Adverse Drug Reaction Monitoring

UG Practical

Department of Pharmacology
VIMSAR, Burla
 OUTLINE
• Definitions
• Why Pharmacovigilance ?
• Magnitude of ADR burden
• History of Medication Disasters
• List of drugs banned since year 2000
• Scenario at VIMSAR
• How to fill up ADR Reporting Form ?
• Causality Assessment of the Reported ADR
 What is Pharmacovigilance ???
• ADR monitoring & its clinical application
• “The science and activities relating to the
detection, assessment, understanding
and prevention of ADRs or any other possible
drug related problems.
• Also includes herbal, traditional medicines,
complementary medicines, biologicals & vaccines.
• Blood products (Hemovigilance) and medical
devices (Materiovigilance).
 Why Pharmacovigilance ???
• Drug is the commonest form of therapeutic
intervention.
• Any drug, no matter how trivial its
therapeutic action, has the potential to do
harm.
• Basic principle of drug therapy: Use drugs
with maximal efficacy and minimal toxicity.
• Anticipated benefit from any therapeutic
decision must be balanced by potential risks.
 NEED FOR PHARMACOVIGILANCE
• Can the risks to the drug be identified during the
drug development process ??
– NUMBER: Only 2000-3000 carefully selected healthy
volunteers & patients receive the new drug upto phase
III clinical trials. (followed up very closely under
controlled conditions, for a limited period of time)
– TIME PERIOD: At most, few hundred patients given the
new drug for more than 3-6 months.
– Only most profound and overt risks that occur
immediately and if the frequency > 1/ 100
administrations can be identified.
 NEED FOR PHARMACOVIGILANCE (contd....)
• ADRs not detected prior to marketing :
That occur late.
That occur less frequently (< 1 in 1000 administrations)
• Consequently, a no. of unanticipated adverse as well as beneficial
effects of drugs are detectable only after the drug is used widely
(after marketing) in large no. of patients with varying presentations
of clinical and other conditions, for a long period of time & with
other medicines.

• Post marketing surveillance (Phase IV) : ADR Monitoring

or Drug Safety Monitoring or Pharmacovigilance; as many
side effects may emerge during this period
 ADR : Magnitude of the problem
• ADRs : Common, yet often preventable cause of illness, disability
and even death, most common cause of iatrogenic disease
• Account for 3-5% of all hospitalizations, considerable morbidity
& mortality
• Once hospitalized, 30% chance of an untoward event related to
drug therapy, Chance of life threatening ADR - 3%/ hospitalized
pt.
• In some countries, ADRs rank among the top 10 leading causes
of mortality, Economic burden on patient & health care system
• India: 4th largest pharmaceutical producer, > 6000 manufacturer,
> 60000 branded formulations
• *ADR accounted for 0.7% of total admissions & death d/t ADR
1.8% of all deaths: a south Indian study
 DEFINITIONS
• Adverse reaction(ADR): Response to a drug which is
noxious and unintended, and which occurs at doses
normally used in human for the prophylaxis, diagnosis or
therapy of disease or modifying a physiological function.

• Side effect: Undesirable effects of a drug that occur at

normal doses used in man, usually bothersome but not
deleterious. (related to pharmacological properties of drug)

• Adverse Drug Event (ADE): Any untoward medical

occurrence that may present during treatment with a
pharmaceutical product but which does not necessarily
have a causal relationship with this treatment.

• Toxic effect: Occurs at higher doses of the drug;

Paracetamol liver damage
 Types of ADRs
• A (Augmented): directly related to Pharmacological action of
the drug; Antihypertensives hypotension
• B (Bizarre): Idiosyncratic & genetically determined;
Primaquine hemolytic anaemia in G6PD deficiency pts.
• C (Continuous use): Associated with long term use of the drug;
Chloroquine retinal damage, neuroleptics tardive
dyskinesia
• D (Delayed): Terratogenicity or carcinogenicity, Phenytoin
cleft lip
• E (End of dose): Abrupt stoppage of the drug; Corticosteroids
Acute adrenal insufficiency
• F (Failure of therapy): Therapeutic failure of the drug
 Severity of ADRs
• Mild: Usually transient in nature, not interfere
with normal activities.
• Moderate: Interfere with normal activities
• Severe: An ADR that is incapcitating & prevents
normal activities, (not serious)
• Serious: Death, life-threatening, require
intervention to prevent permanent damage,
congenital anomalies, need/ prolong
hospitalisation, prolonged impairment, damage,
disability.
 History repeats itself
• Sulfanilamide : in 1930s, death of 105 children due to di-ethylene
glycol, an excellent but highly toxic solvent.

• Thalidomide : Introduced in 1957 and used for tt. of morning

sickness and nausea.
• Caused severe birth defects and banned in 1965
• Now restricted use as immunomodulator.

• 34 cases of phocomelia between 1969 and 1995

• Cerivastatin : Approved in 1997 as a lipid lowering agent.

• 549 cases of rhabdomyolysis by 2000.

• Voluntary withdrawal by the manufacturer in 2001.

 Classical examples of serious and unexpected ADRs

Drug Adverse Reaction

Chloramphenicol Aplastic anemia
Clioquinol Myelooptic neuropathy (SMON)
Erythromycin estolate Cholestatic hepatitis
Methyldopa Hemolytic anemia
Oral Contraceptives Thromboembolism
Practolol Sclerosing peritonitis
Reserpine Depression
Statins Rhabdomyolysis
Thalidomide Cong. malformations
 Recent ADR Reports
Drug ADR

Benzocaine Methaemoglobinaemia
Bisphosphanates Atypical fractures of femur
Buflomedil Convulsions
Celecoxcib Cardiovascular side effects
Inj. Dolasetron Arrhythmia
Ipilimumab Severe immune mediated reactions
Prasugrel Rare but serious hypersensitivity reactions

Rosiglitazone Cardiovascular events

Stavudine Lactic acidosis
 Recent ADR Reports (contd..)
Drug ADR
Tigecycline Increased mortality
Thiazide diuretics, Hyponatremia
Carbamazepine, ARBs, ACEIs
SSRIs, SNRIs
Subcutaneous immunoglobulin Thrombotic events
(Human)
Lenalidomide Second primary malignancies
in myeloma
Natalizumab Progressive multifocal
leukoencephalopathy
TNF blockers, Azathioprine, Hepatosplenic T- cell
Mercaptopurine lymphoma
 Drugs banned Internationally & in India (since2000)

Astemizole Valdecoxib Nimesulide

(< 12 yrs age)
Terfenadine Rimonobant Sibutramine

Phenformin Rosiglitazone Gatifloxacin

(systemic)
Rofecoxib Cisapride D- propoxyphene
 Pharmacovigilance in India

Around 250
Renamed as ADR
NCC for PvPI Monitoring
Pharmacovigila shifted from
nce programme Centers (AMC)
Delhi to IPC,
of India (PvPI) Ghaziabad
Formal ADR under MoHFW,
National
monitoring GOI Present
programme of Apr 2011
center under pharmacovigilance Scenario
DCGI, New JULY 2010
Delhi
2005
PvPI: Pharmacovigilance programme of India
1986
NCC: National Coordination Center
AMC: ADR Monitoring Center
ICSR: Individual Case Safety Report
UMC: Upsala Monitoring Center
 Our scenario
• VIMSAR, Burla Recognized as an ADR Monitoring
Centre (AMC) in April, 2011 under (PvPI).
• Co-ordinator, Deputy Co-ordinator and Technical
Associate.
• Collection of ADR reports in suspected ADR reporting
form (ver 1.4) developed by Uppsala Monitoring
Centre , Sweden.
• Causality assessment by WHO- UMC criteria.
 Organogram of AMC under PvPI

HCP and Patients

NCC
Technical Associate (Indian Pharmacopoeia
Commission)

Causality Assessment Committee (CAC) Pharmacovigilance

Materiovigilance Programme of India
Programme of (PvPI)
India (MvPI) SADRRF (HCP)
&
MDAERF MSERF (Consumers)

Coordinator Co-coordinator Clinician

Prof. & HOD, Assoc. Professor, Professor,

Pharmacology Pharmacology Paediatrics
 Connected with National
Pharmacovogilance Centre,
IPC, Ghaziabad

Burla
 PHARMACOVIGILANCE DATA FLOW

ICSR

VigiAccess: to access the database

 OUR HOSPITAL DATA
Period of Collection : April 2011 to Oct
2016
No. of ADRs Reported : 1448 nos.

380 nos. Of ADRs in Jan’ – Aug’ -2016

42 nos. Of them were marked as serious
380 *
26 nos. Of them were reported by consumers 237 336 26
26
291

139 No. of
ADRs

65

2011 2012 2013 2014 2015 2016

How to fill ADR Reporting Form
and Causality Assessment ???
 ADR Reporting Forms
• Suspected Adverse Drug Reaction Reporting Form
(For voluntary reporting of Adverse Drug Reactions
by Healthcare Professionals) : RED colour
• ADR Reporting Form for Consumer: Blue color
• Transfusion Reaction Reporting Form (TRRF)
(Haemovigilance Program of India)
• Medical Device Adverse Event Reporting Form
(Materiovigilance Program of India)
 SUSPECTED ADR REPORTING FORM
• Version 1.4
• Designed by: UMC, Sweden &
used by NCC, PvPI at IPC, Ghaziabad
• Front: Fields to be filled up
• Back: Advice about reporting
• 4 sections: A, B, C & D and 17 Fields
• Report Type: Initial or Follow up

Section A: Patient Information

Point 1- Patient initials
(Do not write full name)
Point 2- Age or Date of Birth
Point 3- Sex
Point 4- Weight in Kgs

Importance:
Used to identify duplicate reports.
• Section B: Suspected Adverse Reaction (3 Fields)

Point 5- Date of Reaction Started.

Point 6- Date Of Recovery
Point 7- Description of the
Reaction/Problem

• Give maximum information to describe the

nature.
• Its localization, severity and characteristics.
• Do not use single word description of the event.
• Section C: Suspected Medication(s)

– Manufacturer, Batch No./Lot No.

– Expiry Date
– Dose, Route, Frequency
– Therapy Dates: Date started, Date Stopped
– Indication & Causality assessment
• Section C: Suspected Medication(s) (Continued….)
• Section D: Reporter information
Point 16: Name and Professional address
Telephone No., Occupation, Signature
Point 17: Date of the report

Signature of the HCP who is reporting

 What to report?
• Serious or Non-serious ADR
• Known or Unknown ADR
• Frequent or Rare –
Related to medicine, vaccine, herbal
products
 ADVICE ABOUT REPORTING
• Focus on serious ADRs (old/new drugs), any
ADR (New drugs)
• Report even if :
You are not certain about the causality.
You don’t have all the details.
Mandatory Fields:
Points-1, 2, 5, 7,8, 16,17 must be filled up.
Any missing Mandatory Fields : Invalid Report
 Who can report?

• Any healthcare professional

(Drs, Nurses, Pharmacists)

• Medicine side effect Reporting Form

(for patients/consumers- blue color).

 Where to report?
• Nearest ADR Monitoring Center (AMC) –
VIMSAR, Burla

• Directly to NCC, IPC Ghaziabad

• [Link]@[Link]

pvpi@[Link]

• Toll free no. – 1800 180 3024

• ADR Reporting Android app

 Mandatory Fields for Suspected ADR
Reporting Form
• 1. Patient initials
• 2. Age at onset of reaction
• 5. Date of onset of reaction
• 7. Reaction term(s)
• 8. Suspected medication
• 16,17. Reporter information
• Any missing Mandatory Fields : Invalid Report
 WHAT HAPPENS TO THE SUBMITTED ADR
REPORT?
• Information handled in strict confidence
• Causality assessment at AMC by Causality Assessment
Committee (CAC) as per WHO-UMC Scale
• Analysed forms forwarded to NCC through Vigiflow

• Report analysed at and communicated by NCC to the

Global Pharmacovigilance database (WHO Uppsala
Monitoring Center in Sweden)
WHAT HAPPENS TO THE SUBMITTED ADR REPORT? (Contd…)
CONFIDENTIALITY IN ADR REPORTING
• Patient’s identity:

• Held in strict confidence

• Protected to the fullest extent

• Non-liability of Reporter/Manufacturer/Product:

• Submission of report does not constitute an

admission that doctor/manufacturer/drug
caused or contributed to the reaction.
 CAUSALITY ASSESSMENT
• Naranjo probability scale
• WHO-UMC criteria
• Kramer’s scale
• Jones scale
• Karch & Lasagna scale
 WHO-UMC CAUSALITY ASSESSMENT CRITERIA
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 plausible (pharmacologically,
pathologically)
• Event definitive pharmacologically or phenomenologically (i.
e. an objective and specific medical disorder or a recognised
pharmacological phenomenon)
• Rechallenge satisfactory, if necessary
Probable/ • Event or laboratory test abnormality, with reasonable time
Likely relationship to drug intake
• Unlikely to be attributed to disease or other drugs
• Response to withdrawal clinically reasonable
• Rechallenge not required
 WHO-UMC CAUSALITY ASSESSMENT CRITERIA (contd.)
Causality term Assessment criteria
Possible • Event or laboratory test abnormality, with reasonable time
relationship to drug intake
• Could also be explained by disease or other drugs
• Information on drug withdrawal may be lacking or unclear
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 explanations
Conditional/ • Event or laboratory test abnormality
Unclassified • More data for proper assessment needed, or
• Additional data under examination
Unassessable/ • Report suggesting an adverse reaction
Unclassifiable • Cannot be judged because information is insufficient or
contradictory
• Data cannot be supplemented or verified
 What to report ???
• For new drugs (upto 5 yrs post marketing) all suspected
reactions including minor ones

• For established drugs all serious/ unexpected suspected

ADRs
• All life threatening & serious ADRs irrespective of new or
established drugs

• ADRs associated with drug-drug, drug-food or drug-food

supplements (including herbal products)

• Reactions to vaccines, from overdose or medication error

 CLINICIAN’S KEY ROLE IN ADR SURVEILLANCE
• Spontaneous reporting of ADRs:
Only practical way to detect rare events, events that occur after
prolonged use of drug, events having long latency and many drug-
drug interactions
Professional obligation
Serious reactions (most important)
Newly marketed drugs (< 5 years)
Responsible, alert physicians, nurses, pharmacists & students:
sentinel in the detection of unexpected ADR

• Safe drugs, Safer health care, Safest doctors

 CONCLUSION
• Report with honesty and integrity.

• Need for sensitizing and motivating the clinicians.

• ADR Reporting: Should be professional obligation of clinicians.

• Generation of early warning signals about unexpected ADRs.

• Signal (WHO): Reported information on a possible causal relationship

between an adverse event and a drug, the relationship being unknown

or incompletely documented previously. Usually minimum 3 reports are

required to generate signal, depending upon the seriousness of the

event and quality of the information.

• There are no safe drugs, only safe physicians

Madan Lal, a 65-years old male patient weighing 72kg admitted to
hospital on 12.01.2022 with chief complaints of pain in upper abdomen
and nausea since last 5 days. On physical examination, he had yellowish
discoloration of palm, conjunctiva and nail bed.
He had few episodes of psychotic attacks, for which he was on
Chlorpromazine therapy since last 4 weeks. On enquiry, he told that he
was taking Tab. Largactil (Chlorpromazine) 100 mg, 4 tablets at bed time.
He was also taking Tab. Diclofenac 50 mg twice-a-day (self-medication) for
abdominal pain for three days before admitting to hospital. He was
investigated on the day of admission for laboratory parameters which are
as follows: – Alkaline Phosphatase = 180 U/L (Normal range: 25 – 100 U/L)
– ALT = 205 U/L (Normal range: 10 – 40 Units/L) – Total Bilirubin = 5.0 mg/
dL (Normal range: 0.8 – 1.2 mg/dL)
On admission, Chlorpromazine and Diclofenac therapy was stopped. After
7 days of stopping the medications, the intensity of pain decreased. Also,
he was re investigated for above parameters which are as follows: –
Alkaline Phosphatase = 110 IU/L – ALT = 98 Units/L – Total Bilirubin = 1.8
mg/dL
• Note: Tab Chlorpromazine
Brand Name: LARGACTIL Manufacturer: Wedley labs
Batch number: LGL0881 Expiry date: Dec 2023
 Question- 1
Fill up this case scenario in a Suspected ADR Reporting Form
Shivram Das, a 65 year old male, weighing 72 kg was admitted to hospital
on Dt. 12.01.2016 with chief complaints of pain in upper abdomen and
nausea since last 5 days. On physical examination, there was yellow
discoloration of palm, conjunctiva and nail bed.
He had few episodes of psychotic attacks, for which he was on Tab.
Chlorpromazine 100 mg 4 tablets at bed time since last 4 weeks. He was
investigated on the day of admission for laboratory parameters which are as
follows:
Alkaline phosphatase- 180 U/L (Normal range: 25- 100 U/L)
ALT- 205 U/L (Normal range: 25- 100 U/L)
Total Bilirubin- 5 mg/dL (Normal range: 0.3- 1 mg/dL)
Note:-
Tab. Chlorpromazine
• Brand Name: LARGACTIL
• Manufacturer: Wedley labs
• Batch No.: LGL0881
• Expiry Date: Dec 2016
 Question- 2
Fill up this case scenario in a Suspected ADR Reporting Form
Mr. Sushant Patel, a 30 year old male with 68 kg weight was diagnosed as
a case of bacterial meningitis on 15.02.2016. He was started empirically with
Inj. Ceftriaxone 1g IV BD. and Inj. Vancomycin was also given at 10 a.m. on the
same day. After 10 minutes of second drug administration, he started
developing chills, rigors, fever, urticaria and intense flushing. He was treated
with Inj. Pheniramine 25 mg IM, following which the reaction completely
subsided. Inj. Ceftriaxone was continued. However, next doses of Inj.
Vancomycin scheduled on day 1 were not given. On day 2, Inj. Vancomycin
was re-introduced at 10 a.m. to the patient. Similar symptoms developed
again and quickly resolved after Inj. Pheniramine 25 mg IM.
Note:
Inj. Vancomycin ▪ Inj. Ceftriaxone
Brand name: Vanzid Brand name: Taximax
Manufacturer: SWACH Healthcare Manufacturer: Wedley Labs
Batch No: KKIL098 Batch No: OPO659
Expiry Date: Dec 2016 Expiry Date: Dec 2016
 Question- 3

Fill up this case scenario in a Suspected ADR Reporting Form

Parvati Devi, a 27 year old female weighing 47 kg was a known

case of AIDS since 2 months. She was prescribed ART regimen
(Tenofovir-300 mg, Lamivudine- 300 mg, Efavirenz- 600 mg,
Nevirapine- 150 mg PO OD) after food at night with advice not
to take oily food. Therapy started on 06.08.2016. The patient
complained of anorexia, fatigue, dizziness, head reeling and
vertigo after taking the above drugs for 2 months as reported on
10.10.2016. The drugs were retained. The reaction abated after
symptomatic treatment.

Note: TLE- Manufacturer - Aurobindo Pharmaceuticals

Batch No. - XXX1234
Exp. Dt. - 02/2018
 Question- 4
Fill up this case scenario in a Suspected
ADR Reporting Form
Information was received from healthcare
professional regarding a 45 year old female
patient who received chloramphenicol tab.
500 mg q.i.d. + paracetamol tab. 500 mg t.i.
d for fever. Therapy began on 18/10/2016.
The patient developed fixed drug eruption
on left middle finger and peri oral skin
(around lips) after taking the drugs for two
days as reported on 20/10/2016.
Chloramphenicol was withdrawn. Outcome
was “recovering”. The reaction abated after
symptomatic treatment of the reaction.

Note: Paraxin Tab- 500 mg (Nicholas Piramal, CB127, 05/2018)

Calpol Tab- 500 mg (GSK, PB345, 07/2018)