Introduction of Pharmacovigilance:- ‘The science and activities relating to the detection,
assessment, understanding and prevention of adverse effects or any other drug-related problem.
(WHO2002).
4 important terms:
1. Detection: For e.g.: In case of clinical trial, it’s the investigator or in case of post
marketing trial, it’s either the physician or the prescriber or the patient himself who
reports the adverse event or any drug related problem.
2. Assessment: For e.g.: The investigator or the health care professional i.e. HCP would be
assessing if the adverse event or drug related problem is due to the drug or is it due to
some other reason.
3. Understanding: The reporter and safety specialist is involved in the understanding the
adverse event or drug related problem.
4. Prevention: By pro-actively reporting the adverse event or drug related problem to the
regulatory authority and taking precautionary actions would help in preventing the
adverse event in future.
Pharmacovigilance is a branch of pharmacoepidemiology but is restricted to the study, on an
epidemiological scale, of drug events or adverse reactions.
Pharmacovigilance is equal to drug Monitoring
▪ It is the process of monitoring, evaluating and improving the safety of medicines in use
Pharmacovigilance is the science of collecting, monitoring, researching, assessing and
evaluating information from healthcare providers and patients on the adverse effects of
medications, biological products, herbal products and traditional medicines.
▪ Proactive monitoring and reporting on the quality, safety and efficacy of drugs
▪ Assessment of the risks and benefits of marketed medicines
▪ Monitoring the impact of any corrective actions taken
▪ Providing information to consumers, practitioners and regulators on the effective use of
drugs
▪ Designing programs and procedures for collecting and analyzing reports from patients
and clinicians.
▪ Early detection of unknown safety problems
▪ Detection of increases in frequency of Adverse Drug Reactions (ADRs)
▪ Identification of risk factors for ADRs
▪ Risks Analysis & Mitigation
Finally the most important is the Patient safety
Why Pharmacovigilance:
▪ Drug monitoring
▪ Drug surveillance
▪ Alleviating human sufferings
▪ Reduce disease related economical loss
▪ Identifying new information about hazards associated with medicines
▪ Preventing harm to patients.
Who will Report the Adverse events?
▪ Adverse events can be reported by Physicians, Hospitals, Pharmaceutical manufacturers
through Medical Representatives etc.. pharmacists, nurse.
▪ Not only Patients but also their friends, relatives etc can report the adverse events.
▪ In short, anybody either the person consuming the drug or the person knowing the patient
or observing the event can report the adverse event.
What should be reported?
1. For the new drugs, all suspected reactions including the minor or mild in severity adverse
events should be reported.
2. For established or well-known drugs, all serious, unexpected, unusual ADRs
3. If there is a change in the frequency of given reaction, i.e. Increase in frequency of event of
vomiting for a particular drug
4. 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
5. ADRs associated with drug withdrawals –
6. ADRs due to medication errors- for example the drug was prescribed intravenously but the
patient took the drug subcutaneously.
7. ADRs due to lack of efficacy or suspected pharmaceutical defects – for example: the drug was
showing the effects but suddenly the new batch of drug failed to show any efficacy.
What are the various sources of Reports?
Adverse event reports can be reported in 2 ways:
1. Unsolicited sources: Report which is not asked for
2. Solicited: Report which is mandatory reports to be submitted
Unsolicited sources include reports from Spontaneous Report, Literature, Internet and Other
Sources like fax, email
Solicited sources include reports from Clinical Trials: Pre-marketing(Phase I, II & III) or post-
marketing (Phase IV studies)
Key terms in Pharmacovigilance:
Side effect
Adverse events and Adverse reactions
Adverse drug reaction (ADR)
Side effects:
Any unintended effect of a pharmaceutical product occurring at doses normally used in man,
which is related to the pharmacological proprieties of the drug.
Problems that occur when treatment goes beyond the desired effect. Or problems that occur in
addition to the desired therapeutic effect.
Example — A hemorrhage from the use of too much anticoagulant (such as heparin) is a side
effect caused by treatment going beyond the desired effect.
Example — The common side effects of cancer treatment including fatigue, nausea, vomiting,
decreased blood cell counts, hair loss, and mouth sores are instances of side effects that occur in
addition to the desired therapeutic effect.
Adverse event:
Any untoward medical occurrence that may be present during treatment with a pharmaceutical
product but which does not necessarily have a causal relationship with this treatment.
Synonym: adverse experience
All clinical trials have the potential to produce AEs. AEs are classified as serious or minor;
expected or unexpected; and study-related, possibly study-related, or not study-related.
For eg: A patient has taken the study drug and meets with an accident while walking on the
street. Then, accident would be reported as adverse event to the regulatory authority. But this
accident may or may not be due to the drug.
Adverse drug Reaction (ADR)?
A response which is noxious and unintended, and which occurs at doses normally used in
humans for the prophylaxis, diagnosis, or therapy of disease, or for the modification of
physiological function.
An adverse drug reaction, contrary to an adverse event, is characterized by the suspicion of a
causal relationship between the drug and the occurrence, i.e. judged as being at least possibly
related to treatment by the reporting or a reviewing health professional.
ADRs may be classified by e.g. cause and severity.
Cause
Type A: Augmented pharmacologic effects – dose dependent and predictable
Intolerance
Side Effects
Type B: Bizarre effects (or idiosyncratic) – dose independent and unpredictable
Type C: Chronic effects
Type D: Delayed effects
Type E: End-of-treatment effects
Type F: Failure of therapy
Serious adverse event or reaction?
A serious adverse event or reaction is any untoward medical occurrence that at any dose:
Results in death
Requires inpatient hospitalisation or
Prolongation of existing hospitalisation
Results in persistent or significant
Disability/incapacity
Is life-threatening
The American Food and Drug Administration defines a serious adverse event as one when the
patient outcome is one of the above:
Severity is a point on an arbitrary scale of intensity of the adverse event in question. The terms
“severe” and “serious” when applied to adverse events are technically very different. They are
easily confused but can not be used interchangeably, require care in usage.
A headache is severe, if it causes intense pain. There are scales like “visual analog scale” that
help us assess the severity. On the other hand, a headache can hardly ever be serious, unless it
also satisfies the criteria for seriousness listed above.
Entire process of pharmacovigilance:
Its starts with AE study Reports: this involves reporting of all AE and ADR.
All AEs, both serious and unexpected are subject to expedited reporting.
Then comes aggregate reporting which involves reviewing the cumulative safety information
from a wide range of sources, on a periodic basis and submitting the findings to regulators
worldwide.
The next step is signal detection:
It is the Process of determining incidence of particular AEs associated with particular drugs and
comparing the same to that for other similar drugs.
Finally is the Risk Management which is monitoring any reported AE of the Product
(Investigational or Marketed) on a patient or patient population and to seek methods or rationales
to minimise or remove such AE from such patient or a specific patient population.
Evolution of Pharmacovigilance:
• The WHO Programme for International Drug Monitoring came into effect
in 1968, in response to the thalidomide disaster in the 1960s and Close to 10,000 babies
were born with deformities as a result of the adverse effects of thalidomide.
• The programme started out as a pilot project with 10 participating countries, it now
comprises 134 member countries
• In 2000, there were 5 African countries with ‘good pharmacovigilance’ capacity; this
figure has now reached 34 in 2010
• Adverse reactions to drugs (ADRs) are estimated to be between fourth and sixth leading
cause of death in USA
• More than 10% of ADRs lead to hospitalization according to some studies
• Worldwide more than 50% of all medicines are prescribed, dispensed or sold
inappropriately, and 50% of patients fail to take them correctly
• 30% of the total health budget accounts for use of medicines in many countries
Pharmacovigilance’ : The science and activities relating to the detection, assessment,
understanding and prevention of adverse effects or any other drug-related problem. (WHO
Definition).
It is the process of monitoring, evaluating and improving the safety of medicines in use.
4000 BC Sumeria recorded euphoric effect of the poppy
Late 1600s Friedrich Hoffman described adverse effects of ergot & its use prohibited in some
European countries
1839 First observation of anaphylaxis in rabbits by Magenta
1881 The first book on Adverse Drug Reactions published. The untoward effects of
drugs. A pharmacological and clinical manual.
1938 Aspirin noted to be a cause of gastric haemorrhage, 39 years
after its first use.
1960s Oral contraceptives linked to thromboembolism in young women.
1961 Thalidomide disaster: Dr. Widukind Lenz also played an important part in the
recognition of thalidomide’s adverse effects, and gives a brief history of his
experiences in a lecture he delivered in 1992.
1962 The U.S. Kefauver Harris Amendment or “Drug Efficacy Amendment” is a
amendment to the Federal Food, Drug, and Cosmetic Act.
1966 Adverse Drug Reaction Bulletin published.
1966 First description of ‘torasdes de pointes’.
1937 107 people died due to poisoning with sulphanilamide containing diethylene glycol
as solvent
1932-1972 Tuskegee Syphilis Study
Chronologically how did event affect the discovery of the adverse event reporting.
Thalidomide is a sedative-hypnotic, and multiple myeloma medication. The drug is a potent
teratogen in rats, rabbits, and primates including humans: this means that severe birth defects
may result if the drug is taken during pregnancy. It caused various birth defects including
Phacomelia. (amelia is absence of arms and phacomelia means the arms are short and deformed).
In 1962 the drug was banned.
From 1956 to 1962, approximately 10,000 children in Africa and Europe were born with severe
malformities, including phocomelia
Thromboembolism: Formation in a blood vessel of a clot (thrombus) that breaks loose and is
carried by the blood stream to plug another vessel. The clot may plug a vessel in the lungs
(pulmonary embolism), brain (stroke), gastrointestinal tract, kidneys, or leg.
Torsades de pointes, or simply torsades is a French term that literally means “twisting of the
points”. It was first described by Dessertenne in 1966 and refers to a specific variety of
ventricular tachycardia that exhibits distinct characteristics on the electrocardiogram (ECG). Its
Characteristics includes the following ECG findings:
Rotation of the heart’s electrical axis by at least 180º
Prolonged QT-interval LQTS
Preceded by long and short RR-intervals
Triggered by an early premature ventricular contraction(R-on-T PVC).
The ECG reading in torsades demonstrates a rapid, polymorphic ventricular tachycardia with a
characteristic twist of the QRS complex around the isoelectric baseline. It is also associated with
a fall in arterial blood pressure, which can produce fainting.
Kefauver Harris Amendment
The U.S. Kefauver Harris Amendment or “Drug Efficacy Amendment” is a 1962 amendment to
the Federal Food, Drug, and Cosmetic Act.
It introduced a requirement for drug manufacturers to provide proof of the effectiveness and
safety of their drugs before approval, required drug advertising to disclose accurate information
about side effects, and stopped cheap generic drugs being marketed as expensive drugs under
new trade names as new “breakthrough” medications.
Background
The amendment was a response to the Thalidomide tragedy, in which thousands of children were
born with birth defects as a result of their mothers taking thalidomide for morning sickness
during pregnancy. The bill by U.S. Senator Estes Kefauver, of Tennessee, and U.S.
Representative Oren Harris, of Arkansas, required drug manufacturers to provide proof of the
effectiveness and safety of their drugs before approval.
It introduced a “proof-of-efficacy” requirement that was not present before. In addition, the
Amendment required drug advertising to disclose accurate information about side effects and
efficacy of treatments. Finally, cheap generic drugs could no longer be marketed as expensive
drugs under new trade names as new “breakthrough” medications, as they were prior to the
amendment.
The law was signed by President John F. Kennedy on October 10, 1962.
Effect
The Kefauver Harris Amendment strengthened the FDA’s control of experimentation on humans
and changed the way new drugs are approved and regulated. Before the Thalidomide scandal in
Europe, U.S. drug companies only had to show their new products were safe. After the passage
of the Amendment, an FDA New Drug Application (NDA) would have to show that the new
drug was both safe and effective (previously the 1938 Food, Drug and Cosmetic Act was the
main law that regulated drug safety). Informed consent was required of patients participating in
clinical trials, and adverse drug reactions were required to be reported to the FDA.
Initiation of Monitoring Drug Safety:
1960 FDA begin to collect reports of adverse reactions
1964 Yellow Card Scheme started in the UK
1967 WHO International System of Monitoring ADRs established
1952 First edition of Meyler’s Side Effects of Drugs published
Beginning of Early example of a systemic collection of adverse drug reactions
the 19th occurred in the when reactions were reported during a smallpox
Century vaccination campaign in the Netherlands.
Evolving Regulation:
1780 BC The Babylonian Code of Hammurabi details the punishments of medical
harm. “If a physician make a large incision with the operating knife, and
kill him, or open a tumor with the operating knife, and cut out the eye, his
hands shall be cut off.”
460-377 BC Hippocrates’ Primum non nocere, “to do good or to do no harm”
361 AD Licensing system for practicing physicians was established in
Constantinople.
994 AD
New remedies should first be tried in animals’
Drugs Banned:
After the regulations were implemented and the reporting of the adverse events started there
were some drugs which were banned due to their severe reactions. Mentioned above in the tables
are few such drugs that were banned and also the reason for which they were banned.
Sr.no Generic name Use Reason For Ban Brand names
Bone-Marrow
1 Analgin Pain-Killer Depression Novalgin, Baralgan
Irregular heart
2 Cisapride Acidity,Constipation B eat Ciza, Syspride
Irregular heart
3 Droperidol Anti-Depressant Beat Droperol
4 Furazolidone Anti-Diarrhoeal Cancer Furoxone, Lomofen*
5 Nimesulide Pain-Killer, fever Liver Failure Nise, Nimulid
*Denotes it is a combination Product.
Analgin, Furazolidone and Nitrofuzone are banned for use even in animals in the United States.
Analgin is banned even in nepal, Vietnam and Nigeria (Reference:MIMS INDIA, September, 2005)
Sr.no Generic name Use Reason For Ban Brand names
Anti-Bacterial
6 Nitrofurazone Cream Cancer Furacin, Emfurazone
7 Phenolphthalein Laxative Cancer Jetomisol-P*
8 Phenylpropanolamine C oild & Cough Stroke D’Cold*, Vicks Action 500*
Bone-Marrow
9 Oxyphenbutazone NSAID Depression Sioril
10 Piperazine Anti-Worms Nerve Damage Piperazine, Helmazan*
11 Quiniodochlor Anti-Diarrhoeal Damage to sight Enteroquinol
Some more drugs …
Year Drug Toxicity Remarks
1950 Chroramphenicol Aplastic Anemia Still its use continued
1961 Thalidomide Phocomelia National Disaster
1970 Clioquinol SMON After 30 years of use
Adenocarcinoma of the cervix and In utero exposure. Manifestation after 20
1970 Diethylstilbestrol vagina years
1975 Practolol Oculo-mucocutaneous Syndrome 5 Years after marketing
Zomepirac
1976 (NSAID) Anaphylaxis
1980 Ticrynafen Deaths from Liver disease
2004 Vioxx Sudden Cardiac deaths 5 Years after suspecting
Based partly on Pharmacoloepidemiology by Brian L. Strom
Why did Merck &. Co., Inc. announced a voluntary worldwide withdrawal of VIOXXe.
VIOXX is a Non-Steroidal Anti-inflammatory drug (NSAID) used for Arthritis and Acute pain
and Approved by FDA in May 1999. The side effects seen were cardiovascular events and
Gastrointestinal bleeding events
After a marked increase in the side effects Merc decided to perform 2 studies for investigation:
VIGOR study Vioxx Gastrointestinal Outcomes Research [VIGOR] and Adenomatous Polyp
Prevention on Vioxx (APPROVe)
VIGOR study
Vioxx Gastrointestinal Outcomes Research [VIGOR]
conducted by Bombardier, et al., which compared the efficacy and adverse effect profiles of
rofecoxib and naproxen, had indicated a significant 4-fold increased risk of acute myocardial
infarction (heart attack) in rofecoxib patients when compared with naproxen patients (0.4% vs
0.1%, RR 0.25) over the 12 month span of the study. The elevated risk began during the second
month on rofecoxib. There was no significant difference in the mortality from cardiovascular
events between the two groups, nor was there any significant difference in the rate of myocardial
infarction between the rofecoxib and naproxen treatment groups in patients without high
cardiovascular risk. The difference in overall risk was by the patients at higher risk of heart
attack, i.e. those meeting the criteria for low-dose aspirin prophylaxis of secondary
cardiovascular events (previous myocardial infarction, angina, cerebrovascular accident,
transient ischemic attack, or coronary artery bypass).
Vioxx side effects first observed after 18 months of continuous treatment with Vioxx compared
with placebo.
Adenomatous Polyp Prevention on Vioxx (APPROVe)
In the APPROVe trial, Vioxx was compared to placebo (sugar-pill). The purpose of the trial was
to see if Vioxx 25 mg was effective in preventing the recurrence of colon polyps.
Studies conducted for investigation
• VIGOR study report to FDA in June 2000
• New safety information was added to labeling for Vioxx in April 2002
• Merck decided to conduct long term trial for cardiovascular side effects
• APPROVe trial showed high risk of stroke in 18 months
– Merck’s decision to withdraw Vioxx from the market is based on new data from a
trial called the APPROVe [ Adenomatous Polyp Prevention on VIOXX] trial.
This trial was stopped early because there was an increased risk for serious cardiovascular
events, such as heart attacks and strokes.
ADR- Adverse Drug Reaction:
Two main types of effects observed post drug recipient:
▪ Desirable or Beneficial effects
▪ Undesirable or untoward effects or Risks
➢ Expected undesirable effects
➢ Unexpected undesirable effects
Definition of side effects:
▪ Any unintended effect of a pharmaceutical product occurring at normal dosage which is
related to the pharmacological properties of the drug.
▪ Side Effects could be desirable or undesirable
Example: A hemorrhage from the use of too much anticoagulant (such as heparin) is a side effect
caused by treatment going beyond the desired effect.
As per WHO, an Adverse Event or adverse experience is
▪ 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.
▪ Synonym: adverse experience
Example: Liver damage from Paracetamol
As per WHO, an Adverse drug reaction is
A response which is noxious and unintended, and which occurs at doses normally used in
humans for the prophylaxis, diagnosis, or therapy of disease, or for the modification of
physiological function.
An adverse drug reaction, contrary to an adverse event, is characterized by the suspicion of a
causal relationship between the drug and the occurrence, i.e. judged as being at least possibly
related to treatment by the reporting or a reviewing health profession
Examples: Dry mouth from antihistamines.
▪ Adverse drug events extend beyond adverse drug reactions to include harm from
overdoses and under doses usually related to medication errors
▪ A minority of adverse drug events are medication errors, and medication errors rarely
result in adverse drug events.
▪ Not surprisingly, adverse drug reactions are common.
▪ Most adverse drug reactions are relatively mild, and many disappear when the drug is
stopped or the dose is changed.
▪ Some gradually subside as the body adjusts to the drug.
▪ Other adverse drug reactions are more serious and last longer.
▪ About 3 to 7% of all hospital admissions in the United States are for treatment of adverse
drug reactions.
▪ Adverse drug reactions occur during 10 to 20% of hospital admissions, and about 10 to
20% of these reactions are severe.
Classification of ADR.
▪ Classification of ADR is based on :
➢ Onset of Reaction
➢ Severity of Reaction
➢ Cause of Reaction
The first type of classification of ADR is based on onset of ADR:
1. Acute ADRs: The ADRs which occur within 60 minutes
2. Sub-acute ADRs: The ADRs which occur in 1 to 24 hours
3. Latent ADRs: The ADR s which occurs after 2 days
The second type of classification of ADR is based on severity of ADRs
1. Mild: The adverse reactions which are bothersome but requires no change in therapy
Examples: Digestive disturbances, headaches, fatigue, vague muscle aches, malaise,
changes in sleep patterns, etc
2. Moderate: The adverse reactions which requires change in therapy, additional treatment and or
hospitalization
Examples: skin rashes visual disturbances muscle tremor, difficulty with urination, any
perceptible change in mood or mental function, etc
3. Severe: The adverse reactions which result into Disability or are life-threatening
Examples: liver failure, abnormal heart rhythms
The third type of classification: i.e based on cause of reaction
Type A is called as Augmented Adverse Drug Reactions:
▪ These are augmented pharmacologic effects and are often predictable and dose
dependant.
▪ They are normal pharmacological dose-related effect of the drugs and likely to be
detected in clinical trials.
▪ They are largely avoidable with care.
E.g.
▪ Postural hypotension in a patient on anti-hypertensive medication,
▪ Hypoglycemia with anti-diabetics
▪ Anticholinergics and dry mouth,
▪ Sedation with anti-histamines
Type B is known as Idiosyncratic or immunologic reactions
▪ They are rare and unpredictable, the effects are related to abnormal interaction between
patient and drug, it is non-dose related, unrelated to normal pharmacodynamics of the
drug and may have genetic basis.
▪ They are commonly reported in the post marketing surveillance
E.g.
▪ Immunological like rash or anaphylactic reaction associated with Penicillin use
The major differences between Type A & Type B are:
▪ Type A ADRs are common in frequency whereas type B are uncommon.
▪ Type A are often Predictable with known Pharmacology and whereas type B reactions
are not predictable.
▪ Type A are less in severity with low mortality and whereas type B reactions usually more
severe with high mortality.
▪ Type A contribute to 80% of the total ADRs whereas type B contribute to 20% of total
ADRs.
Type C also known as Continuous or Chronic
▪ These are associated with long term use of a drug.
▪ It involves dose accumulation and are dose & time related or
▪ Related to cumulative drug use.
E.g.
▪ Anti-malarial drugs and ocular toxicity,
▪ Iatrogenic cushing’s syndrome with prednisolone
Type D known as Delayed Adverse Drug Reactions
▪ These reactions refer to carcinogenic and teratogenic effects.
▪ These reactions are delayed in onset and are very rare since extensive
▪ Mutagenicity and carcinogenicity studies are done before drug is licensed.
E.g.
▪ Serum sickness is a delayed type of drug allergy that occurs a week or more after
exposure to a medication or vaccine.
▪ Thalidomide during first trimester and Phocomelia limb effects
Type E: End-of-use
▪ This is referred to as end of treatment adverse drug reactions. These reactions occur when
the patient has completed his treatment course.
E.g.
▪ Addisonian crisis after steroid withdrawal
▪ Withdrawal seizures when anti-seizures such as Phenobarbital or Phenytoin
Type F : Failure of therapy or Lack of efficacy
▪ This may be dose related or caused by drug interaction.
▪ Also Primary lack of efficacy like in cases of antibiotic resistance etc.
E.g.
▪ Non- efficacy: failure of oral contraceptive while on enzyme inducer Carbamazepine
▪ Quinine resistance in Malaria
The American Food and Drug Administration defines a serious adverse event as one when
the patient outcome is one of the following: [4]
▪ Death
▪ Life-threatening
▪ Hospitalization (initial or prolonged)
▪ Disability – significant, persistent, or permanent change, impairment, damage or
disruption in the patient’s body function/structure, physical activities or quality of life.
▪ Congenital anomaly
Requires intervention to prevent permanent impairment or damage
Severity is a point on an arbitrary scale of intensity of the adverse event in question. The terms
“severe” and “serious” when applied to adverse events are technically very different. They are
easily confused but can not be used interchangeably, require care in usage.
A headache is severe, if it causes intense pain. There are scales like “visual analog scale” that
help us assess the severity. On the other hand, a headache is not usually serious (but may be in
case of subarachnoid haemorrhage, subdural bleed, even a migrane may temporally fit criteria),
unless it also satisfies the criteria for seriousness listed above
The term drug overdose (or simply overdose or OD) describes the ingestion or application of a
drug or other substance in quantities greater than are recommended or generally practiced. An
overdose may result in a toxic state or death
The cause of a drug overdose is either by accidental overuse or by intentional misuse. Accidental
overdoses result from either a young child or an adult with impaired mental abilities swallowing
a medication left within their grasp. An adult (especially elderly persons or people taking many
medications) can mistakenly ingest the incorrect medication or take the wrong dose of a
medication.
Medication error:
A medical error may be defined as a preventable adverse effect of care, whether or not it is
evident or harmful to the patient. This might include an inaccurate or incomplete diagnosis or
treatment of a disease, injury, syndrome, behavior, infection, or other ailment.
Examples of errors
▪ Misdiagnosis of an illness, failure to diagnose or delay of a diagnosis. This type of error
could be a direct mistake of a doctor or caused when the doctor is acting on incorrect
information supplied by some other person.
▪ Giving the wrong drug or (wrong patient, wrong chemical, wrong dose, wrong time,
wrong route)
▪ Giving two or more drugs that interact unfavorably or cause poisonous metabolic
byproducts
▪ Wrong-site surgery, such as amputating the wrong limb
▪ Retained surgical instruments. In particular, gossypiboma, resulting from a surgical
sponge being left behind inside the patient after surgery
▪ Patients’ implementation of drugs and treatments
▪ Using race as a diagnosis, not a factor
▪ Transplanting organs of the wrong blood type
▪ Incorrect record-keeping
Causes of Medication Errors
▪ Incomplete patient information
▪ Unavailable drug information
▪ Miscommunication of drugs orders,
▪ Lack of appropriate labeling as a drug is prepared and repackaged into smaller units
▪ Environmental factors, such as lighting, heat, noise, and interruptions that can distract
health professionals from their medical tasks.
Medical errors are associated with inexperienced physicians and nurses, new procedures,
extremes of age, complex care and urgent care.[16] Poor communication (whether in one’s own
language or, as may be the case for medical tourists, another language), improper documentation,
illegible handwriting, inadequate nurse-to-patient ratios, and similarly named medications are
also known to contribute to the problem. Patient actions may also contribute significantly to
medical errors. Falls, for example, are often due to patients’ own misjudgements. Human error
has been implicated in nearly 80 percent of adverse events that occur in complex healthcare
systems. The vast majority of medical errors result from faulty systems and poorly designed
processes versus poor practices or incompetent practitioners
Drug-drug Interactions:
▪ Most commonly a drug interaction is taken to mean an interaction between two or more
medicines which is a drug-drug interaction.
▪ A drug-drug interaction is defined as the ‘Pharmacological or clinical response to the
administration of a drug combination different from that anticipated from known effects
of two agents’.
▪ The interaction may result into
➢ Change in nature or type of response to the drug – Pharmacodynamic interaction
OR
➢ A change in magnitude or duration of response to the drug – Pharmacokinetic
interaction
▪ Drug – Food interaction
➢ Interval feeding – drug interaction (Herbal drugs/ herbal teas/ caffeinated
beverages)
➢ Nutrient- Drug interaction (Calcium fortified drinks)
➢ Alcohol – drug interaction
➢ Tobacco – Drug interaction
▪ Drug Herbal/ Botanical interaction
▪ Drug – disease interaction
▪ Drug – laboratory test interaction
Drug hypersensitivity Reactions:
▪ Drug hypersensitivity (allergic reactions) reactions are adverse drug reactions that
involve immunologic mechanisms
▪ ADR are not proven to be immune mediated but resembling hypersensitivity (allergic)
reactions are referred to allergic – like or pseudo-allergic reactions
▪ Immunologically mediated ADRs accounts for 6-10% of all ADRs
▪ The frequency of allergic ADR is diffcult to determine because:
➢ Many reactions may not be reported and
➢ So may be difficult to distinguish from non-allergic ADRs
▪ Dermatological ADRs represent the most frequently recognized and reported form of
allergic ADRs.
Drug hypersensitivity is an immune-mediated reaction to a drug. Symptoms range from mild to
severe and include skin rash, anaphylaxis, and serum sickness. Diagnosis is clinical; skin testing
is occasionally useful. Treatment is drug discontinuation, antihistamines (for symptoms), and
sometimes desensitization.
Drug hypersensitivity results from interactions between a pharmacologic agent and the human
immune system. These types of reactions constitute only a small subset of all adverse drug
reactions.
Classification of Allergic ADRs
Allergic ADRs are divided into four immunological categories
▪ Type I : Anaphylactic reactions (Immediate type)
▪ Type II : Cytotoxic reactions
▪ Type III : Immune complex mediated
▪ Type IV : T- Cell mediated (Delayed type)
Examples of:
1. Type I reaction (IgE-mediated) Anaphylaxis from β-lactam antibiotic
2. Type II reaction (cytotoxic) Hemolytic anemia from penicillin
3. Type III reaction (immune complex) Serum sickness from anti-thymocyte globulin
4. Type IV reaction (delayed, cell-mediated) Contact dermatitis from topical antihistamine
ADR Profile:
Ideally an adverse reaction of a drug should have a profile consisting of the following elements.
▪ Manifestation
▪ Severity and seriousness
▪ Mechanism of action
▪ Frequency of occurrence
▪ Causality
▪ Predisposing factors
▪ Therapy if any
▪ Reversibility or squeal
Causality assessment:
Causality assessment is the method by which the extent of relationship between a drug and a
suspected reaction is established.
▪ The evaluation of the likelihood that a medicine was the causative agent of an observed
adverse reaction.
▪ Causality assessment is usually made according established algorithms.
➢ Prior reports of reaction
➢ Temporal relationship between the suspect drug and adverse event
➢ Improvement after removal of drug: Positive De-challenge
➢ Recurrence of adverse event when administration of drug is resumed: Positive re-
challenge
➢ Dose-response relationship
➢ Alternative etiologies
➢ Objective confirmation
➢ Past history of reaction to same or similar medication
➢ The lack of confounding effect i.e., the event is unlikely to be due to concomitant
disease.
Examples of causality algorithms
▪ Kramer
▪ Naranjo and Jones
Causality outcomes
▪ Highly probable
▪ Probable
▪ Possible
▪ Doubtful
WHO SCALE OF ASSESSMENT
1.CERTAIN :A clinical event, including laboratory test abnormality, occurring in a plausible
time relationship to drug administration, and which cannot be explained by concurrent disease or
other drugs or chemicals. The response to withdrawal of the drug (dechallenge) should be
clinically plausible. The event must be definitive pharmacologically or phenomenologically,
using a satisfactory rechallenge procedure if necessary.
2.PROBABLE/ LIKELY A clinical event, including laboratory test abnormality, with a
reasonable time sequence to administration of the drug, unlikely to be attributed to concurrent
disease or other drugs or chemicals, and which follows a clinically reasonable response on
withdrawal (dechallenge). Rechallenge information is not required to fulfil this definition.ical
event, including laboratory test abnormality, with a reasonable time sequence to administration
of the drug, unlikely to be attributed to concurrent disease or other drugs or chemicals, and which
follows a clinically reasonable response on withdrawal (dechallenge). Rechallenge information is
not required to fulfil this definition.
3.POSSIBLE A clinical event, including laboratory test abnormality, with a reasonable time
sequence to administration of the drug, but which could also be explained by concurrent disease
or other drugs or chemicals. Information on drug withdrawal may be lacking or unclear.
4.UNLIKELY A clinical event, including laboratory test abnormality, with a temporal
relationship to drug administration which makes a causal relationship improbable, and in which
other drugs, chemicals or underlying disease provide plausible explanations.
5.CONDITIONAL/ UNCLASSIFIED A clinical event, including laboratory test abnormality,
reported as an adverse reaction, about which more data is essential for a proper assessment or the
additional data are under examination.
6.UNASSESSIBLE/ UNCLASSIFIABLE A report suggesting an adverse reaction which
cannot be judged because information is insufficient or contradictory, and which cannot be
supplemented or verified.
A METHOD FOR ESTIMATING THE PROBABILITY OF ADVERSE DRUG REACTIONS –
NARANJO et al
SCORING FOR NARANJO’s ALGORITHM
• > 9 = definite ADR
• 5-8 = probable ADR
• 1-4 = possible ADR
• 0 = doubtful ADR