Diagnosis and Management of ADRs
Transcript of Diagnosis and Management of ADRs
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Diagnosis And Managem ent
ofAdver se Drug Reactions
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Side effect
Any unintended effect of a pharmaceutical productoccurring at doses normally used in man, which isrelated to the pharmacological proprieties of the drug.
Essential elements in this definition are the pharmacologicalnature of the effect, that the phenomenon is unintended, and thatthere is no overt overdose.
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Adverse drug r eaction
A response to a drug which is noxious andunintended, and which occurs at doses normally usedin man.
Important: it concerns the response of a patient, in whichindividual factors may play an important role, and the
phenomenon is noxious (an unexpected therapeutic response, for
example, may be a side effect but not an adverse reaction).
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Unexpected adverse dru g reaction
An adverse r eaction, the nature or severity ofwhich is not consistent with m arketauthorisation, or expected fro m thechar acter istics of the drug.
Predom inant elem ent is that the pheno m enonis unknow n.
Not listed in current labeling
Listed in labeling but greater specificity or severity
e.g. renal impairment listed, patient experiences renal failure
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Serious Adverse Drug Experience
Death
Life threatening (per initial reporter) Permanently or significantly disabling
Hospitalization
Congenital anomaly/birth defect Important medical events
ICH E6 guideline:substantially same as above plus:- congenital anomaly/birth defect
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FDA Serious ADR
Result in death Life-threatening
Require hospitalization
Prolong hospitalization Cause disability
Cause congenital anomalies
Require intervention to prevent permanent injury
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Adverse event/adver se exper ience
Any untoward medical occurrence that maypresent dur ing treatm ent with a pharm aceuticalproduct but which does not necessarily have acausal relationship w ith this treatment
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Medication
Errors(preventable)
Adverse DrugEvents(ME & ADR)
Adverse Drug Event:preventable or unpredictedmedication event---with harm
to patient
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Onset of event:
Acute within 60 minutes
Sub-acute
1 to 24 hours Latent
> 2 days
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Severity of reaction:
Mild bothersome but requires no change in therapy
Moderate
requires change in therapy, additional treatment,hospitalization
Severe
disabling or life-threatening
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Type B effects (patient reactions):
occur in only a minority of predisposed,intolerant patients,
little or no dose re lationship, generally rare and unpr edictable,
som etim es serious,
difficult to study .
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Examples of Type B effects (patient reactions):
Drug intolerance:toxic reactions, not related to overdose or diminished elimination
Drug idiosyncrasy:genetically determined abnormal reaction to the drug that may be related to
metabolic or enzyme deficiency
Drug allergy:immunologically meditated reaction that is characterised by specificity,involvement of antibodies or lymphocytes and re-occurence in case of new
contact with the drug
Pseudoallergic reactions:the same clinical symptoms as allergic reaction but without immunologicalspecificity
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Type C effects:
the use of a drug increases the frequency of aspontaneous disease,
may be both serious and common (and includemalignant tumours) and may have pronouncedeffects on public health,
often re late to long term effects,
there is often no suggestive time relationshipand the connection may be very difficult toprove.
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Type D
delayed effects (dose independent) Carcinogenicity (e.g., immunosuppressants)
Teratogenicity (e.g., fetal hydantoin syndrome)
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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
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Common Causes of ADRs
Antibiotics
Antineoplastics* Anticoagulants
Cardiovascular drugs*
Hypoglycemics Antihypertensives
NSAID/Analgesics
Diagnostic agents CNS drugs**account for 69% of fatal ADRs
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Body Systems Commonly Involved
Hematologic
CNS Dermatologic/Allergic
Metabolic
Cardiovascular Gastrointestinal
Renal/Genitourinary
Respiratory Sensory
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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
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ADR Frequency by Drug Use
0
10
20
30
40
50
60
0-5 6-10 11-15 16-20
Number of MedicationsNumber of Medications
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ADV ERSE DRUG REACTION
Size of the pr oblem
An approximate estimate of the burden of ADR isshow n by the follow ing figures.
It accou nts for
- 2.0 3.0 % of hospital consu ltation s
- 0.3 0.5 % of hospital adm issions
- 5.0 10 % of acute m edical adm issions
- 1.0 15 % of h ospital in- patients- 0.2 3.0 % of hospital in patient deaths
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Adverse Reactions:Possible Causes
Intrinsic factors of the drug
Pharmacological
Idiosyncratic
Carcinogenicity, Mutagenicity
Teratogenicity
Extrinsic factors
Adulterants
Contamination
Underlying medical conditions Interactions
Wrong usage
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Epidem iology 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 hospitalizedpatients*
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
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Diagnosis of Adverse Drug Reactions
Is the patient taking medicines? OTC, prescribed, herbal,oral contraceptives, misused drugs, long termprescription drugs.
Medical history right drug in the correct dose
Patients adherence to the prescription instructions
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Time relationship?
Could it be a withdrawal reaction?
Could this be an allergy?
Is the patient pregnant?
Consider known pharmacology
Consider known idiosyncrasy
Consider dose
Consider interactions
Consider risk/benefit for the particular patient
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ACTIVE INGREDIENTS WITHDRAWN
THALIDOMIDE (1961) Congenital limb defects BENOXAPROFEN (1982) Hepatotoxicity PHENFORMIN (1982) Lactic acidosis FENFLURAMINE (1997) Heart-valve abnormalities ASTEMIZOLE Many drug interactions PHENYLPROPANOLAMINE(2000) Haemorragic stroke KAVA KAVA Liver abnormalities
CERIVASTATIN Rhabdomyolysis CISAPRIDE Cardiac arrythmias ROFECOXIB (2004) Cardiovascular events VALDECOXIB (2005) Cardiovascular events,
serious skin reactions COMFREY, SENECIO Nephrotoxicity TEGASEROD (2007) Cardiovascular events CLOBUTINOL (2007) Cardiac arrhythmia
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W HAT SHOULD BE REPORTED
New drugs
Report all suspected reactions including minor ones
For established or well known drugs
All serious, unexpected, unusual ADRs
Change in frequency of a given reaction ADRs to generics not seen with innovator products
ADRs to traditional medicines
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Reporting Requirem ents
Within 15 calendar days if Serious and Unexpected
(domestic and foreign)
Follow-up information
Non-applicant notifies applicant within five calendar
days
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W hen does the Regulator y
Clock Star t? First day a firm or any affiliate receives event data
containing all four elements:
An identifiable patient
An identifiable r eporter
A suspect dru gAn adverse event or fatal outcome
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Managem ent 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 exacerbatethe 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
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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 / coldcompresses, analgesics or antipruritics
Consider rechallenge or desensitization
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Follow -up and Re-evaluation
Patients progress
Course of event
Delayed reactions
Response to treatment
Specific monitoring parameters
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Docum entation and Reporting
Medical record
Description
Management
Outcome
Reporting responsibility Food and Drug Administration
post-marketing surveillance
particular interest in serious reactions involvingnew chemical entities
Pharmaceutical manufacturers
Publishing in the medical literature
C t f ADR R t
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Com ponents 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
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Forms
3500A (Medwatch Form)
Council for International Organization of Medical
Science (CIOMS I Foreign) or other form if approved in
advance
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MEDWATCH 3500A Repor tingForm
https://www.accessdata.fda.gov/scripts/medwatch
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The Value of Adverse Reaction Reports
Signal/hypothesis generation
Facilitates review of other available data-internationaldatabase sources-review of scientific literature
Facilitates consideration of any need for epidemiologicalstudies
Permits revision of product information, +/-otherregulatory action, as appropriate
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