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