ADR

DEFINATION:

 According to WHO Adverse drug reaction is defined as ”A response to a drug which is

noxious and unintended, and which occurs at doses normally used in man for the
prophylaxis, diagnosis, or therapy of disease, or for the modifications of physiological
function.” Excludes overdose (either accidental or intentional), drug abuse, treatment
failure and drug administration errors.
 Adverse event is defined as ” Any medical occurrence temporally associated with the
use of a medicinal product, but not necessarily causally related ”


1958: Thalidomide marketed in West Germany as a non barbiturate hypnotic & for
morning sickness during pregnancy based on animal toxicity report.
 In 1959 - 1961, it was reported in that there was an outbreak of PHOCOMELIA (hypo
plastic and aplastic limb deformities) in the new born babies

TYPE OF ADR:

 Depending on….
• Onset of event: Acute (<60 minutes), Sub-acute (1-24 hrs) and Latent (>2 days)
• Type of reaction: (Wills and brown) Type A (Augmented), B (Bizarre), C
(chemical) (Chronic),D (Delayed), E (End of treatment)
• Severity: Minor, Moderate, Severe, Lethal ADRs
• Others: Side effects, Secondary effects, Toxic effects, Intolerance, Idiosyncrasy,
Drug allergy, Mutagenicity, Photosensitivity, Drug Dependence, Drug
Withdrawal, Reactions, Teratogenicity, Carcinogenicity, Drug induced disease
(Iatrogenic).
Onset of event:

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  Acute (<60 minutes), Sub-acute (1-24 hrs) and Latent (>2 days)
Type of reaction:
 Type A (Augmented) :
 Reactions which can be predicted from the known pharmacology of the drug
• Dose dependent,
• Can be alleviated by a dose reduction
 E.g.
• Anticoagulants Bleeding,
• Beta blockers Bradycardia,
• Nitrates Headache,
• Prazosin Postural hypotension.

 Type B (Bizarre) :
 Cannot be predicted from the pharmacology of the drug
• Not dose dependent,
• Host dependent factors important in predisposition
 E.g.
• Penicillin Anaphylaxis,
• Anticonvulsant Hypersensitivity

 Type C (Chemical)(chronic) :
• Biological characteristics can be predicted from the chemical structure of the
drug/metabolite
 E.g.
• Paracetamol Hepatotoxicity

 Type D (Delayed) :
 Occur after many years of treatment.
• Can be due to accumulation.
 E.g.
• Chemotherapy Secondary tumours
• Phenytoin during pregnancy Teratogenic effects
• Antipsychotics Tardivedyskinesia
• Analgesics Nephropathy

 Type E (Exit/End of treatment) :

 Occur on withdrawal especially when drug is stopped abruptly
 E.g.
• Phenytoin withdrawal Seizures,
• Steroid withdrawal Adrenocortical insufficiency

 Type F (Familial) :
 Type G (Genotoxicity) :

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  Type H (Hypersensitivity) :
 Type U (Un classified) :

Severity:

 Minor ADRs: No therapy, antidote or prolongation of hospitalization is required.

 Moderate ADRs: Requires change in drug therapy, specific treatment or prolongs
hospital stay by at least 1 day.
 Severe ADRs: Potentially life threatening causes permanent damage or requires
intensive medical treatment.
 Lethal ADRs: Directly or indirectly contributes to death of the patient.

Other:
Side effects:
 Unwanted but often unavoidable, occur at therapeutic doses
 Predicted from the pharmacological profile of a drug
 Known to occur in a given percentage of drug recipients
 E.g.
 Atropine dryness of mouth
 Promethazine (anti-allergic) sedation
 Codeine(anti-tussive) constipation Used in Traveller’sdiarrhoea

Idiosyncrasy:

 unusual response to a drug due to genetic abnormality.

 Drug interacts with some unique feature of the individual, not found in majority
subjects, and produces the uncharacteristic reaction.
 E.g.
 Isoniazid: N-Acetylation affects the metabolism of isoniazid
 Slow N-Acetylation: Isoniazid is more likely to cause peripheral neuritis.

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  Fast N-Acetylation: cause hepatotoxicity in this

Drug allergy:

 Acquired, altered reaction of the body to drug.

 Immunologically mediated reaction.
 occur even with much smaller doses
 Also called Drug hypersensitivity
 Not genetic, not occurred in all
 Occurs on re-exposure
 E.g. penicillin→1st time →stimulate antibody →Ag-Abreaction →allergy
 Chief organ: Skin, respiratory tract, GIT, Blood& blood vessels

Intolerance:

 Appearance of characteristic toxic effects of a drug in an individual at therapeutic doses

 Converse of tolerance
 Indicates a low threshold of the individual
 E.g.
 Triflupromazine (single dose) Muscular dystopias in some individuals
 Carbamazepine (few doses) Ataxia in some individuals
 Chloroquine (single tablet) Vomiting and abdominal pain in some individuals

PREDISPOSING FACTORS:
POLY PHARMACY:
 Patients on multiple drug therapy are more prone to develop an ADR
 Alteration of drug effect through interaction mechanism or by synergism
 Risk increases with increase in the no. of drugs administered

MULTIPLE AND INTERCURRENT DISEASE:

 Increased risk due to multiple drugs use for their diseases
 Impaired hepatic and renal status are also at high risk of developing an ADR
 Patient with decreased renal function treated with aminoglycosides increased risk of
nephrotoxicity
AGE:
 Elderly and pediatric patients are more vulnerable to ADRs
 In elderly patients physiological changes
 Eg: nitrate or ACE inhibitor induce postural hypotension
 In neonates drug handling capacity differ compared to adults
 Eg: grey baby syndrome with chloramphenicol

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DRUG CHARACTERISTICS:
 Some drugs are highly toxic in nature
 E.g.: cytotoxic drugs result in nausea and vomiting
 Narrow therapeutic range drugs like digoxin and gentamicin slight increase in
concentration may result in toxicity

GENDER:
 Women are more susceptible to ADRs than males; reasons are physiological,
pharmacokinetic, pharmacodynamic and hormonal.
 Eg: chloramphenicol induced aplastic anaemia and phenylbutazone induced
Agranulocytosis are twice and thrice as common in women as in man, respectively

RACE AND GENETIC FACTORS:

 ADRs are more common in genetically predispose Individuals
 E.g. : G6PD deficient patient high risk of developing heamolysis due to primaquine

STEPS INVOLVE IN ADR MONITORING

1. Identifying adverse drug reaction (ADR).
2. Assessing causality between drug and suspected reaction by using various algorithms.
3. Documentation of ADR in patient’s medical records.
4. Reporting serious ADRs to pharmacovigilance centers /ADR regulating authorities

1.

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2. Causality Assessment between Drug and Suspected reaction
Assessment performed by usually 2 methods includes:
 Clinical Judgment
An individual who is an expert in the area of ADRs would evaluate the case
 Algorithms
Commonly used algorithm is the Naranjo algorithm

3. Documentation of ADRs
Documents used for Reporting ADRs:
 Source Documentation
 e.g. Patient's Medical Records, X-Ray or Diagnostic Reports
 AE/SAE Forms
 Paper Case Report Form (CRF)/ Electronic CRF

4. Reporting Serious ADRs

Information to be captured for Reporting includes the following:
 Patient details
 Initials
 Gender
 Age and date of birth
 Weight
 Height

SUSPECTECTED DRUGS
 Generic name of the drug
 Indication(s) for which suspect drug was prescribed or tested
 Dosage form and strength
 Daily dose and regimen (specify units - e.g., mg, ml, mg/kg)
 Route of administration
 Starting date and time of day

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  Stopping date and time, or duration of treatment
 Other Treatment(s)
Concomitant drugs

Details of Suspected Adverse Drug Reaction(s):

 Full description of reaction(s) including body site and severity, as well as the criteria for
regarding the report as serious, whenever possible, describe a specific diagnosis for the
reaction
 Start date (and time) of onset of reaction Stop date (and time) or duration of reaction
Outcome
 Information on recovery; results of specific tests and/or treatment
 For a fatal outcome, cause of death and its possible relationship to the suspected
reaction; any post-mortem findings
 Any Other information relevant to facilitate assessment of the case, such as medical
history of allergy, drug or alcohol abuse; family history; findings from special
investigations etc

REPORTING RESPONSIBILITIES:
Responsibilities of Sponsor
 SAEs should be reported to the licensing authority within 14 calendar days of awareness
 Submit status report (Periodic Safety Update Reports) to the licensing authority
periodically

Responsibilities of Investigator
 SAEs and unexpected AEs should be reported to the sponsor and licensing authority
within 24hrs
 To their respective Ethics Committee within 7 working days

DETECTION OF ADRS

1. pre- marketing studies

2. Post –marketing surveillance
3. Assessing causality
4. Under reporting
5. Communicating ADRs

1. pre- marketing studies

 During the development of new medicines, their safety is tested in animal models.
 Specific animal studies for carcinogenicity, teratogenicity and Mutagenicity are also
available.

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  Clinical trials are carried out in 3 different phases prior to the submission of a marketing
authorization application.
 Clinical trials normally identifies ADRs of frequency greater that 0.5-1.0%.

2. Post –marketing surveillance

 Pharmacovigilance methodologies are used for detection of risk and for the collection of
risk information.
 Powerful and cost effective system for the identification of unknown drug-related risk is
spontaneous adverse drug reactions reporting.
 Health care practitioner should see it as a part of professional duty report ADR result in
a patient under his care.
 Concerned identifying product defect, intoxicants and abuse and unexpected lack of
therapeutic effect.
Two epidemiological methods are most commonly used are:
1. Cohort studies
2. Case-Control studies

 Cohort studies:
 Patient exposed to a particular drug are followed up actively and systematically and ADR
frequencies are compared to an unexposed control population.
 Case-Control studies :
 Individuals affected by the adverse event being studied are identified.
 Each case is matched with several disease free control patients randomly recruited from
the study base.
 Both cases and controls are investigated their exposure to possible causative agents
prior to occurrence of the event.
 The odd ratio calculated on the basis of exposure data.

3. Assessing causality
 Causality assessment is a method by which the extent of relationship between a drug
and a suspected reaction is established.
 If an ADR is suspected, the assessment starts with the collection of all the relevant data
pertaining to patients demographics; medications including OTCs; time of onset and
duration of reaction; treatment of reaction and it's outcome and reports.
 In assessing causality, any of the following approaches may be appropriate:
- opinion of individual experts
- opinion of penal of experts
- formal algorithms
-
Formal Algorithms
 Naranjo’s algorithm
 Kartch Lasagna’s algorithm

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  WHO probability Scale
 Spanish quantitative imputation scale
 Kramer’s scale
 Jones scale
 European ABO system
 Bayesian System

WHO PROBABILITY SCALE

4. Under reporting

Under reporting varies with no. of factors

1. Reporting higher for new drugs than for old
2. Serious reactions are reported to a higher degree
3. Type B reactions are reported more commonly than their share of events in practice
4. Reporting is affected by promotional claims of the drug sponsor.
5. Reporting is affected by general publicity around the ADR reporting scheme.

The reasons more often by health professionals for not reporting are:
1. Lack of time
2. Lack of knowledge on what, how or where to report
3. The drug-reaction association is uncertain
4. The reaction is already well known

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5. Guilt or fear of litigation
6. Belief that all registered medicines are safe
7. Non-availability of reporting forms

Activities that may increase the reporting rate include

1. Ease of reporting; improve the design of reporting form, using online reporting
2. Providing feedback to clinicians in the form of articles in journals, ADR bulletins, news letters
3. Participate in pre and post graduate education programs
4. Collaboration with local Drug and Therapeutics committees
5. Integrating pharmacovigilance in public healthcare programs

5. Communicating ADRs

Knowledge about rational and safe use of medicines needs to be provided,

1. during basic training of health professionals
2. through continuous education programs to health professionals.
3. by specially designated drug information centers.
4. through packaged inserts and patient counseling

6. Postal survey method

 This consists of a specific drug related questionnaire.

 This method is primarily used for ADR monitoring of new drugs.1-2 years after the drug
is launched.
 The questionnaire asks for details of drug, usage, dose, brand used, number of patients
treated in a given period.
 Common ADRs seen with the drug as mentioned in the literature are listed at the end of
questionnaire.
 The questionnaire along with a prepaid envelope is then mailed to practitioners all over
the city/state who are likely to use the drug.

SEVERITY OF ADR
 Severity describes the extent to which the ADRs influence the everyday life of patients.
 Karch and Lasagna classify severity into minor, moderate, severe and lethal.
 Mild(Minor)
 Moderate
 Severe
 Lethal

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SEVERITY ASSESMENT:
 Hartwig et al categorized ADRs into seven levels as per their severity.
 Level 1 & 2 fall under mild category, level 3 & 4 under moderate and level 5, 6 & 7 fall
under severe category.

SERIOUSNESS OF ADR:
 Seriousness of an ADR is related to its life threatening nature and is defined as any
untoward reaction to the medicinal product that may result in death and requires
patient hospitalization.
 Seriousness of reaction is categorized according to FDA criteria on the basis of their life
threatening nature.
 Death
 Life-threatening
 Hospitalization (initial or prolonged)
 Disability or Permanent Damage
 Congenital Anomaly/Birth Defect
 Required Intervention to Prevent Permanent Impairment or Damage (Devices)

PREVENTABILITY ASSESMENT SCALE:

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  According to WHO factsheet, it is estimated that at least 60% of ADRs are preventable.
In some countries ADR-related costs, suchas hospitalization, surgery and lost
productivity, exceed the cost of the medications.
 Historically, studies have shown that between 20% and 80% of ADEs and ADRs are
preventable with the majority of latter studies showing around 60- 70% preventability.
 Preventability of ADRs is assessed by using Schumock andThornton scale.

PREDICTABILITY :
Type A(Predictable)
 Extension of pharmacologic effect
 Often predictable and dose dependent
 Responsible foe at least 30% od ADRS
 E.g. anticholinergics and dry mouth
Type B(unpredictable)
 Idiosyncratic or immunologic reactions
 Rare and unpredictable
 E.g. chloramphenicol and aplastic anemia, penicillin inducedanaphylactic shock

REPORTING OF ADR :
WHAT TO REPORT
 All types of suspected ADRs- irrespective of whether they are known or unknown,
serious or non-serious, frequent or rare and regardless of a established
causalrelationship.
WHO SHOULD REPORT
 All health care and non-health care professionals, hospitals, health centres, consumers,
Pharmaceutical companies.
HOW AND WHOM TO REPORT
 Use the “Adverse drug reaction reporting form” which is available on official site of
IPCas well as CDSCO.

ROLE OF HEALTH CARE PROFESSIONALS

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  The health care professionals should be very vigilant in detecting ADRs.
 ADR may be detected during ward rounds with medical team
 ADRs detected during review of patient chart , patient counseling, medication history
review, communicating with other health professionals
To assist ADR health care professional should closely monitor patients who are at high risk
include
1. Patients with renal or hepatic impairment
2. Patients taking drugs which have potential to cause ADR .Eg: DIGITOXIN
3. Patient who have had previous allergic reactions
4. Patient taking multiple drugs
5. Pregnant and breast feeding women

First step in the detection of ADRs is collection of data.

Data collected includes,
1. Patients demographic information
2. Presenting complaints
3. past medication history
4. Drug therapy details including over the counter, current medications , medication on
Admission
5. Lab data such as hematological, liver and renal function test.

The information can be obtained from the following sources

1. Patient’s case note and treatment chart
2. Patient interview
3. Laboratory data sources
4. Communication with healthcare professionals

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