# Presentation: 140155

## Clinical Analysis of Adverse Drug Reactions

**Karim Anton Calis, Pharm.D., M.P.H.**
**National Institutes of Health**

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

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

**Objectives**

## 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

**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**

**Definition**

## Adverse Drug Events

**Adapted from Bates et al.**

**Adverse Drug Events**

**Medication **
**Errors**
**(preventable)**

**Adverse Drug Event: preventable or unpredicted medication event---with harm to patient**

**Adverse Drug **
**Events**
**(ME & ADR)**

## 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.

**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.**

**Epidemiology of ADRs**

## 
Onset 
Severity
Type 

**Onset **
**Severity**
**Type **

**Classification**

## 
Onset of event:
Acute 
within 60 minutes
Sub-acute 
1 to 24 hours
Latent 
>  2 days 

**Onset of event:**
**Acute **
**within 60 minutes**
**Sub-acute **
**1 to 24 hours**
**Latent **
**>  2 days **

**Classification**

## 
Severity of reaction:
Mild
bothersome but requires no change in therapy
Moderate
requires change in therapy, additional treatment, hospitalization 
Severe
disabling or life-threatening

**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

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

**Classification - Severity**

## 

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

**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 

**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

**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)

**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

**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**

## Classification - Type

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

**Notes:**
The U.S. Food and Drug Administration (FDA) defines an ADR as any undesirable experience associated with the use of a medical product in a patient.1  Therefore, potential any significant, unusual, unanticipated adverse event is reportable.

1.  Kennedy DL, McGinnis T.  Monitoring adverse drug reactions:  the FDA's new Medwatch program.  P and T 1993;833-4, 839-42.

## Classification - Type

**Hypersensitivity**
**Life-threatening**
**Cause disability**
**Idiosyncratic**
**Secondary to Drug interactions**

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

**Reportable**

**Notes:**
The above list includes types of ADRs which are considered reportable.

## Antibiotics
Antineoplastics*
Anticoagulants
Cardiovascular drugs*
Hypoglycemics
Antihypertensives
NSAID/Analgesics
Diagnostic agents
CNS drugs* 
*account for 69% of fatal ADRs   

**Antineoplastics***
**Anticoagulants**
**Cardiovascular drugs***
**Hypoglycemics**
**Antihypertensives**
**NSAID/Analgesics**
**Diagnostic agents**
**CNS drugs* **
***account for 69% of fatal ADRs****   **

**Common Causes of ADRs**

## 
Hematologic
CNS 
Dermatologic/Allergic
Metabolic
Cardiovascular
Gastrointestinal
Renal/Genitourinary
Respiratory
Sensory

**Hematologic**
**CNS **
**Dermatologic/Allergic**
**Metabolic**
**Cardiovascular**
**Gastrointestinal**
**Renal/Genitourinary**
**Respiratory**
**Sensory**

**Body Systems Commonly Involved**

## 
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

**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 Risk Factors**

## ADR Frequency by Drug Use

- 0-5

- 6-10

- 11-15

- 16-20

**Number of Medications**

**Frequency (%)**

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

**Notes:**
As expected, the more medications in a regimen, the greater likelihood of an ADR.

## 
Subjective report
patient complaint
Objective report:
direct observation of event
abnormal findings
physical exam 
laboratory test
diagnostic procedure

**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

**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**

## 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

**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 child-bearing age; and patients with severe form of disease, multiple co-morbidities, and those taking multiple medications

**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 child-bearing age; and patients with severe form of disease, multiple co-morbidities, and those taking multiple medications**
** **

**ADR Detection in Clinical Trials**

## 
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 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 patient’s current clinical status?
How severe is the reaction?

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

**Determination of urgency:**
**What is the patient’s current clinical status?**
**How severe is the reaction?**
**Appropriate triage:**
**Acute (ER, ICU, Poison Control)**

**Preliminary Assessment **

## Detailed Description of Event PQRSTA Acronym

- P

- Q

- R

- S

- T

**Notes:**
To describe, characterize and document an ADR, the acronym PQRST is often useful.

## 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

**Signs / Symptoms:  PQRSTA**
_**P**_**rovoking or palliative factors**
_**Q**_**uality (character or intensity)**
_**R**_**esponse to treatment, **_**R**_**adiation, **_**R**_**eports in literature**
_**S**_**everity / extent, **_**S**_**ite (location)**
_**T**_**emporal relationship (onset, duration, frequency)**
_**A**_**ssociated signs and symptoms**

**Detailed Description of Event**

## 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

**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

**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 Patient/Disease 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

**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**

## Pertinent Medication Factors

**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**

## Pharmacology
Pharmacokinetics (LADME)
Pharmacodynamics 
Adverse effect profiles
Interactions
drug-drug
drug-nutrient
drug-lab test interference
Cross-allergenicity or cross-reactivity

**Pharmacokinetics (LADME)**
**Pharmacodynamics **
**Adverse effect profiles**
**Interactions**
**drug-drug**
**drug-nutrient**
**drug-lab test interference**
**Cross-allergenicity or cross-reactivity**

**Pertinent Medication Factors**

## ADR Information

**ADR Information**

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

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

**Reference books**
**Medical and pharmacotherapy textbooks**
**Package inserts, PDR, AHFS, USPDI**
**Specialized ADR resources****	****	**
** ****Meyler’s 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 Medica’s Embase
International Pharmaceutical Abstracts 
Current Contents
Biological Abstracts (Biosis)
Science Citation Index
Clin-Alert and Reactions

**MEDLARS databases (e.g., Medline, Toxline, Cancerline, Toxnet)**
**Excerpta Medica’s 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

**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**

**ADR Information Resources**

## 
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

**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

**Examples of causality algorithms**
**Kramer**
**Naranjo and Jones**
**Causality outcomes**
**Highly probable**
**Probable**
**Possible**
**Doubtful**

**Causality Assessment**

## Naranjo ADR Probability Scale

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

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

## 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 patient’s 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

**it can be safely stopped**
**the event is life-threatening or intolerable**
**there is a reasonable  alternative**
**continuing the medication will further exacerbate the patient’s 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

**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**

**Management Options**

## 
Patient’s progress 
Course of event
Delayed reactions 
Response to treatment
Specific monitoring parameters

**Patient’s progress **
**Course of event**
**Delayed reactions **
**Response to treatment**
**Specific monitoring parameters**

**Follow-up and Re-evaluation**

## 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

**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**

**Documentation and Reporting**

## 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

**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**

**Components of an ADR Report**

## MEDWATCH 3500A ReportingFormhttps://www.accessdata. fda.gov/scripts/medwatch