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Recognizing, Reporting and

Reducin Adverse Dru Reactions

Fuziah Abdul Rashid

NPCB

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INCIDENCE OF ADRs ADRs are always under reported

ADRs are the 4th

-6th

largest cause for mortality inthe USA1

ADRs account for approximately 10% of hospitaladmissions

Norway 11.5%, France 13.0% UK 16.0%2

ADRs increase the length of hospital stay andmedical costs

15-20% of hospital budget may be spent dealingwith drug complications31. Lazarou et al.JAMA 1998, 279(15) 1000-5

2. Safety of Medicines. WHO/EDM/QSM/2002.2

3. White et al. Pharmacoeconomics,1999,15(5) 445-458

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Possible Causes of Adverse Reactions Intrinsic factors of the drug

Pharmacological

Idiosyncratic Carcinogenicity, Mutagenicity

Teratogenicity

x r ns c ac ors Adulterants

Contamination

Underlying medical conditions

Interactions

Wrong usage

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HOW KNOWLEDGE ABOUT ADRs IS

CREATED

animal experiments

clinical trials epidemiological

methods

Post-Marketing

Surveillance (PMS)

prescription event

monitoring

Observational studies case reports

case series

intensive hospital

monitoring

case-control studies

record-linkage meta-analysis

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Limitations of Clinical Trials

too few - normally < than 1500

patients

too simple - use patients without

complications, other medical

conditions

too narrow - limited indications

too brief - limited time

too median - very old/very young patients,

pregnant women not included

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identify the suspected drug

identify factors that contributed to the

Aim of Surveillance of Drug Related

Adverse Reactions

such asmultiple drug therapy,drug-drug interactions

drug-herbal interactionsDrug food interactionsExcipients, colouring agents

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Increase information on use in at-risk

population

Identify unlabeled, rare, delayed adverse

reactions

Identif abuse otential

Aim of Surveillance of Drug Related

Adverse Reactions

Follow-up cases where drugs prescribed

intentionally during pregnancy

Monitor outcome of pregnancy

Effect of drug to the foetus/baby MAKE CHANGES TO PRODUCT

INFORMATION BASED ON NEW FINDINGS

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Onset of event:

Acute

within 60 minutes

Classification

Sub-acute 1 to 24 hours

Latent

> 2 days

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Severity of reaction:

Mild

bothersome but requires no change in therapy

Classification - Severity

o erate requires change in therapy, additional treatment,

hospitalization

Severe disabling or life-threatening

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FDA Serious ADR

Result in death

Life-threatening

Classification - Severity

Require ospita ization Prolong hospitalization

Cause disability

Cause congenital anomalies

Require intervention to prevent permanent

injury

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CLASSIFICATION OF ADRS

Type A (Augmented) reactions

Reactions which can be predicted from theknown pharmacology of the drug

,

reduction

E.g. Bleeding with anticoagulants,

bradycardia with beta blockers, headachewith nitrates, postural hypotension with

prazosin

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CLASSIFICATION OF ADRS

Type B (Bizarre) reactions

Cannot be predicted from thepharmacology of the drug

o ose epen en , os epen enfactors important in pre-disposition

E.g. anaphylaxis with penicillin,

anticonvulsant hypersensitivity

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Type C (Chemical) reactions

Biological characteristics can be predicted from the

chemical structure of the drug/metabolite E.g. paracetamol hepatotoxicity

Type D (Delayed) reactions

CLASSIFICATION OF ADRS

Occur after many years of treatment. Can be due toaccumulation

E.g. Secondary tumours after treatment withchemotherapy, teratogenic effects of phenytoin taken

during pregnancy, analgesic nephropathy, tardivedyskinesia with antipsychotic agents

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CLASSIFICATION OF ADRS

Type E ( End of treatment) reactions Occur on withdrawal especially when

E.g. withdrawal seizures on stopping

phenytoin, adrenocortical insufficiency

on withdrawal of steroids

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Type A Type BAssociated with the

pharmacology of theproduct

a r

Predictable a r

Dose related a r

Common a

r

Serious r a

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Antibiotics

Antineoplastics*

Anticoagulants

Cardiovascular drugs*

Common Causes of ADRs

ypog ycem cs Antihypertensives

NSAID/Analgesics

Diagnostic agents

CNS drugs*

*account for 69% of fatal ADRs

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Hematologic

CNS

Dermatologic/Allergic

Body Systems Commonly

Involved

Cardiovascular

Gastrointestinal

Renal/Genitourinary Respiratory

Sensory

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Age (children and elderly)

Multiple medications Multiple co-morbid conditions

Inappropriate medication prescribing, use, or

ADR Risk Factors

monitoring End-organ dysfunction

Altered physiology

Prior history of ADRs

Extent (dose) and duration of exposure

Genetic predisposition

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HOW TO RECOGNIZE ADRs

Since ADRs may act through the samephysiological and pathological pathways as

different disease the are difficult and

sometimes impossible to distinguish

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Drug administered

Pt develops a new condition/symptoms

Drug suspected?

Yes

Documented ? (for the product

or similar class of products)

Yes

Highly suggestive of ADR

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Not documented in literature

Drug continued Drug discontinued

Worsening of symptoms Symptoms improve

(+ve dechallenge)

Drug restarted

Symptoms recur(+ve rechallenge)

ny ot er poss e causes

Concomitant therapy

Underlying conditions

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What to Report and What not to

Scenario 1 You are treating patient with acute

elone hritis with the amino l coside

antibiotic gentamicin. While your patient istaking gentamicin, acute tubular necrosis

develops that requires intermittent dialysis

before recovery. Should this incident be reported?

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Discussion

Nephrotoxicity including acute tubularnecrosis is a well-recognised and well-

documented adverse effect of entamicin

and other aminoglycoside antibiotics.

Therefore, reporting this adverse event

would not provide any new or usefulinformation.

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What to Report and What not to

Scenario 2 You prescribe the recently approved drug

aliskiren (Rasilez), a direct renin inhibitor for

hypertension. One week after starting the drug,your patient reports edema involving the face

and hands.

Should this incident be reported?

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Discussion

Aliskiren was recently approved by DCA. Whilethe drugs PI does list angioedema underwarnings and the adverse reactions sectiondoes include angioedema and edema involving

t e ace, an s or w o e o y t e tota c n caexperience with this drug prior to marketing wasquite modest based on clinical trials (limitedpopulation). Therefore in this scenario, submitting

ADR report will help to determine whether thisadverse experience is likely more common orotherwise.

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Preventing, Reducing and ReportingADRs

Completely avoiding ADRs may beimpossible

occurrence can be applied

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HOW?

Charting all medications when ordered and refilled drug allergies, types of allergy

Close attention to the written prescription correct dosin ro er dosa e form avoid

abbreviations, cautious of drugs with similarnames

Being familiar with all potential side effects,interactions

Choosing the oral route when possible

Taking careful history of patients esp. elderly pts

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CONT.

Initiate a committee of Post-MarketingDrug Risk Management at hospital level

relying on spontaneous reporting)

Assess whether physicians are following

recommended DCA warnings Having a high index of suspicion for ADRs

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ADR Reporting

Intensive safety surveillance New Zealand

US, UK

Spontaneous adverse drug reaction monitoring

Australia, Malaysia

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SPONTANEOUS REPORTINGSYSTEM

Passive surveillance system

Spontaneous ADR reporting system has 3

p ases: Data collection most problematic

Data processing

Data analysis and interpretation

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SPONTANEOUS REPORTING

Advantages large population/not specificpts groups

all medicines

Disadvantages underreporting

difficult to detect

hospital and out-patient care May generate rapid alerts

Least likely to influence

prescribing behaviour

Low set-up/costs

delayed reactions

reactions with high

background incidence

number of exposed

unknown bias

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HOW TO REPORT

ON-LINE REPORTING

www.bpfk.gov.my

ADR Forms

REP RTIN ME HANI M

Directly by the prescribers

Through the pharmacists

Through the drug companies

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Tertiary

Reference books

Medical and pharmacotherapy textbooks

Package inserts, PDR, AHFS, USPDI

ADR Information Resources

pec a ze resources

Meylers Side Effects of Drugs

Textbook of Adverse Drug Reactions

Drug interactions resources

Micromedex databases (e.g., TOMES, POISINDEX,

DRUGDEX)

Review articles

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Secondary

MEDLARS databases (e.g., Medline, Toxline,

Cancerline, Toxnet)

Excerpta Medicas Embase

ADR Information Resources

International Pharmaceutical Abstracts Current Contents

Biological Abstracts (Biosis)

Science Citation Index

Clin-Alert and Reactions

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Primary

Spontaneous reports or unpublished data

FDA

Manufacturer

ADR Information Resources

nec ota an escr pt ve reports

Case reports, case series

Observational studies

Case-control, cross-sectional, cohort Experimental and other studies

Clinical trials

Meta-analyses

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E-mail: far@bpfk.gov.mywww.bpfk.gov.my