The document discusses adverse drug reactions (ADRs), including definitions, classifications, reporting and management. Some key points: - ADRs occur in 5-10% of patients annually. An ADR is an unintended reaction to a drug that occurs at normal doses. - Serious ADRs result in death, hospitalization, disability or birth defects. Suspected ADRs have a reasonable possibility of being caused by a drug. - ADRs can be classified based on dose (augmented, bizarre), time (early, late), or susceptibility (gender, age, genetics). - Healthcare providers should report all suspected ADRs to monitoring centers to identify safety issues. Prevention

1. Adverse
Drug
Reactions
Dr. Ajith JS
Asst. Professor
Department of Pharmacology
Sanjivani College of Pharmaceutical Education & Research,
Kopargaon

2. 5-10%
Annual Incidence

3. Adverse Drug Reactions (ADRs)
“A response to a drug which is noxious and unintended and which
occurs at doses normally used in human for prophylaxis, diagnosis, or
therapy of disease or for modification of physiological function”
- ICH E2A

4. Adverse Event (AE)
“Any untoward medical occurrence in a patient or clinical
investigation subject administered a pharmaceutical product and
which does not necessarily have to have a causal relationship with
this treatment”.
- ICH E2A

5. Serious Adverse Effects /Adverse Drug
Reactions (SAE/SAR)
“Any untoward medical occurrence that at any dose
-Results in death
-Is life threatening
-Requires inpatient hospitalization or prolongation of existing hospitalization
-Persistent or significant disability or incapacity
-Is a congenital anomaly or birth defect”
- ICH E2A

6. The term life-threatening in the definition of serious refers to
an event in which the patient was at risk of death at the time
of the event; it does not refer to an event that hypothetically
might have caused death if it were more severe

7. • Important medical events that may not be immediately life threatening or result in
death or hospitalization but may jeopardize the patient or may require intervention to
prevent one of the other outcomes listed in the definition above
• These should also usually be considered serious
Eg: Intensive treatment in an emergency room or at home for allergic bronchospasm
Blood dyscrasias or convulsions that do not result in hospitalization
Development of drug dependency or drug abuse

8. Suspected Adverse Drug Reaction (SADR)
“A noxious and unintended response to any dose of a drug or biologic
product for which there is a reasonable possibility that the product caused
the response”.
A reasonable possibility - the relationship cannot be ruled out
- ICH E2A

9. Suspected, Unexpected, Serious Adverse
(Drug) Reaction (SUSAR)
“An untoward and unintended response to a study drug which is
not listed in the applicable product information and meets one of
the serious criteria”
- ICH E2A

10. Traditional Classification
- 1970s
ADR
Bizzare
Augmented

11. TYPE A (Augmented) TYPE B (Bizarre)
Dose – related Non dose – related
Predictable Unpredictable
Common Uncommon
Normally reversible Maybe serious / irreversible
Manageable with dosage adjustment Drug discontinuation needed
Eg. Warfarin - Bleeding Eg. Beta blockers - Bronchospasm

12. - Rowlins and Thompson
Type Name Example
Type C Chronic Corticosteroid – adrenal suppression
Type D Delayed Neuroleptics – Tardive dyskinesia
Type E End of use Opiates – Withdrawal syndrome
Type F Failure of therapy Decreased effect due to antibiotic
resistance

13. DoTS Classification
DoTS
Susceptibility
Time Course
Dose Relatedness

14. DoTS Classification
Dose
Hyper
susceptibility
ADRs that can
even occur in
low,
subtherapeutic
doses
Collateral
ADRs that can
happen in
usual
therapeutic
range
Toxic
ADRs that are
generally
observed with
drug levels that
are too high

15. 15
DoTS Classification
Time
Dependant
Independent:
NSAIDs –
Renal Failure
Early: nitrate
induced
headache
Intermediate:
Type II, III, IV
hypersensitivity
Late:
Antipsychotics –
tardive
dyskinesia
Delayed:
Cancer
Withdrawal:
Opiates –
withdrawal
syndrome
First dose:
Penicillin
anaphylaxis
Rapid
administratio
n:
Vancomycin
– red man
syndrome

16. 16
DoTS Classification
Susceptibility
Gender:
-Females are
more prone to
ADRs
Age:
- Elderly and
pediatrics
-Elderly
patients are
more
sensitive to
antipsychotic
s and
anxiolytics
Ethnic origin:
G6PD
deficiency
High risk of
hemolysis
with
nitrofurantoin
or quinolone
antibtiotics
Genetics:
CYP2C9
polymorphism
s - bleeding
Disease:
Hepatic or
renal disease
– kinetics is
altered

17. Examples
1. Corticosteroids – Osteoporosis
Dose – Collateral
Time - Late
Susceptibility – Age & sex
2. Anaphylaxis of penicillin
Dose: hypersensitivity
Time – First dose
Susceptibility – requires previous sensitization

18. DoTS Classification
 Gaining acceptance
 ADRs do not clearly fit in the traditional classification
 Provides pointers on how specific ARDs can be avoided

19. ADR - Reporting
Who can report?
 Healthcare Professionals (physicians, family practitioners, medical specialists, and dentists,
nurses, pharmacists)
 Patients & their relatives
 Marketing authorization holder (MAH)

20. ADR - Reporting
What should be reported?
Patient – related details
Age at time of reaction or date of birth
Weight
Sex
Patient initials

21. ADR - Reporting
Name (INN and brand name)
Strength
Dose, Frequency
Dosage form
Suspected medicine
Batch number
Duration of use
Indication for use
Route of administration

22. ADR - Reporting
Suspected adverse reaction
Description of the reaction
Expectedness of the reaction
Date the reaction started, stopped
Outcomes
Relevant tests/laboratory data

23. ADR - Reporting
Reported Details
Qualification
Contact details
Address
Name, initials

24. Where to report
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)

25. As soon as possible
Reports on all suspected adverse reactions – known or
not, serious or not – are welcome and useful
If there is any doubt about whether or not it is an ADR;
always it is best practice to submit a report

26. How to recognize ADRs in patients
1. Ensure that the medicine ordered is the medicine received and actually taken by the patient at the dose
advised
2. Take a proper history and do a proper examination of patient (comorbidities, concomitant medications, OTC
drugs taken, drug or food allergies)
3. Establish time relationships
4. Carry out a thorough physical examination with appropriate laboratory investigations if necessary
5. Effect of Dechallenge and Rechallenge should be determined
Dechallenge (withdrawal of the suspected medicine)
Rechallenge (re-introducing the suspected medicine after a dechallenge)
6. Check the known pharmacology of the medicine

27. MedWatch
 US FDA safety information and adverse event reporting programme for both health
professionals and consumers
 Voluntary for consumers and health professionals, and mandatory for drug/biologic
manufacturers/ packers and medical device manufacturers, distributors and user-facilities
 Reporting can take place online – by telephone or by submitting the specified form
(MedWatch 3500 form) by mail or fax
 ADR reports - entered into the Adverse Event Reporting System database
 The FDA Office of Post-marketing Drug Risk Assessment (OPDRA) electronically identifies
serious reactions that are not mentioned in the drug’s labelling

28. Causality Assessment
 Causality assessment of ADRs is a method used for estimating
the strength of relationship between drug(s) exposure and
occurrence of adverse reaction(s)
 Used to decide whether or not a drug is responsible for an
adverse event
 ADR Several Causality Assessment Tools (ADR - CATs) are
available

29. Bradford Hill’s Criteria
Published by Sir Austin Bradford Hill in 1965
Includes “nine” criteria for evaluating the causality:
Strength Temporality
Specificity
Consistency
Biological
Gradient
Analogy
Experiment
Coherence
Plausibility

30. Causality Assessment Scales
 WHO – UMC Causality Assessment Scale
 Karch and Lasagna
 Modified Hartwig and Seigel
 Naranjo ADR Probability Scale
 Swedish method by Wilholm et al
 Dangaumou’s french method
 CIOMS scale
 Liverpool ADR scale

31. Naranjo ADR Probability Scale

32. Naranjo ADR Probability Scale
 Widely accepted method
 Simple
 Limitations: Method only explains the causality of one individual drug; no explanations regarding
the causality of drug interactions

33. WHO–UMC Causality Categories

34. WHO–UMC Causality Categories
 WHO-UMC method is less time consuming
 Oriented more on the subjective medical opinion
 Careful attention must be paid to selecting adept, unbiased, diligent and
experienced evaluators to pave the way for consistently accurate causality
assessment under WHO-UMC method

35. ADR CATs
 No one particular method is endorsed by any regulatory authority
 It is left at the judgement of the sponsor/manufacturer to choose the best suited
method for their process
 As a result, causality assessment is bound to get complicated and disputed on
certain occasions
 It is, however, mandatory to state within the report the method used for the
causality assessment and the final evaluation according to it

36.  While managing an ADR, always have a clear therapeutic objective in mind
 Do not treat for longer than necessary
 Review the patient regularly and simplify management
Management of ADRs

37. Management of ADRs
 Educate prescribers.
 Change formulary or standard treatment guidelines, if necessary, to obtain a medicine of proven
safety.
 Modify patient monitoring procedures.
 Report to national drug authority and the manufacturer, especially with regard to serious reactions, a
new ADR, or an unusual manifestation of a known ADR.
 After all ADRs, educate and warn patients to reduce the possibility of ADR recurrence.

38. Prevention of ADRs
 Many authorities agree that over 50 percent of ADRs may be preventable
 Without a prevention program, many ADRs will occur needlessly, producing an increase in
morbidity and associated health care cost
 There is a general lack of knowledge concerning ADRs, including the incidence, severity, and
impact on health care
 Many ADRs are related to the prescribing of an incorrect dose and to administration of a
medicine to a patient with a known allergy

39. Review ADR reports regularly, and inform the professional staff of the incidence and impact of ADRs
in the region
Discuss changes in the formulary or standard treatment guidelines for significant or recurring
problems with ADRs
Identification and close monitoring of high-risk patient populations, including pregnant women,
breast-feeding women, the elderly, children, and patients with renal or liver dysfunction
Review medication errors and product quality complaints to ensure they are not contributing to the
incidence of ADRs at the hospital.
Measures for the Prevention of ADRs

40. Educate staff, especially providers, concerning ADRs
o In-service education
o Face-to-face education with providers
o Medicine information bulletins
o Reports of collected adverse events
o Identify medicines on the formulary that are high risk and should be monitored closely by physicians
and pharmacists. For example⎯ Aminoglycosides, Antineoplastics, Digoxin, Heparin, Warfarin