MHRA Yellow Card Scheme
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The document discusses the Yellow Card Scheme in the UK for reporting adverse drug reactions (ADRs). It defines an ADR and describes how common ADRs are, causing 6.5% of adult hospital admissions. It outlines how ADRs can be classified and factors that influence them. The Yellow Card Scheme acts as an early warning system to identify new ADRs and risks. Healthcare professionals, patients and the public can report suspected ADRs to the scheme to help continual drug safety monitoring.
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MHRA Yellow Card Scheme
- 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’ ADRs1 – 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. • 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) ADRs can also…
- 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 on 5 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/year1 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. 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
- 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? Provision of information Commit to database Report details entered to Sentinel database Risk-benefit evaluation and advice from CHM Signal detection Assessment Yellow Cards - Adverse Drug Reaction reports Impact Analysis Signal Evaluation and Prioritisation Regulatory action and communication Acknowledgmen t and/or follow- up for more info
- 43. 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
- 44. Drug Safety Update •Published monthly •Register for alerts http://www.mhra.gov.uk/Pu
- 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
- 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 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
- 51. Where to find ADR information • Reference texts – British National Formulary (BNF) – Summary of Product Characteristics (SPC) – Martindale – AHFS Drug information – Meyler’s 'The Side effects of drugs – Davies’ textbook Adverse Drug Reactions – Lee’s textbook Adverse Drug Reactions • Journals – Adverse Drug Reaction Bulletin – Drug Safety Update – Medline/Embase/Pharmline search • Electronic sources – Micromedex – www.mhra.gov.uk
- 52. “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
- 53. If you suspect an ADR…. do not assume someone else will report it! www.mhra.gov.uk/yellowcard
Editor's Notes
- This is what we plan to cover in this session. (You may also wish to refer to any workshops which are included in the session)
- Be aware that whenever a patient takes a drug (however inert the drug), there is a potential risk of an adverse reaction to that drug. There are many definitions for an adverse drug reaction but this is the one used by Medicines and Healthcare products Regulatory Agency (MHRA).
- The terms "adverse reaction" and "adverse event" are often used interchangeably, however this is not always correct. An adverse event is seen from the point of view of the patient, whereas an adverse reaction is seen from the point of view of the drug. The term ‘side effect’ is often also used. The Yellow Card scheme monitors ADRs not adverse events. Therefore, this adverse event would not be reported via the Yellow Card scheme. Remember to think laterally – e.g. patient on carbamazepine trips outside surgery and breaks arm. Probably just an adverse event if pavement is uneven but check in case the patient felt dizzy due to carbamazepine thus causing fall. Also check if carbamazepine could have caused osteoporosis making bone more likely to break. Need to delve more deeply before deciding if ADR or adverse event.
- The examples given show that ADRs can range from relatively minor effects to very serious effects. Minor effects tend to be the most common reactions while serious effects are more uncommon. Very Common >10% ( >1/10) Nausea with paroxetine Common 1-10% ( >1/100, <1/10) Dizziness with paroxetine Uncommon 0.1-1% ( >1/1000, <1/100) Skin rashes with paroxetine Rare ( >1/10,000, <1/1,000) Hyponatraemia with paroxetine Very rare ( <1/10,000) including isolated cases] Gastro-intestinal bleeding with paroxetine 80% reactions are type A those due to the primary pharmacology of the drug (i.e. augmentation of drug’s therapeutic action) and secondary actions of the drug action different from the drugs therapeutic action, but known from the pharmacology. E.g. Beta blockers bradycardia and heart block primary actions, bronchospasm is secondary action. Toxicity in overdose – e.g. hepatic failure with paracetamol Side-effect – e.g. sedation with antihistamines Secondary effect – e.g. diarrhoea with antibiotic therapy due to altered GI bacterial flora Drug interaction - e.g. theophylline toxicity with ciprofloxacin Ref: Lancet 2000;356: 1505-11
- Clinical trials do not detect type B reactions. This is due to ADRs like the type B reactions may have incidence of 1 in 10,000 or less and their occasional occurrence during clinical trials may be considered a coincidence. Type B Uncommon Occur only in susceptible individuals idiopathic defined as uncharacteristic reactions that are not explicable in terms of actions of drug Usually discovered post-marketing Immunological and genetic factors important E.g. Hypersensitivity – immunological reaction – anaphylaxis with penicillin Abnormalities in drug metabolism – isoniazid induced peripheral neuropathy in slow acetylators (i.e. those deficient in N-acetyl transferase) Pyridoxine. Concomitant disease – e.g. HIV increases the idiosyncratic toxicity with co-trimoxazole.
- TYPE C Adverse effects that occur with prolonged but not short duration therapy. For example, phenothiazine-induced tardive dyskinesia. TYPE D Occur some time after discontinuation of treatment. TYPE E Effects occur on withdrawal of a drug, especially when treatment is stopped abruptly, e.g. the benzodiazepine withdrawal syndrome, adrenocortical insufficiency after steroid treatment.
- Type G adverse reactions involve irreversible genetic damage. Carcinogens: Some drugs such as azathioprine, an immunosuppressant, have been found to be carcinogens – azathioprine increases the risk of developing non-Hodgkins lymphoma. Cyclophosphamide linked with bladder cancer Genotoxins: Some drugs, fungal infections and solvents used in drug manufacture may be genotoxic i.e. alter DNA synthesis in vivo. Certain anti-cancer drugs are also genotoxic Teratogens: Some drugs, when taken during pregnancy can damage the fetus e.g. isotretinoin for acne or ACE inhibitors for hypertension or heart failure
- Common ADRs e.g. nausea common and usually mild, but have substantial effect on patient and can lead to changes in therapy or affect quality of life. Most severe drug induced events are generally the most rare e.g. blood dysgrasia e.g. agranulocytosis or aplastic anaemia Certain serious diseases e.g. MI are also sometimes drug induced but drugs only account four a small proportion of their occurrence. E.g. cox-II and NSAID’s CVS risk Ref: lancet 2000;356:1339-43
- Adverse drug reactions are a major clinical problem. Studies have found that around 6.5% of hospital admissions are due to adverse drug reactions, with 10 000 of all admissions to hospital being due to ADRs. Furthermore 10 to 20% of patients will experience an adverse reaction during their stay in hospital. Of these approx 7% will be serious and 0.1-0.3% fatal. It is therefore clear to see that, adverse drug reactions increase hospital admission rates, increase morbidity and mortality and thus significantly increase health care costs. Up to 40% patients receiving drugs in the community are though to experience ADRs. It is difficult to study ADRs in the community and there are very few well designed studies Ref for 4) In a 1979 study in general practice 41% of 817 patients surveyed were thought to have certainly or probably experienced an ADR. 1225 admissions related to ADR 6.5% ADR directly related to admission in 80% cases 76% patients > 65 years old Mean hospital stay 8 days 2.3% (28 patients) died as direct result of ADR 15 GI bleeding 17 Aspirin implicated (alone or combination) 5 Renal failure (diuretic and/or ACE) ADRs responsible for death of 0.15% of patients 72% reactions defined as avoidable 95% ADR’s defined as type A
- Less severe reactions A patient may decide to stop taking their medication if they are experiencing an adverse reaction to it. This non-compliance may lead to re-emergence of the original disease and can be particularly important if the treatment is prophylactic. E.g malaria prophylaxis, the oral contraceptive. For example, if a patient has an antibiotic allergy, this limits the options for treating infections. For example a first-line drug may have to be stopped due to an adverse reaction, and a less effective second-line drug started. Obviously experiencing an adverse reaction is not pleasant so drug therapy can affect the patients quality of life. In some cases medicines may have a greater impact on the patient than the symptoms of the disease itself. e.g. Drugs used to treat hypertension often produce adverse effects while hypertension itself often has no symptoms. Drug-induced disease is rarely specific and usually mimics naturally occurring disease thus causing diagnostic problems.
- Point 1 reference: Pharm World & Science 2002;24(2):46-54)
- Dose optimisation E.g.. reducing doses once responded to treatment – high dose steroids reducing as per BTS. Risks of unnecessary lengths of course steroids adrenal suppression. CHM Current Problems in Pharmacovigilance, volume 31, May 2006 Avoid / reduce interactions Many drugs interact with warfarin NB herbal interactions. St Johns Wort reducing efficacy of theophylline, etc mechanism. CHM Current Problems in Pharmacovigilance Food stuff - warfarin and cranberry juice to increase effect INR, Simvastatin and grapefruit juice, CHM Current Problems in Pharmacovigilance Prophylactic therapy PPI cover for low dose aspirin for IHD cover in patients at high risk of GI problems, to prevent GI bleeds due to low dose aspirin – incidence. Bisphosphonates for patients on long term oral steroids to prevent osteoporosis (evidence) Avoid new / black triangle drugs Only given to few 1000 patients allows detection of common ADR’s but not rare ones. Information on rare or long term ADRs not known. Avoid prescribing contra-indicated drugs use of a non-selective beta-blocker in an asthmatic bronchospasm Drug use in an inappropriate clinical indication or medically unnecessary antibiotics for a viral infection will not cure the infection but will expose patients to the adverse effects of the drug. Monitoring treatment BMJ 2003;327;1179-1181 e.g. diuretics in CHF patients monitor U+E to ensure not dehydrated or low K, also monitor symptoms of HF. Optimise dose through robust monitoring – multi disciplinary approach using specialist nurses, non-medical prescribers, Drs and patient. Patient counselling BMJ 2006;333:522 telephone counselling patients improves compliance in the elderly on poly pharmacy (can consider non-compliance as an adverse event). Better communication on ADR’s between healthcare professionals may reduce unnecessary re-prescription of discontinued medicines and reduce ADRs in elderly. 27% drugs discontinued in hospital were re-prescribed in primary care . Re-prescription after ADR in the elderly Archives of Internal medicine 2006;145(4):284-293 better communications between HCP re ADR’s may reduce unnecessary re-prescription and thereby reduce the occurrence of ADR’s. 3. High dose steroids (ensuring patients have steroid cards (multi-disciplinary responsibility to ensure medicines are used safely). Fatal case of child in Scotland on high dose inhaled steroids, poor communication. Ref: NeLM Further information available in BNF Factors predisposing to pharmacological actions Pharmacokinetic -Digoxin toxicity due to decreased elimination if renal function impaired Pharmacodynamic - Indomethacin causing LVF due to water and sodium retention Drug-drug interaction -Clarithromycin inhibits the metabolism of atorvastatin increasing the risk of myopathy. Elderly patients - Altered drug handling, Co-morbidity, PolypharmacyPrescription of 5 drugs simultaneously increases chance of ADR occurring by 50% Children - Action and pharmacokinetics different to adults, Not tested in children / ‘off-label use’, May develop delayed ADRs not seen in adults Patients with renal and liver impairment Pregnant or breastfeeding women
- Not all ADRs will be apparent to the patient or the health care professional as ADRs can mimic any disease process. Always be alert to the possibility of ADRs as a cause of the patients symptoms. Some common criteria to look out for would be the timing of the reaction with the drug treatment, did it happen soon after treatment started, after a dosage increase, disappeared when treatment stopped or reappeared when restarted. Abnormal clinical and laboratory measurements can also be a good criteria for diagnosing ADR. Patients can be a really important source of information about ADRs , listen to them and ask questions about how their medication is suiting them
- Temporal relationship What is the timing between the start of drug therapy and the reaction? Most reactions occur soon after starting treatment. Anaphylactic reactions can occur within hours, whereas hypersensitivity reactions typically take 2-6 weeks. Other reactions, such as bone density changes secondary to steroids may be delayed for years. Rechallenge What happens when patient is rechallenged with the drug? Recurrence rechallenge provides good evidence that the drug is responsible for the Adverse effect. However, rechallenge is rarely possible, particularly for serious reactions, because of the danger to the patient. More rapid occurrence following re-exposure to the drug than on secondary exposure to the drug indicates an immune-mediated response. Exclusion Have concomitant drugs and other non-drug causes been excluded? ADR is a diagnosis of exclusion, as no specific lab tests are available. Important to exclude non-drug causes both clinically and by performing relevant investigations. Novelty Has the reaction been reported before? If the reaction is well recognised, it may mentioned in the SPC or reported in the medical literature. Information regarding management useful particularly of rare reaction. Dechallenge Does the reaction improve when the drug is withdrawn or the dose is reduced? Most, but not all, reactions improve on drug withdrawal, although recovery phase can be prolonged. In rare instances an autoimmune phenomenon may be set up and this reaction will not improve on drug withdrawal.
- Up to 40% patients receiving drugs in the community are though to experience ADRs. It is difficult to study ADRs in the community and there are very few well designed studies NSAID use is associated with significant morbidity and mortality in the UK each year. There is a strong association between NSAID use and likelihood for upper GI emergency admission. Ref for 2) The data recorded in the trial was extrapolated to give the estimated UK figures. The study was a retrospective survey of case notes of all emergency upper GI admissions per annum attributable to NSAID use. The study was undertaken at 2 District General Hospitals in the North West of England (catchment population 550,000). Matched controls were emergency admissions not caused by upper GI diagnoses. (Blower et al. Emergency admissions for upper gastrointestinal disease and their relation to NSAID use. Aliment Pharmacol Ther 1997; 11: 283-291)
- The Yellow Card Scheme is run by the MHRA and Commission on Human Medicines and collects, collates and investigates reports of Suspected ADRs The thalidomide tragedy of the late 50’s and early 60’s highlighted the urgent need for routine monitoring of the safety of medicines by a central body independent of the pharmaceutical industry. This disaster prompted the establishment of The Yellow Card Scheme which was introduced in 1964. It was the worlds first spontaneous reporting scheme for the reporting suspected adverse drug reactions and is the cornerstone of post marketing drug safety surveillance in the UK. The scheme is referred to as spontaneous as it voluntary and relies on observation and interpretation by health professionals in normal clinical practice. However this now includes reports from patients.
- Identify previously unrecognised hazards – and thus act as an early warning system Evaluate changes in risks and benefits e.g. to assess comparative toxicity within therapeutic groups (e.g. relative gastro-intestinal safety of oral NSAIDs) Take action to promote safer use -Continual safety monitoring of drug throughout marketed life - no other scheme monitors the safety of all drugs on the market Provide optimal information to users e.g. Identification of predisposing factors like age, race and disease state. Elderly patients with a history of peptic ulcer disease are at greater risk of GI toxicity from NSAIDs than young healthy patients For a reaction occurring 1 in 10, 000 people at least 30,000 patients need to be exposed to detect it with certainty.
- Advantages One of the most effective (and in some cases only) method of identifying rare adverse reactions. It can work rapidly and is readily accessible. It can be applied widely across all drugs throughout their marketing life. It is also fairly cheap to operate.
- Problems In some respects the scheme could be viewed as an uncontrolled and biased sample of anecdotes, e.g. media interest in certain drugs or reactions will stimulate reporting. Under-reporting of reactions is a significant problem. It is estimated that no more than 10% of serious reactions are notified to the CHM. An example where under-reporting proved to be a problem Practolol in the early 1970’s, 4 years after the introduction of a beta-blocker called practolol, the ‘practolol syndrome’ was uncovered. The syndrome included severe eye problems (including blindness), hearing impairment, sclerosing peritonitis and resulted in 23 deaths in the UK. Before the pre-case study – few reports. But after publication of case studies in the BMJ, 200 reports were received in next two months, and the drug was withdrawn. The delay in discovery spurred efforts to improve post-marketing surveillance. There may be uncertainty whether a drug is actually causing a given reaction and invariably further investigation is required before action is taken.
- Available in the back of the BNF, BNFc Medicines Compendium, Mims Copies can be downloaded to print from www.yellowcard.com or online
- The MHRA wish to receive all suspected ADRs associated with black triangle products in order to confirm the risk:benefit profile established during the pre-marketing phase. Because there are limited data on ADRs in children, all ADRs should be reported. Ideally all drug interactions should be reported to identify the actual frequency of occurrence. Because there is very little information about ADRs in herbal medicines, report all of them. Recent concerns about chinese herbal medicines containing aristolochia which causes renal failure and cancer highlighted via MHRA.
- Black triangle products are monitored closely for a minimum of two years and the black triangle symbol is not removed until the safety of the medicine is well established.
- MHRA also has a number of specialist interests which they would like you to report. (Point 1): Report all suspected ADRs which occur in children, even if it is an established drug, regardless of whether the medicine is licensed for use in children - over 50% of the medicines used in children are not licensed for use in this age group children not exposed to new drugs in clinical trials (Point 2): The elderly are more susceptible to ADRs, as they may metabolise medicines less effectively, be on many medications, and be more sensitive to their effects. Be alert to any potential ADRs in the elderly and report them according to the reporting guidelines (Point 3): Report any suspected delayed drug effects e.g. cancers or retroperitoneal fibrosis which may occur years after drug exposure (Point 4): If baby is born or fetus aborted with congenital anomalies report if suspect ADR (Point 5): Report suspected ADR to any herbal remedy and possibly keep sample for future analysis (Point 6): Report all serious reports on any OTC products – MHRA very keen to identify issues with OTC medicines (Point 7): Report all serious reports in HIV medicines – area of special interest and because we expect patients to have ADRs with them they often go unreported.
- [ To say at the end]: Information may be published in Drug Safety Update – the first issue of which was released on 1st August 2007. This can be accessed online via the MHRA website and you can register to have the latest issue downloaded to your PC at the beginning of every month.– Prior to this information was disseminated via “Current Problems in Pharmacovigilence” which came out several times a year. (Show recent copies of these to students) Established drugs may be assigned “drugs on alert” status if it appears that a number of problems are being reported
- (Point 1) – Restriction in use e.g. metformin and renal impairment. Reduction in dose e.g. Tramadol dose. Special warnings and precautions e.g. alendronate and other bisphosphonates taken with 200ml water and remaining upright (Point 5 )– Product withdrawn. Rarely a drug may need to be withdrawn from the market if risks outweigh benefits (i.e. product license withdrawn or voluntary withdrawal by the company) e.g. lumiracoxib (Prexige) has been withdrawn because of hepatotoxicity
- Points to consider when using DAPs: • Information included in DAPs cannot be used to estimate the likelihood of having an adverse drug reaction from taking a medicine because not all adverse reactions are reported and we do not know how many people have taken that medicine without having a reaction • Reporters are asked to send a Yellow Card if they suspect that a medicine may have caused an adverse reaction. Therefore, the inclusion of a report for a particular reaction on a DAP does not prove that the medicine in question caused the reaction • Determination of whether a particular medicine caused an adverse drug reaction is usually complex: other factors may have played a part in the reaction such as disease(s) for which the patient is receiving treatment, other medicines being taken by the patient, or a naturally occurring event or other unknown factor
- Has this reaction been reported before? Finding out about suspected adverse drug reactions reported to the MHRA Drug Analysis Prints (DAPs) are anonymised listings of suspected adverse drug reactions reported to the MHRA by healthcare professionals and patients through the Yellow Card Scheme. We have recently reformatted and updated all DAPs. Every DAP lists all suspected reactions that have been reported to the MHRA during a defined period for a particular medicine by name of active ingredient. DAPs are available in pdf format on our website in the Safety Information section
- DAP layout: • A DAP for a medicine lists individually all suspected adverse reactions that have been reported for that medicine on a Yellow Card Front pages shows administrative information and lists products containing aspirin for which ADRs have been reported, and hence are included in the DAP. ADRs reported against the active substance only are also included. Access DAPs at http://www.mhra.gov.uk/daps
- The summary pages of the DAP (usually page 2 or 3) shows the total number of suspected adverse drug reactions and total number of Yellow Card reports submitted for a particular medicine. Yellow Cards may contain more than one suspected reaction and the total number of suspected reactions listed may be higher than the number of reports received for a medicine • Data are given for reports when the medicine was given as a single active ingredient or when it was a given in a product that contained several active ingredients; for every reaction, the total number of reports are listed, as is the number with a fatal outcome • Adverse drug reactions are listed according to MedDRA (Medical Dictionary for Regulatory Activities) classifications of System Organ Class (eg, musculoskeletal and connective tissue disorders), High Level Term (eg, muscle pains), and Reaction Name (eg, myalgia) For more information about MedDRA see http://www.meddramsso.com/MSSOWeb/index.htm
- Interpretation of DAPs DAPs provide a useful overview of reporting patterns for medicines and are a valuable tool that form part of our continual monitoring of the safety of medicines. Healthcare professionals may find DAPs useful—for example, to see whether a suspected adverse drug reaction for a particular medicine has been reported to us previously. However, DAPs are not a complete account of the risks that may be associated with a medicine. Conclusions about the risks and benefits of a medicine cannot be made on the information in DAPs alone. More comprehensive information about the safety profile of a medicine can be found in the Summary of Product Characteristics or Patient Information Leaflet. Summaries of Product Characteristics and Patient Information Leaflets for a medicine can be viewed at http://emc.medicines.org.uk/; see also the British National Formulary (www.bnf.org).
- BNF – very comprehensive, quick reference however side effects not graded into incidence, severity or grouped into body systems, just a list of side-effects. SPC - side effects, usually split into organ class. Often gives an indication of incidence. Martindale- More detailed information than BNF. Can give information on effects of drug on body systems. Mentions case reports and gives references, which can be useful. Amount of information under different entries is variable. AHFS Drug Information- very detailed information on side effects. Sometimes gives incidence and time of onset and duration of adverse effect. American, therefore range of drugs can be different from UK practice. Updated yearly. http://www.ahfsdruginformation.com/ Meylers the Side Effects of Drugs 15th edition 2006 – Arranged alphabetically by drug in 6 volumes. Has two indexes in last volume. The first enables searching for individual drugs, the second allows searching for an individual side effect. It is the standard reference on adverse effects. It is written by an international list of authors who provide comment and evaluation. Fully referenced and detailed. Can date quickly as it is published only every four years. Davies‘s textbook of adverse drug reactions 5th, 1998 - Side effect under body system. Includes case reports and is fully referenced. Current edition is becoming outdated. Adverse Drug Reactions – Lee A 2nd edition 2006. ADRs described by organ class. Gives commonly implicated drugs and practical tips on management of suspected ADRs. Drugdex - Detailed information on side effects, referenced. Adverse effects listed under affected body systems. Regularly updated. American. Good for searching when you’ve lots of drugs to look up. Drug Analysis Prints http://www.mhra.gov.uk/daps List of all suspected adverse reactions reported to the MHRA. Classified by System Organ Class. Updated monthly. Refer to guidance on interpretation of the information. Manufacturers Medical Information Department – in-house case reports. Obliged to follow up all suspected ADRs with an adverse event reporting form (forward to enquirer)
- Never assume someone else will report It does not matter if someone else has reported, duplicates are picked up and usually complement each other. It doesn’t matter if it turns out not to be an ADR. Don’t not report just because you are not sure. An important safety signal may be lost.