The Yellow Card Scheme: Reporting Adverse Drug Reactions

1. The Yellow Card Scheme: Reporting Adverse Drug Reactions

2. 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

3. 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.

4. 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.

5. Classification of ADRs • Common ADRs • Type A (‘Augmented’) • Predictable, dose related • Constipation with opioids • Usually not severe • Peptic ulceration following NSAID use

6. 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

7. 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.

8. 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

9. 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

10. 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 Cushing’s syndrome on stopping treatment (withdrawal) paroxetine withdrawal syndrome delayed clear cell cancer with stilbestrol

11. 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

12. 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

13. 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 suffer`serious’ 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

14. 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 patient’s confidence in their healthcare professional(s)

15. 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

16. Who is most at risk from ADRs? • The elderly • Children • Co-existing diseases • Females • Atopic individuals • Polypharmacy • 50% of patients on5 drugs or more

17. 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 2002;24(2):46-54)

18. 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 ADR’s 2 • Better monitoring of treatment 3 • Better communication 4 1 Howard et al BJCP 2007 Feb;63(2):136-47 2 BMJ 2006;333:522 3 BMJ 2003;327;1179-1181 4 Archives of Internal medicine 2006;145(4):284-293

19. 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

20. 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

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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

27. 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

28. Completing a Yellow Card

29. Simple Fast Drop-down menus Allows reporter to register on the site The Yellow Card can be saved at any time On-line www.yellowcard.gov.uk

31. 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

32. 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

33. 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

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

35. 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

36. 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

37. 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

38. 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

39. 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

40. 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

41. 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

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

43. How is the Yellow Card data used to improve patient safety? • Changes to SPC e.g. restriction in use, special warnings and precautions • Publication of • Issue of ‘Dear Healthcare professional’ letters • Drug Analysis Prints (DAPs) • Withdrawal of a medicines if patient safety is threatened

44. Published monthly Register for alerts http://www.mhra.gov.uk/Publications/Safetyguidance/DrugSafetyUpdate/index.htm Drug Safety Update

45. 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

48. System Organ Class Totals

49. Reactions under High Level Term (HLT) Reaction Preferred Term (PT)

50. 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 andrevised 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