Diagnosis And Management

of
Adverse Drug Reactions
 Definition

WHO
response to a drug that is noxious and unintended and that occurs
at doses used in humans for prophylaxis, diagnosis, or therapy of
disease, or for the modification of physiologic function

excludes therapeutic failures, overdose, drug abuse,

noncompliance, and medication errors
Cont..

Side effect

Any unintended effect of a pharmaceutical product

occurring at doses normally used in man, which is
related to the pharmacological proprieties of the drug.

Essential elements in this definition are the pharmacological

nature of the effect, that the phenomenon is unintended, and that
there is no overt overdose.
Cont..

Adverse drug reaction

A response to a drug which is noxious and

unintended, and which occurs at doses normally used
in man.

Important: it concerns the response of a patient, in which

individual factors may play an important role, and the
phenomenon is noxious (an unexpected therapeutic response, for
example, may be a side effect but not an adverse reaction).
Cont..

Unexpected adverse drug reaction

An adverse reaction, the nature or severity of
which is not consistent with market
authorisation, or expected from the
characteristics of the drug.
Predominant element is that the phenomenon
is unknown.
• Not listed in current labeling
– Listed in labeling but greater specificity or severity

• e.g. renal impairment listed, patient experiences renal failure

 Serious Adverse Drug Experience

• Death
• Life threatening (per initial reporter)
• Permanently or significantly disabling
• Hospitalization
• Congenital anomaly/birth defect
• Important medical events

ICH E6 guideline:
substantially same as above plus:
- congenital anomaly/birth defect
Cont..

− FDA Serious ADR

– Result in death
– Life-threatening
– Require hospitalization
– Prolong hospitalization
– Cause disability
– Cause congenital anomalies
– Require intervention to prevent permanent injury
 Adverse event/adverse experience

• 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
 Adverse Drug
Events
(ME & ADR)

Medication
Errors
(preventable)
Adverse Drug Event:
preventable or unpredicted
medication event---with harm
to patient
 Classification

− Onset
− Severity
− Type
Cont..

− Onset of event:
• Acute
• within 60 minutes
• Sub-acute
• 1 to 24 hours
• Latent
• > 2 days
Cont..

− Severity of reaction:
• Mild
• bothersome but requires no change in therapy
• Moderate
• requires change in therapy, additional treatment,
hospitalization
• Severe
• disabling or life-threatening
Different types of adverse events

Type A effects (‘drug actions’):

due to pharmacological effects,

fairly common,
dose related (i.e. more frequent or severe with high
doses) and may often be avoided by using doses which
are appropriate to the individual patient,
can usually be reproduced and studied experimentally
and are often already identified before marketing.

Drug interactions - may be classified as Type A effects,

although they are restricted to a defined sub-population of patients,
i.e. those taking interacting drugs
Cont..

Type B effects (‘patient reactions’):

• occur in only a minority of predisposed,

intolerant patients,
• little or no dose relationship,
• generally rare and unpredictable,
• sometimes serious,
• difficult to study .
Cont..

Examples of Type B effects (‘patient reactions’):

Drug intolerance:
toxic reactions, not related to overdose or diminished elimination

Drug idiosyncrasy:
genetically determined abnormal reaction to the drug that may be related to
metabolic or enzyme deficiency

Drug allergy:
immunologically meditated reaction that is characterised by specificity,
involvement of antibodies or lymphocytes and re-occurence in case of new
contact with the drug

Pseudoallergic reactions:
the same clinical symptoms as allergic reaction but without immunological
specificity
Cont..

• Type C effects:

• the use of a drug increases the frequency of a

‘spontaneous’ disease,
• may be both serious and common (and include
malignant tumours) and may have pronounced
effects on public health,
• often relate to long term effects,
• there is often no suggestive time relationship
and the connection may be very difficult to
prove.
Cont..

• Type D
• delayed effects (dose independent)
• Carcinogenicity (e.g., immunosuppressants)
• Teratogenicity (e.g., fetal hydantoin syndrome)
Cont..

− Types of allergic reactions

• Type I - immediate, anaphylactic (IgE)
• e.g., anaphylaxis with penicillins
• Type II - cytotoxic antibody (IgG, IgM)
• e.g., methyldopa and hemolytic anemia
• Type III - serum sickness (IgG, IgM)
• antigen-antibody complex
• e.g., procainamide-induced lupus
• Type IV - delayed hypersensitivity (T cell)
• e.g., contact dermatitis
 Common Causes of ADRs

• Antibiotics
• Antineoplastics*
• Anticoagulants
• Cardiovascular drugs*
• Hypoglycemics
• Antihypertensives
• NSAID/Analgesics
• Diagnostic agents
• CNS drugs*
*account for 69% of fatal ADRs
 Body Systems Commonly Involved

• Hematologic
• CNS
• Dermatologic/Allergic
• Metabolic
• Cardiovascular
• Gastrointestinal
• Renal/Genitourinary
• Respiratory
• Sensory
 ADR Risk Factors

• Age (children and elderly)

• Multiple medications
• Multiple co-morbid conditions
• Inappropriate medication prescribing, use, or
monitoring
• End-organ dysfunction
• Altered physiology
• Prior history of ADRs
• Extent (dose) and duration of exposure
• Genetic predisposition
 ADR Frequency by Drug Use

60

50

40

30

20

10

0
0-5 6-10 11-15 16-20
Number of Medications
 ADVERSE DRUG REACTION
Size of the problem

An approximate estimate of the burden of ADR is

shown by the following figures.
It accounts for

- 2.0 – 3.0 % of hospital consultations

- 0.3 – 0.5 % of hospital admissions
- 5.0 – 10 % of acute medical admissions
- 1.0 – 15 % of hospital in- patients
- 0.2 – 3.0 % of hospital in – patient deaths
 Adverse Reactions:Possible Causes

• Intrinsic factors of the drug

– Pharmacological
– Idiosyncratic
– Carcinogenicity, Mutagenicity
– Teratogenicity
• Extrinsic factors
– Adulterants
– Contamination
• Underlying medical conditions
• Interactions
• Wrong usage
 Epidemiology of ADRs

− substantial morbidity and mortality

− estimates of incidence vary with study methods,
population, and ADR definition
− 4th to 6th leading cause of death among hospitalized
patients*
− 6.7% incidence of serious ADRs*
− 0.3% to 7% of all hospital admissions
− annual dollar costs in the billions
− 30% to 60% are preventable
 Diagnosis of Adverse Drug Reactions

• Is the patient taking medicines? OTC, prescribed, herbal,

oral contraceptives, misused drugs, long term
prescription drugs.

• Medical history –right drug in the correct dose

• Patient’s adherence to the prescription instructions

Cont..

• Time relationship?

• Could it be a withdrawal reaction?

• Could this be an allergy?

• Is the patient pregnant?

• Consider known pharmacology

• Consider known idiosyncrasy

• Consider dose

• Consider interactions

• Consider risk/benefit for the particular patient

ACTIVE INGREDIENTS WITHDRAWN
– THALIDOMIDE (1961)
– BENOXAPROFEN (1982)
– PHENFORMIN (1982)
– FENFLURAMINE (1997)
– ASTEMIZOLE
– PHENYLPROPANOLAMINE(2000)
– KAVA KAVA
– CERIVASTATIN
– CISAPRIDE
– ROFECOXIB (2004)
– VALDECOXIB (2005)
– COMFREY, SENECIO
– TEGASEROD (2007)
– CLOBUTINOL (2007)
Congenital limb defects
Hepatotoxicity
Lactic acidosis
Heart-valve abnormalities
Many drug interactions
Haemorragic stroke
Liver abnormalities
Rhabdomyolysis
Cardiac arrythmias
Cardiovascular events
Cardiovascular events,
serious skin reactions
Nephrotoxicity
Cardiovascular events
Cardiac arrhythmia
 WHAT SHOULD BE REPORTED

• New drugs
– Report all suspected reactions including minor ones
• For established or well known drugs
– All serious, unexpected, unusual ADRs
• Change in frequency of a given reaction
• ADRs to generics not seen with innovator products
• ADRs to traditional medicines
Cont..

• All suspected drug-drug, drug-food, drug-food

supplement interactions
– Statement highlighting marine source of supplements
such as glucosamine so that can be avoided by those
with allergy to sea food
• ADRs associated with drug withdrawals
• ADRs due to medication errors
– eg vincristine given IT
• ADRs due to lack of efficacy or suspected pharmaceutical
defects
 Reporting Requirements

• Within 15 calendar days if Serious and Unexpected

(domestic and foreign)

• Follow-up information

• Non-applicant notifies applicant within five calendar

days
 Periodic Report

• Quarterly and Annual Reports

– Serious & Expected ADEs

– All Non-serious
 When does the Regulatory
Clock Start?
• First day a firm or any affiliate receives event data
containing all four elements:
– An identifiable patient
– An identifiable reporter
– A suspect drug
– An adverse event or fatal outcome
 Management Options

z Discontinue the offending agent if:

• it can be safely stopped
• the event is life-threatening or intolerable
• there is a reasonable alternative
• continuing the medication will further exacerbate
the patient’s condition
– Continue the medication (modified as needed) if:
• it is medically necessary
• there is no reasonable alternative
• the problem is mild and will resolve with time
Cont..

– Discontinue non-essential medications

– Administer appropriate treatment
• e.g., atropine, benztropine, dextrose,
antihistamines, epinephrine, naloxone, phenytoin,
phytonadione, protamine, sodium polystyrene
sulfonate, digibind, flumazenil, corticosteroids,
glucagon
– Provide supportive or palliative care
• e.g., hydration, glucocorticoids, warm / cold
compresses, analgesics or antipruritics
– Consider rechallenge or desensitization
 Follow-up and Re-evaluation

• Patient’s progress
• Course of event
• Delayed reactions
• Response to treatment
• Specific monitoring parameters
 Documentation and Reporting

− Medical record
• Description
• Management
• Outcome
− Reporting responsibility
• Food and Drug Administration
• post-marketing surveillance
• particular interest in serious reactions involving
new chemical entities
• Pharmaceutical manufacturers
• Publishing in the medical literature
 Components of an ADR Report

− Product name and manufacturer

− Patient demographics
− Description of adverse event and outcome
− Date of onset
− Drug start and stop dates/times
− Dose, frequency, and method
− Relevant lab test results or other objective evidence
− De-challenge and re-challenge information
− Confounding variables
 AE Information Management

Call Center Reports / Queries

Data Mining Regulatory

Applications Submission database

Clinical (MedDRA) / Investigator Portal

Drug Dictionaries AE
database
Clinical Risk Mgt.
Clinical Trial data
Regulatory Agencies
Imaging System
Business Partners
Product Labeling Clinical Literature
 Forms

• 3500A (Medwatch Form)

• Council for International Organization of Medical

Science (CIOMS I Foreign) or other form if approved in
advance
MEDWATCH 3500A Reporting
Form

https://www.accessdata.
fda.gov/scripts/medwatch
 The Value of Adverse Reaction Reports

• Signal/hypothesis generation

• Facilitates review of other available data-international

database sources-review of scientific literature

• Facilitates consideration of any need for epidemiological

studies

• Permits revision of product information, +/-other

regulatory action, as appropriate
 MONITORING DRUG SAFETY
Sonja Brajovic, M.D., PSI International, Inc., USA

The Path to Drug Safety The Language of Drug Safety

Pre Approval Data Known Drug Class International Conference on Harmonization (ICH) initiatives are
• Pre-
Pre-clinical Effects standardizing the global drug development regulations and maintaining
• Clinical trialsDa safeguards on quality, safety and efficacy

h e ar c
ta
in

S
pu
t

Adverse Event Profile ICH Guidelines Related to Drug Safety

• E2A – All clinical trials expedited safety reporting
• E2B – Safety reporting data elements specifications
Post Approval Data • E2C – Postmarketing periodic safety reporting - PSURs
Pharmacovigilance • M1 – MedDRA as international standard for post marketing reporting
• M2 – Electronic submission
The Safety Signal • E2D – Post marketing expedited electronic standard

Sources • E2E – Pharmacovigilance planning

• New unlabeled adverse events
• Observed increase in labeled event in its severity
or specificity
• New interactions
• Newly identified at risk population
• Process
Medication error, actual or potential Regulatory authorities (EMEA’s EudraVigilance, FDA-AERS, MHLW) and the regulated

Regulatory
biopharmaceutical industry utilize the Medical Dictionary for Regulatory Activities (MedDRA)
Generation Evaluation Clinical
Significance
Action through the entire regulatory process, from pre-marketing to post-marketing, for data entry,
retrieval, evaluation and presentation. MedDRA is a global terminology with global usage
Safety signals may be identified through clinical trials, known for the drug class, observed
standard and global version synchronization.
through the adverse event reporting systems and in medical literature.
literature. Clinically
significant Safety signals undergo a continuous Drug Risk Management
Management Process.

Premarketing
Risk Assesment

Pharmacovigilance SOC 26

System Organ Class

Risk Minimization MedDRA HLGT

High Level Group Term
~330

Program HLT ~1,700

High Level Term

Regular Label SSC PT ~16,500
Withdrawal Further
practices Modifications Preferred Term
from Market Studies Special Search Category
Periodic
reporting SMQ LLT ~c60,000
n9,000
Low Level Term
Standard MedDRA Query

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