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 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) 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)

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. 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). 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).

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. 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 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.

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

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 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. 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.

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. 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 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.

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 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 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

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 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 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

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 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 AAdverse 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

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) 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. 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.

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 Point 1 reference: Pharm World & Science 2002;24(2):46-54)Point 1 reference: 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 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 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

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 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 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

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 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. 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.

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 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) 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)