ADVERSE DRUG REACTIONS
The WHO defines an adverse drug reaction (ADR) as ‘any response to a drug which
is noxious and unintended, and which occurs at doses normally used in man for
prophylaxis, diagnosis or therapy of disease, or for the modification of physiological
function’.
Thus, this definition excludes overdose (accidental or intentional), drug abuse, treatment
failure and drug administration errors.
Often, the terms ‘adverse drug reaction’ and ‘adverse drug event’ are used synonymously,
although they are not. An adverse drug event (ADE) is a broader term and includes ‘any
untoward medical occurrence presenting during the administration of a drug’. Thus, an ADR
can also be considered as an ADE, but not all ADEs are ADRs.
CLASSIFICATION
There are many ways of classifying ADRs and different authors have classified
ADRs in their own way.
Rawlins and Thompson classification:
Type A (Augmented): Commonest (up to 70%). These reactions are usually the
exacerbation of the pharmacological effects of a drug and are thus dose-dependent. An
example is insulin-induced hypoglycaemia; Benzodiazepines induced sedation. These
reactions are usually predictable due to the known pharmacology of a drug and are thus
preventable.
Type B (Bizarre): These reactions are hypersensitivity reactions and are not dose-
dependent. An example is a penicillin induced hypersensitivity reaction. These
reactions are often not predictable and preventable in the individual case (unless the
patient has a known history of this type of reaction). This type is associated with high
morbidity and mortality.
Type C (Continuous drug use): Occurs as a result of continuous drug use. May be
irreversible, unexpected and unpredictable. E.g. Dementia by anticholinergics.
Type D (Delayed): Delayed occurrence of ADRs, even after the cessation of the
treatment. E.g. Pulmonary or peritoneal fibrosis by methysergide.
Type E (End of dose): Withdrawal reactions. Occurs typically with the depressant
drugs. Hypertension and restlessness in opiates abstainer.
Type F (Failure of therapy): Results from the ineffective treatment. E.g. Accelerated
hypertension because of inefficient control.
Types based on Onset of event:
Acute -within 60 minutes
Sub-acute -1 to 24 hours
Latent -> 2 days
Types based on Severity of ADRs
Minor: No need of treatment/ Antidote can give, causes prolongation of hospitalization.
Moderate: Requires treatment or change in treatment. prolongation of hospital stays by at
least one day
Severe: Requires intensive treatment. It’s a life threatening condition and causes permanent
damage.
Lethal: Indirectly contributes to the death of the patient.
PREDISPOSOING FACTORS
Many factors can predispose a patient to the occurrence of ADRs. Patients who have one or
more of the following predisposing factors are at high risk of developing an ADR:
Polypharmacy: Patients on multiple drug therapy are more prone to develop an ADR either
due to alteration of drug effect through an interaction mechanism or by synergistic effect.
Multiple and intercurrent diseases: Patients with multiple diseases are at increased risk of
developing an ADR due to multiple drug use for their diseases. Similarly, patients with
impaired hepatic or renal status are also at high risk of developing an ADR to drugs which
are eliminated by these organs. For example, a patient with decreased renal function who is
treated with aminoglycosides is at increased risk of developing nephrotoxicity unless
appropriate dose adjustments are made.
Age: Elderly and paediatric patients are more vulnerable to ADRs. Elderly patients are more
susceptible to ADRs due to the physiological changes (pharmacokinetic and
pharmacodynamic) which accompany ageing, and also because they often take many drugs
for chronic and multiple diseases. Nitrate or an angiotensin converting enzyme inhibitor–
induced postural hypotension in an elderly patient is an example Paediatric patients may
develop serious ADRs to some drugs since all children, especially neonates, differ in their
drug handling capacity compared to adults. An example of such a serious reaction is the grey
baby syndrome with chloramphenicol.
Drug characteristics: Some drugs are highly toxic in nature and patients who are treated
with these agents are at an increased risk of ADRs. For example, nausea and vomiting is a
common ADR seen in patients treated with cytotoxic anti-cancer drugs.
Gender: Women are reported to be more susceptible to ADRs than men, for a number of
reasons: Physiological, pharmacokinetic, pharmacodynamic and hormonal.
Chloramphenicol-induced aplastic anaemia and phenyl butazone-induced agranulocytosis
are twice and thrice as common in women as in men, respectively.
Race and genetic factors: It is evident that ADRs are more common in genetically
predisposed individuals. For example, patients who are deficient in glucose-6-phosphate
dehydrogenase (G6PD) are at higher risk of developing haemolysis due to primaquine than
those who are not.
DETECTION AND MONITORING OF ADRs
[A] Pre-marketing Studies
(a) Non Clinical Study: The safety of new medicines is tested in animal models. A great
deal of risk information may be obtained from such tests, for example the level of acute
toxicity, which organs will be affected in case of toxicity and dose dependency of such tissue
injuries. Specific animal tests for carcinogenicity, teratogenicity and mutagenicity are also
available. The predictive value of the different animal tests is uncertain in all instances. If
animal tests do not reveal particularly worrying results, safety tests proceed onto testing in
humans in clinical trial programmes.
(b) Clinical Study: Clinical trials are carried out in three different phases prior to the
submission of a marketing authorisation application, with a stepwise increase in the number
of individuals being exposed. Prior to the general release of a new product, not more than
4000 individuals have normally been exposed to the new drug. This implies that clinical
trials, normally, only have the power to identify adverse reactions of a frequency greater that
0.5—1.0 per cent.
Children and the elderly are normally actively excluded from the studies. For cost reasons
clinical trials often have a very short duration, which means they cannot generate information
about long-term adverse effects. The consequence of the above is that, at the time of general
marketing of a new medicine, only the most common, dose-related (type A) adverse reactions
will be known.
[B] Post-marketing Surveillance
The different methods which are used commonly in post marketing surveillance
include:
a) Spontaneous case reporting
b) Cohort studies
c) Case control studies
d) Hospital based population studies
a) Spontaneous case reporting: - The most sensitive, powerful and cost-effective system
for identification of unknown drug-related risks is spontaneous case reporting. It is
mainly the presentation of experience of a single patient and usually presented as a way
that supports hypothesis. When common experience of more than one patient are
presented, this referred as “case series”. Obviously, the grater the number of common
experience, stronger the conclusion.
Here doctors are asked to report all suspected adverse reaction and all suspected
reaction to newer product. For this purpose, the Committee on Safety of Medicine
(CSM) set a spontaneous reporting agency, to felicitate the reporting of adverse events.
This also provides valuable early warning or signals of possible adverse drug reactions.
The CSM introduced a yellow card system for the detection of adverse events which
ask doctors and pharmacists to report all suspected reactions of drug. In the set up
ADRs may be detected during ward rounds or during review of the patient chart.
Patient counselling, medication history interview, and communicating with other
health care professionals may provide additional clues.
The first step in the detection of ADRs is collection of data. The data to be collected
including patient’s demographic data, presenting complaints, past medication history,
drug therapy, current medications, lab data etc.
b) Cohort Studies: - Cohorts are groups. In cohort studies, patients exposed to a
particular drug are followed up actively and systematically and adverse reaction
frequencies are compared to an unexposed control population.
c) Case control studies: - Methodologically, case control studies are opposite of cohort
studies. It involves studying patients who have been affected by an adverse reaction
and linking it with drug use prior to the reaction. In case of control study, one first
identifies a group of patient with a common event or disease. E.g. if an investigator
wishes to determine whether a certain drug causes aplastic anaemia (rare event), firstly
the patient with aplastic anaemia could be identified. Case control studies are
particularly useful for the study of rare adverse reactions.
d) Hospital based population studies: - These are useful for determining the incidence
of ADR in hospitalized patients. A clinical pharmacist can easily have conducted the
type of ADR monitoring by prescriptions, chart review or by ward round participation.
Causality Assessment
Causality assessment is the method by which the extent of relationship between a drug
and a suspected reaction is established. The assessment of causality relationship is often
highly subjective, based upon an individual clinician’s assessment.
If an ADR is suspected, the assessment starts with collection of all the relevant data
pertaining to patient demographics, medications including non-prescription drugs (OTC),
comprehensive ADR details including a description of reaction, time of onset and duration
of reaction, complications, treatment of the reaction & outcome of the treatment and relevant
investigation reports.
The collected data should be used to correlate and categorise the relationship between
the suspected drug and adverse drug reaction. This can be done by using one or more
causality assessment scales. Some of the important causality assessment scales used for
assessing the causality relationship include Naranjo’s scale, WHO, European ABO system,
Kramer etc.
Different scales categorise the causality relationship in different ways. For example,
the WHO scale categorises the causality relationship in certain, probable, possible,
unassessable/unclassifiable, unlikely, conditional/unclassified. The Naranjo’s scale
categorises the reactions as either definite, probable, possible or unlikely.
NARANJO CAUSALITY SCALE
Do not
SL.NO QUESTIONS yes no know/ Not score
done
Are there previous conclusive reports on
1 this reaction? +1 0 0
Did the adverse event appear after the
2 suspected drug was given? +2 -1 0
Did the adverse reaction improve when the
3 drug was discontinued or a specific +1 0 0
antagonist was given?
Did the reaction appear when the drug was
4. readministered? +2 -1 0
Are there alternative causes that could
5. have caused the reaction? -1 +2 0
Did the reaction reappear when a placebo
6. was given? -1 +2 0
Was the drug detected in any body fluid in
7. toxic concentrations? +1 0 0
Was the reaction more severe when the
8. dose was increased or less severe when the +1 0 0
dose was decreased?
Did the patient have a similar reaction to
9. the same or similar drugs in any previous +1 0 0
exposure?
TOTAL =
SCORING
> 9 = Definite ADR
5-8 = Probable ADR
1-4 = Possible ADR
0 = Doubtful ADR
REPORTING OF ADR
Health professionals are in the best position to report on suspected ADRs observed in
their everyday patient care. All healthcare providers (physicians, pharmacists, nurses,
dentists and others) should report as part of their professional responsibility.
What should be reported
For ‘new drugs’- report all suspected reactions, including minor ones.
For established or well-known drugs- report all serious or unexpected suspected
ADRs.
Report all suspected ADRs associated with drug-drug, drug-food interactions.
Report ADRs in drug use in pregnancy and during lactation.
Report when suspected ADRs are associated with drug withdrawals.
Report ADRs occurring from overdose or medication error, etc.
Thus report all suspected ADRs of clinical importance as soon as possible.
How to report ADR
Local Case Report Forms (CRF) should be obtained from the National Drug Regulatory
Authority. Some countries have included CRF in their National Formularies (BNF,
Formularies of South Africa etc.)
There are different case report forms in different countries, but all of them have at least four
sections which should be completed.
1. Patient information: Name, Age at the time of event, gender, weight etc.
2. Nature of adverse event: description of reaction, date & time of onset and duration
of reaction, complications and relevant investigation reports.
3. Suspected medication: Name, dose, frequency, route of administration, event abated
after use stopped or dose reduced, batch number, expiry date, event reappeared after
reintroduction of the treatment, concomitant medical product etc.
4. Reporter: Name, address, speciality, contact number etc.
Method of reporting
Spontaneous reporting: The most common way that regulatory bodies collect ADR
information for medicines once they are on the market is through voluntary, spontaneous
reporting structures. In UK, for this purpose, the Committee on Safety of Medicine (CSM)
set a spontaneous reporting agency, to felicitate the reporting of adverse events. This also
provides valuable early warning or signals of possible adverse drug reactions. The CSM
introduced a yellow card system for the reporting of adverse events. When the yellow card
scheme was first introduced, only doctors and dentists could submit reports. Gradually this
has been extended and now all healthcare professionals, including pharmacists and nurses
are able to report ADRs via this scheme.
Yellow card system should be submitted to either the MHRA (Medicines and Healthcare
Products Regulatory Agency) directly or to one of five regional monitoring centres (RMC).
Paper yellow cards are available and Electronic Yellow Cards were introduced in 2002 and
can be downloaded from either the MHRA or the RMC website. MHRA also receives ADR
report from pharmaceutical companies, which have a statutory obligation to report suspected
ADRs. If a doctor passes details of an ADR to the pharmaceutical firm which markets the
drug, this information will subsequently be passed on to the MHRA.
In India, Under the aegis of Ministry of Health & Family Welfare, Government of India, The
Central Drugs Standard Control Organisation (CDSCO), New Delhi has initiated a
nation-wide pharmacovigilance programme. The programme is coordinated by The
Indian Pharmacopoeia Commission (IPC) located at Ghaziabad. Now many regional
centres are also established. Indian Pharmacopoeia Commission understands the need for
establishing local hospital based centres across the nation for the better patient safety.
Duly filled Suspected Adverse Drug Reaction Reporting Form can be send to the nearest
Adverse Drug Reaction Monitoring Centre (AMC) or directly to the National Coordination
Centre (NCC) OR Call on Helpline (Toll Free) 1800 180 3024 to report ADRs. Or can
directly mail this filled form to pvpi@ipcindia.net or pvpi.ipcindia@gmail.com
Health care professionals need to be aware that patients, parents, or carers, are now also able
to take part in spontaneous reporting of ADRs.
ADVERSE DRUG REACTION MANAGEMENT
1. Assess the nature and severity of the reaction: Whether an urgent action is required or
can be managed by primary care. Eg: whether an anaphylactic shock or something minor.
2. Review on the presenting symptoms:
Timing: Time of start of the reaction after giving the drug; Time taken to abate after the
stopping of drug or reducing the dose.
Relationship to dose: Whether reaction minimized with reducing the dose; symptoms
resolve when the medicine withdrawn and recur when reintroduced.
Other possible causes: Possibility of underlying illness or other disease; other medications
(including OTC and Herbals); drug interactions (including diet).
3. Take complete drug history - Review any History of Allergy or previous ADR: When
the drug was started, dose, other drugs, OTC and herbal. Past ADRs and review the adverse
effect profile of the drugs, and check how common it is.
4. Further Examination and Investigations if required: Specific investigations and
laboratory tests required. Eg; Liver and Renal Function Tests.
5. Review the treatment: Either withdraw the suspected drug or reduce the dose. Manage
the symptoms of ADR and provide supportive therapy. Acute therapy is directed toward
enhancement of oxygenation and maintenance of normal tension. Requisite measures include
the use of epinephrine, oxygen, and adequate fluid replacement; in some instances,
vasopressors or corticosteroid drug therapy may be warranted. Emergency measures may be
needed to maintain the airway.
6. Record the ADR in the individual’s health record. Consider the submission of an ADR
report (Yellow Card) if appropriate.
7. Documentation for the future purpose.
