Adverse drug reactions (ADR)

monitoring & Causality

assessment

12/8/2021 Adverse Drug Reaction Monitoring 1

 Define ADR monitoring Appreciate the
and list the sources of importance of ADR
ADR reports. monitoring.

Objectives of
today’s class
Understand the
concept and Do a causality
organization of the assessment and report
PvPI an ADR to a monitoring
(Pharmacovigilance centre .
program of India).

12/8/2021 Adverse Drug Reaction Monitoring 2

Problem statement
4th
leading cause of
Median length of
These events death stay in hospital =
Adverse drug are the most 8.7 days
events as a top common type
70% of admissions
safety priority of iatrogenic
estimated to be
injury preventable

Physicians
ADEs occur
often do not
almost daily in
recognize or 6.7% of patients
medium-sized
appropriately
hospitals and 0.7 % of admissions
treat instances
outpatient
of drug-related 0.32% fatal
panels
harm

Source: Preventable ADRs-FDA website

3
Historical Reminders

McBride WG (1962). Thalidomide and

congenital abnormalities. Lancet 2:1358. 4
12/8/2021 Adverse Drug Reaction Monitoring 5
 Some banned drugs in India

• Gatifloxacin - Hypo/hyperglycemia
• Rosiglitazone - Adverse Cardiac events
• Sibutramine - Adverse Cardiac events
• Rimonabant - Suicidal Ideation
• Phenylpropanolamine - Hemorrhagic
stroke
• Analgin- myelosuppression
A study on drug safety monitoring program in India
Patel et al
 Pharmacovigilance (WHO, 2002)

Study deals with drug safety

The science and activities relating to the

detection, assessment, understanding
and prevention of adverse effects or any
other possible drug-related problems

pharmakon (Greek), “drug;” and vigilare (Latin), “to keep awake or alert, to
keep watch.”
7
Some definitions…

“Any untoward medical occurrence that

may present during treatment with a
Adverse event pharmaceutical product but which does not
necessarily have a causal relationship with
this treatment”. ICH, 1995

“a response to a drug which is noxious and

unintended and which occurs at doses
Adverse Drug normally used in man for prophylaxis,
Reactions diagnosis, or therapy of disease or for the
modification of physiologic function”. ICH,
1995

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Some definitions…
Serious adverse event

 Events resulting in death

 Life-threatening experiences
 Prolonged or initial hospitalization
 Clinically significant or persistent
disability Congenital anomaly or
 Require intervention to prevent one of
the above

12/8/2021 Adverse Drug Reaction Monitoring 9

Why pharmacovigilance?

Humanitarian concerns: Hippocrates’

admonition “First, do no harm”

Do drugs on the market fulfill their intended

role in society (alleviating human suffering,
reduce disease related economical loss)

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Why Pharmacovigilance ? Contd.,

• Systematic surveillance
of drug safety in real
world setting
• Clinical trials cannot
detect all ADRs
• Long term adverse
effects like any delayed
organ damage,
teratogenicity or rare
ADRs

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ADR expected incidence
Expected Required number of patients for
incidence of
ADR 1 event 3 events

1 in 100 300 650

1 in 200 600 1300

1 in 1000 3000 6500

1 in 2000 6000 13000

1 in 10000 30000 65000

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 Need for Pharmacovigilance in developing
countries
• Wide genetic and ethnic variability
• Disease prevalence and patterns of drug
usage
• Multimodal pratice of medicine
• Larger over the counter drugs usage
• Substandard drug quality.

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 Who should report safety data ?
 Physicians and other healthcare professionals
 Pharmacists
 Pharmaceutical companies qualified persons –
(Pharmacovigilance/Regulatory manager)
 Investigational products (clinical trials)
 Post-approval reporting – Individual Case Safety
Report (ICSR), Periodic Safety Update Report (PSUR)
 In many countries patients are encouraged (but not
obligated) to report side effects

12/8/2021 Adverse Drug Reaction Monitoring 14

 Sources of ADRs reports
• Unsolicited reports – Spontaneous
reporting, reports critiqued in any media or
newsletters , case reports
• Solicited reports – Clinical trials, Post-
marketing surveillance (PMS).
• Regulatory reports – Periodic safety
update reports (PSUR), PMS.

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What to report ?– WHO
recommendations
 Every single problem related to the use of a drug,
because probably nobody else is collecting such
information
 All suspected adverse reactions
 ADRs associated with contrast media in radiology,
vaccines, diagnostics, drugs used in traditional
medicine, herbal remedies, cosmetics, medical
devices and equipment
 Lack of efficacy and suspected pharmaceutical
defects
 Counterfeit pharmaceuticals
 Development of resistance
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Pharmacovigilance Program of India
(PvPI)
• In 2010: Restarted (PvPI) by Central Drug Standard
Control Organisation (CDSCO) with total funding from
Govt. of India.
• UMC has agreed to allow entry of ADR data into WHO
Uppsala Global Database (Vigibase) through data entry
package (Vigiflow) free of cost
ADR monitoring centres
National coordinating centre, (AMC)
Indian Pharmacopoeia Dept. of Pharmacology/
commission, Ghaziabad Clinical Pharmacology
• Tertiary care hospitals
• Private hospitals

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 ADR monitoring centers in India

NATIONAL COORDINATING
CENTRE (NCC) IPC
Ghaziabad
S.G.S.M.C.
ADR Monitoring Centers (AMC) – 250 ADR Monitoring
& KEM H
centers
JIPMER LHMC RGKM DMCH SMSMC
Puducherry New Delhi Kolkatta Punjab Jaipur

MMC PGIMER KEM HIMS SMU

Chennai Chandigarh Mumbai Dehradun Ghaziabad

CMC Govt.MC PGIMC SKIMS STM

Vellore Jammu Haryana Srinagar Kolkatta

JSS SAIMS GVSM MC STM

Mysore Indore Kanpur Guwahati Kolkatta
 WHO-UMC, Sweden

CDSCO, NCC- IPC, Ghaziabad

New Delhi
Vigiflow
 Clinical trials
 National Health
Programmes
AMCs  Pharmaceutical
companies

Decision/ action
(Restricted use of drug/
ban) Voluntary reports
HCPs, Patients

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12/8/2021 Adverse Drug Reaction Monitoring 20
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 WHO- UMC at Uppsala, Sweden IPC, Ghaziabad

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 Signal

“Reported information on a possible causal relationship

between an Adverse event and a drug, the relationship
being unknown or incompletely documented previously”
WHO, 1991
Considered important to investigate
further

New information on an already known

association

Usually more than a single report is

required to generate a signal

23
Regulatory actions

Do nothing, Initiate Alter product

Inform health
wait for more further information
professionals
information studies

 animal studies
 clinical trials
 case-control
 cohort
Suspend/
Change Limit Limit permanentl
marketing y withdraw
conditions indications availability from
market

24
SMROF DER
RED FORMS
MROF EULB
BLUE FORM
SMROF WOLLEY
YELLOW FORMS
 Other reporting tools

Toll Free No. PvPI: 1800 180 3024

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CAUSALITY ASSESSMENT
 Causality assessment scales
• WHO-UMC scale
• Naranjo’s algorithm
• Other scales
– Karch & Lasagna scale
– Kramer’s scale
– Jones scale
34
 CERTAIN

Significant temporal Dechallenge

association + information +

Rechallenge
information +

36
 Probable/Likely

Rechallenge information
is not available (-)

SIGNIFICANT
SIGNIFICANT
TEMPORAL
TEMPORAL
DECHALLENGE
DECHALLENGE
ASSOCIATION +
INFORMATION +
 Possible

Significant temporal
association +

Rechallenge
Dechallenge
information lacking (-)
information lacking (-)
 Unlikely

Absent or unlikely
temporal association

Rechallenge
information Dechallenge
lacking information
lacking
Conditional/ Unclassified

Insufficient
Data
 Unassessible/ unclassifiable

Rechallenge

? ?
information Dechallenge

?? ? ?
information

Significant temporal
association
Naranjo scale
TASKS
COMMON TASK 1:
1. Sources of ADR reports :

- Unsolicited reports: Spontaneous reporting, reports

critiqued in any media or newsletter, case reports
- Solicited reports: Clinical trials, Post-marketing
surveillance (PMS)
- Regulatory reports - Periodic safety update reports
(PSUR), PMS

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 COMMON TASK: 1 (contd.)
Types of ADRs
 Type A - Augmented e.g. postural hypotension, hypoglycemia
 Type B - Bizarre e.g. Idiosyncratic reactions
 Type C - Chronic e.g. analgesic nephropathy, dyskinesias
 Type D - Delayed e.g. Carcinogenesis, teratogenesis
 Type E - End of dose response e.g. Rebound hypertension
 Type F - Failure of therapy e.g. contraception failure
 Type G – Genotoxicity e.g. genetic mutations with
chemotherapeutic agents

12/8/2021 Adverse Drug Reaction Monitoring 45

 COMMON
TASK 2
Adverse drug reaction: Dizziness induced by
Prazosin

Disease: Essential Hypertension

Temporal association - Present

Dechallenge - Present

Rechallenge - Done
 Group task 1
1. A 48 year old male was started on
tab. Aspirin 150 mg/day after the
attack of myocardial infarction 1 week
after taking the drug he complained of
epigastric pain. Assess the causality.
 ANSWER KEY 1
• ASPIRIN
• ADR: EPIGASTRIC PAIN
• Temporal association: present (the epigastric pain
appeared after the administration of tab. Aspirin)
• Dechallenge: Not done
• Rechallenge: Not done
• Biological plausibility: present (aspirin inhibits the
gastroprotective effects of prostaglandins by COX -1
inhibition.
• Concomitant drug/ disease: present (MI also causes
epigastric pain)
• Causality assessment: POSSIBLE
2. A 60 year old hypertensive and
diabetic was on tab. Enalapril 10 mg
BD. He developed dry cough after 2
months of taking the drug. It was
replaced with tab. Losartan 50 mg od.
The cough subsided. Assess the
causality of this scenario.
 ANSWER KEY 2
• ENALAPRIL
• ADR: DRY COUGH
• Temporal association: Present (Dry cough appeared
after the administration of tab. Enalapril)
• Dechallenge: Present (It was replaced with tab.
Losartan, symptoms subsided)
• Rechallenge: Not done
• Biological plausibility: Present (Enalapril inhibits
ACE enzyme thereby increase the levels of
bradykinin)
• Concomitant drug/ disease: No
• Causality assessment: CERTAIN
 Group task 2
1. A 52 year old male patient who was
diagnosed as hypertension and started on
tab. Amlodipine 10 mg b.d. after 1 week he
developed edema over the ankles.
Amlodipine was withdrawn and he was
started on tab. Losartan 50 mg o.d. Ankle
edema resolved. Assess the causality of
this ADR.
 ANSWER KEY 1
• AMLODIPINE
• ADR: ANKLE EDEMA
• Temporal association: Present (Ankle edema appeared
after the administration of tab. Amlodipine)
• Dechallenge: Present (It was replaced with tab.
Losartan, symptoms subsided)
• Rechallenge: Not done
• Biological plausibility: Present (Amlodipine is calcium
channel blocker causing vasodilation leading to fluid
extravasation in surrounding tissue)
• Concomitant drug/ disease: No
• Causality assessment: CERTAIN
2. A 40 year old unmarried female
patient was diagnosed as schizophrenia
and started on tab. Haloperidol 5mg o.d.
After 2 weeks of therapy, she developed
tremors and muscular dystonia.
Haloperidol was replaced with tab.
Olanzapine symptoms were subsided.
Do the causality of this ADR.
 ANSWER KEY 2
• HALOPERIDOL
• ADR: TREMORS & MUSUCULAR DYSTONIA
• Temporal association: Present (Tremors and muscular
dystonia appeared after the administration of tab.
Haloperidol) Dechallenge: Present (It was replaced with
tab. olanzapine, symptoms subsided)
• Rechallenge: Not done
• Biological plausibility: Present (Haloperidol causes D2
blockade thereby produces extra pyramidal symptoms)
• Concomitant drug/ disease: No
• Causality assessment: CERTAIN
 Group task 3
1. A 35yr old female patient was diagnosed
to have generalized tonic clonic convulsions.
She was started on tab. Phenytoin 100mg
bd for 5 months. Recently she developed
gum hypertrophy which subsided by
discontinuation of drug. Tab phenytoin was
replaced by tab phenobarbitone. Do the
causality assessment for this case.
 ANSWER KEY 1
PHENYTOIN
ADR: PHENYTOIN INDUCED GUM HYPERTROPHY
• Temporal association: Present (The gum hypertrophy
appeared after the administration of tab. Phenytoin)
• Dechallenge: Present (tab. phenytoin was replaced by tab.
Phenobarbitone and the gum hypertrophy was subsided)
• Rechallenge: Not done
• Biological plausibility: Present (phenytoin induces a decrease
in the Ca2+ cell influx leading to a reduction in the uptake of
folic acid, thus limiting the production of active collagenase)
• Concomitant disease / drug: No
• Causality assessment: CERTAIN
2. A 25yr old female was diagnosed as
generalized tonic clonic convulsions and
started on tab. Valproate 200mg tds. Mean
while she become pregnant. In first
trimester ultra sound abdomen showed
neural tube defect. valproate was replaced
wit tab. Phenobarbitone. Do the causality
assessment for this ADR.
 ANSWER KEY 2
VALPROATE
ADR: VALPROATE INDUCED NEURAL TUBE DEFECT
• Temporal association: Present (Neural tube defect
appeared after the administration of tab. Valproate)
• Dechallenge: Done ( Replaced by Tab. Phenobarbitone)
• Rechallenge: Not done
• Biological plausibility: Present (The specific inhibition by
VPA of histone deacetylase and changes in gene
expression may explain the teratogenicity of this drug)
• Concomitant disease / drug: No
• Causality assessment: CERTAIN
 Group task 4
1.A 35 year old lady developed symptoms
and signs of urinary tract infection for
which she was given Inj. Ciprofloxacin.
She developed pain and erythematous
rash at the site of injection within 15
minute. The reaction reappeared after the
second dose also. Comment on this ADR
scenario and make causality assessment
for this ADR.
 ANSWER KEY 1
CIPROFLOXACIN
ADR: PAIN AND RASH AT INJECTION SITE
• Temporal association: present (Pain and
erythematous rash at the site of injection appeared
within 15 minute after injection)
• Dechallenge: Not done
• Rechallenge: present (The reaction reappeared after
the second dose also)
• Biological plausibility: present (injection site reaction)
• Concomitant drugs/ disease: absent
• Causality assessment: CERTAIN
2. A 67 year old woman presented to
hospital with rigidity, bradykinesia, tremor,
and parkinsonian gait over 2 weeks.
History revealed that she was diagnosed
to have depression and was on
citalopram for 6 months.
 ANSWER KEY 2
CITALOPRAM
ADR: PARKINSONISM LIKE SYMPTOM
• Temporal association: present (H/O
depression on treatment for past 6 months)
• Dechallenge: Not done
• Rechallenge: Not done
• Biological plausibility: absent
• Concomitant drug/ disease: absent
• Causality assessment: Probable
 Group task 5
1. A 9 yr old child was diagnosed as a case of tuberculosis.
He was started with HRZE regimen in initial intensive phase
of 2 months given 3 times per week(INH-150mg,
Rifampicin-300mg,Pyrazinamide-750mg,Ethambutol-450mg)
.At the end of 6 weeks he started developing symptoms of
diminished vision. On ophthalmic examination diagnosed
as optic neuritis all drugs were continued for 2 months and
completed intensive phase then switched over to HR
regimen at same doses vision started improving. Discuss
the causality assessment.
 ANSWER KEY 1
HRZE regimen
ADR: Optic neuritis
• Temporal association: Present (appeared after 6
weeks of onset of treatment)
• Dechallenge: Present (symptoms improved after
the withdrawal of ethambutol)
• Rechallenge: Not mentioned
• Biological Plausibility: Present (Ethambutol causes
optic neuritis)
• Concomitant drugs/diseases: No
• Causality assessment: CERTAIN
2. 22 year old male was on the treatment
regimen of Dapsone and Rifampicin for
paucibacillary leprosy. After 6 weeks he
started developing fatigue on minimal
exertion. On hematological examination
Hb-7g %, reticulocyte count-6%, and blood
picture suggesting hemolytic anemia. Give
your opinion regarding causality
assessment.
 ANSWER KEY 2
DAPSONE & RIFAMPICIN
ADR: Hemolytic anemia
• Temporal association: Present (appeared
after 6 weeks of onset of treatment)
• De-challenge: Not mentioned
• Re-challenge: Not mentioned
• Biological Plausibility: Present (Dapsone
causes hemolytic anemia)
• Concomitant drug/diseases: No
• Causality assessment: POSSIBLE
 Group task 6
1. A 64 year old male was diagnosed with
carcinoma testis 1 year back and started on
chemotherapy with cisplatin, etoposide and
bleomycin. Patient developed continuous
nausea and vomiting. After completing the
first cycle it was subsided and reappeared
during second cycle. Do causality
assessment for this case.
 ANSWER KEY 1
CISPLATIN, ETOPOSIDE AND BLEOMYCIN
ADR: Chemotherapy induce nausea & vomiting
• Temporal Association – Present (nausea and vomiting
developed only after starting with cisplatin, bleomycin
and etoposide)
• Dechallenge - Present
• Rechallenge – Present
• Biological Plausibility – Present (chemotherapeutic
regimens releases neurotransmitters like serotonin and
substance P which stimulate NTS in area postrema)
• Concomitant Drugs/diseases – absent
• Causality Assessment - CERTAIN
2. A 45 year old female was diagnosed as a
case of rheumatoid arthritis 1 year back and
was taking NSAIDs but her condition was not
improving. She was started on tab.
Methotrexate. She was on regular monitoring.
After 2 weeks her Hb- 8 mg/dl and peripheral
blood smear shows Anisocytosis, Poikilocytosis,
Macrocytes. The drug was stopped and within
a month the blood report was normal. Do the
causality assessment for this case.
 ANSWER KEY 2
• METHOTREXATE
• ADR: Anaemia
• Temporal Association - Present (Anaemia developed
Only after starting the therapy with methotrexate)
• Dechallenge - Present
• Rechallenge - Absent
• Biological Plausibility – Present (Methotrexate inhibits
dihydrofolate reductase enzyme cause folate deficiency
led To bone marrow suppression.)
• Concomitant Drugs/ Diseases – Absent
• Causality Assessment – CERTAIN
 Group task 7
1. A 25 year old female diagnosed to have
systemic lupus erythematosus was started
on prednisolone 10 mg bd. The baseline
creatinine was 1.7 and after 3 days of
starting prednisolone was 1.8. Do the
causality assessment for this case.
 ANSWER KEY 1
• PREDNISOLONE
• ADR: Nephrotoxicity
• Temporal Association – Present after 3 days (developed
Only after starting the therapy)
• Dechallenge - Not done
• Rechallenge - Not done
• Biological Plausibility – Present (Creatinine can be
elevated to increase protein catabolism).
• Concomitant Drugs/ Diseases – Present (Lupus nephritis
can cause renal failure leading to elevation in creatinine)
• Causality Assessment - POSSIBLE
2. A 75 year old woman with a history of deep
venous thrombosis of the lower limbs was treated
with sunitinib for renal cancer with hepatic and
pulmonary secondaries. While on this treatment,
she developed painful ulcers of the right lower
limb, despite having never previously presented leg
ulceration. On discontinuation of sunitinib, the
lesions improved and resumption of this drug,
even at a lower dosage, resulted in relapse of her
ulcers.
 ANSWER KEY 2
• SUNITINIB
• ADR: Ulcers
• Temporal Association – Present (developed Only after
starting the therapy)
• Dechallenge - Present
• Rechallenge - Done
• Biological Plausibility – Present (Antiangiogenic effect -
VEGF inhibition)
• Concomitant Drugs/ Diseases – Absent
• Causality Assessment - CERTAIN