Diagnosis and Management of ADRs

8/14/2019 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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Cont..

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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Diagnosis and Management of ADRs

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