Adverse Drug Reactions

Rahil Khan H.O.D Clinical Research ICRI Mumbai

Objectives
Define adverse drug reactions Discuss epidemiology and classification of ADRs Describe basic methods to detect, evaluate, and document ADRs

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

Adverse Drug Events

Adapted from Bates et al.
Adverse Drug Events (ME & ADR)

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

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
*JAMA. 1998;279:1200-1205.

Classification
Onset Severity Type

Classification
Onset of event:
Acute
within 60 minutes

Sub-acute
1 to 24 hours

Latent
> 2 days

Classification - Severity
Severity of reaction:
Mild
bothersome but requires no change in therapy

Moderate
requires change in therapy, additional treatment, hospitalization

Severe
disabling or life-threatening

Classification - Severity
FDA Serious ADR Result in death Life-threatening Require hospitalization Prolong hospitalization Cause disability Cause congenital anomalies Require intervention to prevent permanent injury

Classification

Type A
extension of pharmacologic effect often predictable and dose dependent responsible for at least two-thirds of ADRs e.g., propranolol and heart block, anticholinergics and dry mouth

Classification

Type B
idiosyncratic or immunologic reactions rare and unpredictable e.g., chloramphenicol and aplastic anemia

Classification

Type C
associated with long-term use involves dose accumulation e.g., phenacetin and interstitial nephritis or antimalarials and ocular toxicity

Classification

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

Classification
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

Classification - Type

Reportable
- All significant or unusual adverse drug reactions as well as unanticipated or novel events that are suspected to be drug related

Classification - Type
Reportable Hypersensitivity - Life-threatening - Cause disability - Idiosyncratic - Secondary to Drug interactions

- Unexpected detrimental effect - Drug intolerance - Any ADR with investigational drug

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

Frequency (%)

40 30 20 10 0

0-5 6-10 11-15 16-20 Number of Medications

May FE. Clin Pharmacol Ther 1977;22:322-8

ADR Detection
- Subjective report
patient complaint

- Objective report:
direct observation of event abnormal findings
physical exam laboratory test diagnostic procedure

ADR Detection
- Medication order screening
abrupt medication discontinuation abrupt dosage reduction orders for tracer or trigger substances orders for special tests or serum drug concentrations

- Spontaneous reporting - Medication utilization review

Computerized screening Chart review and concurrent audits

ADR Detection in Clinical Trials

- Methods
Standard laboratory tests Diagnostic tests Complete history and physical Adverse drug event questionnaire
Extensive checklist of symptoms categorized by body system Review-of-systems approach Qualitative and quantitative

ADR Detection in Clinical Trials

Limitations
exposure limited to few individuals
rare and unusual ADRs not detected 3000 patients at risk are needed to detect ADR with incidence of 1/1000 with 95% certainty

exposure is often short-term

latent ADRs missed

external validity
may exclude children, elderly, women of childbearing age; and patients with severe form of disease, multiple co-morbidities, and those taking multiple medications

Preliminary Assessment
Preliminary description of event:
Who, what, when, where, how? Who is involved? What is the most likely causative agent?
Is this an exacerbation of a pre-existing condition? Alternative explanations / differential diagnosis

When did the event take place? Where did the event occur? How has the event been managed thus far?

Preliminary Assessment
Determination of urgency:
What is the patients current clinical status? How severe is the reaction?

Appropriate triage:
Acute (ER, ICU, Poison Control)

Detailed Description of Event PQRSTA Acronym

Detailed Description of Event

History of present illness Signs / Symptoms: PQRSTA
Provoking or palliative factors Quality (character or intensity) Response to treatment, Radiation, Reports in literature Severity / extent, Site (location) Temporal relationship (onset, duration, frequency) Associated signs and symptoms

Pertinent Patient/Disease Factors

Demographics
age, race, ethnicity, gender, height, weight

Medical history and physical exam

Concurrent conditions or special circumstances
e.g., dehydration, autoimmune condition, HIV infection, pregnancy, dialysis, breast feeding

Recent procedures or surgeries and any resultant complications

e.g., contrast material, radiation treatment, hypotension, shock, renal insufficiency

Pertinent Patient/Disease Factors

End-organ function Review of systems Laboratory tests and diagnostics Social history
tobacco, alcohol, substance abuse, physical activity, environmental or occupational hazards or exposures

Pertinent family history Nutritional status

special diets, malnutrition, weight loss

Pertinent Medication Factors

Medication history
Prescription medications Non-prescription medications Alternative and investigational therapies Medication use within previous 6 months Allergies or intolerances History of medication reactions Adherence to prescribed regimens Cumulative mediation dosages

Pertinent Medication Factors

Medication
Indication, dose, diluent, volume

Administration
Route, method, site, schedule, rate, duration

Formulation
Pharmaceutical excipients
e.g., colorings, flavorings, preservatives

Other components
e.g., DEHP, latex

Pertinent Medication Factors

Pharmacology Pharmacokinetics (LADME) Pharmacodynamics Adverse effect profiles Interactions
drug-drug drug-nutrient drug-lab test interference

Cross-allergenicity or cross-reactivity

ADR Information
Incidence and prevalence Mechanism and pathogenesis Clinical presentation and diagnosis Time course Dose relationship Reversibility Cross-reactivity/Cross-allergenicity Treatment and prognosis

ADR Information Resources

Tertiary
Reference books
Medical and pharmacotherapy textbooks Package inserts, PDR, AHFS, USPDI Specialized ADR resources Meylers Side Effects of Drugs Textbook of Adverse Drug Reactions Drug interactions resources Micromedex databases (e.g., TOMES, POISINDEX, DRUGDEX)

Review articles

ADR Information Resources

Secondary
MEDLARS databases (e.g., Medline, Toxline, Cancerline, Toxnet) Excerpta Medicas Embase International Pharmaceutical Abstracts Current Contents Biological Abstracts (Biosis) Science Citation Index Clin-Alert and Reactions

ADR Information Resources

Primary
Spontaneous reports or unpublished data
FDA Manufacturer

Anecdotal and descriptive reports

Case reports, case series

Observational studies
Case-control, cross-sectional, cohort

Experimental and other studies

Clinical trials Meta-analyses

Causality Assessment
Prior reports of reaction Temporal relationship De-challenge Re-challenge Dose-response relationship Alternative etiologies Objective confirmation Past history of reaction to same or similar medication

Causality Assessment
Examples of causality algorithms
Kramer Naranjo and Jones

Causality outcomes
Highly probable Probable Possible Doubtful

To assess the adverse drug reaction, please answer the following questionnaire and give the pertinent score.

Naranjo ADR Probability Scale

Naranjo CA. Clin Pharmacol Ther 1981;30:239-45

1. Are there previous conclusive reports on this reaction? 2. Did the adverse event appear after the suspected drug was administered? 3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered? 4. Did the adverse reactions appear when the drug was readministered? 5. Are there alternative causes (other than the drug) that could on their own have caused the reaction? 6. Did the reaction reappear when a placebo was given? 7. Was the drug detected in the blood (or other fluids) in concentrations known to be toxic? 8. Was the reaction more severe when the dose was increased, or less severe when the dose was decreased? 9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure? 10. Was the adverse event confirmed by any objective evidence?

Yes +1 +2 +1 +2 -1 -1 +1 +1 +1 +1

No 0 -1 0 -1 +2 +1 0 0 0 0

Do Not Know 0 0 0 0 0 0 0 0 0 0 Total Score

Score ____ ____ ____ ____ ____ ____ ____ ____ ____ ____ ____

Total Score 9 5-8 1-4 0

ADR Probability Classification Highly Probable Probable Possible Doubtful

Management Options

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 patients 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

Management Options
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

Patients progress Course of event Delayed reactions Response to treatment Specific monitoring parameters

Documentation and Reporting

Medical record
Description Management Outcome

Reporting responsibility
JCAHO-mandated reporting programs 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

MEDWATCH 3500A Reporting Form

https://www.accessdata. fda.gov/scripts/medwatch