Description
The PPT explains on adverse drug reactions, Discusses epidemiology and classification of ADRs and Describes basic methods to detect, evaluate, and document ADRs .It also covers casualty assessment, management options and followup.
Clinical Analysis of Adverse Drug Reactions
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 patient’s current clinical status? • How severe is the reaction?
? Appropriate triage:
• Acute (ER, ICU, Poison Control)
Detailed Description of Event PQRSTA Acronym
R
P
T
Q
S
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 • 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
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 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
Follow-up and Re-evaluation
• • • • • Patient’s 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
doc_837275223.ppt
The PPT explains on adverse drug reactions, Discusses epidemiology and classification of ADRs and Describes basic methods to detect, evaluate, and document ADRs .It also covers casualty assessment, management options and followup.
Clinical Analysis of Adverse Drug Reactions
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 patient’s current clinical status? • How severe is the reaction?
? Appropriate triage:
• Acute (ER, ICU, Poison Control)
Detailed Description of Event PQRSTA Acronym
R
P
T
Q
S
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 • 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
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 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
Follow-up and Re-evaluation
• • • • • Patient’s 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
doc_837275223.ppt