Adverse drug reaction monitoring

ADVERSE DRUG
REACTION
MONITORING
DR. KHUSHBOO BHOJWANI
BDS, MSC CLINICAL RESEARCH

CONTENT
Terminologies
What is ADR?
Classification of ADR
Objective of ADR monitoring
Why ADR is important?
Adverse drug reaction reporting form.
Reporting of adverse drug reaction.
Haemovigilance
Adverse event following immunization
Causality Assessment of Adverse Event

ADVERSE DRUG REACTION
In the pre-approval clinical experience with a new
medicinal product or its new usages, particularly as
the therapeutic dose(s) may not be established: all
noxious and unintended responses to a medicinal
product related to any dose should be considered
adverse drug reactions. The phrase responses to a
medicinal product means that a causal relationship
between a medicinal product and an adverse event
is at least a reasonable possibility, i.e. the
relationship cannot be ruled out

ADVERSE EVENT
Any untoward medical occurrence in a patient
or clinical investigation subject administered a
pharmaceutical product and which does not
necessarily have a causal relationship with this
treatment.

SERIOUS ADR
Any untoward medical occurrence that at any dose:
• Results in death,
• Is life-threatening,
• Requires inpatient hospitalization or prolongation of
existing hospitalization,
• Results in persistent or significant
disability/incapacity,
• Is a congenital anomaly/birth defect.

AN ADVERSE DRUG REACTION
(ADR) CASE REPORT
A case report in ADR monitoring
programme is a notification relating to
a patient with an adverse effect or
laboratory test abnormality suspected
to be induced by a medicinal product

INTRODUCTION
• According to WHO, adverse drug reaction is
defined as “any response to a drug that is noxious
and unintended and that occurs at doses used in man
for prophylaxis, diagnosis or therapy.”
• All drugs are capable of producing adverse effects
and whenever a drug is given a risk is taken.
• Adverse effect may develop promptly or only after
prolonged medication or even after stoppage of the
drug.

CLASSIFICATION OF ADVERSE
DRUG REACTION

TYPE A OR EXPECTED
UNDESIRABLE EFFECTS
• Type a adverse effects are called augmented
effects.
• These are largely predictable and dose dependent.
• There incidence rate is high but mortality is rare
or very low
• Reduction in dose can minimize these adverse
effects.

SIDE EFFECTS
• Undesirable effects which are observed even with the
therapeutic doses of the drug
• Usually mild and manageable
• Example:
dicyclomine (an anticholinergic drug)
• Desirable effect- antispasmodic action
• Side effect- dryness of mouth
Promethazine ( an antihistaminic drug)
• Desirable effect- antiallergic action
• Side effect- sedation
Atropine (preanaesthetic medication)
• Desirable effect- antisecretory action
• Side effect- dryness of mouth

SECONDARY EFFECTS
These are the indirect consequences of a primary action
of the drug.
Example:
• Development of superinfection after suspension of
bacterial flora by antibiotics

TOXIC EFFECTS
• These are the result of excessive pharmacological action of
the drug due to the over dosage or prolonged use.
• Over dosage may be absolute or relative
• Toxic effects are predictable and dose related
• Toxicity may result from extension of the therapeutic effect
itself
• Example:
• Bleeding due to high doses of heparin.
• Hallucination, delirium with overdoses of atropine causes
atropine poisoning.
• Hypoglycaemia due to insulin

UNEXPECTED UNDESIRABLE
EFFECTS (TYPE B ADR OR BIZARRE
EFFECTS
• These arise unexpectedly, even when the drug is used
in therapeutic doses.
• These are grouped as unpredictable responses
because there is no linear relationship with drug
doses.
• These are relatively uncommon but, if occur
mortality rates are high.
• Reduction in the dose does not reduce the risk for
type B adr.

DRUG ALLERGY
• Allergic responses to drug occur when there has been
previous exposure to drug and when this sensitised
individual is re exposed to the same drug again.
• During the first uneventful exposure, the drug acts as a
hapten, which after combing with the host protein become
antigenic, specific antibodies are formed against this antigen.
• On reexposure, there is then antigen antibody response
which results in the release of the chemical mediators of
allergy(histamine, leukotriene) causing effects like urticaria,
rhinitis, pruritis, asthma.

TYPE 1 OR IMMEDIATE TYPE
• Allergy develops within minutes and lasts for 2-3
hour.
• The drug causes formation of tissue sensitizing IgE
antibodies that are fixed to mast cell or leucocyte.
• The subsequent exposure to drug activates the
release of chemical mediators of allergy.
• Results into itching, asthma, rhinitis, urticaria or
anaphylactic shock.

TYPE 2 OR ACCELERATED ALLERGY
OR ANTIBODY DEPENDENT
CYTOTOXIC HYPERSENSITIVITY
• It results when a drug(antigen) binds to RBC and is
recognized by IgG antibody.
• The antigen-antibody reaction then triggers the lysis of RBC
either by activating complement system or by the action of
cytotoxic T cell or by phagocytosis by macrophages.
• Example:
• Thrombocytopenia, agranulocytosis, fever and systemic lupus
erythematous after the use of quinidine, penicillin G.
• It results within 72 hours of drug administration.

TYPE 3 OR SERUM SICKNESS
TYPE
• It occurs after 72 hrs. but within 1-2 weeks of drug
administration.
• Soluble antigen-antibody form complexes which are
deposited on vascular endothelium and active complement.
• It is characterized by allergic inflammatory reactions in
tissue, glomerular nephritis and serum sickness(fever,
urticaria, lymphadenopathy

TYPE 4 OR DELAYED OR CELL
MEDIATED HYPERSENSITIVITY
• These reaction are mediated by sensitised T cells
following contact with an antigen.
• The activation of sensitised T cell results in the
release of cytokines which activate macrophages,
granulocytes and natural killer cells to generate an
inflammatory response
• Example:
• Photosensitivity and rashes with fever
• Contact dermatitis

IDIOSYNCRATIC DRUG
RESPONSE
• It is genetically determined abnormal reactivity to a chemical
• Certain adverse effects of some drugs are largely restricted to
individuals with a particular genotype
• These are harmful and sometimes fatal reactions that occur in a
small minority of individuals, for which the cause is yet poorly
understood
• Examples:
• Barbiturates causes excitement and mental confusion in some
individual
• Occurrence of aplastic anaemia with a single dose or either low
doses of chloramphenicol is in approximately 1:50000 patients.

TYPE C (CHRONIC EFFECTS) DRUG
• These are the adverse effects that are associated with prolonged use of drug.
• Drug dependence:
• Drugs are capable of altering mood and feelings are liable to repetitive use
to derive euphoria, withdrawal from reality, social adjustment etc
• Physiological dependence:
• It is said to have developed when the individual believes that optimal state
of wellbeing is achieved only through the actions of the drug.
• Physical dependence:
• It is an altered physiological state produced by repeat administration of drug
which necessitates the continued presence of the drug to maintain
physiological equilibrium.
• Discontinuation of the drug results in a characteristic withdrawal syndrome.
• Drug producing physical dependence are-
• Barbiturates
• benzodiazepines

• Drug abuse:
• refers to use of a drug by self medication in a manner and
amount that deviates from the approved medical and social
pattern in a given culture at a given time.
• Drug addiction:
• it is a pattern of compulsive drug use characterized by
overwhelming involvement with the use of drug even after
withdrawal most addicts tend to relapse.
• Drug habituation:
• it denotes less intensive involvement with the drug, so that its
withdrawal produces only mild discomfort.
• Consumption of tea, coffee, tobacco, social drinking are
regarded as habituating, not dependence.

TYPE D(DELAYED EFFECT)
DRUGS
• These are the adverse effects that occur remotely from the
treatment i.e., delayed adverse effect in patients years after
the treatment, or effects appearing in their children who did
not receive that treatment.
• Teratogenic effects are also type D ADR
• Drugs can affect the foetus at three stages:
• Fertilization and implantation
• Organogenesis: 18 to 55 days of gestation, most vulnerable
period, deformities are produced
• Growth and development: 56 days onwards, development
and functional abnormalities can occur
• Ace inhibitors can cause hypoplasia of lungs

TYPE E (END OF TREATMENT
EFFECTS) DRUG
• These ADRs occur when a drug is suddenly discontinued.
• It mostly result in the worsening of clinical condition for
which the drug was being used.
• Examples:
• Withdrawal seizures after suddenly stopping
phenytoin(antiepileptic)
• Withdrawal symptoms of barbiturates include anxiety,
nausea, hallucination, seizures
• Worsening of angina pectoris or myocardial infarction may
result from stoppage of beta blockers

OBJECTIVE OFADR MONITORING
• To detect the nature and frequency of ADRs including
periodic reevaluation of the benefit-risk ratio of medicinal
products in order to assist the drug regulatory authority,
public health programs, scientists and consumer society take
appropriate action to minimise risks of ADR
• Providing updated drug safety information to health care
professionals
• Upgrading package insert, design appropriate package insert
information and dissemination of information which may
constitute withdrawal of the product in the market or
restrictions for marketing

• Initiation of further studies for education value. For
example benefit of the drug especially in long term for
prevention of relapse or study of new indication, overuse,
possible mechanism underlying the adverse reaction
observed or misuse
• To identify risk factors that may predispose, induce or
influence the development, severity and incidence of
adverse reactions in the population examples;
• i. Patient factors: genetics, racial differences, diets,
diseases, prescribing practices, culture of drug use and
traditions of the people e.g. high carbohydrate, fat diet etc.
• ii. Drug interactions, drug distribution, storage and use
including indications, dose, availability and other
underlying conditions

WHYADVERSE
DRUG REACTION IS
IMPORTANT???

HOW TO FILL THE ADR
REPORTING FORM????

PATIENT INFORMATION
1. Patient initials: A reporter should only mention the
initials of a patient instead of the full name. For e.g.:
Madhu Gupta should be written as MG.
2. Age at time of event or date of birth: A reporter
must report either the date of birth or age of the
patient at the time the event or reaction occurred.
3. Sex: A reporter must mention the gender of the
patient.
4. Weight: The weight of the patient should be in
kilograms.

SUSPECTED ADVERSE
REACTION
5. Date of reaction started: A reporter must report the
date on which the reaction was first observed.
6. Date of recovery: If the reaction recovered, the date
on which the reaction recovered should be reported.
7. Describe reaction: A reporter must briefly describe
the event in terms of nature, localization etc.

SUSPECTED
MEDICATION
8. The details of suspected medication(s) such as the drug
name (brand or generic name), manufacturer, batch no/lot
no, expiry date, dose used, route used, frequency, dates of
therapy started and stopped, and indication of use must be
provided by the reporter

9. De-challenge details: A reporter must report the status of
de-challenge as:
A) ‘Yes’- if reaction abated or reduced after de-challenge
B)‘No’- if reaction did not abated after de-challenge
C) ‘Unknown’- if information on de-challenge is not
confirmed or not known
D) ‘Not Applicable’ or ‘NA’- if de-challenge is not possible as
in case of anaphylaxis, life threatening events, anaesthetic
drugs or where a single dose is given.
E) ‘Reduced dose’- If dose at which the reaction occurred is
reduced
Note: Also mention the reduced dose

10. Re-challenge details: A reporter must report the status of
re-challenge as:
‘Yes’- if reaction reappeared after re-challenge
‘No’- if reaction did not reappear after re-challenge
‘Unknown’- if information on re-challenge is not confirmed
or not known
‘Not Applicable’ or ‘NA’- if re-challenge is not applicable as
in the case of injections.
‘Re-introduced dose’- If the drug is reintroduced is it a
reduced dose or is it the same dose at which adverse event
occurred initially.

11. Concomitant drugs: A reporter should include
all the details of concomitant drugs including self
medication, OTC medication, herbal remedies with
therapy dates (start and stop date.)
12. Relevant tests/ laboratory data: A reporter must
mention any laboratory data (if available) relevant
to the adverse event that occurred.
13. Other relevant history: A reporter must mention
any relevant history pertaining to the patient
including pre-existing medical conditions (e.g.
allergies, pregnancy, smoking, alcohol use,
hepatic/renal dysfunction).

14. Seriousness of the reaction: If any event is serious in nature, a reporter must
select the appropriate reason for seriousness :
‘Death’- if the patient died due to the adverse event
‘Life-threatening’- if patient was at substantial risk of dying because of the
adverse event
‘Hospitalisation/prolonged’- if the adverse event led to hospitalization or increased
the hospital stay of the patient
Disability’- if the adverse event resulted in a substantial disruption of a person's
ability to conduct normal life functions
‘Congenital anomaly’- if exposure of drug prior to conception or during
pregnancy may have resulted in an adverse outcome in the child.
‘Required intervention to prevent permanent impairment/damage’- if medical or
surgical intervention was necessary to preclude permanent impairment of a body
function, or prevent permanent damage to a body structure
‘Other’ -when the event does not fit the other outcomes, but the event may put the
patient at risk and may require medical or surgical intervention to prevent one of
the other outcomes. Examples include serious blood dyscrasias (blood disorders)
or seizures/convulsions that do not result in hospitalization, development of drug
dependence or drug abuse

15. Outcomes: The reporter must tick the outcome of
the event as:
‘Fatal’- if the patient dies due to the adverse event
‘Continuing’- if the patient is continuing to have the
symptoms of the adverse event which occurred
‘Recovering’- if the patient is recovering from the
existing adverse event
‘Recovered’- if the patient has recovered from the
event
‘Unknown’- if the outcome is not known

REPORTER
16. Name and Professional address: A reporter must
mention his/her name and professional address on the
form. The identity of the reporter will be maintained
confidential
17. Causality assessment: The reporter (if trained)
must perform the causality assessment.
18. Date of report: Mention the date on which he/she
reported the adverse event

WHO CAN REPORT?
All healthcare professionals (clinicians,
dentists, pharmacists, nurses etc) and non-
healthcare professionals including consumers
can report suspected adverse drug reaction.

WHY TO REPORT?
As a healthcare professional, it is a moral responsibility to
report adverse reactions associated with use of medicines and
safeguard the health of public. The safety of more than 1.2
billion population is a concern and occurrence of ADR
constitute a significant economic burden on the patient and
government. India has a vast genetic and ethnic variability
with different disease prevalence. Use of multi-modal
practices, poor patient compliance are the other factors
requires ADR reporting.

WHAT TO REPORT
• In order to foster the culture of reporting, PvPI encourages
reporting of all types of suspected ADRs- irrespective of whether
they are
• known or unknown,
• serious or non-serious,
• frequent or rare and regardless of a established causal relationship.
• Although pharmacovigilance is primarily concerned with
pharmaceutical medicines and vaccines, adverse reactions
associated with drugs used in traditional medicine (e.g. herbal
remedies)
• special field of interest associated with the drug use in
pregnancy, lactation, paediatric and geriatric.

HOWAND WHOM TO
REPORT?
Use the “suspected adverse drug reaction reporting
form” which is available on the official website of
IPC (www.ipc.gov.in) as well as CDSCO
(www.cdsco.nic.in) to report any ADR.

HAEMOVIGILANCE
• Haemovigilance programme in India is a process of data
collection and analysis of transfusion related adverse
reactions in order to investigate their causes and outcomes
and prevent their occurrence and recurrence.
• Haemovigilance was launched across the country under the
following term of references:
• To track adverse reactions/events and incidence associated
with blood transfusion and blood product
administration.(Haemovigilance)
• To help in identifying trends, recommend best practises and
interventions required to improve patient care and safety,
while reducing overall cost of the healthcare system.

GUIDANCE FOR REPORTING
ADVERSE EVENT FOLLOWING
IMMUNIZATION
• AEFI is defined as a medical event that takes place after
immunization, causes concern and is believed to be caused by
immunization. The AEFI should be handled effectively in
order to maintain/restore public faith in immunization
programme.
• AEFIs may occur due to intrinsic property of vaccines and
constituents like stabilizers, adjuvant, antibiotics, diluents,etc
added to vaccines or hypersensitivity of some individuals to
vaccine component.
• AEFI may also result as a result of inappropriate storage,
improper handling, preparation and administeration,etc. of
vaccines.

• AEFI surveillance monitors immunization safety,
detects and respond to adverse event, corrects unsafe
immunization practises, reduces the negative impact of
the event on health and contributes to the quality of
immunization activities.

CAUSALITYASSESSMENT
• Causality assessment is defined as the evaluation of the
likelihood that a medicine was the causative agent of an
observed adverse event.
• Whether or not an adverse drug reaction is attributable
to the drug can be established by causality assessment
using the following parameters:
• Timing(between administration of a drug and
development of an ADR)
• Dose-response relationship
• Nature of reaction
• Absence of alternative etiologies
• Past history of reaction to same or related medication.

NARANJOALGORITHM FORASSESSING
PROBABILITY OFAN ADR
The Naranjo algorithm, Naranjo Scale, or Naranjo
Nomogram is a questionnaire designed for determining
the likelihood of whether an ADR is actually due to the
drug rather than the result of other factors.

SCORING
≥ 9 = definite ADR
5-8 = probable ADR
1-4 = possible ADR
0 = doubtful ADR

WHO-UMC CAUSALITY ASSESSMENT
SCALE
Causality term Assessment criteria
Certain • Event or laboratory test abnormality, with plausible time
relationship to drug intake.
• Cannot be explained by disease or other drugs
• Response to withdrawal possible(pharmacologically,
pathologically)
• Rechallenge satisfactory, if necessary.
Probable/likely • Event or laboratory test abnormality, with reasonable time
relationship to drug intake
• Unlikely to be attributed to disease or other drug
• Response to withdrawal clinically reasonable
• Rechallenge not required
Possible • Event or laboratory test abnormality, with reasonable time
relationship to drug intake
• Could also be explained by disease or other drug
• Information on drug withdrawal may be lacking or unclear

Causality term Assessment criteria
Unlikely • Event or laboratory test abnormality, with a time to
drug intake that makes a relationship improbable(but
not impossible)
• Disease or other drugs provide plausible explanation
Conditional/
unclassified
• Event or laboratory test abnormality
• More data for proper assessment needed or
• Additional data under examination
Unassessable/
unclassifiable
• Report suggesting an adverse reaction
• Cannot be judged because information is insufficient
or contradictory
• Data cannot be supplemented or verified

Adverse drug reaction monitoring

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