Dr.

Bintoo Sharma
NIPER JEE All India Rank 10th

[Link]

B. PHARM

PHARM D (POST BACCALAUREATE)

Assistant professor, SDGI Global University,

(Ghaziabad)

UNIT-1 (Part-2)

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”
Classification of ADR:
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).
ADR Classification Based on Severity
 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
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.
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 reported in the
hospital or directly to the health District
Detection Method of ADRs
1. Pre-marketing Studies: (i) The safety test of new formulated medicines is done on
animal models.
(ii) Specific animal studies for carcinogenicity, teratogenicity and mutagenicity are
easily accessible.
(iii) distinct phases of clinical trials are performed before submitting the final report
to a marketing authorisation application (MAA).
(iv) 4) ADRs having frequency greater than 0.5-1.0% can be easily identified by
performing clinical trials
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 diseasefree 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.
[Link] 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.

[Link] 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.

[Link] 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.

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.
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
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 WHOUMC 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.
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).

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.
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.
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)

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
[Link] 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): Uppsala Monitoring Centre(UMC)
Causality Assessment Criteria
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.
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)
SEVERITY ASSESSMENT AND SERIOUSNESS ASSESSMENT
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.
According to Karch and Lasanga severity was classified into minor, moderate,severe and lethal.

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.
PREDICTABILITY AND PREVENTABILITY ASSESSMENT
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.
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. 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.
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.