The Yellow Card Scheme: Reporting Adverse Drug Reactions

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The Yellow Card Scheme Reporting Adverse Drug
Reactions
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Objectives

• What is an Adverse Drug Reaction (ADR)?
• Classification of ADRs
• How common are ADRs?
• Identifying an ADR
• How to avoid ADRs
• The Yellow Card Scheme
• What to report
• Information to include on a Yellow Card

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What is an adverse drug reaction?

• An adverse drug reaction (ADR) is an unwanted
  or harmful reaction experienced following the
  administration of a drug or combination of drugs
  under normal conditions of use and is suspected
  to be related to the drug.

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Adverse drug reaction or adverse event

• Terms often used interchangeably not always
  correct.
• Adverse drug reaction is an unwanted or harmful
  reaction experienced following the administration
  of a drug e.g. patient experiencing anaphylaxis
  shortly after taking a drug.
• Adverse event is any undesirable event
  experienced by a patient while taking a drug,
  regardless of whether the drug is suspected to be
  related to the event e.g. patient having a road
  traffic accident while on a specific medication.

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Classification of ADRs

• Common ADRs
• Type A (Augmented)
• Predictable, dose related
• Constipation with opioids
• Usually not severe
• Peptic ulceration following NSAID use

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Classification of ADRs

• Uncommon but often well recognised ADRs
• Type B (Bizarre)
• Unpredictable, not dose related
• May be very severe / fatal
• Achilles tendonitis caused by quinolone
  antibiotics
• Stevens-Johnson syndrome following lamotrigine
  therapy
• With new drugs ADRs not well recognised

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Classification of ADRs

• Type C (Chronic treatment effects)
• osteoporosis with steroids
• Type D (Delayed effects)
• drug induced cancers
• Reports of skin cancers, lymphomas and other
  cancers following topical pimecrolimus and
  tacrolimus 1
• Type E (End of treatment effects)
• withdrawal syndromes
• Headache, anxiety, dizziness sleep disturbances,
  gastro-intestinal disturbances after stopping
  paroxetine.

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Classification of ADRs

• Type F (Failure of therapy)
• unexpected failure of therapy due to drug
  interaction
• St Johns Wort reducing efficacy of combined
  hormonal contraceptives
• Type G (Genetic or genomic)
• Irreversible genetic damage
• Carcinogens
• Genotoxins
• Teratogens

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Important factors in ADRs DoTS

• 3 factors Dose, Time, Susceptibility
• Dose (response) The ADR can occur
• at doses below therapeutic doses
• anaphylaxis with penicillin
• in the therapeutic dose range
• nausea with morphine
• at high doses
• liver failure with paracetamol

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Important factors in ADRs

• Time (course) can be characteristic
• with the first dose
• anaphylaxis with penicillin
• early, or after a time, or with long-term
  treatment
• first few days nitrate induced headache
• 10 days 10 weeks toxic epidermal necrolysis
• several weeks drug-induced Cushings syndrome
• on stopping treatment (withdrawal)
• paroxetine withdrawal syndrome
• delayed
• clear cell cancer with stilbestrol

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Important factors in ADRs

• Susceptibility of patients can be defined
• Genetics haemolysis with chloroquine in G6PD
  deficiency
• Age parkinsonism with prochlorperazine in the
  elderly
• Sex ACE-inhibitor induced cough in women
• Physiological state phenytoin in pregnancy
• Exogenous drugs or foods warfarin, cranberry
  juice, and increased INR
• Disease gentamicin deafness in renal failure

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Examples of ADRs

• Common and well established ADRs
• Constipation with opioids
• Abdominal pain and diarrhoea with erythromycin
  therapy.
• Nausea when starting fluoxetine
• Gastrointestinal symptoms with NSAIDs
• Uncommon but well recognised ADRs
• Achilles tendonitis caused by quinolone
  antibiotics
• Visual field defects with vigabatrin
• Uncommon emerging ADRs
• Depression with rimonabant
• AF with bisphosphonates
• Hepatoxicity with lumiracoxib

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Why are ADRs important?

• Major clinical problem increase morbidity and
  mortality.
• ADRs are related to 6.5 hospital admissions in
  adults, and 2.1 in children 2
• 6.7 hospitalised patients sufferserious ADRs
  1
• 0.15 of hospital patients suffer fatal ADRs (
  5700 deaths per year) 1,2
• ADRS are 4th leading cause of death in the USA 1
• Increase hospital stay. ADRs result in the use of
  seven 800 bed UK hospitals per year.2
• Financial burden on NHS 466m 2
• Up to 40 patients in the community experience
  ADRs 3

1 Lazarou J, Pomeranz BH, Corey PN. Incidence of
ADRs in hospitalised patients. JAMA .1998 279
1200-1205. 2 Pirmohamed M, James S, Meakin S et
al. Adverse drug reactions as cause of admission
to hospital prospective analysis of 18 820
patients. BMJ. 2004 329(7456)15-9. 3 Martyrs
C. Adverse reactions to drugs in general
practice. BMJ 1979 2 1194-1197
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ADRs can also

• Adversely affect patient compliance
• Reduce available choice of drug treatment
• Reduce potential efficacy of drug treatment
• Reduce quality of life
• Cause diagnostic confusion
• Reduce a patients confidence in their healthcare
  professional(s)

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Who might get an ADR?

• Anyone who takes a medicine!
• Differential diagnosis should include the
• possibility of an ADR if the patient is taking
  any
• form of medication

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Who is most at risk from ADRs?

• The elderly
• Children
• Co-existing diseases
• Females
• Atopic individuals
• Polypharmacy
• 50 of patients on 5 drugs or more

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ADRs are an increasing public health problem

• Factors
• Increase in elderly population (4 x as likely to
  have ADR)1
• Increase in polypharmacy
• Increase in availability of OTC medicines
• Increase in use of herbal/traditional medicines
• Increase in medicines available via the internet

1 Pharm World Science 200224(2)46-54)
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Are ADRs avoidable?

• 70 ADRs are potentially avoidable 1
• More rational Prescribing
• Avoid unnecessary drug use
• Dose optimisation identify drugs known to
  produce dose-related side effects
• Avoid / reduce drug interactions
• Consider prophylactic therapy where appropriate
• Avoid new / black triangle drugs
• Avoid prescribing contra-indicated drugs
• Drug use in an inappropriate clinical indication
• Check drug history before prescribing
• Consider risk factors for ADRs
• Polypharmacy
• Age extremes
• Reduced hepatic and renal function
• Patient counselling re ADRs 2
• Better monitoring of treatment 3
• Better communication 4

1 Howard et al BJCP 2007 Feb63(2)136-47 2 BMJ
2006333522 3 BMJ 20033271179-1181 4
Archives of Internal medicine 2006145(4)284-293
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What should raise your suspicion?

• Timing with drug treatment.
• Abnormal clinical measurements while on drug
  therapy e.g. B.P, temp, pulse, blood glucose and
  weight
• Abnormal laboratory results while on drug
  therapy. Could be biochemical or haematological
• New therapy started which could be used to treat
  ADR
• Patient risk factors
• Listen to patients own concerns

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Assessing causality

• Nature of the reaction
• Timing
• Relationship to dose
• Other possible causes for the symptoms
• Improvement when drug(s) stopped
• Has reaction been reported before
• Dechallenge/Rechallenge

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How common are ADRs?

• Drugs most commonly implicated include NSAID,
  aspirin, diuretics and warfarin1
• Aspirin was most frequent cause for admission 2
• 18 ADR related admissions
• 162 (74) patients on aspirin 75mg OD
• 157 (72) gastro-intestinal bleeding
• In the UK Non Steroidal Anti-Inflammatory Drug
  (NSAID) use alone accounts for3
• 65,000 emergency admissions/year
• 12,000 ulcer bleeding episodes/year
• 2,000 deaths/year

1 Howard RL et al. Which drugs cause preventable
admissions to hospital? A systematic review. Br J
Clin Pharmacol 2007 63(2)136-147 2 Pirmohamed
M et al. Adverse drug reactions as cause of
admission to hospital prospective analysis of
18 820 patients. BMJ. 2004 329(7456)15-9. 3.
Blower et al. Emergency admissions for upper
gastrointestinal disease and their relation to
NSAID use. Aliment Pharmacol Ther 1997 11
283-291
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The Yellow Card Scheme

• Introduced in 1964 after thalidomide tragedy
• Spontaneous reports of suspected adverse drug
  reactions.
• Acts as an early warning system to identify ADRs
  and risk factors
• Over 600,000 confidential reports have been
  received in UK
• Doctors, dentists, pharmacists, coroners, nurses,
  midwifes, health visitors
• Non-medical prescribers
• and now patients
• MHRA can detect duplicate reports

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• Patients can report suspected side effects
• online at www.yellowcard.gov.uk
• using the form inside this leaflet found in
  pharmacies
• by calling the Yellow Card hotline on 0808 100
  3352

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Why report ADRs?

• Important role in patient safety
• Allows continual safety monitoring of drugs
• old new
• New drugs - lack of experience on adverse effects
• Exposure in about 1500 people only
• Short duration
• Unlikely to detect ADRs
• Less frequent than 1/1500
• With long latency
• Lack of experience in special patient groups
• Elderly, children, pregnancy, multiple disease,
  polypharmacy
• To detect rare adverse effects

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Strengths of Yellow Card Scheme

• Acts as early warning system for identification
  of previously unrecognised reactions
• Provides information about factors which
  predispose patients to ADRs
• Allows comparisons of ADR profiles between
  products within same therapeutic class
• Continual safety monitoring of a product
  throughout its life span as a therapeutic agent

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Weaknesses of Yellow Card Scheme

• Cannot provide estimates of risk as
• true number of cases is underestimated
• total number of patients exposed is unknown
• Relies on ADR being recognised
• Not all ADRs are reported
• Only 10 serious reactions reported
• May be stimulated by promotion and publicity
• Reporting high for newly marketed drugs and falls
  off over time
• Reports do not imply causality

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Why are reporting rates low?

• Too busy
• Not sure what to report
• Uncertain of the threshold for a serious reaction
• Not easy to find a Yellow Card
• Not my responsibility
• It takes too long to complete a card
• Reporting generates too much extra work
• Duplication
• Belief that serious ADRs will be identified in
  clinical trials
• Confidentiality

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Completing a Yellow Card
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On-line

• Simple
• Fast
• Drop-down menus
• Allows reporter to register on the site
• The Yellow Card can be saved at any time

www.yellowcard.gov.uk
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Who can report?

• Doctors, dentists, coroners
• Hospital pharmacists - 1997
• Community pharmacists - 1999
• Nurses, midwives and health visitors - 2002
• Patients 2008 (pilot scheme from October 2005)
• Pharmaceutical companies have a legal obligation
  to report
• Over 600,000 reports received to date on
  voluntary basis
• MHRA can detect duplicate reports

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What to report

• Report all suspected adverse drug reactions for
• new drugs (marked ?) - even if mild
• established drugs that are serious - even if well
  recognised
• Serious reactions include those which are
  fatal, life-threatening, disabling or
  incapacitating, result in or prolong
  hospitalisation, congenital abnormalities or
  medically significant
• Reactions in children
• Drug interactions
• Herbal medicines
• Causality does not need to be established

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Black triangle drugs?

• ?indicates that the CHM/MHRA are intensively
  monitoring that product
• ?will be assigned to a product because-
• the drug is new to the UK market
• the drug is being administered to the patient
  either by a new route of administration or a new
  formulation which is considered may have an
  impact on the already established risk/benefit
  profile of that drug
• The drug is being administered for a new
  indication

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Areas of special interest

• Children
• Elderly
• Delayed drug effects (e.g. cancers)
• Congenital anomalies
• Herbal remedies
• OTC medicines
• HIV medicines

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If you suspect an ADR

• Do not assume someone else will report it
• Only 2-4 of all ADRs are reported
• Only 10 of serious suspected ADRs are reported
• Do you have to be completely certain that what
  you have seen is an ADR?
• No

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Information to include on a Yellow Card

• 4 critical pieces of information that must be
  included on the report -
• Suspected drug(s)
• Suspect reaction(s)
• Patient details
• Reporter details

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Suspected Drug(s)

• Name of medicine
• including brand and batch number if known
• Route of administration
• Daily dose
• Date medicine started
• and stopped if applicable
• Reason why the medication was given
• Multiple drugs can be listed if more than one
  drug is suspected of causing the reaction

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Suspect reaction(s)

• Describe the reaction
• Include a diagnosis if relevant
• Include when the reaction occurred
• whether the reaction was considered to be serious
  and complete tick box for reasons why
• Document if any treatment was given for the
  reaction
• Eventual outcome tick relevant box

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Patient Details

• Sex of the patient
• Age at time of reaction
• Weight if known
• Do not need to know name or DOB as this could
  identify patient and break patient
  confidentiality
• Patients initials and local identification number
  (hospital or practice number) which will identify
  patient to you in the event of future
  correspondence

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Reporter details

• Must be completed in all cases
• Name and full address
• Need to acknowledge receipt of report and follow
  up further information if necessary.
• Profession

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Additional useful information

• Other medication in the last three months
  including herbal and over the counter meds.
• Use additional sheets if necessary.
• If no other meds are being taken or if no more
  information is available say so
• Include details of any
• rechallenges
• relevant medical history
• test results
• known allergies
• suspected drug interactions

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What happens to a Yellow card once received?
Provision of information
Acknowledgment and/or follow-up for more info
Commit to database
Report details entered to Sentinel database
Assessment
Yellow Cards - Adverse Drug Reaction reports
Risk-benefit evaluation and advice from CHM
Signal detection
Signal Evaluation and Prioritisation

Impact Analysis
Regulatory action and communication
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How is the Yellow Card data used to improve
patient safety?

1. Changes to SPC e.g. restriction in use, special
   warnings and precautions
2. Publication of
3. Issue of Dear Healthcare professional letters
4. Drug Analysis Prints (DAPs)
5. Withdrawal of a medicines if patient safety is
   threatened

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Drug Safety Update

• Published monthly
• Register for alerts
• http//www.mhra.gov.uk/Publications/Safetyguidance
  /DrugSafetyUpdate/index.htm

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Drug Analysis Prints (DAPs)

• Complete list of all suspected ADRs reported via
  yellow card scheme for named suspect drug
• Inclusion of a particular reaction does not
  necessarily mean it has been caused by the drug
• Certain reported reactions are conditions which
  occur spontaneously
• Should not be used for determining incidence
• Reporting rates are influenced by seriousness of
  ADR, ease of recognition, extent of use
• www.mhra.gov.uk/daps

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System Organ Class
Totals
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Reactions under High Level Term (HLT)
Reaction Preferred Term (PT)
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Examples of ADRs identified by Yellow Card Scheme

• Vigabatrin and visual field defects
• 3 reports severe persistent visual field
  constriction
• detected 2-3 years after starting therapy
• resulted in a change of recommended dosage, range
  of indications and addition of warnings
• Cyproterone acetate and hepatotoxicity
• dose related
• restricted indications
• requirement for hepatic function monitoring
• Alendronate and severe oesophageal reactions
• warnings and revised dosing instructions
• Varenicline and depression and suicidal ideation
• reports received in the 1st 12 months after
  launch
• addition of warnings and monitoring in patients
  with
• history of psychiatric illness

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Where to find ADR information

• Reference texts
• British National Formulary (BNF)
• Summary of Product Characteristics (SPC)
• Martindale
• AHFS Drug information
• Meylers 'The Side effects of drugs
• Davies textbook Adverse Drug Reactions
• Lees textbook Adverse Drug Reactions
• Journals
• Adverse Drug Reaction Bulletin
• Drug Safety Update
• Medline/Embase/Pharmline search
• Electronic sources
• Micromedex
• www.mhra.gov.uk

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All health-care professionals have a
responsibility to inform colleagues about
clinically important adverse drug reactions that
they detect, even if a well-recognised or causal
link is uncertain. Edwards IR and Aronson
JK. Adverse drug reactions definitions,
diagnosis, and management. Lancet 2000 356
1255-59
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If you suspect an ADR. do not assume someone
else will report it!
www.mhra.gov.uk/yellowcard