Pharmacovigilance (Thakur Publication)

Introduction to Pharmacovigilance ( Chapter 1 ) ( tppl . org .
in ) 15
CHAPTER Introduction to
1 Pharmacovigilance
1.1. PHARMACOVIGILANCE
1.1.1. Definition
The historical development of word “Pharmacovigilance ” includes the Greek
word phannacon = ‘drug’ or ‘medicinal substance and the Latin word vigilare
'
=
‘to keep watch ’ As per WHO. pharmacovigilance has been defined as “the
science and activities concerned with the detection, assessment , understanding
and prevention of adverse reactions to medicines” ( particularly long term and
short term adverse effects ).
However, as per the European Commission (EU ) , pharmacovigilance is
defined as “the science and process to monitor the safety of medicinal drugs and
take actions for increasing the benefits and reducing risks of medicines”.
1.1.2. Objectives
1 ) To improve patient care and safety associated with the use of medicines as
well as all medical and paramedical interventions.
2 ) To improve public health and safety associated with the use of medicines.
3) To identify complications associated with the use of medicines and
conveying it in an appropriate manner.
4 ) To evaluate advantage, efficacy and risk of medicines as well as promoting
safe, rational and more effective ( including cost -effective ) use of these
drugs.
5) To encourage education, understanding and clinical training in
pharmacovigilance along with its effective communication to the health care
workers and the public.
1.1.3. Scope
There are several areas where pharmacovigilance plays a very critical role in
providing safety from toxic effects of the therapeutic drugs such as:
1 ) In Herbal Medicine: The safety and efficacy of herbal medicines has
become the key concern to both general public and national health
authorities. However, use of herbal plants in the traditional and ancient
medicine system continues to expand rapidly all over the world. Now -a days -
people are shifting towards the herbal medicinal system or herbal drugs for
the treatment of any type of disease.
2 ) In Disease Control Public Health Programmes: The major concern today
in countries having no such safety monitoring or regulatory system
16 Pharmacovigilance
or in remote areas having few or no health care

( pharmacovigilance )
surveillance or infrastructure is monitoring the safety of medicines or
therapeutic drugs.
However, the primary problem occurs in the specific communities where
the use of medicines becomes difficult, for example, for the treatment of
tropical diseases such as leishmaniasis, malaria and schistosomiasis, and
for the treatment of tuberculosis and HIV / AIDS. Pharmacovigilance must
be a priority for every country with a public health disease control
programme.
3) Ecopharmacovigilance: Adverse drug reactions related to drugs within the
ecosystem with all consequences in human beings and other organisms in
environment are included in the ecopharmacovigilance such as the waste and
expired drugs removed from hospitals are dumped in the sewage system, etc.
other examples includes:
i ) Patient excretion of drugs or its metabolites through sewage system
ii) Hospital or self -disposal of unused expired or unwanted drugs through
flushing or trash
iii ) Direct release of drugs and its byproducts from the manufacturing units
into the waste water system
iv ) Terrestrial deposition leading from solid waste landfills and sludge
application to lands
v ) Rapid breakdown of acetylsalicylic acid which leads to their deposition in
the lands
vi ) Clofibric acid, active metabolite of clofibrate detected in drinking water
vii ) Fluoroquinolone, a fat soluble and stable drug gets absorbed to sludge
particles through sewage treatment process.
4 ) Blood Bank: In blood banks, pharmacovigilance also plays an important role
as it keeps a record of all the donors donating blood, their health safety data,
etc. for example, if a person has suffered from dengue fever in the past
donates blood and any type of adverse reaction is observed in patient
receiving the same blood, then the pharmacovigilance team keeps a record of
the adverse drug reaction occurred due to the donated blood.
5 ) Immunisation and Vaccination: Pharmacovigilance plays a crucial role
in vaccination. There are certain vaccines which have been given to
patients and serious adverse reactions have been observed or when the
dosage form gets changed , then any kind of adverse event must be checked
from time to time , for example , polio vaccine initially being given as
polio drops, but recently the manufacturers changed the dosage form to
injectable, therefore after vaccination of polio injections the site of inject
has to be kept on check for any kind of inflammation, thrombosis, or other
skin reactions.
6 ) In Dermatology: In order to keep a check on any type of skin reactions or
adverse events related to skin diseases, pharmacovigilance plays an
important role in the area of dermatology.
Introduction to Pharmacovigilance ( Chapter 1 ) ( tppl .org . in ) 17
1.1.4. History and Development

1 ) About 169 years ago in 1848 (January 29), the history of Pharmacovigilance
marked its first milestone when the first adverse reaction was observed in a
young girl ( Hannah Greener ) of north England who died out of receiving
anesthesia chloroform before the infected toenail was removed.
2) However , Sir James Simpson found that chloroform was a powerful and
safer anesthesia and it was him who introduced it clinically. The death of
Hannah still remained unknown but the reason being investigated for her
death was found to be pulmonary aspiration or lethal arrhythmia.
3) In 1937, the use of sulfanilamide elixir which contained diethyl glycol as
the solvent resulted in death of 107 persons in USA. It was found that the
solvent was responsible for causing the deaths, however the pharmaceutical
companies did not knew about the toxic effect of diethyl glycol.
4 ) Douthwaite in 1938 suggested that Acetylsalicylic Acid ( ASA ) is
responsible for causing melena. In 1955 the studies proved that ASA could
cause gastrointestinal diseases and hence patients suffering from
gastrointestinal ulcers must be contraindicated.
5) Then, in 1961. Thalidomide tragedy made the milestone in the origin and
development of European pharmacovigilance. The drug was prescribed to
pregnant women ’s as harmless treatment for nausea and morning sickness.
The drug was tested in about 300 patients without any prior toxicity studies.
6) However, an Australian doctor, Dr. McBride soon suggested the co-relation
between congenital malformation of babies and thalidomide which caused
phocomelia which is a condition involving malformations of babies’ arms
and legs resulting in seal like limbs. Therefore, it was discontinued in 1962
after it was reported under pharmacovigilance.
7 ) Pharmacovigilance in India
( i ) Pharmacovigilance in India was introduced in 1986 with the formal
introduction of adverse drug reaction monitoring system under the
guidance of drug controller of India. The main purpose of the program
was to generate data on adverse reactions through different types of
reporting especially spontaneous reporting. However, at that time it
consists of a total of 12 main centers each covering population of about
50 millions. Some of the centers were in Delhi, Mumbai , Lucknow,
Chandigarh, Pondicherry and Kolkata. District hospitals and primary
health posts were to be affiliated to these main centers.
(ii) In 1997, a significant revision took place in the program in which India
became a part of WHO Program for International Drug Monitoring
controlled by Uppsala Monitoring Centre in Sweden.
( iii) However, the regulatory agencies revitalized the Pharmacovigilance program
in the country for the second time six centers across the country including
New Delhi (designated as the National Centre and located at the All India
Institute of Medical Sciences), Mumbai (a special center at the King Edward
VII Memorial Hospital ), Lucknow, Kolkata, Chandigarh, Aligarh and
Pondicherry. Later, both the attempts were failed due to many reasons.
Introduction to Pharmacovigilance ( Chapter 1 ) ( tppl .org . in ) 19
1.1.5. WHO International Drug Monitoring Programme

1 ) The WHO Programme for International Drug Monitoring ( PIDM ) was
established in 1968. This Programme provides a forum for Member States of
WHO for working together in monitoring of drug safety. It also facilitates in
identifying and analyzing the adverse reaction signals from the documented
data handed over to the WHO global individual case safety report ( ICSR )
database by the respective member countries.
2 ) There are more than 150 countries in the WHO Programme for International
Drug Monitoring. All these countries have a common vision of safer and
more effective use of medicines. They operate their working nationally and
internationally work as a team for identification and monitoring the harm
caused by medicines, to reduce patient’s risks and to establish the
pharmacovigilance systems and standards globally. However, since 1978 the
Uppsala Monitoring Centre ( UMC ) controls and operates all the technical
and operational aspects of the programme.
3) In 1968 the WHO programme was established to make sure that all the data
on adverse reactions on patients was collected from maximum sources. This
would allow the individual countries to become alert about the pattern of
adverse reactions occurring all over the world and that may not be evident
from the local reported adverse drug reactions only.
4) The WHO programme includes three-part network:
( i) The headquarters of WHO located in Geneva, Switzerland managesall
theissues related to any type of policy.
( ii ) National pharmacovigilance centers from member countries of WHO
coordinated for all the case reports sent to the WHO Individual Case
Study Report ( ICSR ) database. The Uppsala Monitoring Centre ( UMC)
located in Sweden manages all the reports.
(iii ) The Uppsala Monitoring Centre
( UMC) supervises the WHO Uppsala Monitoring Centre
programme operations, including: ( Sweden )
a ) Collection, assessing and 7
WHO headquarters £
communicating the
i
•
( Geneva ) |
a
information from all the National pharmacovigilance £

WHO member countries centres from Who member
about the effectiveness, toxic countries
effect, benefits, and risks of medicinal products,
b ) Collaboration with member countries for practice and developing
pharmacovigilance,
c) Warning the National Regulatory Authorities ( NRAs ) of member
countries about probable drug safety problems through WHO signal
process.
5 ) As per the data, more than 100 countries joined the WHO programme till
June 2012, and more than 30 members associated were waiting for
compatibility between the national and international formats of reporting.
1.1.6. Importance of Safety Monitoring of Medicine

1 ) Drug safety monitoring is a risk mitigation exercise in which adverse drug
reactions ( ADRs ) caused by medicinal drugs, devices, or biologicals can be
explored, minimized or prevented. It is the process in which expected and
unexpected adverse reactions occurring due to the use of medicines in the
post-marketing phase can be identified .
2) Pharmacovigilance is used to describe the process of drug safety monitoring and
can be defined as the branch of science that carries out activities related to
understanding, assessment, detection, and prevention of adverse drug reactions.
3) It aims primarily at rational use of medicines to ensure patients safety. Thus
pharmacovigilance has become a key aspect of effective clinical practice in
many countries.
4) According to the Article 17 of the RA Law “On Drugs” “Drugstores, Health care
institutions, institutions and the organizations which are using and consuming
therapeutic drugs, are indulged to inform about the development of all the
unknown adverse reaction cases immediately to the authorized government body”.
5) According to the order of the Ministry of Health, which is an authorized
governmental body, ADR monitoring in RA is carried out by the Scientific
Centre of Drug and Medical Technologies Expertise, which has been a
member of the WHO International Program of the ADR Monitoring
( Uppsala, Sweden ) since 1997.
6) For the purpose of ADR monitoring and according to the international
recommendations, the Report Form for ADR registration has been developed
at the centre, and it is being actively spread among the workers of public
health services.
1.1.7. Pharmacovigilance Programme of India ( PvPI )

Directorate General of Health Services, Central Drugs Standard Control
Organization (CDSCO), under the guidance of Ministry of Health & Family
Welfare, Government of India in collaboration with Indian Pharmacopeia
commission , Ghaziabad initiated a nation -wide Pharmacovigilance Programme
( PVPI ) for the protection of patient’s health by providing safety from the drugs.
However, Indian Pharmacopeia commission ( IPC ), Ghaziabad coordinates these
Programs as a National Coordinating Centre ( NCC ).
1 ) On 14th July 2010 the Government of India started the Pharmacovigilance
Programme of India ( PvPI) with All India Institute of Medical Sciences
( AIIMS ), New Delhi as its first National Coordination Centre ( NCC ) for
monitoring Adverse Drug Reactions ( ADRs ) in the country for purpose of
safety and protection of public health.
2) 22 ADR monitoring centres including AIIMS, New Delhi in the year 2010
were set up under this Programme.
3) However, on 15th April 2011 the National Coordination Centre was later shifted
to Indian Pharmacopoeia Commission ( IPC ), Ghaziabad, Uttar Pradesh from All
India Institute of Medical Sciences ( AIIMS, New Delhi ) in order to safeguard
and protect implementation of this programme in a better way.
Introduction to Pharmacovigilance (Chapter 1 ) ( tppl .org . in ) 21
4 ) July, 2015 onwards Indian Pharmacopoeia Commission - Pharmacovigilance

Programme in India ( IPC-PvPI ) became the National Coordination Centre
( NCC) for Materiovigilance Programme of India ( MvPI ).
5) In July, 2017 Indian Pharmacopoeia Commission ( IPC), National
Coordination Centre for Pharmacovigilance Programme in India ( NCC-PvPI )
became a WHO Collaborating Centre for Pharmacovigilance in Public
Health Programmes & Regulatory services.
Mission: To protect the health of Indian population by ensuring that the benefits
of medicine used overshadow the risks associated with its use.
Vision: To improve patient safety and welfare in Indian population by monitoring
the drug safety and thereby reducing the risk associated with use of medicines.
Objectives
1 ) A nation -wide system must be formed for reporting of patient safety
2) Identification and analysis of new ADR ( signal ) from the reported cases
3) Analysis of benefit - risk ratio of marketed pharmaceutical products
4 ) Evidence based information must be generated on safety of medicines
5) Supporting the regulatory agencies in the process of decision making on use
of medicines.
6) Emerging as a national center of excellence for pharmacovigilance activities
7 ) Communicating over the safety information on use of medications to
different stakeholders for minimizing the risk
8 ) Collaborating with other national centers for data management and exchange
of information.
9 ) Providing consultancy and training support to other National Coordination
Centre for Pharmacovigilance Programme in India located across the
world.
1.2. SUMMA RY
The details given in this chapter can be summarised as follows:
1 ) “Pharmacovigilance” includes the Greek word pharmacon = ‘drug’ or ‘medicinal
substance ' and the Latin word vigilare = ‘to keep watch’.
2) As per WHO. pharmacovigilance has been defined as “the science and activities
concerned with the detection, assessment, understanding and prevention of adverse
reactions to medicines” ( particularly long term and short term adverse effects ).
3) As per the European Commission ( EU ), pharmacovigilance is defined as “the
science and process to monitor the safety of medicinal drugs and lake actions for
increasing the benefits and reducing risks of medicines” .
4) In Herbal Medicine, the safety and efficacy of herbal medicines has become the key
concern to both general public and national health authorities.
5) Ecopharmacovigilance, the adverse drug reactions related to drugs within the
ecosystem with all consequences in human beings and other organisms in
environment are included in the ecopharmacovigilance.
6) In blood banks, pharmacovigilance also plays an important role as it keeps a record

of all the donors donating blood, their health safety data, etc.
7) Pharmacovigilance plays a crucial role in vaccination.
8) About 169 years ago in 1848 ( January 29 ), the history of Pharmacovigilance marked
its first milestone.
9) .
However Sir James Simpson found that chloroform was a powerful and safer
anesthesia and it was him who introduced it clinically.
10 ) In 1937, the use of sulfanilamide elixir which contained diethyl glycol as the
solvent resulted in death of 107 persons in USA.
11 ) Douthwaite in 1938 suggested that Acetylsalicylic Acid ( ASA ) is responsible for
causing melena.
12) Then, in 1961. Thalidomide tragedy made the milestone in the origin and
development of European pharmacovigilance.
13) .
However, an Australian doctor Dr. McBride soon suggested the co-relation between
congenital malformation of babies and thalidomide which caused phocomelia.
14) Pharmacovigilance in India was introduced in 1986 with the formal introduction of adverse
drug reaction monitoring system under the guidance of drug controller of India.
15 ) On 1st January 2005. WHO-sponsored and World Bank funded National
Pharmacovigilance Programme of India ( PvPI ) was started in India .
16 ) The National Pharmacovigilance Advisory Committee located at the office of the
Central Drugs Standard Control Organization ( CDSCO),
17) The WHO Programme for International Drug Monitoring (PIDM ) was established in 1968
18) There are more than 150 countries in the WHO Programme for International Drug
Monitoring.
19 ) In 1968 the WHO programme was established to make sure that all the data on
adverse reactions on patients was collected from maximum sources.
20) Drug safety monitoring is the process in which expected and unexpected adverse reactioas
occurring due to the use of medicines in the post-marketing phase can be identified.
21 ) On 14th July 2010 the Government of India started the Pharmacovigilance
Programme of India ( PvPI )
22) 22 ADR monitoring centres including AIIMS, New Delhi in the year 2010 were set
up under this Programme.
1.3. EXERCISE
1.3.1. Very Short Answer Type Questions
1) Define pharmacovigilance.
2) Define pharmacovigilance as per European Commission.
3) When was pharmacovigilance introduced in India?
4) What is the main objective of pharmacovigilance?
1.3.2. Short Answer Type Questions

1 ) Discuss about the importance of safety monitoring of medicine.
2) Write a short note on the scope of pharmacovigilance.
3) Explain WHO Programme for International Drug Monitoring ( PIDM ).
1.3.3. Long Answer Type Questions

1 ) Briefly discuss about pharmacovigilance with its history and development.
2 ) Explain in detail about Pharmacovigilance Programme of India ( PvPI )
Introduction to Adverse Drug Reactions (Chapter 2 ) 23
CHAPTER Introduction to Adverse

2 Drug Reactions
2.1. ADVERSE DRUG REACTIONS ( APRS)

2.1.1. Definition
Adverse drug reactions can be defined by different terms by different scientists.
1) Schatz et al in 2015 defined ADR as “undesirable, unwanted effect of any
drug that occurs when used at any usual clinical condition ".
2 ) Edwards et al in 2000, defined adverse drug reaction as “an unpleasant or
appreciably harmful reaction occuring due to an intervention related to
medication use, which might predict harm from forthcoming administration
and permits specific treatment or prevention, or change in the the dosage
regimen, or product withdrawal .”
3) Adverse drug reactions as per WHO ( 2005 ) can be defined as “any response
to a drug which is noxious and unintended and which occurs or doses
normally used in a man of prophylaxis diagnosis or therapy of disease or for
the modification of physiologic function ”.
2.1.2. Classification of ADRs

Adverse drug reactions can be classified into five types depending on :
1 ) Depending on Onset of Event: Acute ( <60 minutes ), Sub-acute ( 1 -24
hours), latent (> 2 days)
2 ) Based on Type of Reactions:
i) Rawlins and Thompson classification (1991): Type A ( Augmented
Reactions), Type B ( bizarre reactions ), Type C ( chronic reactions), Type
.
D ( Delayed type reactions) Type E (end of treatment ).
ii) Wills and Brown Classification: Type A ( Augmented Reactions), Type B
.
( bizarre reactions ) Type C (chronic/Chemical reactions), Type D ( Delayed
.
type reactions), Type E (end of treatment ), Type F ( Familial reactions) Type
G (Genotoxicity ), Type H ( Hypersensitivity ), Type U ( Unclassified ).
3) Based on Severity: Minor, Moderate, Severe, Lethal.
4 ) Depending on Whether They Could Take Place in Any Patient, or in a
Specific Susceptible Population:
i ) Reactions that might take place in anyone: Drug overdose, Drug side
effect , Drug interaction.
ii ) Reactions that Take Place Only in Susceptible Individuals: Drug
.
intolerance, Drug idiosyncrasy Drug allergy, Pseudoallergic reaction.
5) Others: Secondary effects, Toxic effects, photosensitivity, drug dependence,
drug withdrawal reactions, teratogenicity, mutagenicity, carcinogenicity,
drug induced disease ( Iatrogenic reactions ).
2. I . 2. I . ADR C lassification Based on Severity

Severity Description Examples
Mild No treatment or antidote for • Opioids causing constipation
overdosage required; Longer duration • Antihistamines cause some
hospitalization also notrequired drowsiness
Moderate Specific or change in the existing • Non-steroidal anti-inflammatory
treatment may be required , but the drugs cause edema and
drug is not necessarily discontinued hypertension
(e.g., addition of drug to the regimen, • Hormonal contraceptives causing
dose modification ) venous thrombosis
Severe The drug reaction can cause a • Phenothiazines: abnormal heart
potential life threatening event, drug rate
and specific treatment of drug reaction • ACE inhibitors: Angioedema
must be discontinued
Lethal An adverse reaction can cause death of • Overdosage of Anticoagulants:
the patient, either directly or indirectly Hemorrhage
• Overdosage of acetaminophen:
liver failure
2.1 .2.2. Rawlins and Thompson Classification of ADR ( 1991 )

. .
S No Type of Adverse Features Examples
drug reaction
1 ) Type A • Common and Dose related • Nausea from digoxin
( Augmented • Occurs as a result of dru’s • Bleeding from warfarin
Reactions ) pharmacological action • Glyceryltrinitrate
• Predictable ( GTN ) causing
• Low morbidity and mortality headache
• Low therapeutic index
2) Type B • Also called idiosyncratic • Penicillin antibiotic
( bizarre reactions) • Uncommon and not related causing anaphylaxis
to dose of drug • Hepatotoxicity due to
• Unpredictable ( not occurin paracetamol
necessarily due to • Aminoglycosides
pharmacological effect ) causing ototoxicity
• High morbidity and mortality • Tinnitus caused by
aspirin
3) TypeC • Occurs due to continuous use • Nephropathy due to use
( chronic reactions ) for longer time of analgesics
• Uncommon and related to • Chronic use of
cumulative dose antipsychotic drugs
causing tardive
dyskinesia
• Continuous use of high
dose glucocorticoid
therapy causing
osteoporosis
4) Type D • Reactions occur due to • Phenytoin: cause fetal
( Delayed type teratogenic and carcinogenic hydantoin syndrome
reactions) effects • Tetracyclines: causes
• These are delayed in onset teeth malformation and
Introduction to Adverse Drug Reactions ( Chapter 2 ) 25
• Uncommon (occurs rarely )- discolouration of teeth

as mutagenecity and due to chelate formation
carcinogenecity studies are with calcium ions
done before drug approval • Teratogenic
• Dose related ( usually ) thalidomide:resulted in
fetal phocomelia
• Sodium valproate:
causes spina bifida
5) TypeE • Uncommon • Opiate withdrwal
(end of treatment ) • Occurs soon after drug syndrome
withdrawal • Tachycardia on sudden
withdrawal or
discontinuation of P-
adrenoceptor blockade
• Occurance of second
malignancies after
successful chemotherapy.
2.1 . 2.3. Wills and Brown Classification for ADR

.
S.No Type of Adverse Features Examples
drug reaction
1 ) Type A Relatively common i) Hypoglycemia with
( Augmented Pharmacologically predictable sulfonylureas
Reactions ) Dose related Improves if ii ) Bradycardia with P-
medicine is withdrawn blockers
2) Type B Involves interaction with a i ) broad -spectrum antibiotics
( bizarre reactions microorganism
) causing oral thrush
Pharmacologically ii) Dental caries with sugar
predictable coated tablets
Improves if medicine is iii) resistance due to overuse
withdrawn of any one antibiotic, etc.
3 ) Type C Related to drug concentration Extravasation reactions
( chronic/ chemical An irritant reaction Phlebitis
reactions )
4 ) Type D Caused by method of i) Inflammation or infection
( Delayed type administration or nature of around implant
reactions ) formulation ii) particles
Improves if medicine is iii ) Infection at site of injection,
withdrawn or method of iv) a tablet lodging in the throat,
delivery changed v ) inhaling the ‘dust cap’ of
an inhaler,
vi) cough after using a dry
powder inhaler
5 ) Type E Pharmacologically predictable Withdrawal reactions due
(end of treatment ) Begins only when the medicine to opoids, benzodiazepines,
is stopped or dose is reduced clonidine, P- blockers.
Improves if medicine Is
reintroduced
6 ) Type F occurs only in the genetically i ) Hemolytic anemia with
( Familial predisposed primaquin in glucose 6-
reactions ) phosphate dehydrogenase
deficient individuals.
ii ) esterase inhibitor deficiency,

iii ) porphyria
iv ) sickle cell anaemia.
7) Type G causes irreversible genetic Teratogenic agents like
(Genotoxicity ) damage thalidomide causing genetic
damage in the fetus.
8) Type H Requires activation of i ) Anaphylaxis with penicillin
( Hypersensitivity ) immune system ii ) allergic skin reactions with
Improves if medicine is antimicrobial agents,
withdrawn iii ) Stevens-Johnson syndrome,
iv ) photoallergy ,
v ) acute angioedema,
9) Type U Mechanism not understood i ) Taste disturbances with
( Unclassified ) simvastatin
ii ) Nausea and vomiting with
gaseous anesthetic .
iii ) muscular adverse effects of
Simvastatin
2.1.3. Objectives of ADR Monitoring

1 ) To identify the nature and frequency of ADRs
2 ) To assist the Drug Regulatory Authority, Public Health Programmes,
Scientists and Consumer Society to minimise ADRs.
3) To deliver updated Drug Safety Information to Health Care Professionals.
4) To spread information by organising proper education programme to consumers.
5) To find the risk factors which can predispose induce or influence the
development , severity and incidence of ADRs.
2.1 .4. Benefits of ADR Monitoring

1 ) It provides information regarding quality and safety of pharmaceuticals
products.
2 ) It introduces risk management plans.
3) It inhibits the possible adverse effects and assists in determining ADR
occurrence.
4) It provides information to health care team, patients, pharmacists and nurses
regarding adverse drug effects and spread awareness about ADRs.
2.2. DETECTION OF ADRS

Patients susceptible to adverse drug reactions must be properly identified and
monitored. However, specific group of patients include:
1 ) Those having muliple disease processes.
2 ) Those patients taking multiple medicines in large number
3) Those having history of adverse drug recations.
4 ) Thosepatients alreay suffering from kidney or liver diseases
5) Paediatric or geriatric patients
6 ) Patients who are undergoing treatment with medicines having high incidence
of adverse effects
7 ) Patients treated with medicines having low therapeutic index

8) Patients undergoing treatment with medicines already known to be associated
with serious adverse effects
9 ) Patients having abnormal investigation results.
Subsequently the ADRs might act through the same pathological and
physiological pathways for different diseases there it becomes sometimes
difficult or impossible to distinguish that whether the toxic effect is due to
pathological effect or physiological effect. However, the following step wise -
-
approach might be helpful in assessing possible drug related ADRs:
1 ) It must be ensured that the ordered medicine is correct and is actually
administered to the patient at the advised dose.
2) The onset of the suspected reaction must be verified that it occurred after and
not before the administration of drug and also the observation made by the
patient must be carefully discused.
3) It helps in determining the interval of time between the beginning of
treatment of drug and the onset of the event;
4 ) Suspected ADR must be evaluated after the drug is discontinued or the dose
is reduced and then after the status of the patient must also be monitored.
However, if found suitable, then the drug treatment must be restarted and
relapse of any adverse events must be monitored regularly.
5) Alternative causes must be analysed ( other than the drug ) that could have
caused the reaction on their own.
6) Relevant updated literature and personal experience as a health care worker
on drugs and their adverse reactions must be used and also must be verified
that whether there are any earlier conclusive reports on the same reaction .
7) The Drug regulation authority and National Committee are very important
resources to obtain information on any type of adverse drug reactions. The
drug manufacturer can also be a resource to consult .
8) Any suspected ADR to the person nominated for ADR reporting must be
eeported in the hospital or directly to the health District.
Detection Method of ADRs

1 ) Pre- marketing studies 2) Post - marketing surveillance
3) Assessing Causality 4) Communicating ADRs
5 ) Postal Survey Method.
2.2.1. Pre - marketing Studies

1 ) The safety test of new formulated medicines is done on animal models.
2 ) Specific animal studies for carcinogenicity, teratogenicity and mutagenicity
are easily accessible.
3) 3 distinct phases of clinical trials are performed before submitting the final
report to a marketing authorisation application ( MAA ).
4) ADRs having frequency greater than 0.5-1.0% can be easily identified by
performing clinical trials.
28 Pharmaco vigilance
2.2.2. Post- marketing Surveillance

1 ) Pharmavigilance methodologies can be used for identifying the drug-related
risk as well as for collecting related information.
2 ) Spontaneous adverse drug reactions reporting are powerful and cost
effective system for detecting unknown drug - related risk.
3) ADR result ( in a patient ) can be seen as a part of professional duty
report by health care practitioner under their provision .
4) In this product defect like intoxicants in the drug, drug abuse and
unexpected lack of therapeutic effect in the drug are concerned and
identified .
5 ) The two commonly used epidemiological methods are as follows:
i ) Cohort Studies: Patient exposed to a particular drug should be
monitored in active as well as systematic way, and its ADR frequencies
should be compared to an unexposed control population.
-
ii ) Case Control Studies
a ) Person affected due to adverse event being studied should be
recognised . Each case should be compared with several disease -
free control patients who are randomly hired from the study
base.
b) Before the event occurs, both cases and controls should be examined
for their exposure to possible causative agents.
c ) On the basis of exposure data, the odd ratio should be calculated .
2.2.3. Assessing Casuality

1) Causality assessment is a process of establishment of a relationship between
a drug and a suspected reaction.
2 ) In case an ADR is suspected , then the assessment starts with the collection of
the relevant data related to patient’s demographics like medications including
OTCs; time of onset and duration of reaction; treatment of reaction and its
outcome and reports.
3) Following approaches may be appropriate in assessing causality:
i ) Opinion of individual experts.
ii ) Opinion of penal of experts.
iii ) Formal algorithms.
2.2.4. Communicating ADRs

By the following ways the knowledge about rational and safe use of medicines
are provided:
1) At the time of basic training of health professionals.
2 ) By conducting constant education programmes for health professionals.
3) By specifically designated drug information centres.
4) By inserting package ( document having information about that drug and its
use ) and by counselling the patient as well.
2.2.5. Postal Survey Method

1 ) This method comprise of a specific drug related questionnaire.
2 ) It is mainly used for monitoring ADR of new drugs i.e. within 1 to 2 years
after the drug has been launched.
3) The questionnaire should inquire the details about drug, usage, dose, brand
used, and number of patients treated in a given period .
4 ) As mentioned in the literature, the common ADRs seen along with the drug
should be listed at the end of questionnaire.
5) The questionnaire including a prepaid envelope should be mailed to medical
practitioners all over the city/state who are likely to use the drug.
2.3. REPORTING OF ADRS

Reporting of an adverse drug reaction ( ADR ) is one of the most important
parameter of medical treatment . ADR or adverse event reporting involves the
triage, receipt, data entering , distribution , assessment, archiving and reporting of
adverse event data and documentation.
2.3. 1. Benefits
1 ) It helps in evaluating the safety of drug therapies, especially of those drugs
that are approved recently.
2 ) It offers updated drug safety information to health care professionals and
other stakeholders.
3) It aids in evaluating the economic impact of ADR inhibition by reducing
hospitalisation, using optimal and economical drug, and by minimising
organisational liability.
4 ) It ensures patient ’s safety by carrying out following regulatory action on the
basis of ADR reports:
i ) Advancing Inserting package
ii ) Marketing Authorisation Recall ( withdrawal )
iii ) Recalling batch on the basis of ADR cluster
iv ) Classification changes such as:
a ) From over the counter to prescription only medicines.
b ) Special prescription.
c) Restricted prescription.
2.3. 2. Procedure
Who can Report
1 ) All healthcare professionals including clinicians, dentist, pharmacist, nurses,
physician, physiotherapist, etc.
2 All non -healthcare professionals including consumers, patients, etc.
)
When to Report
1 ) ADR should be reported immediately .
2 ) The report can be incorrect and unreliable if the ADR reporting is delayed.
What to Report
1 ) All ADRs as a result of Prescription and Non -Prescription medicinal
products.
2) All suspected ADRs irrespective to product information delivered by the
company.
3) Unpredicted reaction of the ADRs along with the product irrespective of their
nature and severity.
4 ) A serious reaction ( whether expected or not ).
5 ) All suspected ADRs related with drug-drug, drug-food or drug-food
supplements interactions.
6 ) Overdose or medication error leading to ADRs.
7 ) Uncommon lack of efficacy or detection of suspected pharmaceutical flaws.
How to Report
1 ) Standardised ADR reporting form should be used for reporting.
2 ) ADRs in the reporting from should be filled appropriately in case an ADR is
encountered.
3) Separate forms with complete information should be used for every
individual.
4 ) The completely filled ADR form should be then returned to the nearest
adverse drug reaction monitoring Centre ( AMC) or to National Coordinating
Centre.
5 ) Any follow-up information should be forwarded by another ADR form, in
case of an ADR case that has been reported already. It can also be
communicated by telephone, fax or e- mail.
6 ) Follow-up reports should be recognisable including following points:
i) Follow-up Information
ii ) Date of Original Report
iii ) Patient Identity
What Happens to Submitted Information

1 ) At Adverse Drug Reaction Monitoring Centres ( AMCs) by using WHO-
UMC scale the causality assessment should be carried out.
2 ) The analysed forms should be forwarded to the National Coordinating Centre
via ADR database.
3) At last the data should be examined and sent to the Global
Pharmacovigilance Database that is managed by the WHO Uppsala
Monitoring Centre in Sweden.
4) The reports should be revised from time to time by the National Coordinating
Centre ( PvPI ).
5 ) The information produced based on these reports aids in continuous
evaluation of the benefit-risk ratio of medicines.
SUSPECTED ADVERSE DRUG REACTION REPORTING FORM

For VOLUNTARY reporting of Adverse Drug Reactions by Healthcare Professionals
Indian Pharmacopoeia Commission FOR AMC/NCC USE ONLY
( National Coordination Centre Pharmacovigilancc AMC Report No. :
Programme of India ) Ministry of Health & Family Reg . No . / IPD No . /OPD No. /CR No . :
Welfare, Government of India Sector-23, Raj Nagar, Worldwide Unique No.:
Ghaziabad, 201002
Report Type Initial Follow up 12. Relevant tcsts/laboratory data with dates
A . PATIENT INFORMATION
1. Patient 2. Age of time of 3 . M DFC Other 0
Initials. Event of Date of
Birth
4 . Weight Kgs
B. SUSPECTED ADVERSE REACTION 13. Relevant medical/ mcdication history je .g . .
5 . Date of reaction started ( ddmmyyyy ) allergies, race, pregnancy, smoking, alcohol use,
6. Date of recovery ( dd/ mm/ yyyy ) hepatic/renal dysfunction, etc. )
7 . Describe the reaction of problem
14. Seriousness of the reaction: No if Yes
( please tick anyone )
Death ( dd/ mm/yyyy ) Congential -anomaly
Life threatening Required intervention to
D Prevent permanent
Hospitalisation/Prolong impairment/damage
ed - Other ( specify )
C Disability
15. Outcomes
C Recovering Not recovered
Recove
red
Fatal U Recovered with sequelae L Unknown
C. SUSPECTED MEDICATK ) N ( S )
S. No. 8 . Name Manufactur Batch Exp. Dose Route Frequen Therapy dates Indica Causality
( Brand/ er No. Date used used cy tion Assessme
Generic ) ( if known ) /Lot ( if ( OD, nt
No. known ) BD.
etc . )
Date Date
started stoppe
d
i)
in
iii )
iv )
S . No. 9 . Action Taken ( please tick ) 10. Reaction reappeared after reintroduction ( please
( as per tick )
£i
S . No. Name Dose Route Frequency Therapy dates Indication
{ Brand/Generic ) used used ( OD, BD.
etc . }
i) Date started Date stopped
.
i )
iii )
iv )
11 . Concomitant media product including self-medication and herbal remedies with therapy dates ( Exclude
those used to treat reaction )
S . No . Name Dose used Route used Frequency Therapy dates Indication
( Brand/Generic ) ( OD, BD, etc . )
Date started Date stopped
i)
H)
iii )
Additional Information: .
D REPORTED DETAILS
16. Name and Professional Address:
Pin: - _
.E mail
Tel. No. { with STD code )
Occupation: Signature
17. Date of this report { dd /mm/yyyy }:

Confidentiality: The patient s identity is held in strict confidence and protected to the fullest extent.
'
Programme staff is not expected to and will not disclose the reporter’s identity in response to a request from the
public. Submission of a report does not constitute an admission that medical personnel or manufacturer or the
product caused or contributed to the reaction.
Adverse Drug Reaction ( ADR ) Reporting in India

How Indian Population Getting Benifited
ADR Monitoring
Centre (s) ( AMC’s]
.
Healthcare professionals Patients or Pharmaceutical
100 . may report ADR cither directly Industries
Safety Alerts -
to the NCC PvPl or AMCs via Mobile
80 Communication App or Toll Free Number
Reportin
Toll Number
- -
1800 180 3024
[
l ?nd Qtr 3rd Qtr 4th Q»
* Qtr
Case Processing/Quality Review
Case Case
Reverted Invalid/Incomplete Report Reverted
Valid/Complete Report
Uppsala
Monitoring
Causality assessment and data
Centre
mining of reports
Regulatory
I Global safety data collection I action
T ( Signal
Figure 2.1: Adverse Drug Reaction ( ADR ) Reporting in India
2.3.3. Sources of ADR Reports

The source of adverse event reports may include spontaneous reports, expedited
reports, clinical trial reports, and aggregate reporting.
1 ) Expedited Reporting: This type of reporting is also called as Individual
Case Safety Reports ( ICSRs ). It includes a serious and unlabelled event
( event not detailed in the labelling of drug ) which is considered to be related
to drug use . An individual safety report must be submitted to the FDA within
15 days timeframe from the time the pharmaceutical companies receive
notification on day “0”.
In case of reporting in clinical trials such type of cases are are known as
SUSAR ( suspected unexpected serious adverse reaction ) and if it involves an
life-threatening or fatal event then the time frame required for submittig
becomes 7 -day clock .
2 ) Clinical Trial Reporting: This type of reporting is alaso known as serious

adverse event reporting. These reports provide data from clinical trials and
safety information from clinical studies. It provides a tool in estabilishing the
safety of a drug that whether it should be approved for use in human beings
or should deny market authorization. These reports occur as a result of study
on patients or subjects who experinece any serious adverse effect at the time
of clinical trial phases.
3) Spontaneous Reporting: This reporting system is the core data generating
system of international pharmacovigilance. In this the system depends on the
helathcare workers for identifying and reporting any adverse reaction to their
respective national pharacovigilance system (center), recognised helath
authority or directly to the pharmaceutical company manufacturing the drug.
4) Aggregate Reporting: These reports are also known as periodic reporting. They
paly a cricical role in the safety assessement of the drugs. In this type of reporting
system the safety data of a drug is is compiled for a longer period of time ranginf
from month to years. It provides an advantage over other reporting systems that it
rpovides a broader view of the safety profile of a drug. The ost important
aggregate report all arounf the world is Periodic Safety Update Report ( PSUR ).
2.4. METHODS IN CAUSALITY ASSESSMENT

Causality assessment can be defined as the assessment of relationship between the
treatment with any drug treatment and incidence of an adverse reacion or event. It
helps in checking and also evaluating that whether the particular treatment due to
which an adverse event or reaction has occured is co-related with the drug or not.
Casuality assessment is an important part of ADR reporting system and important
task, conducted by National Pharmacovigilance Programme in every country.
2.4. 1 . Objectives
1) Setup relationship between the medicine and events.
2 ) Detection of signal (“a possible causal corelation between the drug and an
adverse event, the relationship being either incompletely documented
previously or unknown ".)
3) Better evaluation of the toxic or beneficial effects of drugs.
4 ) Plays an important part for evaluating ADR reports for regulatory purposes
and in early warning systems.
2.4. 2. Methods
1) Various researchers developed different causality assessment methods by
using applying criteria such as- Chronological relationship between drug
administration and incidence of adverse reaction, any type of prior
information on similar ADRs, Screening for drug and non drug related
causes, confirming the adverse reactions by in-vitro or in -vivo test, etc.
2 ) However , there are no such method that can be accepted universally for
assessing adverse drug recations causality. Therefore, the methods are borad
classified into three categories as follows:
i ) Expert judgment /global introspection

ii ) Algorithms
iii ) Probabilistic methods ( Bayesian approaches)
Methods
Classified under three broad categories
r 1
Expert Judgment /Global Algorithms Probabilistic Methods
Introspection 1 ) Dangaumou’s French 1 ) Australian method
1 ) Swedish method by method 2 ) Bayesian Adverse
Wilholm et al. 2) Kramer et al. method Reactions
2 World
) Health 3) Naranjo scale Diagnostic
Organisation ( WHO) - 4 ) Balanced assessment Instrument
Uppsala Monitoring method ( BARDI )
Centre ( UMC) causality 5 ) Drug Interaction 3) MacBARDI
assessment criteria Probability Scale spreadsheet
( DIPS ), etc.
Figure 2.2: Classification of Causality Assessment Methods
2.4. 2.1 . Expert Judgment /Global Introspection

Expert judgments are individual evaluation on the basis of previous knowledge
and experience in the field . These judgments are made without using any
standardized tool for getting the conclusions regarding causality.
In this process, the expert considers all the relevant and available data about the
possibility of causing the drug event and the expresses the judgment . Adverse
drug reaction is assessed either by individual expert evaluator or by a group of
evaluators (experts). However, the assessment and evaluation of adverse drug
reactions by the evaluators (experts) is based totally on the knowledge,
experience and subject of interest of individual expert.
There are two methods based on expert opinion or global introspection:
1 ) Swedish method by Wilholm et al.: Evaluates the causal relationship by
considering seven different factors:
i ) Aforementioned drug information ii ) The temporal sequence
iii ) Rechallenge iv ) Dose relationship
v) Alternate etiological candidates vi ) Response pattern to drug
vii Associated drugs
)
Events can be categorized as possible or probable and unlikely or non -
assessable **.
Limitation: This method has a drwaback that it has small number of
categories into which causality can be placed, due to which the chances of
overlapping increases and the adverse reactions can be evaluated wrongly.
2 ) World Health Organization ( WHO )
( UMC ) Causality Assessment Criteria
-
Uppsala Monitoring Centre
i ) This method is globally and worlwide accepted.

ii ) WHO- UMC system provides practical tool for assessing the case reports
for International monitoring of drugs.
iii) System helps in detecting the unexpected and unknown adverse reactions.
iv ) The assessment is based on following four criteria :

a ) Absence of other competing causes like, medications, disease
process itself , etc.
b ) Time relationships between the use of drug and adverse drug
reaction or event.
c) Response to re-administration of drug ( re-challenge ).
d ) Response to dose reduction or withdrawal of drug ( de-challenge ).
Based on number of the above criteria that match, the level of causality
association is grouped further into four categories as follows:
i ) Certain: When all the four criteria (a, b,c,d ) match
ii) Probable: When criteria a, b and c meet
iii ) Possible: When only criteria a is met
iv ) Unlikely: When criteria a and b are not met
However, ADR can also be classified into following classes:-

i ) Unclassified/Conditional : Applied when more data is needed and such
data is being sought or is already under examination.
ii ) Unassessable/ Unclassifiable : Finally when the information in a report
is incomplete or contradictory and cannot be verified, then it is
Unclassifiable.
Table 2, 1; Classification of level of Causality
Causality term Assessment criteria ( all points should he reasonably complied )
Certain i) Event or laboratory test abnormality , with plausible time
relationship to drug intake
ii) Cannot be explained by disease or other drugs Response to
withdrawal plausible ( pharmacologically, pathologically )
iii ) Event definitive pharmacologically or phenomenologically ( ie.
an objective and specific medical disorder or a recognized
pharmacologic phenomenon )
iv ) Rechallenge satisfactory, if necessary
Probable/likely i) Event or laboratory test abnormality, with reasonable time
ii) Unlikely to be attributed to disease or other drugs
iii ) Response to withdrawal clinically reasonable
iv ) Rechallenge not required
Possible i) Event or laboratory test abnormality, with reasonable time
ii) Could also be explained by disease or other drugs
iii ) Information on drug withdrawal may be lacking or unclear
Unlikely i) Event or laboratory test abnormality, with a time to drug intake
that makes a relationship improbable ( but not impossible )
ii ) Disease or other drugs provide plausible explanation
Conditional/uncla i) Event or laboratory test abnormality
ssifie d ii ) More data for proper assessment needed , or
iii ) Additional data under examination
Unassessable/uncl i) Report suggesting an adverse reaction
assif iable ii ) Cannot be judged because information is insufficient or contradictory
iii ) Data cannot he supplemented or verified .
Examples
1 ) Certain:
i ) Dizziness after % hour of ingestion of an antihypertensive drug orally with
no concomitant drugs - adverse effect stops on cessation of drug ( positive
dechallenge ) and occurs again when restarted ( positive rechallenge ).
ii ) Reaction at site of injection after 30 seconds of subcutaneous injection.
iii ) A large tablet gets stuck in the pharynx ( obstruction ) at the time of
degglutition and must be removed in the ER .
2 ) Probably:
i ) Diarrhea after ingestion of ampicillin.
ii ) Thrombocytopenia after administration of an oncology drug.
iii ) Vaginal candidiasis after an antibiotic for bronchitis.
3) Possibly:
i ) Headache
ii ) Abnormal liver function tests post antihistamine administration.
iii ) Dyspepsia experienced after ingestion of tablet or capsule.
4 ) Unlikely:
i ) Colon cancer diagnosed after 3 doses of antibiotic.
ii ) Myocardial infarction 3 weeks after taking a drug that has a terminal half
life of 10 minutes.
2.4.2.2. Algorithms
Algorithms are sets of specific questions with associated scores for calculating
the likelihood of a cause-effect relationship. It consists of a problem-specific
flow chart with step-by -step instruction on how to arrive at an answer. Actually,
its form contain some questionnaire , whose answers provide the causality of
particular ADR. It give structured and standardized methods of assessment in a
systematic approach. Assessment of ADRs based on parameters such as Time to
onset of the ADR or temporal sequence, Previous drug /adverse reaction history,
Dechallenge and Rechallenge.
Types of Algorithms Method

There are many algorithmic methods of causality assessment but no single
algorithm is accepted as the “gold standard", because of many shortcomings.
Important Algorithmic Methods are:
1) Dangaumou ’s french method
2 ) Kramer et al. method
3) Naranjo et al. method ( Naranjo scale )
4) Balanced assessment method (Lagier et al .)
5) Summary time plot (Castle et al.)
6) Ciba geigy method ( Venulet et al.)
7 ) Roussel Uclaf causality assessment method ( RUCAM )
8) Maria and Victorino ( M and V ) scale
9) Drug Interaction Probability Scale ( DIPS )
Dangaumou’s French Method

The scores are clustered into likely, possible and dubious in this method. The
advantage of this method is that it allows administration of certain drugs
excluding the suspect drug, as each drug is imputed separately. Hence, this
method requires more time in comparison to other algorithms.
This methods uses following seven criteria in two different tables i.e., three
chronological and four semiological:
1 ) The chronological criteria are:
i ) Drug challenge
ii ) Dechallenge
iii ) Rechallenge with an overall score of four possible categories.
2 ) The semiological criteria are:
i ) Semiology (clinical signs ) per se (suggestive or other )
ii) Favouring factor
iii ) Alternative non -drug-related explanation ( none or possible )
iv ) Specific laboratory test with three possible outcomes ( positive, negative
or no test for the event-drug pair ).
Kramer et al. Method

In this method algorithm is applied to a single clinical exhibition that can occur
after administration of a single suspect drug. When multiple drugs are involved,
every drug can be evaluated separately.
Transparency of this algorithm is one of its advantages. Though, certain levels of

expertise, experience and time are obligatory for the effective use of this method.
Naranjo et al. Method ( Naranjo Scale )

1) This method is widely accepted
2 ) This method facilitates in determining the likelihood of whether an adverse
drug reaction ( ADR ) is actually due to the therapeutic drug rather than the
other factors result.
3) It consists of ten questions that are answered as “yes", “no", and “ unknown”
( don"t know)
4 ) These answers are assigned by a score termed as: Definite, Probable,
Possible Or Doubtful.
i ) Definite- when a total score of > 9.
ii ) Probable- when a total score of 5-8.
iii ) Possible- when a total score of 1-4.
iv) Doubtful- when a total score of < 0.
Question
—
Table 2.2: Naranjo ADR Probability Scale Items and Score
Yes No Don' t know
Are there previous conclusion reports on this reaction? + 1 0 0
Did the adverse event appear after the suspect drug was + 2 -1 0
administered ?
Did the AR improve when the drug was discontinued + 1 0 0
or a specific antagonist was administered?

Did the AR reappear when drug was re -administered? +2 -1 0
Are there alternate causes [ other than the drug ] that -1 +2 0
could solely have caused the reaction?
Did the reaction reappear when a placebo was given ? -1 +1 0
Was the drug detected in the blood or other fluids in a +1
[ ] 0 0
concentration known to be toxic?
Was the reaction more severe when the dose was + 1 0 0
increased or less severe when the dose was decreased?
Did the patient have a similar reaction to the same or + 1 0 0
similar drugs in any previous exposure?
Was the adverse event confirmed by objective evidence? + 1 0 0
Scoring for Naranjo algorithm: >9 = definite ADR 5 8 = probable ADR ; 1 -4 =
; -
possible ADR ; 0 = doubtful ADR .
Balanced Assessment Method ( Lagier etal )

In this method , the case reports are evaluated on a series of Visual Analogue
Scales ( VAS ) based on the possibility of fulfilling each condition. Considering
the possibility of an alternative to causation for every factor ( not as separate
factor) is one of its advantages.
However, each case is evaluated by two independent assessors and their

knowledge level. Thus for giving a reliable evaluations result, an evaluator needs
to be an expert in the specific area.
Ciba Geigy Method ( Venulet et al )

This method was updated and replaced with a checklist of 23 questions that splits
into following three sections:
1 ) History of present adverse reaction
2) Patients past adverse-reaction history
3) Monitoring-physician’s experience
Loupi et al Method
This method is introduced for evaluating the teratogenic potential of drug. If
the drug is not implicated in the origin of the abnormality, then the first
sections of the algorithm ( chrono-semiological axis) allows it to be excluded .
Weight of bibliographical data can be examined by second section
( bibliographical axis ).
The three questions that are considered in this method to arrive at a conclusion on
causality are as follows:
1 ) Alternative etiological candidates other than the drug;
2 ) Chronology of the suspect drug and
3) Other bibliographical data.
Roussel Uclaf Causality Assessment Method ( RUCAM )

This method is developed to determine the disease states before any major
consequences may occur like; liver and dermatological injuries. It can be used for
examining particular organ at a time and is easy quite to process.
Maria and Victorino ( M and V ) Scale

This scale is introduced by Maria and Victorino for diagnosing Drug Induced
Liver Injury ( DILI ). In this scale, the probability can be expressed as a score
between 6 and 20 which is divided into following five causality degrees:
1 ) >17: Definite -
2) 14 17: Probable -
3) 10 13: Possible
-
4) 6 9: Unlikely 5) < 6: Excluded
2.4.2.3. Probabilistic Method ( Bayesian Approaches )

This method is used in case of specific findings while transforming the estimate
of prior probability into posterior probability of drug causation. With the help of
epidemiological information , prior probability can be calculated and posterior
probability combines with the previous information along with the evidence of
the particular case to find out an approximate of causation.
Australian Method
1 ) It is one of the first probabilistic methods used .
2) In this method the conclusions can be drawn based on internal evidence i.e.
timing as well as laboratory information from reported case.
3) While proceeding in the evaluation process, previous knowledge on the
suspect-drug profile is purposely excluded.
Bayesian Adverse Reactions Diagnostic Instrument ( BARDI ):
1 ) It is established to overcome the numerous limitations allied with expert
judgements and algorithms.
2 ) It is used for calculating the odds of a specific drug by comparing adverse
event with an alternative cause. These odds can be known as posterior odds.
The posterior odds factor is calculated by considering six assessment subsets
i.e., one deals with background epidemiologic or clinical trials information
( the prior odds) and the other five deal with case specific information ( the
likelihood ratios). With the help of six assessment subsets, the posterior odds
factor can be calculated. In this, one deal with background epidemiologic or
clinical trials information which is said to be the prior odds and the other five
deal with case specific information that are known as likelihood ratios.
The Five Likelihood Ratios ( LRs):
i ) Patient history ( Hi ).
ii) Timing of the adverse event with respect to drug administration ( Ti ).
iii ) Characteristics of the adverse event (Ch ).
iv ) Drug dechallenge ( De ), ( any signs, symptoms, or occurrences after drug
withdrawal ).
v) Drug re-challenge or re-administration ( Re ) of the suspected causal drug( s).
The product of these factors is the prosterior odds ( PsO).
=
PsO PrO x LR ( Hi ) x LR ( Ti ) x LR (Ch ) x LR ( De ) x LR ( Re )
vi) On either paper or computer, the Bayesian approach can be implemented
as a spreadsheet programme.
vii ) It calculates and provides instant numerical and graphical feedback
immediately after new pieces of evidence of the suspected ADR are evaluated.
2.5. SEVERITY AND SERIOUSNESS

ASSESSMENT
2.5. 1 . Severity of ADRs
Severity defines the extent to which the ADRs effects livelihood of the patient
Modified Hartwig and Siegel Severity Scale
Severity was evaluated according to the classification provided in llartwig's
Severity Assessment Scale, which can be used for severity assessment. On the
basis of severity of the suspected reaction, this scale can be divided into three
categories i.e. mild , moderate, and severe.
Severity describes the extent to which the ADRs influence the everyday life of
the patients. According to Hartwig’s Severity Assessment Scale adverse drug
reactions was categorized into 7 levels of severity by J Seigel and PJ Schneider:
1 ) Level 1: In this level no change is needed in treatment with the suspected
drug in case of ‘mild ' type reaction.
2) Level 2: In this level , the ADR requires that the suspected drug to be
withdrawn or changed. Antidote or other treatment is not required , and the
patient does not require further hospitalisation.
3) Level 3: It is same as level 2
4) Level 4: It is classified in two parts:
i ) Level 4(a ): The patient requires further hospitalisation (at least for a day )
because of level 3 reactions.
ii) Level 4( b ): The patient can be hospitalised due to ADR .
5) Level 5: In this level the produced reactions may need an intensive care unit
attention in the severe type of ADR .
6 ) Level 6: In this level the reactions may cause permanent harm to the patient.
7) Level 7: In this level the patient may die directly or indirectly due to ADR .
Table 2.3: Hartwig’s Severity Assessment Scale
Level 1 An ADR occurred but required no change in treatment with the suspected drug .
Level 2 The ADR required that treatment with the suspected drug be held, discontinued ,
or otherwise changed . No antidote or other treatment requirement was required .
No increase in Length of Stay ( LOS ) .
Level 3 The ADR required that treatment with the suspected drug be held , discontinued ,
or otherwise changed .
and/Or
An antidote or other treatment was required . No increase in Length of Stay ( LOS ).
Level 4 Any level 3 ADR which increases length of stay by at least 1 day .
Or
The ADR was the reason for the admission .
Level 5 Any level 4 ADR which requires intensive medical care.
Level 6 The adverse reaction caused permanent harm to the patient .
Level 7 The adverse reaction either directly or indirectly led to the death of the patient .
Mild = level 1 and 2, moderate = level 3 and 4, severe = 5, 6 and 7.
However, according to Karch and Lasanga severity was classified into minor,
moderate, severe and lethal .
1 ) Minor Severity: Antidote is not required ; drug therapy or prolongation of
hospitalization may be required.
2 ) Moderate Severity: In this the drug therapy might requires some change in
the drugs, specific treatment or the time duration for hospitalization might
increase by at least 1 day .
3) Severe: This class includes all potentially life threatening reactions that can cause
permanent damage to any body organ or might require serious medical care.
4) Lethal: These types of reactions are so dangerous that it can directly or
indirectly result in the death of the patient.
Table 2 ,4: Karch and Lasanga Severity Classification
Severity Description Example
Mild No antidote or treatment is required ; 1 ) Some Antihistamines ( some ) .
hospitalisation is not prolonged . 2) Drowsiness.
3 ) Opioids; constipation .
Moderate A charge in the treatment e.g. , modified 1 ) Hormonal Contraceptives:
(
dosage, addition of a drug ), but no Venous thrombosis.
necessarily discontinuation if drug is 2 ) NSAIDs : Hypertension and
required; hospitalisation may be prolonged, oedema.
or specific treatment may he required .
Severe ADR may be life threatening and 1 ) ACE Inhibitors: Angioedema.

requires immediate discontinuation of 2) Phenothiazines: Abnormal
drug and specific treatment for ADR . heart rhythm .
Lethal Contributes to patient ’s death. 1 ) Acetaminophen Over Dosage:
Liver failure.
2 ) Anticoagulants: Haemorrhage.
2.5.2. Seriousness of ADRs

The seriousness of any adverse drug reaction is associated with the life
threatening nature of that adverse reaction. It can be defined as any unwanted,
undesired or untoward reaction of the therapeutic or medicinal drug that can
cause death, requires hospitalization of the patient, extended hospitalization of
the existing admitted patient, resulting in tenacious or significant disability, is a
birth defect or congenital anomaly, or is a medically important event or reaction.
A serious adverse event or reaction is any untoward medical occurrence

associated with the use of a medical product in a patient that at any dose, the
outcome is one of the following:
1 ) Death: Report if the patient 's death is suspected as being a direct outcome of
the adverse reaction.
-
2 ) Life Threatening: Report if the patient was at substantial risk of dying at the
time of the adverse reaction or it is suspected that the use or continued use of
the product would result in the patient 's death.
3) Hospitalization ( Initial or Prolonged ): Report if admission to the hospital
or prolongation of a hospital stay results because of the suspected adverse
reaction .
4) Disability: Report if the adverse reaction resulted in a significant, persistent, or

permanent disability/ incapacity; (change, impairment, damage, or disruption in
the patient's body function/structure, physical activities, or quality of life).
5) Congenital Anomaly: Report if there are suspicions that exposure to a
medical product prior to conception or during pregnancy resulted in an
adverse outcome in the child ( birth defect ).
6) Medically Important Event or Reaction: Medical and scientific judgment
should be exercised in deciding whether other situations should be
considered serious such as important medical events that might NOT be
immediately life-threatening or result in death or hospitalization but might
cause danger to the patient or might require intervention to prevent one of the
other outcomes as listed above.
2.6. PREDICTABILITY AND PREVENTABILITY

ASSESSMENT
2.6. 1 . Predictability
1 ) Type A ( Predictable ):
i ) Extension of pharmacologic effect.
ii ) Often predictable and dose dependent.
iii ) Responsible for at least 30% of ADRS.
iv ) E.g., anticholinergics and dry mouth .
2 ) Type B ( Unpredictable )
i) Idiosyncratic or immunologic reactions.
ii ) Rare and unpredictable.
iii ) E.g., chloramphenicol and aplastic anaemia, penicillin induced
anaphylactic shock.
By the classification of ADRs predictability can be determined. Aronson
classification was followed in this study according to which adverse drug
reactions are classified into following six types:
1 ) Type A: Augmented, dose-related.
2) Type B: Bizarre, non-dose-related.
3) Type C: Chronic, dose and time-related.
4) Type D: Delayed , time related.
5) Type E: End of use, withdrawal reactions.
6) Type F: Failure of therapy.
Type A, C, D, E and F were assumed to be predictable in the current study ,
whereas Type B was unpredictable.
2.6.2. Preventability
Preventability Assessment Scale
1 ) According to WHO factsheet , it is assessed that at least 60% of ADRs are
preventable. In several countries ADR -related costs like hospitalisation ,
surgery and lost productivity, goes beyond the cost of the medications.
2 ) From the previous studies it is found that 20% to 80% of ADEs and ADRs
are preventable having majority of later studies showing around 60-70%
preventability.
By using Schumock and Thornton scale preventability of ADRs can be evaluated
( Table 1). Any answer of “yes” to any question in this scale proposes that the
ADR might have been preventable. ADRs can be categorised as definitely
preventable, probably preventable or not preventable.
Table 2.5: Modified Schumock and Thornton Scale
Questions for Assessment of Preventability
Definitely Preventable
1 ) Was there a history of allergy or previous reactions to the drug?
2 ) Was the drug involved inappropriate for the patient 's clinical condition?
3) Was the dose, route or frequency of administration inappropriate for the patient’s
age, weight or disease state?
4 ) Was a toxic serum drug concentration ( or laboratory monitoring test ) documented ?
5 ) Was there a known treatment for the Adverse Drug Reaction ?
Probably Preventable
1 ) Was required therapeutic drug monitoring or other necessary laboratory tests not
performed?
2 ) Was a drug interaction involved in the ADR ?
3 ) Was poor compliance involved in the ADR ?
4 ) Were preventative measures not prescribed or administered to the patient?
Not Preventable
If all above criteria not fulfilled.
2.7. MANAGEMENT OF ADRS

The main and primary step in management is withdrawal of suspected drugs.
However, in case the reaction is expected to be dose related, then dose of the
drug must be reduced , and treatment for suspected reaction must be considered.
When an adverse drug reaction is managed, clear therapeutic objective must be
maintained. The drug treatment must not be unnecessarily continued for longer
time period and the patient must be reviewed regularly and simplify management
should be followed. Commonly used plan of action while dealing with suspected
adverse drug reaction is as follows:
Following steps must be followed during the managemnt of any type of
suspected, or unexpected adverse drug recations.
1) Monitoring patient who are at greater risk of developing ADRs.
2) Monitoring patients who are prescribed with drugs highly likely to cause ADRs.
3) Assessing and documenting the patient’s previous allergic status.
4) Assessing patient’s drug therapy for its appropriateness
5) Changing dose of drug
6) Replacement with alternate medicine
7 ) Use of prophylactic regimen
8) Assessing possible drug interactions in multiple therapies
9) Assistant health care professionals in the detection and assessment of ADRs
10) Stimulating health care professionals in reporting an ADR .
11 ) Documentation of suspected reported reactions for further references

12) Obtaining feedback about the reported reaction
13) Educating health care professionals about the importance of reporting an ADR
14) Educating patients
15 ) Creating awareness about ADRs amongst health care professionals, patients
and public
16) Presentation of reports in meetings and conferences
17 ) Conducting workshops/seminars/conferences on ADRs for health care
professionals.
Medical history - symptoms, detailed medication list, temporal
sequence Physical examination Clinical laboratory data
Yes
I
Ls a drug reaction likely? No
l -
Is there a suspicion of drug induced
1
Other etiology likely
hypersensitivity/immunologic reaction ?
I i
Evaluate and treat other
Immune mechanism:
Yes No
I
Non-immune mechanism:
causes of symptoms.
-
1 ) IgE mediated 1 ) Pharmacologic side effect
2) Drug toxicity
2) Cytotoxic
3) Immune complex 3) Drug-drug interactions
-
4 ) Delayed , cell mediated 4) Drug overdose
5) Pseudoallergic
5) Other immune mechanism
6) Idiosyncratic
7) Intolerance
i
Evaluate with appropriate
confirmatory tests
Management:
i
I
Are tests supportive of
1 ) Modify dose.
2) Try drug substitution.
immune drug reaction ? 3) Treat side effects.
I 4) Consider graded challenges.
Yes No
1 3) Implement patient education.
Does test have high negative

predictive value? Yes
Diagnosis of drug
hypersensitivity/immunolo
gic reaction confirmed
No 1
Administer drug with observation.
Management :
1 ) Consider desensitisation ( IgE ) or
-
graded challenge ( non IgE) before
administration, as appropriate.
2) Anaphylactic reactions require
prompt emergency treatment .
3) Avoid drug if possible.
4 ) Consider prophylactic regimen
before administration ( if shown to be
effective).
5) Prudent use of drugs in future.
6 ) Patient education.
Figure 2.3: Process of Management of ADR’S
Introduction to Adverse Drug Reactions (Chapter 2 ) 45
2.8 . SUMMARY
1 ) Adverse drug reactions as per WHO ( 2005 ) can be defined as “any response to a
drug which is noxious and unintended and which occurs or doses normally used in a
man of prophylaxis diagnosis.
2 ) Reporting of an adverse drug reaction ( ADR ) is one of the most important parameter
of medical treatment .
3) ADR or adverse event reporting involves the triage, receipt, data entering ,
distribution, assessment , archiving and reporting of adverse event data and
documentation.
4) Expedited reporting is a type of reporting is also called as Individual Case Safety
Reports ( ICSRs ). It includes a serious and unlabelled event which is considered to be
related to drug use.
5 ) Clinical Trial reporting is a type of reporting is alaso known as serious adverse
event reporting which provide data from clinical trials and safety information from
clinical studies.
6 ) These reports occur as a result of study on patients or subjects who experinece any
serious adverse effect at the time of clinical trial phases.
7 ) Spontaneous reporting is a reporting system is the core data generating system of
international pharmacovigilance.
8) In spontaneous reporting the system depends on the helathcare workers for
identifying and reporting any adverse reaction to their respective national
pharacovigilance system ( center ).
9 ) Aggregate reporting are also known as periodic reporting. In this type of reporting
system the safety data of a drug is is compiled for a longer period of time ranginf
from month to years.
10) Causality assessment can be defined as the assessment of relationship between the
treatment with any drug treatment and incidence of an adverse reacion or event.
11 ) Casuality assessment is an important part of ADR reporting system and important
task, conducted by National Pharmacovigilance Programme in every country.
12) Various researchers developed different causality assessment methods by using
applying criteria such as chronological relationship between drug administration and
incidence of adverse reaction , any type of prior information on similar ADRs.
13 ) The assessment and evaluation of adverse drug reactions by the evaluators ( experts )
is based totally on the knowledge, experience and subject of interest of individual
expert.
14) Algorithms are sets of specific questions with associated scores for calculating the
likelihood of a cause-effect relationship. It consists of a problem-specific flow chart with
step-by-step instruction on how to arrive at an answer.
15 ) Kramer et al. Method , algorithm is applied to a single clinical exhibition that can
occur after administration of a single suspect drug.
.
16 ) Balanced Assessment Method ( Lagier et al ) y the case reports are evaluated on a
series of Visual Analogue Scales ( VAS ) based on the possibility of fulfilling each
condition.
17 ) Loupi et al. method is introduced for evaluating the teratogenic potential of drug.
18 ) Roussel Uclaf Causality Assessment Method ( RUCAM ) is developed to determine

the disease states before any major consequences may occur like; liver and
dermatological injuries.
19 ) Probabilistic method ( Bayesian Approaches ) is used in case of specific findings
while transforming the estimate of prior probability into posterior probability of drug
causation.
20 ) Severity assessment scale, which can be used for severity assessment. On the basis
of severity of the suspected reaction, this scale can be divided into three categories
i.e. mild , moderate, and severe.
21 ) The main and primary step in management is withdrawal of suspected drugs. However,
in case the reaction is expected to be dose related , then dose of the drug must be reduced,
and treatment for suspected reaction must be considered.
2.9 . EXERCISE
2.9. 1. Very Short Answer Type Questions
1) Define adverse drug reaction .
2) What do you mean by algorithm?
3) What is the main objective of ADR monitoring?
4) Define Probabilistic Method .
5 ) Enlist any Two source of ADR reporting.
2.9.2. Short Answer Type Questions

1) Explain the management of ADRs.
2) Discuss two methods in causality assessment .
3) Write a short note on severity and seriousness assessment .
4) Explain severity of ADRs.
2.9.3. Long Answer Type Questions

1 ) Explain adverse drug reaction with classification.
2) Discuss about the detection of ADRs.
Basic Terminologies Used in Pharmacovigilance ( Chapter 3 ) 47
CHAPTER Basic Terminologies Used

3 in Pharmacovigilance
3.1. TERMINOLOGIES OF ADVERSE

MEDICATION RELATED EVENTS
1) Drug/ Medicine: It is any physiological and pathological change
experienced by the beneficiary after having pharmaceutical product. It
comprise of complete formulated and registered product, including the
presentation , packaging as well as associated information .
2 ) Adverse Event
i ) Adverse event, also known as adverse experience, can be defined as any
unexpected/ inappropriate or untoward medical incidence associated with
drug use in humans, with or without any relationship to the drug.
ii) It can be any unintended or unfavorable sign, symptom, or disease
associated temporarily with the use of any drug.
iii ) For example: Physical findings ( increase in B. P. or temperature ),
abnormal laboratory values, symptoms ( nausea, headache, dizziness,
etc.) and medical errors ( miscalculation, misunderstanding of verbal
orders, name confusion in drugs, overdose , route of drug administration,
etc.), transfusion reactions, accidental injuries, Surgery.
3) Adverse Drug Reaction
i ) It can be defined as “Any unintended , noxious or undesirable effect of
drug occurring at doses used normally in humans for the purpose of
diagnosis, prophylaxis or therapy of disease, or for any changes to be
done in physiological function”.
ii) For example: Cough, nausea, vomiting, diarrhea, headaches, skin
reactions ( redness, rashes, itching ), anaphylaxis, anemia, etc.
4) Suspected Adverse Reaction: It occurs when there is a reasonable
possibility that the adverse event is caused by the specific drug. Reasonable
possibility indicates a causal relationship between the adverse event and
drug.
5) Serious Adverse Event or Reaction: It can be defined as any unintended , or
untoward medical intervention at any dose resulting in significant disability
or life threatening death. A serious adverse needs hospitalization of inpatient
or its prolongation.
6) Unexpected Adverse Reaction: It is an adverse reaction in which the nature
or severity of drug is not constant that is mentioned in the domestic labeling
or market approval or is a known characteristic of the medicine.
7 ) Side Effect: It is an undesirable physical symptom caused by taking a drug

or undergoing medical treatment or therapy. For exampe: Diarrhea,
constipation, dermatitis or skin rash, dizziness, dry mouth, headache,
drowsiness, insomnia, etc.
8) Drug Alerts: It is an action of informing a large group of people in
comparison to the initial information holders of alleged relation between a
drug and an adverse reaction. Generally, the term can be used in different
contexts that are confusing like an alert may be from a manufacturer to a
regulator or from a regulator to the public.
9 ) Individual Case Safety Report ( ICSR ): It is a document containing
complete information associated to an individual case. This is provided by a
primary source to describe alleged adverse reactions related to the
administration of one or more medicinal products to a particular patient at a
certain point of time.
10 ) Lack of Efficacy: It is a situation in which an unexpected medicine failure
occur which produce a desired effect determined by previous scientific
investigation.
11 ) Prescription Event Monitoring: It is a system that is generated to monitor
adverse drug events in a population. For identified patients who are receiving
an specified medicine, prescribers are requested to report all events
irrespective to whether they are suspected adverse events.
12 ) Rechallenge: It is a point at which the recipient administers repeats a
medicine once the previous dose is extracted out.
13 ) Dechallenge: It indicates the withdrawal of a drug from a patient. It is that
condition at which the adverse effects might disappear, get reduced , or the
continuity might get broken down.
14 ) Record Linkage: It is a process of assembling information comprising of
two or records, for example, in different sets of medical charts, or in vital
records ( birth and death certificates ) . By this the significant health events can
be easily associated with each other irrespective of different time and place.
3.2. REGULATORY TERMINOLOGIES

1 ) Adverse Event (AE): It can also be called as adverse experinece. Any
unintended , untoward or unexpected , medical incidence or clinical
investigation undergoing in a patient administered with the medical drug,
which might or might not necessarily have any causal relationship with the
drug. Therefore, it can be any unintended or unfavorable sign, symptom , or
disease associated temporarily with the use of any pharmaceutical product,
e.g., Physical findings ( increase in B. P. or temperature ), abnormal laboratory
values, symptoms ( nausea, headache, dizziness, etc.) and medical errors
( miscalculation, misunderstanding of verbal orders, name confusion in drugs,
overdose, route of drug administration , etc.), transfusion reactions, accidental
injuries, Surgery.
Basic Terminologies Used in Pharmacovigilance ( Chapter 3) 49
2 ) Adverse Event of Special Interest ( AESI ): It can be a notable event for any
specificied pharmaceutical product or class of products that can be monitored
carefully by the sponsor. The event can either be serious or non -serious, for
exampe, loss of hair, impotence, loss of taste, etc. It might also include
conditions that coud be potential precursors or can indicate any early for
causing illness or onset of any serious medical conditions in susceptible
individuals. These type of events must be described in protocols or protocol
amendments, and also the investigators must be provided with the
instructions that how and when they must report to the sponsor.
3) Adverse Drug Reaction ( ADR ): As per WHO , adverse drug reaction can be
defined as “any response to a drug which is noxious and unintended, and
which occurs at doses normally used in man for prophylaxis, diagnosis, or
therapy of disease, or for the modification of physiological function.” It is
however considered to necessarily have a causal relationship between the
treatment and the occurrence, i .e. judged as being at least possibly related to
drug ( medical product ) being administered by the reports or a reviewing
health worker.
4) Risk : It can be considered as the probability of developing any outcome or
that something can happen. It can be referred to as a “negative term” but ,
not necessarily always.

5) Absolute Risk or Incidence Rate: It indicates the risk in exposed person’s
population. It is the possibility in a particular population that any event can
affect its members, for example, 1 person in a population of 1000
individuals. It can be measured over time ( indicating incidence ) or at a given
time ( indicating prevalence ).
6) Attributable Risk: It is also known as excess risk. It can be defined as
percentage of difference between the incidences among exposed population
( absolute risk ) and non-exposed ( reference risk ) with incidence among
exposed. It results from an absolute comparison between outcome frequency
measurements, like incidence.
AR
_ ( Incidenceamnng Exposed - Incidence among Non - Exposed ) x 100
IncedenceamongExpose
7 ) For example, if the exposed persons with a specific disease ( outcome ) are A,
and the exposed persons without the disease ( outcome ) are B. The
unexposed persons with disease ( outcome ) are C and the unexposed persons
with disease ( outcome ) are D, then the attributable risk can be calculated by
formula:
[ A / ( A+ B )] - [C / (C+ D)].
8) Potential Risk: It can be defined as any unintended or untoward incidence
for which the pharmaceutical product can be suspected but in condition when
it has not been confirmed. For example, Pre-clinical safety concerns that
have not been observed in clinical studies, adverse effects observed but with
a comparative effect ( with placebo) not large enough to suggest a causal
relationship, and event known to be associated with other products of the
same class.
9 ) Benefit : It is a predictable gain for any individual person or a population .

10 ) Benefit - Risk Analysis: It is the analysis of the beneficial (favorable) and
critical ( unfavorable ) results of undertaking a specific course of action.
11 ) Biological Products: It is a therapeutic or medical products obtained
( prepared ) from biological material of animals, humans or microbiologic
origin, like blood products, vaccines, insulin , etc.
12 ) Causality Assessment: It is the evaluation of the probability that the
therapeutic drug can be the cause of an observed adverse reaction. Causality
assessment is usually made according established algorithms.
13 ) Data - mining: In this Uppsala Monitoring Centre ( UMC) uses an automated
tool , based on Bayesian logic, for the scanning of the WHO database
( Vigibase ) in the process of detecting drug-adverse reaction associations.
14) Case Control Studies: It is the studies that compare cases with an outcome
(disease ) to controls without the outcome (disease ), looking for differences in
precursor exposures.
15 ) Case Reports: They are reports of the ADR of single patients. These types
of reports describe about single patient exposed to a drug and experience a
particular disease (outcome ), usually an adverse event.
16) Case series: Reports of collections of patients who have a common exposure
to examine about their clinical outcomes. In these reports no control group is
present.
17 ) Cohort Studies: It is the studies that identify defined populations and follow
them forward in time, examining their rates of disease. Cohort studies
generally identify and compare exposed patients to unexposed patients or to
patients who receive a different exposure.
-
18) Cross Sectional Studies: These studies examine exposures and outcomes in
populations at one point in time; they have no time sense.
19 ) Descriptive Studies: These studies that do not have control groups, such as
case series, case reports, and analyses of secular trends. They contrast with
analytic studies.
20 ) Development Safety Update Report ( DSUR ): It is a periodic summary
report of safety information for regulators that includes any changes in the
benefit-risk relationship, for a drug, biological or vaccine under
development. These are prepared by the sponsor of all its clinical trials.
21 ) Good Clinical Practice ( GCP): It is a standard for the design, perform,
conduct, monitor, audit, record, analyses, and reporting of clinical trials that
provides assurance that the data and reported results are credible and
accurate. It also assures for the protection of rights, integrity, and
confidentiality of trial subjects.
22 ) Medication Errors: It is any type of error in the medication use process, like
monitoring, prescribing , dispensing, transcribing, and administering.
23) Observational Study: This study includes the investigator who does not
control the therapy, but observes and evaluates the results of ongoing
medical care.
24 ) Periodic Safety Update Report ( PSUR ): These reports include format and
content for providing an evaluation of the risk -benefit balance of a medicinal
product for submission by the marketing authorisation holder at defined time
points during the post-authorisation phase
25 ) Pharmacoepidemiology: It is the study of the utilization and the effects of
drugs in large numbers of people or population.
26 ) Randomised Controlled Trial ( RCT ): It is a study where the
investigator assigns patients randomly to different therapies or drug
treatment studies.
27 ) Suspected Unexpected Serious Adverse Reaction (SUSAR ): It is a
reaction which is both unexpected and serious in nature.
28 ) Excipients: They are all the pharmaceutical substances included to make a
pharmaceutical formulation such as tablet, capsule, ointment , etc., except the
active drug substance.
29) Formulary: It includes a list of medicinal drugs with their methods of
administration, uses, available dose forms, side effects, etc, It also sometimes
includes their methods of preparation and formulas.
30) Incidence: It is the extent or rate of occurrence, especially the number of
new cases of a disease in a population over a period of time.
31 ) MedDRA or Medical Dictionary for Regulatory Activities: It is a
clinically -validated international medical terminology used by regulatory
authorities and the regulated biopharmaceutical industry. The terminology is
used through the entire regulatory process, from pre -marketing to post -
marketing, and for data entry, retrieval , evaluation, and presentation.
32 ) Prescription Event Monitoring ( PEM ): It is a System created to monitor
adverse drug events in a population. Prescribes are requested to report all
events, regardless of whether they are suspected adverse events, for
identified patients receiving a specified drug. Also more accurately named
"cohort -event monitoring".
33 ) Prescription Only Medicine ( POM ): The therapeutic drug or medicinal

product becomes available to the public only on showing prescription.
34 ) Regulatory Authority : It is the regulatory body with the legal authority in
any country having all the responsibility of regulating all matters related with
the drugs.
35 ) Vigibase: It is the name for the WHO International ADR Database.
36 ) Vigimed: E- mail conferencing facility, exclusive to member countries of the
WHO Programme for International Drug Monitoring.
52 Pharmaeovigilance
3.3. SUMMARY
1 ) Drug/ Medicine is any physiological and pathological change experienced by the
beneficiary after having pharmaceutical product.
2) Adverse event, also known as adverse experience, can be defined as any unexpected/
inappropriate or untoward medical incidence associated with drug use in humans,
with or without any relationship to the drug.
3) Adverse Drug Reaction may be defined as “Any unintended , noxious or
undesirable effect of drug occurring at doses used normally in humans for the
purpose of diagnosis, prophylaxis or therapy of disease.
4) Suspected Adverse Reaction occurs when there is a reasonable possibility that the
adverse event is caused by the specific drug
5 ) Serious Adverse Event or Reaction can be defined as any unintended , or untoward
medical intervention at any dose resulting in significant disability or life threatening
death.
6) Side Effect is an undesirable physical symptom caused by taking a drug or
undergoing medical treatment or therapy.
7 ) Individual Case Safety Report ( ICSR ) is a document containing complete
information associated to an individual case.
8) Record Linkage is a process of assembling information comprising of two or
records, for example, in different sets of medical charts, or in vital records ( birth and
death certificates).
9) Adverse Event of Special Interest ( AESI ) can be a notable event for any
specificied pharmaceutical product or class of products that can be monitored
carefully by the sponsor .
10 ) Risk can be considered as the probability of developing any outcome or that
something can happen .
11 ) Absolute Risk or Incidence Rate indicates the risk in exposed person’s
population . It is the possibility in a particular population that any event can affect
its members.
12 ) Potential Risk can be defined as any unintended or untoward incidence for which
the pharmaceutical product can be suspected but in condition when it has not been
confirmed.
13 ) Biological Products is a therapeutic or medical products obtained ( prepared ) from
biological material of animals, humans or microbiologic origin, like blood products,
vaccines, insulin, etc.
14 ) Causality Assessment is the evaluation of the probability that the therapeutic drug
can be the cause of an observed adverse reaction.
15 ) Case Control Studies is the studies that compare cases with an outcome (disease ) to
controls without the outcome ( disease ).
16 ) Cohort Studies is the studies that identify defined populations and follow them
forward in time, examining their rates of disease.
3.4 . EXERCISE
3.4. 1 . Very Short Answer Type Questions
1) Define the following terms:
i ) Adverse Drug Reaction.
ii ) Individual Case Safety Report ( ICSR ).
iii ) Rechallenge.
iv) Risk.
v ) Attributable Risk.
vi) Potential Risk.
i) Biological Products.
ii ) Data - mining.
iii ) Case Reports.
iv) Cohort Studies.
v) Descriptive Studies.
vi ) Development Safety Update Report ( DSUR ).
i) Good Clinical Practice (GCP).
ii ) Pharmacoepidemiology.
iii ) Suspected Unexpected Serious Adverse Reaction (SUSAR ).
iv ) Prescription Event Monitoring ( PEM ).
v ) Prescription Only Medicine ( POM ).

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Introduction to Pharmacovigilance ( Chapter 1 ) ( tppl . org .

or in remote areas having few or no health care

1.1.4. History and Development

1.1.5. WHO International Drug Monitoring Programme

information from all the National pharmacovigilance £

1.1.6. Importance of Safety Monitoring of Medicine

1.1.7. Pharmacovigilance Programme of India ( PvPI )

4 ) July, 2015 onwards Indian Pharmacopoeia Commission - Pharmacovigilance

6) In blood banks, pharmacovigilance also plays an important role as it keeps a record

1.3.2. Short Answer Type Questions

1.3.3. Long Answer Type Questions

CHAPTER Introduction to Adverse

2.1. ADVERSE DRUG REACTIONS ( APRS)

2.1.2. Classification of ADRs

2. I . 2. I . ADR C lassification Based on Severity

2.1 .2.2. Rawlins and Thompson Classification of ADR ( 1991 )

• Uncommon (occurs rarely )- discolouration of teeth

2.1 . 2.3. Wills and Brown Classification for ADR

ii ) esterase inhibitor deficiency,

2.1.3. Objectives of ADR Monitoring

2.1 .4. Benefits of ADR Monitoring

2.2. DETECTION OF ADRS

7 ) Patients treated with medicines having low therapeutic index

Detection Method of ADRs

2.2.1. Pre - marketing Studies

2.2.2. Post- marketing Surveillance

2.2.3. Assessing Casuality

2.2.4. Communicating ADRs

2.2.5. Postal Survey Method

2.3. REPORTING OF ADRS

What Happens to Submitted Information

SUSPECTED ADVERSE DRUG REACTION REPORTING FORM

17. Date of this report { dd /mm/yyyy }:

Adverse Drug Reaction ( ADR ) Reporting in India

2.3.3. Sources of ADR Reports

2 ) Clinical Trial Reporting: This type of reporting is alaso known as serious

2.4. METHODS IN CAUSALITY ASSESSMENT

i ) Expert judgment /global introspection

Figure 2.2: Classification of Causality Assessment Methods

2.4. 2.1 . Expert Judgment /Global Introspection

i ) This method is globally and worlwide accepted.

iv ) The assessment is based on following four criteria :

However, ADR can also be classified into following classes:-

Types of Algorithms Method

Dangaumou’s French Method

Kramer et al. Method

Transparency of this algorithm is one of its advantages. Though, certain levels of

Naranjo et al. Method ( Naranjo Scale )

or a specific antagonist was administered?

possible ADR ; 0 = doubtful ADR .

Balanced Assessment Method ( Lagier etal )

However, each case is evaluated by two independent assessors and their

Ciba Geigy Method ( Venulet et al )

Roussel Uclaf Causality Assessment Method ( RUCAM )

Maria and Victorino ( M and V ) Scale

2.4.2.3. Probabilistic Method ( Bayesian Approaches )

2.5. SEVERITY AND SERIOUSNESS

Severe ADR may be life threatening and 1 ) ACE Inhibitors: Angioedema.

2.5.2. Seriousness of ADRs