SYNOPSIS OF PRACTICE SCHOOL

ON
PHARMACOVIGILANCE
Submitted to

Department of Pharmacy Practice

K.K. College of Pharmacy

KRA Campus, 1/161, Sankaralinganar Road,
Gerugambakkam Main Rd, Chennai, Tamil Nadu
600128

Submitted by
VISHAL N
560021504597
[Link] 7TH SEMESTER
SEPTEMBER 2025
 INDEX

S. No PARTICULARS Pg. No.

MODULE-I (INTRODUCTION TO PHARMACOVIGILANCE)

1 EVOLUTION OF PHARMACOVIGILANCE AND NEED FOR MONITORING 3

SAFETY
2 ORGANISATION OF PHARMACOVIGILANCE 5
3 PHARMACOVIGILANCE PROGRAM OF INDIA 6

4 SAFETY MONITORING WITH TRADITIONAL MEDICINES 7

5 VACCINE SAFETY 9
6 STANDARD TERM AND TERMINOLOGY IN PHARMACOVIGILANCE 10

MODULE-II (CLINICAL PHARMACOLOGY OF ADRs)

7 CLASSIFICATION WITH MECHANISM 12

8 DRUG ALLERGY AND HYPERSENSITIVITY WITH THE MECHANISM 12

9 DRUG SAFETY IN SPECIAL POPULATION – ELDERLY, PEDIATRIC, 13
PREGANCY AND LACTATION
10 DRUG INTERACTION 15

MODULE-III (EVALUATION, MANAGEMENT AND REPORTING OF ADRs)

11 APPROACH TO EVALUATE AN ADR 16

12 REPORTING ADR IN STANDARD FORM 18

13 METHODS OF ADR REPORTING 20
14 POST-MARKETING ADVERSE DRUG REACTION REPORTING – SUMMARY 21
REPORTS (PSUR, PBRER)
15 MANAGEMENT OF ADRs 22

MODULE-IV (CAUSALITY ASSESSMENT)

1
16 CAUSALITY MODELS AND ASSESSMENT WITH CASE STUDIES 24
17 PHARMACOVIGILANCE DATABASES AND SIGNAL DETECTION 26

18 STATISTICAL REASONING AND ALGORITHMS IN PHARMACOVIGILANCE 28

19 RISK ASSESSMENT AND MANAGEMENT 30

MODULE-V (CASE PROCESSING)

20 INDIVIDUAL CASE SAFETY REPORTING 33
21 NARRATIVE WRITING IN PHARMACOVIGILANCE 34
22 MedDRA – INTRODUCTION AND CODING WITH MedDRA 36
23 CASE STUDY AND ASSIGNMENT 39
24 REFERENCE 46

MODULE-I
2
 INTRODUCTION TO PHARMACOVIGILANCE

I. Evolution of Pharmacovigilance
Pharmacovigilance (PV) evolved as a response to drug-related tragedies and the growing
realization that pre-marketing trials cannot detect all possible adverse effects.
1. Pre-1960s – No Formal PV Systems
 Drugs were marketed with minimal post-marketing safety monitoring.
 1937 – Sulfanilamide Tragedy (USA): 107 deaths due to diethylene glycol solvent →
led to US Federal Food, Drug, and Cosmetic Act (1938).
 1950s – Chloramphenicol-induced aplastic anemia highlighted rare but severe
ADRs.
2. 1960s – Birth of Modern PV
 1961 – Thalidomide Disaster: Used in pregnancy for morning sickness → caused
~10,000 cases of phocomelia and birth defects worldwide.
 Triggered global drug safety reforms:
o Strengthened drug approval requirements.
o Mandatory ADR reporting.
o Birth of WHO Programme for International Drug Monitoring in 1968 (pilot
in 10 countries).
3. 1970s–1980s – Structured PV Systems
 Establishment of national PV centers in many countries.
 WHO established the Uppsala Monitoring Centre (UMC) in Sweden (1978) to
manage global ADR data (VigiBase).
4. 1990s – Harmonization
 Creation of International Council for Harmonisation (ICH) – developed
standardized safety reporting guidelines (e.g., ICH E2A for clinical safety data
management).
 Introduction of Periodic Safety Update Reports (PSURs).
 Electronic databases like FAERS (FDA) and EudraVigilance (EMA).
5. 2000s–Present – Expansion of Scope
 PV now includes:

3
 o Vaccines (AEFI monitoring).
o Herbal & traditional medicines.
o Medical devices and biologics.
o Post-marketing surveillance for rare, long-term ADRs.
 Real-time electronic reporting and patient participation.
 Risk–benefit evaluation is now continuous through a product’s life cycle.
Need for Monitoring Drug Safety
1. Limitations of Pre-Marketing Trials
 Small sample sizes (usually a few thousand).
 Short duration (weeks–months).
 Exclude vulnerable groups (pregnant women, elderly, children, patients with
comorbidities).
 Cannot detect rare ADRs (incidence <1/10,000) or long-term effects.
2. Changing Drug Use Patterns
 Widespread polypharmacy increases drug–drug interaction risk.
 Rapid drug approvals for emerging diseases (e.g., COVID-19) need close post-
marketing watch.
3. Public Health Importance
 ADRs are a major cause of morbidity, mortality, and hospitalization.
 WHO estimates ADRs are among the top 10 causes of death in some countries.
 Monitoring ensures early detection, timely intervention, and prevention of harm.
4. Regulatory & Ethical Responsibility
 Continuous benefit–risk evaluation is essential for regulatory approval maintenance.
 Protects patients and maintains trust in healthcare systems.
 Informs label changes, dose adjustments, contraindications, or drug withdrawals.
5. Learning from Past Disasters
 Thalidomide, rofecoxib (Vioxx), cisapride, and others showed the cost of inadequate
monitoring.
 PV aims to prevent repetition of such tragedies.
[Link] of Pharmacovigilance
4
Introduction:
Pharmacovigilance is the science and activities related to the detection, assessment,
understanding, and prevention of adverse effects or any other drug-related problems. The
references provided in the image suggest a comprehensive approach to pharmacovigilance,
involving various organizations and resources.
Key Organizations and Resources
1. World Health Organization (WHO)
- WHO plays a crucial role in global pharmacovigilance through initiatives like the WHO
Programme for International Drug Monitoring.
- Resources: WHO website, pharmacovigilance guidelines, Vigiflow (a platform for
managing pharmacovigilance data), and Vigibase (WHO's global database of individual case
safety reports).
2. European Medicines Agency (EMA)
- EMA is responsible for the evaluation and supervision of medicines in the European
Union.
- Resources: EMA website, guidelines on pharmacovigilance, and the Pharmacovigilance
Risk Assessment Committee (PRAC).
3. National Center for Biotechnology Information (NCBI)
- NCBI provides access to a wide range of biomedical literature and resources, including
information on pharmacovigilance.
- Resources: PubMed, books, and databases.
Activities and Processes
1. Signal Detection
- Identifying potential safety issues related to drugs.
- Resources: Vigibase, signal detection tools, and data analysis software.
2. Risk Assessment
- Evaluating the risks associated with drugs.
- Resources: Guidelines from EMA and WHO, risk assessment committees like PRAC.

3. Data Management
- Collecting, managing, and analyzing pharmacovigilance data.
5
 - Resources: Vigiflow, pharmacovigilance databases, and data management systems.
4. Regulatory Compliance
- Ensuring adherence to pharmacovigilance regulations and guidelines.
- Resources: Regulatory guidelines from EMA and WHO, compliance training programs.
5. Communication and Education
- Informing healthcare professionals and patients about drug safety issues.
- Resources: Educational materials, safety alerts, and public health campaigns.
Importance
- Pharmacovigilance is essential for ensuring drug safety and protecting public health.
- The organization of pharmacovigilance involves a collaborative effort among various
stakeholders, including regulatory agencies, healthcare professionals, and patients.
Challenges
- Ensuring timely and accurate reporting of adverse events.
- Managing and analyzing large volumes of pharmacovigilance data.
- Balancing the need for drug safety with the need for access to effective treatments.
Future Directions
- Leveraging technology, such as artificial intelligence and machine learning, to improve
pharmacovigilance.
- Enhancing global collaboration and data sharing.
- Increasing patient engagement and empowerment in pharmacovigilance.

[Link] Program of India (PvPI):

The Pharmacovigilance Program of India (PvPI) is a government initiative that aims to
identify and respond to drug safety problems in India. Established in July 2010 by the
Central Drugs Standard Control Organization, the program initially had the All-India
Institute of Medical Sciences, New Delhi, as its National Coordination Centre. Later, the
Indian Pharmacopoeia Commission in Ghaziabad took over ¹.

Key Aspects of PvPI-

Objective:
6
Safeguard the health of the Indian population by ensuring the benefits of medicines outweigh
the risks associated with their use.
Scope:
The PvPI addresses challenges like counterfeit drugs, antimicrobial resistance, and
surveillance during mass vaccinations and national programs.
Operations:
The program has established 250 adverse drug monitoring centers across India and provides
training to healthcare professionals.
History of Pharmacovigilance in India:
 Pharmacovigilance in India began in 1986 with a formal adverse drug reaction (ADR)
monitoring system.
 India joined the World Health Organization (WHO) Program for International Drug
Monitoring in 1998.
 The National Program of Pharmacovigilance launched in 2005 was later renamed
PvPI in 2010.

[Link] MONITORING WITH TRADITIONAL MEDICINE

INTRODUCTION:
Traditional medicine (TM) includes systems such as Ayurveda, Siddha,
Unani, Yoga, Naturopathy, and Homeopathy. In India, Ayurveda and Siddha (originating in
Tamil Nadu) are widely used. While these systems have provided healthcare for centuries,
safety monitoring is essential to ensure that products are effective and free from harmful
effects.
NEED FOR SAFETY MONITORING:
 Herbal preparations in Ayurveda and Siddha may contain potent plant extracts,
minerals, and metals (e.g., mercury, arsenic, lead in processed form).
 If improperly prepared, these can cause toxicity.
 Contamination with microbes, pesticides, or incorrect plant species can lead to adverse
effects.
 Herb–drug interactions may occur when TM is combined with allopathic medicines.

PHARMACOVIGILANE IN AYURVEDA & SIDDHA:

 AYUSH Pharmacovigilance Programme of India (PvPI-AYUSH) monitors ADRs
related to Ayurveda, Siddha, Unani, and Homeopathy medicines.
7
  Involves detection, documentation, and reporting of adverse events.
 Reports are sent to the National Pharmacovigilance Centre for AYUSH Medicines.

SAFETY MONITORING:
QUALITY CONTROL MEASURES:
 Standardization of raw materials in Ayurveda & Siddha.
 Testing for heavy metals, microbial contamination, pesticide residues.
 Following Good Manufacturing Practices (GMP) as per Drugs and Cosmetics Act,
1940.
ADVERSE EVENT REPORTING SYSTEMS:
 Use of AYUSH yellow card for ADR reporting.
 Collection of ADR data from Ayurvedic/Siddha hospitals, pharmacies, and
practitioners.
RISK– BENEFIT ASSESSMENT:
 Scientific validation of traditional formulations.
 Evaluating clinical safety and efficacy with modern research tools.
REGULATION & POLICY:
 Licensing of Ayurveda & Siddha medicines under AYUSH Ministry.
 Mandatory labelling with ingredients, dosage, contraindications, and precautions.
ROLE OF PHARMACISTS IN AYURVEDA & SIDDHA SAFETY MONITORING:
 Educating patients about correct dosage and preparation.
 Advising on possible interactions with allopathic medicines.
 Ensuring purchase from licensed AYUSH manufacturers.
 Reporting ADRs to PvPI-AYUSH.

[Link] SAFETY
[Link]
Pharmacovigilance is the science and activities relating to the detection, assessment,
understanding, and prevention of adverse effects or any other vaccine-related problems.
For vaccines, safety monitoring is crucial because they are given to healthy individuals, often
children.

2. Why Vaccine Safety is Important ?

8
Vaccines are administered to large populations. Prevents loss of public confidence in
immunization programs. Early detection of safety issues helps avoid severe adverse effects
and ensures continued public health protection.
3. Key Concepts
 Adverse Event Following Immunization (AEFI): Any medical occurrence after
vaccination, which may or may not be caused by the vaccine.
 Adverse Drug Reaction (ADR): A harmful or unintended response to a vaccine at
normal doses.
 Signal Detection: Identifying patterns of adverse events to determine potential safety
concerns.

4. Vaccine Safety Monitoring in Pharmacovigilance

 Pre-marketing
 Clinical trials (Phase I–III) assess vaccine safety, dosage, and efficacy.
 Limitations: Small sample sizes may miss rare adverse events.
 Post-marketing (Phase IV)
 Surveillance systems (e.g., VAERS, WHO’s VigiBase) collect reports from healthcare
providers, manufacturers, and the public.
 Passive surveillance (spontaneous reporting) and active surveillance (targeted
monitoring) are used.

5. Steps in Vaccine Pharmacovigilance

 Collection of AEFI reports.
 Evaluation for seriousness, causality, and frequency.
 Signal detection for unusual patterns.
 Risk assessment to determine if action is needed.
 Risk communication with healthcare professionals and the public.
 Regulatory action (e.g., label changes, withdrawal).

6. Examples of Safety Issues

 Allergic reactions (e.g., anaphylaxis to vaccine components).
 Febrile seizures in children.
 Guillain–Barré Syndrome (rare, with some vaccines).

7. WHO Guidelines
 WHO recommends the Global Vaccine Safety Initiative (GVSI).
 Ensures harmonized AEFI reporting and investigation worldwide.

[Link] TERM AND TERMINOLOGY IN PHARMACOVIGILANCE

1. Core Definitions
9
  Adverse Drug Reaction (ADR)
A harmful and unintended response to a drug, occurring at normal doses for
prophylaxis, diagnosis, or therapy.
(WHO definition – excludes overdose, abuse, or medication errors)
 Adverse Drug Event (ADE)
Any untoward medical occurrence during treatment with a drug — not necessarily
caused by the drug.
 Side Effect
Any unintended effect of a drug occurring at normal doses and related to its
pharmacological properties.

2. Pharmacovigilance-Specific Terms

 Pharmacovigilance (PV)
Science and activities related to the detection, assessment, understanding, and
prevention of adverse effects or any other drug-related problems.
 Signal
Reported information suggesting a new potentially causal association between a drug
and an event — requires further evaluation.
 Causality Assessment
The process of determining the likelihood that a drug caused an observed ADR (e.g.,
Naranjo Algorithm, WHO-UMC scale).
 Dechallenge
Improvement of an ADR after stopping the suspected drug.
 Rechallenge
Recurrence of an ADR when the suspected drug is re-administered.
 Medication Error
Any preventable event that may cause or lead to inappropriate medication use or
patient harm.
 Risk–Benefit Ratio
Comparison of the potential risks of a drug versus its expected therapeutic benefits.

3. Reporting & Regulatory Terms

 Individual Case Safety Report (ICSR)

A documented report of an adverse event in an individual patient.
 Spontaneous Reporting
Voluntary reporting of suspected ADRs by healthcare professionals or consumers.
 Intensive Monitoring
Active surveillance of selected drugs or populations.
 Periodic Safety Update Report (PSUR)
A report submitted at defined time intervals summarizing safety data for a drug.
 Development Safety Update Report (DSUR)
Annual safety report for drugs under clinical development.

10
  Risk Management Plan (RMP)
A plan to identify, characterize, prevent, or minimize risks related to a drug.
 Black Box Warning
Strongest warning by regulatory authorities about serious or life-threatening risks.

MODULE-II

CLINICAL PHARMACOLOGY OF ADRs

[Link] Classification with Mechanisms

Type Name Mechanism Example
A Augmented Dose-dependent, predictable from Hypoglycemia with insulin
pharmacology

11
B Bizarre Immune or idiosyncratic, unpredictable Penicillin anaphylaxis

C Chronic Long-term cumulative toxicity Steroid osteoporosis

D Delayed DNA/teratogenic damage, late onset Thalidomide teratogenesis

E End-of-use Withdrawal or rebound Benzodiazepine

withdrawal
F Failure Lack of efficacy, resistance Contraceptive failure with
rifampicin

[Link] Allergy and Hypersensitivity Classification

Type Immunologic Pathophysiology Onset Examples
Mechanism
Type I IgE-mediated Drug binds to Minutes to Penicillin
(Immediate, protein → hours anaphylaxis,
Anaphylactic) immune system urticaria,
produces IgE → angioedema
binds to mast cells
→ re-exposure
causes
degranulation
(histamine,
leukotrienes)
Type II IgG or IgM- Antibody binds to Hours to days Hemolytic anemia
(Cytotoxic) mediated drug-modified with methyldopa,
against drug- cell → thrombocytopenia
bound cells complement with quinidine
activation → cell
lysis
Type III IgG or IgM + Complement 1–3 weeks Serum sickness
(Immune antigen → activation, with cefaclor,
complex) immune inflammation vasculitis with
complexes sulfonamides
deposit in
tissues
Type IV T-cell Sensitized T cells 48–72 hrs (or Contact dermatitis
(Delayed, Cell- mediated release cytokines longer) with topical drugs,
mediated) → macrophage Stevens–Johnson
activation → syndrome from
12
 tissue damage sulfonamides

[Link] SAFETY IN SPECIAL POPULATION

1. Pediatrics (Children & Adolescents)
Key Considerations:
 Immature organs: Liver enzymes and kidney filtration are not fully developed in
neonates and infants → altered metabolism and clearance.
 Different body composition: Higher total body water and lower fat → affects drug
distribution.
 Dosage adjustment: Weight-based or body surface area dosing is common.
 Formulation issues: Liquids or dispersible tablets preferred; excipients (e.g., benzyl
alcohol) may be harmful.
 Examples of safety risks:
o Gray baby syndrome with chloramphenicol in neonates.
o Reye’s syndrome risk with aspirin in viral infections.
o Opioid sensitivity (e.g., codeine → morphine metabolism variability).
2. Pregnancy
Key Considerations:
 Physiological changes: Increased blood volume, cardiac output, renal clearance;
altered absorption and metabolism.
 Placental transfer: Many drugs cross the placenta and may cause fetal harm.
 Teratogenic risk periods:
o Pre-implantation (0–2 weeks): "All or none" effect (either no effect or
miscarriage).
o Organogenesis (3–8 weeks): Highest risk of congenital malformations.
o Fetal period (9 weeks–birth): Risk of growth restriction or functional defects.
 FDA Pregnancy Categories (Old system) → Now replaced by Pregnancy and
Lactation Labeling Rule (PLLR).
 Examples of teratogens:
o Isotretinoin → severe birth defects.
o Warfarin → fetal bleeding, bone deformities.

13
 o ACE inhibitors → renal dysgenesis in later pregnancy.
3. Lactating Mothers
Key Considerations:
 Drug transfer into breast milk: Depends on lipid solubility, protein binding, molecular
weight, and milk pH.
 Infant exposure: Usually low, but some drugs can accumulate and cause toxicity.
 Timing of dose: Feeding just before taking the drug may minimize infant exposure.
 Examples of unsafe drugs in breastfeeding:
o Chloramphenicol → bone marrow suppression.
o Amiodarone → thyroid suppression in infant.
o Radioactive isotopes → contraindicated.
 Safer alternatives: Penicillins, cephalosporins, paracetamol generally safe.
4. Elderly (Geriatric Population)
Key Considerations:
 Physiological changes: Reduced renal function, liver mass, cardiac reserve, and total
body water; increased fat proportion.
 Polypharmacy risk: Higher chance of drug–drug interactions.
 Increased sensitivity: CNS effects (e.g., benzodiazepines → sedation, falls).
 Beers Criteria: List of potentially inappropriate medications in the elderly.
 Examples of high-risk drugs:
o Long-acting benzodiazepines (e.g., diazepam).
o NSAIDs → GI bleeding, kidney injury.
o Anticholinergics → confusion, urinary retention.

[Link] INTERACTIONS

DEFINITION

A drug interaction occurs when the effect of one drug is altered by the presence of another
drug, food, beverage, or environmental chemical.

Drug Interaction Types and Classification

Category Sub-type Mechanism Example

14
A. Absorption One drug alters the Antacids ↓
Pharmacokinetic absorption of another absorption of
Interactions (pH change, chelation, tetracycline via
motility change) chelation
A. Distribution Competition for plasma Sulfonamides
Pharmacokinetic protein binding or displace warfarin
Interactions changes in tissue from albumin
binding
A. Metabolism Enzyme induction or Rifampicin induces
Pharmacokinetic inhibition affecting CYP450 → ↓ effect
Interactions drug breakdown of oral
contraceptives;
A. Excretion Altered renal clearance Probenecid ↓ renal
Pharmacokinetic (pH, transporters, blood excretion of
Interactions flow) penicillin
B. Additive/Synergistic Drugs with similar Alcohol +
Pharmacodynamic effects → enhanced benzodiazepines →
Interactions effect excessive CNS
depression
B. Antagonistic Drugs with opposite NSAIDs ↓
Pharmacodynamic effects → reduced antihypertensive
Interactions effect effect of ACE
inhibitors
C. Pharmaceutical Physical/Chemical Occurs in syringe, IV Mixing heparin
(Incompatibility) interaction before line, storage with hydrocortisone
administration in same syringe →
precipitation
D. Food–Drug Pharmacokinetic Food alters Grapefruit juice
Interactions absorption/metabolism inhibits CYP3A4
→ ↑ statin levels
E. Laboratory Test False results Drug interferes with Biotin supplements
Interference assay chemicals cause false
high/low lab results

MODULE-III
EVALUATION, MANAGEMENT AND REPORTING OF ADRs

[Link] to Evaluate an Adverse Drug Reaction (ADR)

Definition:
An Adverse Drug Reaction (ADR) is any unintended, harmful, or unpleasant response to a
15
medication that occurs at normal doses used for prevention, diagnosis, or treatment of a
disease. ADRs can range from mild symptoms (e.g., skin rashes) to severe and life-
threatening conditions (e.g., anaphylaxis).
Importance of Evaluation:
Evaluating an ADR helps:
 Prevent recurrence.
 Ensure patient safety.
 Improve quality of healthcare.
 Confirm if a suspected reaction is truly drug-related.
1. Recognition of a Possible ADR
 Identify new or unusual symptoms after starting a medication.
 Remember: not all unwanted symptoms are drug-related; they may be due to the
illness or other factors.
 Consider known side effects of the medication.
 Example: Swelling and itching shortly after penicillin → suspect allergic ADR.
2. Collection of Detailed History
 Patient details: Age, gender, weight, medical history, known allergies.
 Drug details: All medications (prescribed, OTC, herbal, traditional), start/stop dates,
doses, routes.
 Event details: Time of onset, symptom description, duration, factors affecting
reaction.
3. Establishing the Time Relationship
 Did the reaction occur after starting the drug?
 Was the time interval appropriate for that reaction?
 Did symptoms improve when the drug was stopped (dechallenge)?
 Did symptoms return on restarting (rechallenge – rarely done for safety)?
 Example: Nausea 30 minutes after drug intake that resolves on stopping suggests
causality.
4. Considering Alternative Causes
 Could it be the disease itself?
 Could another drug, food, or environmental factor cause it?
16
  Avoid stopping essential medication without clear evidence.
5. Causality Assessment
Structured methods reduce bias:
 Naranjo Algorithm – scoring system to classify as definite, probable, possible,
doubtful.
 WHO–UMC Criteria – certain, probable, possible, unlikely, conditional,
unassessable.
6. Assessing Severity
 Mild: Minimal symptoms, no treatment needed.
Example: Mild headache.
 Moderate: Requires treatment or change in therapy.
Example: Drug-induced hypoglycemia.
 Severe: Life-threatening, causes hospitalization, disability, or death.
Example: Anaphylactic shock.
7. Classifying the Type of ADR
 Type A (Augmented): Predictable, dose-related. Example: Bleeding with
anticoagulants.
 Type B (Bizarre): Unpredictable, allergic/idiosyncratic. Example: Penicillin
anaphylaxis.
 Type C (Chronic): From long-term use. Example: Steroid osteoporosis.
 Type D (Delayed): Appears after time. Example: Drug-induced cancer.
 Type E (End-of-use): Withdrawal. Example: Benzodiazepine withdrawal seizures.
 Type F (Failure): No effect. Example: Antibiotic resistance.
8. Documentation and Reporting
 Record all ADR details in patient file.
 Notify healthcare team to avoid re-exposure.
 Report to national pharmacovigilance systems or hospital ADR monitoring centers.

[Link] ADR IN STANDARD FORM

ADR Reporting
- ADR are among the leading causes of death in many countries (according to WHO 2008).

17
- Constitutes a significant economic burden on the patient and government.

Benefits of ADR
- Assess the safety of drug therapies.
- Provides updated drug safety information to health care professionals and other stake
holders.
- Measuring the economic impact ADR prevention.
- Regulatory action on the basis of ADR reports to ensure patients safety.

Who can report?

- All health care professionals like clinicians, dentist, pharmacists, nurses etc.
- All non - healthcare professionals including patients can also report.

ADR Reporting process

HEALTHCARE PROFESSIONAL → PERIPHERAL CENTRES → REGIONAL
CENTRES → ZONAL CENTRES → Centre Drugs Standard Comet Organ → WHO/UMC

ADR Reporting Form

- Patients demographic details.
- Prescriber's details.
- Suspected drugs.
- Date of drug administration started and stopped.
- Date of ADR started.
- Brief description of reaction.
- Name and address of reporting centre with reporting date.

How to Report?
- Report should be on a standard ADR reporting form.
- Duly filled the ADR's in the reporting form when an ADR is encountered.
- Use a separate form for each patient and filled with complete information.
- The completed ADR form is then returned to the nearest Adverse drug reaction Monitoring
office (AMC) or the National Coordinating Centre.
- Any follow up information for an ADR case that has already been reported can be sent on
another ADR form, or communicated by telephone, fax or email.
- Follow up reports should be identifiable and the following should be indicated on the report
- Follow up information.
- Date of original report.
- Patient identity should be recorded.

18
Different Approaches of ADR Reporting
- Cohort study: involves short term and long term clinical trials and post marketing
surveillance of established and new drug. Also known as longitudinal study or forward
looking study. Cohorts are identified prior to appearance of disease under investigation. The
study groups are observed over a period of time to determine the frequency of disease among
them.

Framework of Cohort Study

COHORT POPULATION → EXPOSED / UNEXPOSED
- Spontaneous reports of suspected adverse drug reaction occurs when prescribers report
suspected reaction to investigator agency.

1. Passive surveillance system.

- Data acquisition which depends largely on the input information derived from reports
submitted by the health professionals who have encountered what they suspect is an ADR.
- Data assessment which involves assessment of the individual case reports and assessment
of pooled data obtained from various sources such as the international database of the WHO.
- Data interpretation - based on the available data and the assessments made, a signal
related to the adverse reaction may be generated.

2. Review of vital statistics.

-regular review of national and regional vital statistics.

3. Case control studies.

- patients with suspected drug induced diseases are compared with a reference population.
It is a retrospective study. A case controlled study is an observational study in which subjects
are sampled based upon presence or absence of disease and then their prior exposure status is
determined.

[Link] OF ADVERSE DRUG REACTION (ADR) REPORTING

Adverse drug reaction reporting is a key component of pharmacovigilance, aimed at
detecting, assessing, and preventing drug related problems. common methods include,
[Link] (voluntary) reporting: spontaneous ADR reporting is a passive method of
pharmacovigilance where healthcare professionals or consumers voluntarily report suspected
adverse drug reactions to regulatory authorities or pharmaceutical companies, without being
prompted by a study or organized data collection.
19
Limitation: under reporting, incomplete data.
2. Stimulated reporting: stimulated ADR reporting refers to methods used to encourage and
facilitate healthcare professionals to report suspected adverse drug reactions in specific
situations, often through proactive measures and targeted interventions.
Limitation: May cause selective reporting bias.
[Link] (prospective) monitoring: Intensive monitoring of ADR is a post- marketing
surveillance method that involves actively and continuously collecting detailed information
on patients experiences with a drug, especially from the first day of its use, to identify and
assess potential ADRs.
Limitation: Resource and time intensive.
4. Cohort event monitoring (CEM): cohort event monitoring is a prospective, observation
method used in pharmacovigilance to monitor adverse drug reactions in a defined group of
patients taking a specific medication. This method helps identify potential safety signals,
especially for new or focused medications, and complements other pharmacovigilance
approaches like spontaneous reporting.
Limitation: Expensive, requires follow up.
5. Targeted reporting: Targeted ADR reporting is a method where specific safety concerns
related to a drug or a group of patients are actively monitored and reported. It focuses on
enhancing reporting of ADRs within a defined context, often involving health professionals
who already managing the patients.
Limitation: Resource intensive, potential bias, data quality issues.
6. Electronic health record (EHR): Electronic health record ADR reporting method refers
to the system within an EHR where healthcare professionals document and report adverse
drug reactions. This system allows for the recording of details about the reaction, the
suspected drug and other relevant information, facilitating the identification, monitoring and
management of ADRs.
Limitation: Requires advanced IT infrastructure.
7. Direct patient reporting: Direct patient reporting of ADR refers to the process where
patients or consumers directly report suspected ADRs to pharmacovigilance systems, without
the involvement of a healthcare professional.
Limitation: may lack medical details.

20
IV. Post-Marketing Adverse Drug Reaction Reporting – Summary Reports: PSUR &
PBRER
Post-marketing adverse drug reaction (ADR) reporting is a core component of
pharmacovigilance, aimed at ensuring the continued safety and efficacy of medicines after
they have been approved for marketing. Two key periodic reporting formats used globally
for this purpose are the PSUR (Periodic Safety Update Report) and PBRER (Periodic
Benefit–Risk Evaluation Report).
1. Periodic Safety Update Report (PSUR)
Definition: A structured regulatory document that summarizes global safety data for a
medicinal product at defined intervals, focusing primarily on identifying new risks,
changes in known risks, and updates to the safety profile.

Purpose:
• Continuous monitoring of safety post-approval.
• Early detection of new or altered risks.
• Support regulatory decisions regarding labelling and usage.

Key Content:
Title Page & Introduction, Marketing Authorization Status, Actions Taken for Safety
Reasons, Changes to Reference Safety Information, Exposure Estimates & Use Patterns,
ADR Summary Tables, Significant Safety Findings, Signal and Risk Evaluation,
Conclusions & Actions

2. Periodic Benefit–Risk Evaluation Report (PBRER)

Definition: An updated format introduced under ICH E2C (R2) that not only evaluates safety
but also integrates an assessment of the overall benefit–risk balance of the product.

Purpose:
• Provide an integrated analysis of safety and efficacy.
• Ensure benefits continue to outweigh risks.
• Support regulatory decision-making on labelling, restrictions, or market withdrawal.

Key Content:
Executive Summary & Introduction, Worldwide Marketing Authorization Status, Actions
for Safety Reasons, Changes to Reference Safety Information, Exposure Estimates & Use
Patterns, Safety Data Summaries & Signal Evaluation, Risk Evaluation, Benefit Evaluation
(clinical & real-world data), Integrated Benefit–Risk Analysis, Conclusions & Actions

21
V. MANAGEMENT OF ADR:
(Adverse Drug Reaction) involves a systematic approach to identify, treat, and prevent drug-
related harm while ensuring patient safety.
1. Recognition
 Early identification of signs and symptoms of an ADR (rash, fever, GI upset, breathing
difficulty, abnormal lab results, etc.).
 Differentiate ADR from disease progression or other conditions.
2. Assessment
 Take a detailed history (drug name, dose, route, timing, previous exposures, allergies).
 Review drug chart for potential interactions.
 Classify the ADR:
o Type A (predictable, dose-related) – e.g., hypoglycemia with insulin.
o Type B (unpredictable, idiosyncratic/allergic) – e.g., anaphylaxis to penicillin.
 Use causality assessment tools (e.g., Naranjo Algorithm).
3. Immediate Management
 Mild reactions (nausea, mild rash): Stop or adjust the drug, give symptomatic
treatment.
 Moderate reactions: Withdraw the offending drug, start alternative therapy, treat
symptoms.
 Severe/life-threatening reactions:
o Stop drug immediately.
o Maintain Airway, Breathing, Circulation (ABC).
o Give specific antidotes if available (e.g., naloxone for opioid toxicity).
o Supportive measures (oxygen, IV fluids, vasopressors).
o Hospitalization if needed.
4. Specific Interventions
 Antihistamines – for allergic reactions.
 Corticosteroids – for severe inflammation or hypersensitivity.
 Epinephrine (Adrenaline) – for anaphylaxis.

22
  Activated charcoal / gastric lavage – for recent oral overdoses.
 Antidotes – based on drug (e.g., N-acetylcysteine for paracetamol toxicity).
5. Monitoring
 Vital signs, urine output, ECG, and relevant labs.
 Watch for delayed effects (e.g., drug-induced liver injury).
6. Documentation & Reporting
 Document in patient’s file and discharge summary.
 Report to pharmacovigilance program (e.g., PvPI in India, WHO-UMC globally).
 Educate patient on avoiding the same drug in the future.
7. Prevention
 Review medication history before prescribing.
 Avoid unnecessary polypharmacy.
 Adjust doses for age, kidney/liver function.
 Monitor high-risk drugs closely.

MODULE-IV
CAUSALITY ASSESMENT
[Link] MODELS AND ASSESMENT WITH CASE STUDIES:
1. Introduction

23
Causality assessment in pharmacovigilance is the process of determining the likelihood that
a drug caused an observed adverse drug reaction (ADR).
It helps in:
 Regulatory decision-making
 Risk–benefit evaluation of medicines
 Clinical management of patients
2. Common Causality Assessment Models
A. WHO–UMC (World Health Organization–Uppsala Monitoring Centre) System
Categorizes ADRs as:
1. Certain – clear temporal relationship, response to withdrawal (dechallenge),
recurrence on re-exposure (rechallenge), and no alternative explanation.
2. Probable / Likely – reasonable time relationship, unlikely due to disease or other
drugs, response to dechallenge present, no rechallenge required.
3. Possible – temporal relationship present, but could also be explained by other factors.
4. Unlikely – time relationship makes a drug cause improbable, and other explanations
more likely.
5. Conditional / Unclassified – more information needed for proper assessment.
6. Unassessable / Unclassifiable – insufficient or contradictory information.
B. Naranjo Algorithm (ADR Probability Scale)
A questionnaire with 10 weighted questions about:
 Temporal association
 Alternative causes
 Drug levels
 Dose–response relationship
 Previous patient exposure
 Dechallenge and rechallenge effects
Score & Interpretation:
 ≥ 9 → Definite
 5–8 → Probable

24
  1–4 → Possible
 0 → Doubtful
C. European Medicines Agency (EMA) Model Focuses on:
 Time to onset
 Biological plausibility
 Response to withdrawal/rechallenge
 Literature evidence
3. Factors Considered in Causality Assessment
 Temporal Relationship (drug administration → onset of ADR)
 Dechallenge/Rechallenge outcome
 Alternative explanations (disease, other drugs, chemicals)
 Dose–response relationship
 Previous evidence (published reports, pharmacology data)
 Biological plausibility
4. Example Case Studies
Case 1 — WHO–UMC
Scenario:
A patient developed a skin rash 3 days after starting amoxicillin. Rash disappeared within 2
days of stopping the drug; no other medications were taken.
Assessment:
 Temporal relationship: Present
 Dechallenge: Positive
 Alternative cause: None
 Rechallenge: Not performed
WHO–UMC classification: Probable / Likely
Case 2 — Naranjo Algorithm
Scenario:
A patient on isoniazid developed jaundice 4 weeks after starting therapy.
 No alcohol use, viral hepatitis tests negative.
25
  Symptoms improved after stopping isoniazid.
 Rechallenge not done.
Naranjo scoring:
 Temporal relationship (+2)
 No alternative causes (+2)
 Dechallenge positive (+1)
 Previous conclusive reports (+1)
 Total score: 6 → Probable
Case 3 — Confounding factor
Scenario:
A patient developed dizziness after starting metoprolol for hypertension, but also had
hypoglycemia due to skipped meals.
Assessment:
 Temporal relationship: Present
 Alternative cause: Present (hypoglycemia)
 Causality: Possible under both WHO–UMC and Naranjo.
5. Conclusion
 No model is perfect — causality assessment is an aid, not proof.
 WHO–UMC is widely used for qualitative categorization, while Naranjo is useful for
structured probability scoring.
 Multiple models together give better confidence in ADR assessment.
[Link] DATABASES AND SIGNAL DETECTION
Pharmacovigilance database is a system used to collect, manage, and analyze reports of
adverse drug reactions (ADRs). These databases are crucial for monitoring drug safety,
detecting potential safety signals, and supporting risk-benefit assessments.

Pharmacovigilance Databases

1. VigiBase (WHO-UMC Global Database)

• Maintained by the Uppsala Monitoring Centre (UMC), Sweden.
• World's largest international database of spontaneous adverse drug reaction (ADR) reports.
26
• Contains over 30 million individual case safety reports (ICSRs) from over 150 countries.

2. EudraVigilance (European Union Database)

• Maintained by the European Medicines Agency (EMA).
• Collects and manages data on suspected adverse reactions for medicines authorized in the
European Economic Area (EEA).
• Mandatory for pharmaceutical companies to report ADRs.

3. FAERS (FDA Adverse Event Reporting System – USA)

• Managed by the U.S. Food and Drug Administration (FDA).
• Supports post-marketing safety surveillance.
• Includes both mandatory and voluntary reports.

4. CDSCO-PvPI (India – Pharmacovigilance Programme of India)

• Maintained by Indian Pharmacopoeia Commission (IPC) under Central Drugs Standard
Control Organization (CDSCO).
• Promotes ADR reporting through AMC (Adverse Drug Reaction Monitoring Centres).
• VigiFlow software is used to upload reports to WHO-VigiBase.

5. Yellow Card Scheme (UK – MHRA)

• Managed by the Medicines and Healthcare products Regulatory Agency (MHRA).
• Reports collected via public, patients, pharmacists, and healthcare professionals.
• Available through website and mobile apps.

Functions of Pharmacovigilance Databases

• Collect and store adverse event reports
• Enable data mining and signal detection
• Support regulatory decision-making
• Help in risk assessment and communication
• Facilitate international collaboration on drug safety

Signal Detection in Pharmacovigilance

What is a Signal Detection?
In pharmacovigilance, signal detection refers to the process of identifying potential safety
signals from usage of drug related data which indicating a possible new unknown adverse
event or risk associated with a medication.

Signal Sources:
• Spontaneous reporting systems
• Clinical trials
27
• Literature review
• Epidemiological studies
• Post-marketing surveillance

Signal Management Process:

1. Signal Detection
2. Signal Validation
3. Signal Confirmation
4. Signal Analysis and Prioritization
5. Signal Assessment
6. Recommendation for Action

Applications of PV Databases & Signal Detection:

• Identifying new ADRs early and preventing public health hazards
• Post-marketing surveillance and product label updates
• Enhancing drug safety education to healthcare professionals
• Supporting regulatory decisions (drug withdrawal, restriction)
• Ensuring safe dispensing and patient counseling by pharmacists
• Monitoring biosimilars, vaccines, and complex biologics

Role of Pharmacist in Signal Detection:

• Encourage spontaneous ADR reporting by patients and HCPs
• Contribute to national and global databases
• Educate patients about drug safety and ADR monitoring
• Collaborate in signal management teams in hospitals or industry
• Participate in research on drug safety profile
[Link] REASONING & ALGORITHMS IN PHARMACOVIGILANCE
Pharmacovigilance (PV) is the science of detecting, assessing, understanding, and preventing
adverse effects or any other drug-related problems. The volume and complexity of safety
data (spontaneous reports, EHRs, clinical trials, social media, registries) demand statistical
methods for signal detection and algorithms to automate triage, de-duplication, pattern
discovery, and causality assessment. Good statistical reasoning avoids false alarms (noise)
and missed true safety signals.
Key concepts and reasoning foundations
Data types & structure
 Spontaneous reporting systems (SRS): individual case safety reports (ICSRs) with
drugs, reactions, dates, patient demographics, reporter type. Example: Vigibase,
FAERS.
28
  Electronic Health Records (EHR): longitudinal clinical data, lab tests, diagnoses,
medications, timestamps.
 Exposure-outcome datasets: cohort or case–control formats from claims or registries.
 Textual sources: narrative sections of ICSRs, social media posts, scientific literature.
Causal reasoning vs association
 Association ≠ causation. Signals are statistical associations that require further
clinical, pharmacological, and sometimes epidemiologic confirmation
(dechallenge/rechallenge, biological plausibility).
 Use Bradford Hill considerations and formal causality tools (WHO-UMC, Naranjo) as
follow-up.
Frequentist vs Bayesian reasoning
 Frequentist: hypothesis testing, p-values, confidence intervals — useful for classical
tests and some disproportionality metrics.
 Bayesian: explicitly models prior information and shrinks noisy estimates toward prior
expectation — very valuable for sparse data and early signal detection (e.g., EBGM,
Bayesian Confidence Propagation Neural Network).
Data preprocessing & quality — the crucial first step
 De-duplication: identify multiple reports for the same case (rule-based matching on
patient, event date, narrative similarity, hash of narratives).
 Standardization: map drug names to standardized vocabularies (e.g., RxNorm), map
reactions to MedDRA preferred terms, normalize date formats.
 Missing data handling: document extent; use conservative approaches (sensitivity
analyses), or imputation in EHR-based studies where appropriate.
 Stratification fields: age groups, sex, dosage, seriousness, reporter type — stratify to
detect confounding and effect modification.
 Time windows: define risk windows (e.g., onset within X days of exposure) carefully.
Causality assessment algorithms (post-signal evaluation)
 WHO-UMC criteria: categories like certain / probable / possible / unlikely based on
timing, dechallenge/rechallenge, alternative causes.
 Naranjo algorithm: a point-scoring system (structured questionnaire) — useful in
clinical settings.

29
  Bayesian causality scoring: some groups model causality probabilities using priors on
biologic plausibility and observed data.
Machine learning and AI approaches
Modern PV increasingly uses ML and NLP. Key areas:
NLP for ICSRs & literature
 Tasks: ADR mention extraction, drug–event relation extraction, named entity
recognition (NER), entity linking to ontologies (MedDRA/RxNorm).
 Approaches: rule-based (lexicons), classical ML (CRF, SVM), deep learning
(BiLSTM-CRF, Transformers like BERT / ClinicalBERT).
 Output: structured drug–event pairs from free-text narratives enabling downstream
signal detection.
Supervised ML for known adverse events
 Train classifiers to predict whether a report is a valid ADR (labelled data needed).
 Features: co-occurrence counts, temporal features, narrative embeddings, seriousness
flags.
 Unsupervised and anomaly detection
 Clustering, autoencoders, and density-estimation methods to find unusual patterns in
multidimensional safety data.
 Common approaches: isolation forest, one-class SVM, LOF (local outlier factor).
[Link] ASSESSMENT AND MANGEMENT
It is the process of Identifying, analyzing, and evaluating the potential risks
associated with a suspected Adverse Drug Reactions to determine the livelihood that the drug
cause the event.
RISK ASSESSMENT
Common tool
[Link] /RECHALLENGE:
Dechallange is stopping a suspected drug to see if the reaction improves, while
Rechallange is giving the drug again to see if the reaction return, improvement or recurrence
supports a drug reaction.
[Link]'s scale:

30
 It is a standardized questionnaire used to assess the likelihood that an adverse
drug reaction (ADR) is actually due to a suspected drug. It's consists of 10 QUESTION with
assigned scores and the total score classifies causality as
i. DEFINITE ( 9 or above)
ii. PROBABLE (5 to 8 )
iii. POSSIBLE ( 1 to 4)
iv. DOUBT FULL (0)
[Link]-UMC CAUSALITY:
i. CERTAIN (9 or more)
ii. PROBABLE/LIKELY (5--8)
iii. Possible (1- 4)
iv. UNLIKELY (0 or below)
v. CONDITIONAL/UNCLASSIFIED
vi. UNASSESSABLE /UNCLASSIFIABLE
4. HARTWIG'S SEVERITY ASSESSMENT SCALE
It is used to categorize the severity of an ADR into MILD (LEVEL 1—2)
MODERATE (LEVEL 3--4), SEVER (LEVEL 5--7).
RISK MANGEMENT
 Monitoring patience who are at great risk of developing ADR.
 Monitoring patients who prescribed with highly likely to produce ADR.
 Assessing and documenting the patients previous allergic stating patients drug therapy
for its appropriateness.
 Changing dose of drug.
 Replacing with alternative medicine.
 Use of proliferative medicine.
 Assessing healthcare professional in detection and assessments of ADR.
 Stimulating healthcare professional in healthcare in reporting ADR.
 Assessing Possible drug interactions in multiple therapies.
 Dose on suspected report for further.
 Obtaining feedback about the reported ADR.
 Educating patients, healthcare professional about the importance of reporting AD

31
 MODULE – V
CASE PROCESSING
I. INDIVIDUAL CASE SAFETY REPORTING (ICSR)
Introduction
32
An Individual Case Safety Report (ICSR) is a document containing detailed information on
an adverse drug reaction (ADR) observed in a single patient. It is a key component of
pharmacovigilance and is used by regulatory authorities, pharmaceutical companies, and
healthcare professionals to monitor and evaluate drug safety.
Purpose of ICSR
• To detect potential new risks associated with medicines.
• To support signal detection and safety monitoring.
• To provide data for risk-benefit assessment.
• To comply with national and international regulatory requirements.
Sources of ICSR
• Spontaneous reports from healthcare professionals or patients.
• Clinical trial reports during the investigational phase.
• Post-marketing surveillance programs.
• Published literature (case reports in journals).
• Regulatory authority databases.
Minimum Required Information in an ICSR (ICH E2D)
1. Identifiable Reporter – Name, occupation, and contact details.
2. Identifiable Patient – Age, sex, initials, or other unique identifiers.
3. Suspect Drug(s) – Name, dosage, route, batch number, manufacturer.
4. Adverse Event(s) – Description, date of onset, seriousness, outcome.
Types of ICSRs
• Spontaneous ICSR – Reported voluntarily, not linked to a clinical trial.
• Solicited ICSR – Obtained from structured data collection systems (e.g., patient support
programs, registries).
• Clinical Trial ICSR – Submitted as part of trial safety reporting.
Data Elements in an ICSR
• Patient demographic details.
• Medical history and concomitant medications.
• Description of adverse event.

33
• Laboratory and diagnostic test results.
• Drug dosage and treatment duration.
• Outcome of the reaction.
Transmission Standards
• E2B (R3) format for electronic submission to regulatory bodies.
• Uploaded to global databases like VigiBase, EudraVigilance, or FAERS.
Importance of ICSR in Pharmacovigilance
• Enables early detection of new ADRs.
• Helps in regulatory decision-making (label change, restriction, withdrawal).
• Improves patient safety and awareness.
• Facilitates international collaboration on drug safety monitoring.

II. NARRATIVE WRITING IN PHARMACOVIGILANCE

Definition:
Narrative writing in pharmacovigilance is the process of preparing a concise, chronological,
and medically meaningful summary of an adverse event or reaction involving a patient,
based on available case information.
Purpose:
 To communicate complex safety data in a simple, clear, and structured way.
 To help regulatory bodies (like CDSCO, US FDA, EMA) assess causality and
seriousness.
 To document events accurately for future reference, clinical trials, or legal needs.
Key Components of a Pharmacovigilance Narrative:
A good narrative must include:
1. Patient Details – age, sex, relevant medical history, lifestyle factors.
2. Event Details – description, onset date, duration, severity, outcome.
3. Drug Details – suspect drug name, dosage, route, start/stop dates, indication.
4. Concomitant Medications – other drugs patient was taking.
5. Timeline – chronological order of events.
6. Relevant Investigations – lab reports, imaging, ECG, etc.
34
7. Clinical Course & Outcome – what happened after intervention, any recovery.
8. Reporter Details – who reported the case (doctor, nurse, pharmacist).
Step-by-Step Narrative Writing Process:
Step 1: Gather all case details from the ICSR form, source documents, lab data, and medical
records.
Step 2: Arrange events chronologically, ensuring clarity & accuracy.
Step 3: Maintain neutral and objective tone — avoid personal opinions.
Step 4: Follow company or regulatory format (usually a set structure).
Step 5: Review for completeness, medical sense, and grammar.
Software used in:
 Argus Safety (Oracle) - Widely used pharmacovigilance system for ICSR entry, case
processing, and narrative generation.
 ARISg (Aris Global) - Automates narrative creation and manages safety reports.
 VigiFlow (WHO-Uppsala) - Used by national pharmacovigilance centres for case
entry and reporting.
 MedDRA Browser Helps in standard medical terminology coding for narrative
consistency.
 Microsoft Word / Google Docs Drafting and formatting narratives manually.
 Grammarly Grammar and clarity improvement.
 Adobe Acrobat - PDF formatting, highlighting, and securing reports before
submission.
 QMS Tools (like TrackWise) - For quality checks and approval workflow.
Importance in Pharmacovigilance:
 Supports Causality Assessment
 Regulatory Compliance
 Clinical Decision Making
 Signal Detection
III. MedDRA – Introduction
Definition:
MedDRA is an internationally standardised medical terminology used to classify and code
medical information — such as diseases, symptoms, diagnoses, laboratory findings, surgical
procedures, and adverse events — in a consistent and uniform way for use in drug
development, clinical trials, and pharmacovigilance.

35
Purpose in Pharmacovigilance:
In pharmacovigilance, MedDRA is used for coding and classifying Adverse Event (AE) data
so that information can be stored, searched, retrieved, and analysed consistently across
countries and organisations.
Background & Development:
Developed by the International Council for Harmonisation (ICH) in the late 1990s.
Managed by the MedDRA Maintenance and Support Services Organization (MSSO).
Updated twice yearly (March & September) to include new terms and improve definitions.
Widely used by regulatory authorities (like US FDA, EMA, CDSCO) and pharmaceutical
companies globally.
Use of MedDRA in Pharmacovigilance Workflow:
1. Data collection – AE reported by healthcare professional, patient, or literature.
2. Term identification – Exact words from reporter are recorded (verbatim).
3. Coding – Coder matches verbatim term to MedDRA’s LLT.
4. Storage – The coded data is stored in a safety database.
5. Retrieval & analysis – Data is searched using PTs, HLTs, or SOCs for:
Signal detection
Regulatory reports (e.g., ICSR, PSUR, PBRER)
6. Submission – Coded reports sent to authorities via ICH E2B format.

MedDRA in coding:

36
MedDRA coding is the process of translating verbatim medical information (as reported by a
healthcare provider, patient, or literature source) into the standardised medical terms found in
MedDRA.
This ensures all safety data is stored in a consistent format for analysis and reporting.
Purpose of MedDRA coding in PV:
Standardisation: Avoids confusion from synonyms and local terms.
Regulatory compliance: Most regulatory authorities (FDA, EMA, CDSCO, PMDA) require
MedDRA-coded AE data in safety reports (ICSRs, PSURs, PBRERs).
Search & analysis: Enables accurate retrieval of cases for signal detection.
Global communication: Facilitates sharing between multinational teams.
Tools for MedDRA Coding:
 MedDRA Browser (Free from MSSO website for registered users)
 MedDRA Desktop Browser
 Integrated modules in safety databases:
 Argus Safety
 ARISg
 Veeva Vault Safety
 Oracle Clinical
Example: From Verbatim to MedDRA Hierarchy

Case: Reporter says — “Patient had itchy red rash on arms after injection.”
Coding:
LLT: Rash erythematous, Pruritus
PT: Erythema, Pruritus
HLT: Rashes, eruptions and exanthems NEC, Pruritus NEC
HLGT: Skin appendage conditions
SOC: Skin and subcutaneous tissue disorders

37
 PRACTICE SESSION
In Classification of ADRs:
 Respiratory depression with Morphine – Type A (Augmented)
 Chemolysis with primaquine – Type B (Bizarre)
 Sedation with Diazepam – Type A (Augmented)
 Phenytoin withdraw seizure – Type E (End of Use)
 Secondary tumor with chemotherapy – Type D (Delayed)

In Drug Allergy/ Hypersensitivity

 Anaphylactic shock with penicillin – Type I Hypersensitivity
 Leukopenia with Ticlopidine (Anticoagulant) – Type II Hypersensitivity
38
  Thrombocytopenia with carbamazepine – Type II Hypersensitivity
 Serum Sickness Syndrome with penicillin – Type III Hypersensitivity
 Angio edema with Losartan – Type I Hypersensitivity
 Steven Johnson Syndrome with carbamazepine – Type IV Hypersensitivity
 Contact dermatitis with topical Bleomycin – Type IV Hypersensitivity

Following Reaction Causing Drugs:

 Leukopenia
 Clozapine [Anti-psychotic drug]
 Minocycline [Antibiotic]
 Thrombocytopenia
 Heparin
 Methyldopa
 Rifampicin
 Neutropenia
 Phenytoin
 Phenobarbital
 Methimazole
 Propyl Thiouracil

Drug interaction:
Using Lexicomp For detection of drug interaction
 Ciprofloxacin + Erythromycin
 QT-prolonging agent (Intermediate Risk- Avoid) may increase QTC- Prolonging
effects of QT-Prolonging Agents (Moderate risk)
 Severity: Minor Reliability
 Risk: Intermediate-Low
 Enalapril + Amiloride

39
  Potassium sparing diuretics may increase hyperkalemic effects of Angiotensin –
Converting Enzyme inhibitors.
 Severity Major Reliability Rating: Highest
 Risk: Monitor
 Enalapril + Aspirin
 Salicylates may decrease therapeutic effects of ACE Inhibitors. Salicylate may
increase nephrotoxic effects of ACE Inhibitors
 Severity Major Reliability Rating: Moderate
 Risk: Intermediate -Low
 Amiodarone + Warfarin
 Amiodarone may increase anti-coagulant effects of vitamin K Antagonist –
Amiodarone may increase serum concentration of vitamin K Antagonists
 Severity Major Reliability Rating : Intermediate
 Risk: Consider therapy modification

Case Study:
1. Patient Information
 Patient Initials: R.K.
 Age / Date of Birth: 54 years
 Gender: Female
 Weight: 64 kg
 Suspected Adverse Reaction
Description:
 The patient developed generalized rash, itching, and swelling of the face and lips
approximately 3 hours after taking the second dose of the antibiotic amoxicillin–
clavulanic acid.
 Symptoms worsened within the next 1 hour, with mild difficulty in breathing.
 Date & Time of Onset: 12 July 2025, 10:00 AM

40
  Seriousness of Reaction: Yes – required hospitalization (due to airway involvement)
 Outcome: Patient recovered after treatment with IV antihistamines, corticosteroids,
and oxygen supplementation within 24 hours.
 Relevant Laboratory Tests: CBC normal; no eosinophilia; liver and renal function
tests normal.
 Other Relevant History: No previous known drug allergies; history of mild seasonal
allergy to pollen.
 Suspected Medication(s)
 Drug Name: Amoxicillin–Clavulanic Acid (625 mg tablet)
 Batch No.: AMX/0725/01
 Manufacturer: ABC Pharmaceuticals Pvt Ltd
 Expiry Date: June 2026
 Indication: Acute sinusitis
 Dose & Route: 1 tablet orally every 8 hours
 Therapy Start Date: 11 July 2025
 Therapy Stop Date: 12 July 2025 (discontinued after reaction)
 Action Taken: Drug withdrawn immediately
 Concomitant Medication(s) (taken in the last month)
 Paracetamol 500 mg – as needed for fever, started on 10 July 2025, no adverse effects.
 Cetirizine 10 mg – as needed for seasonal allergy, taken occasionally.
 Suspected Drug–Event Relationship
 Temporal Association: Yes – reaction occurred soon after drug administration.
 Dechallenge: Positive (symptoms improved after stopping the drug).
 Rechallenge: Not done (due to seriousness of reaction).

2. Patient Information
 Patient Initials: M.S.
 Age 38 years / Male
 Weight: 72 kg
41
 Suspected Adverse Reaction
Description:
 The patient developed fatigue, loss of appetite, nausea, and yellowish discoloration of
eyes after 14 days of anti-tubercular therapy (ATT).
Liver function tests revealed:
 ALT: 356 U/L (normal < 40 U/L)
 AST: 285 U/L (normal < 40 U/L)
 Total bilirubin: 5.2 mg/dL (normal 0.2–1.2 mg/dL)
 Date & Time of Onset: 28 June 2025
 Seriousness of Reaction: Yes – required hospitalization for observation and IV fluids
 Outcome: Improved after discontinuation of suspected drugs and supportive care.
 Relevant Laboratory Tests: Viral hepatitis panel negative; ultrasound – mild
hepatomegaly.
 Other Relevant History: No alcohol consumption; no history of liver disease; no herbal
drug intake.
 Suspected Medication(s)
a. Drug Name: Isoniazid 300 mg tablet
 Batch No.: INH/0625/04
 Manufacturer: HealthPharma Ltd.
 Expiry Date: May 2027
 Indication: Pulmonary Tuberculosis
 Dose & Route: 300 mg orally once daily
 Therapy Start Date: 14 June 2025
 Therapy Stop Date: 29 June 2025 (stopped after reaction)
 Action Taken: Drug withdrawn
b. Drug Name: Rifampicin 600 mg capsule
 Batch No.: RIF/0625/12
 Manufacturer: MedLife Pharma
 Expiry Date: April 2027
42
  Indication: Pulmonary Tuberculosis
 Dose & Route: 600 mg orally once daily
 Therapy Start Date: 14 June 2025
 Therapy Stop Date: 29 June 2025 (stopped after reaction)
 Action Taken: Drug withdrawn
 Concomitant Medication(s)
 Pyridoxine 10 mg – started with ATT, continued without issues.
 No other medications in last month.
 Suspected Drug–Event Relationship
 Temporal Association: Yes – liver injury occurred 2 weeks after starting drugs.
 Dechallenge: Positive – LFT values improved after stopping the drugs.
 Rechallenge: Not attempted (due to risk of recurrence and severity).

43
44
45
 REFERENCE

1. Brown EG, Wood L, Wood S. The medical dictionary for regulatory activities
(MedDRA). Drug Saf. 1999 Feb;20(2):109–117. DOI: 10.2165/00002018-199920020-
00002 PubMed
2. Nagarajan S, Mahapatro G. Meddra Coding in Pharmacovigilance: A comprehensive
review of Its role, challenges, and best practices in adverse event reporting and
regulatory compliance. Int J Pharmaceuticals and Health Care Research, 2024; Vol
12(4):389–392. DOI: 10.61096/ijphr.v12.iss4.2024.389-392 ResearchGate
3. Pearson RK et al. Influence of the MedDRA® hierarchy on pharmacovigilance data
mining results. Int J Med Inform. 2009;78:e97–e103. DOI:
10.1016/[Link].2009.01.001 PLOS
4. Sharma L et al. CHARTING THE COURSE: An Overview of Pharmacovigilance
History. Journal of Population Therapeutics and Clinical Pharmacology,
2024;31(6):38–47. DOI: 10.53555/jptcp.v31i6.6439 J Popul Ther Clin Pharmacol
5. Trifirò G, Crisafulli S. A New Era of Pharmacovigilance: Future Challenges and
Opportunities. Frontiers in Drug Safety and Regulation, 2022;
[Link] Frontiers
6. Bellavite, P. Causality Assessment of Adverse Events Following Immunization: The
Problem of Multifactorial Pathology. F1000Research, 2020;9:170. DOI:
10.12688/f1000research.22600.1 PMC (listed reference)
7. Adverse Drug Reactions and quality deviations monitored by… (covers ADR reporting
profiles). DOI: (You may need access to Wiley/Elsevier for DOI) ScienceDirect
8. Signals of Adverse Drug Reactions Communicated by Pharmacovigilance
Stakeholders: A Scoping Review of the Global Literature. Drug Saf., 2023;46:109–
120. DOI: 10.1007/s40264-022-01258-0 SpringerLink
9. Hodel, K. V. S. et al. Pharmacovigilance in Vaccines: Importance, Main Aspects,
Perspectives, and Challenges – A Narrative Review. Pharmaceuticals (Basel),
2024;17(6):807. DOI: 10.3390/ph17060807 PubMedPMC
10.A narrative review of vaccine pharmacovigilance during mass … Br. J. Clin.
Pharmacol., 2023. DOI: (accessible via Wiley site) BPS Publications
[Link] Review: Understanding Vaccine Safety and the Roles of the FDA and the CDC.
N. Engl. J. Med., published ~3 years ago. DOI: 10.1056/NEJMra2200583 New
England Journal of Medicine
[Link] et al. Vaccine Safety and Surveillance for Adverse Events Following
Immunization (AEFI) in India. Indian J. Pediatr., 2018;85(2):139–148. DOI:
10.1007/s12098-017-2532-9 PubMed

46
[Link] Hunsel, F., & Kant, A. A National Pharmacovigilance Centre Perspective on
Pandemic Preparedness – Lessons Learned from the COVID-19 Pandemic. Front.
Drug Saf. Regul., 2025 [exact issue]. DOI: accessible on the Frontiers site Frontiers
[Link] Narrative Review: Transforming Population-Based Monitoring of Post-
Approval… – Real-time surveillance methods like Rapid Cycle Analysis (RCA) in
vaccine safety (2018–2024). DOI: accessible on the MDPI page MDPI
[Link] safety monitoring of COVID-19 vaccines. Ther. Adv. Drug Saf., ~2022. DOI:
on Sage Journals site SAGE Journals
[Link] Y, Wu Y, Jiang T, Xing H, Xu J, Li C, et al. Opportunities and challenges of
pharmacovigilance in special populations: a narrative review of the literature.
Therapeutic Advances in Drug Safety. 2023;14:1–21. DOI:
10.1177/20420986231200746 ResearchGate
[Link] J, Virk MK, Kalk E, Carlucci JG, Chepkemoi A, Bernard C, et al.
Pharmacovigilance in Pregnancy Studies, Exposures and Outcomes Ascertainment,
and Findings from Low- and Middle-Income Countries: A Scoping Review. Drug
Safety. 2024;47:957-990. DOI: 10.1007/s40264-024-01445-1 SpringerLink
[Link] C, Colley T, Macdonald TD. Paediatric pharmacovigilance: Methodological
considerations, data gaps and regulatory implications. British Journal of Clinical
Pharmacology. 2021;(Volume)? DOI: 10.1111/bcp.15119 BPS Publications
[Link] G, Zambon A, Picardi M, et al. Signals of Adverse Drug Reactions
Communicated by Pharmacovigilance Stakeholders: A Scoping Review of the Global
Literature. Drug Safety. 2023;46:109–120. DOI: 10.1007/s40264-022-01258-0 arXiv
[Link] C, Zorzi M, Pozzani G, Moretti U. From narrative descriptions to MedDRA:
automagically encoding adverse drug reactions. arXiv (preprint). 2016.
[Link] R, Olsson S, Waitt C. Pharmacovigilance in low- and middle-income
countries: A review with particular focus on Africa. Br J Clin Pharmacol.
2023;89(2):491–509. DOI: 10.1111/bcp.15193 ResearchGateScite
[Link] O, van Eeuwijk P, Maigetter K, et al. Pharmacovigilance processes in low-
and middle-income countries: moving from data collection to data analysis and
interpretation. Ther Adv Drug Saf. 2025 Jun;16. DOI: 10.1177/20420986241300006
PubMed
[Link] J, Rafeek NR. Pharmacovigilance in India in Comparison With the USA and
European Union: Challenges and Perspectives. Ther Innov Regul Sci.
2019;53(6):781–786. DOI: 10.1177/21684790188127

47