format in which reports of adverse
reactions are to be made. The form has been given in the appendix. There are specific
instructions for filling up the form. Due to these instructions ambiguities in filling up the
form are minimized. A similar form designed by USFDA is also available. The form by any
regulatory authorities includes basic information about the patient, details about the
suspected adverse reaction, details about all medications given to the patient, relevant
laboratory data, and information about seriousness of the event is presented. Advice about
what constitutes a serious adverse reaction, who can report, where the information is to be
sent and what happens to the information is documented.
1.3 CAUSALITY ASSESSMENT
While reporting any adverse reaction, it is necessary to establish causal relation
between the suspected drug and the observed effect. It is also possible that one of the
disease process, interaction of the drug on disease process or even lack of effect of a drug
exacerbating the disease process may be involved in the observed effect. In order to
understand all such events, there is classification of adverse reactions based on causality. It
is given below.
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