Adverse Drug Reaction

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• Adverse Drug Reaction
• Reporting

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Plan

• What is an Adverse Drug Reaction?
• How Common are ADRs
• How to avoid ADRs (at risk groups)
• Types of ADRs
• Identifying an ADR
• Yellow Card Scheme
• Criteria for Reporting an ADR
• Completing a Yellow Card

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Adverse Drug Reaction (ADR)

• Definition - An unwanted or harmful reaction
  experienced following the administration of a
  medication or a combination of medications and is
  suspected to be related to the medication. The
  reaction may be a known side effect of the
  medication or it may be a new previously
  unrecognised ADR.

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Adverse Drug Reaction vs Side Effect?
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Adverse Drug Reaction vs Adverse Event?
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Adverse Drug Reaction vs Defective Medicine
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• How common are ADRs?

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ADRs cause morbidity mortality

• ADRs are related to 6.5 hospital admissions in
  adults, and 2.1 in children
• ADRs are responsible for 15 of admissions in
  Elderly people
• 7 adults will experience an ADR during their
  hospital stay
• 9.5 of children experience an ADR while in
  hospital

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ADRs cause morbidity mortality

• 6.7 hospitalised patients suffer serious ADRs
• 0.3 incidence of fatal ADRs in hospitalised
  patients

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• Why are ADRs a
• problem?

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ADRs are increasing public health problem

• Factors
• increase in elderly population ( 4X as likely to
  have ADR)
• increase in polypharmacy
• Increase in availability of OTC medicines
• Increase in use herbal/traditional medicines
• Estimated to cost the NHS an extra 466 million
  in hospital bed costs alone

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Other reasons why ADRs are important (I)

• Reduce a patients quality of life
• Complicate existing drug therapy
• Affect compliance with treatment
• Reduce potential efficacy of drug treatment

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Other reasons why ADRs are important (II)

• Reduce available choice of drug treatment
• Delay cure
• Reduce a patients confidence in their health care
  professional(s)

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ADRs are avoidable

• Up to 70 are preventable
• Incorrect dosing or administration
• Obvious interactions
• Use of contra-indicated drug
• Use in an inappropriate clinical indication

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How to Minimise ADRs

• Avoid unnecessary drug use
• Check Drug History before prescribing
• Identify patients with co-existing disease
• Avoid drug interactions with drugs and foods
• Patient counselling
• Identify drugs known to produce dose-related side
  effects

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High Risk Patient Groups
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High Risk Patient Groups

• Elderly
• Neonates
• Renal or Hepatic impairment
• Polypharmacy
• Multiple Disease States
• Asian Origin
• Female

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High Risk Drug Groups for ADRs
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High Risk Drug Groups for ADRs

• NSAIDs (including low dose aspirin)
• Diuretics
• Anticoagulants
• ACE Inhibitors and Angiotensin II Blockers
• Antidepressants
• Beta Blockers
• Opiates
• Digoxin
• Prednisolone
• Clopidogrel
• Hypoglycaemics
• Antiepileptics (in paediatrics)

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Classification of Reactions

• Type A (Augmented)
• Dose dependent
• Predictable from pharmacology
• Genetic influence may be important (e.g.
  Cytochrome P450 gene polymorphisms)
• Common
• Usually mild
• Detected in Phase I to III trials

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Stages in the development of a new medicine
Clinical trials 3 phases phase I (50-100
vol) phase II (50-200 pts) phase III (3000
pts) 5 years

• Synthesis
• biological testing
• Pharmacological
• screening
• 5 years

Basic research
Product license application 2 years
Post marketing evaluation
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Examples of Type A Reactions

• Drug Adverse reaction
• Typical Tardive dyskinesia
• antipsychotics
• Ibuprofen G I Bleeds
• Warfarin Haemorrhage
• Co-dydramol Constipation

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Classification of Reactions

• Type B (Bizarre)
• Usually not dose dependent
• Not predictable
• Host factors usually key (often uncharacterised)
• Rare
• Often severe
• Usually detected in post-marketing surveillance

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Examples of Type B Reactions

• Drug Adverse reaction
• Carbamazepine Severe
  hypersensitivity
• reactions
• Clozapine Agranulocytosis
• Allopurinol Toxic epidermal
  necrolysis
• Gold Proteinuria,
  dermatological reactions,
  thrombocytopenia

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Classification of Reactions

• Type C Chronic Treatment Effects
• Dose-related and time related
• Uncommon
• Related to cumulative dose
• e.g. osteoporosis with steroids

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Classification of Reactions

• Type D Delayed effects
• Time related
• Uncommon
• Occurs or becomes apparent some time after the
  use of the medication
• e.g. drug induced cancers

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Classification of Reactions

• Type E End of Treatment Effects
• Uncommon
• Occurs soon after withdrawal of medication
• e.g. withdrawal syndrome with paroxetine

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Classification of Reactions

• Type F Failure of therapy
• Poor compliance (not ADR as such)
• Incorrect diagnosis
• Drug resistance
• Drug interaction
• Inappropriate dose or dosage form e.g. if fast
  acetylator

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Classification of Reactions

• Type G genetic or genomic
• Irreversible genetic damage
• Carcinogens
• Genotoxins
• Teratogens

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ADRs criteria for diagnosis

• Timing with drug treatment
• Improvement after drug discontinued or dose
  reduced
• Worsening of reaction occurs after dose increase
• If a patient is rechallenged the reaction occurs
  again

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Algorithm to assist in identifying ADRs
NO
Was drug taken prior to development of symptom?
Not ADR
YES
NO
Are symptoms related in time to use of drug?
ADR Unlikely
NO
YES
NO
NO
Is the ADR documented in BNF/Data
Sheet/Martindale?
Is it a ?drug?
Is there any other evidence of ADR, eg
rechallenge, dechallenge, past history?
YES
YES
Consider possible ADR
YES
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Yellow Card Scheme

• Introduced in 1964
• The worlds first ADR reporting scheme
• Spontaneous reporting
• Voluntary reporting
• Receives 20,000 reports per year
• gt500,000 reports received since started

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Online Reporting

• www.yellowcard.gov.uk
• www.mhra.gov.uk

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Aims of the Yellow Card Scheme

• Early warning of previously unrecognised ADRs
  (signal generation)
• Identification of predisposing factors
• Comparing ADR profiles of drugs in the same
  therapeutic class
• Continual safety monitoring of a drug throughout
  its marketed life

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Successes of the Yellow Card Scheme

• Clozapine - myocarditis
• Remoxipride - aplastic anaemia
• Cyproterone - hepatotoxicity
• Alendronate - oesphageal
  problems
• Tacrolimus - cardiomyopathy
• Tramadol - psychiatric reactions
• Quinolones - convulsions
• Terfenadine - ventricular arrythmias
• Paroxetine - withdrawal syndrome
• Cerivastatin - rhabdomyolysis
• Kava-kava - hepatic damage
• Glucosamine - interaction with warfarin

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Strengths of Yellow Card System

• Identification of previously unrecognised
  reactions
• Information about factors that predispose
  patients to ADRs

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Weakness of Yellow Card Scheme

• Under reporting
• Cannot provide estimates of risk as
• Total number of patients taking the drug is
  currently unknown
• True number of cases is underestimated
• unusual reactions rather than serious

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Weakness of Yellow Card Scheme

• reporting rates highest following introduction
  and falls off over time
• reactions reported once they are associated with
  the drug

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Objectives of YCC Scotland

• To stimulate and support local reporting of ADRs
  through the Yellow Card Scheme
• To follow up Yellow Cards when required

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Changes which can occur from reporting?

• Restriction in use
• Reduction in dose
• Special warnings and precautions
• Product withdrawn

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Who can report to the Yellow Card Scheme?

• Doctors
• Pharmacists
• Dentists
• Coroners /
• Procurator Fiscals

• Nurses
• Midwives
• Health Visitors
• Radiographers
• Optometrists
• Non-Medical Supplementary Prescribers
• The Public

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Criteria for reporting

• Report all reactions for
• Newly marketed black triangle drugs and vaccines
• Reactions in children
• Suspected drug interactions
• Herbal remedies

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Criteria for reporting

• Report serious reactions only for
• established drugs
• established vaccines

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What is a serious reaction?

• Fatal
• Life-threatening
• Disabling
• Incapacitating
• Result in or prolong hospitalisation
• and/or medically significant
• Congenital abnormalities

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Criteria for reporting

• Areas of special interest
• Children
• Elderly
• Delayed drug effects (e.g. cancers)
• Congenital anomalies
• Herbal remedies
• OTC Medicines
• HIV Medicines

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How certain do I need to be before reporting an
ADR?

• Reasonably suspicious
• association vs 100 certainty

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Completing a yellow card
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Essential information to include on a yellow card

• Suspect drug
• Suspect reaction
• Patient details
• Reporter details

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What happens to the Yellow Card once received?
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Feedback to reports

• Letter of acknowledgement of receipt
• Drug analysis print if requested. Also available
  on www.mhra.gov.uk

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Follow-up requests

• Copy of discharge summary
• Outcome of serious reactions
• Test results
• Patient and/or clinician details
• Post mortem results

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How to contact YCCScotland

• Telephone [phone]
• E-mail YCCScotland_at_luht.scot.nhs.uk
• Internethttp//www.yccscotland.scot.nhs.uk
• By post Freepost
• NAT3271
• Edinburgh
• EH16 4BR

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Your mission if you choose to accept it ..

• IMPROVE
• REPORTING

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Remember

• All health-care professionals have a
  responsibility to inform their colleagues about
  clinically important adverse drug reactions that
  they detect, even if they are well-recognised, or
  a causal link is uncertain.

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More Information

• www.mhra.gov.uk
• BMA Reporting Adverse Drug Reactions A Guide to
  Healthcare Professionals May 2006