Who are we? Adverse Drug Reactions Applying Theory to Clinical Practice. WS SIG-MI Barcelona October

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1 Adverse Drug Reactions Applying Theory to Clinical Practice Stephane Steurbaut, Brussels - Belgium Yolande Hanssens, Doha - Qatar ESCP Barcelona 30 October 2012 Who are we? yhanssens@hmc.org.qa y_hanssens@hotmail.com stephane.steurbaut@uzbrussel.be WS SIG-MI Barcelona October

2 3 Objectives To appreciate the importance of early recognition of possible ADRs and differentiate them from disease related events. To practice the causality scales to assist in a prompt identification of ADRs. To become familiar with information sources providing relevant details about ADRs. WS SIG-MI Barcelona October

3 Outline of this session Introduction & definitions Practical clinical guidance, sources of information & causality assessment Case studies in small groups Feedback from the groups What is happening at the European level? Current status & Conclusions ADRs - Definition Any noxious, unintended, and undesired effect of a drug that occurs at doses used in man for prevention, diagnosis, or treatment of disease, or modification of physiological function Any unwanted effect WHO, 1966 WS SIG-MI Barcelona October

4 ADRs - Terminology Adverse effect/reaction: all unwanted effects Side effect: beneficial or unwanted via same or other mechanism dose-related or not Adverse event: adverse outcome not necessarily related to drug Toxic effect: Medication error increase of the desired therapeutic effect, dose-related ADRs - Terminology I m allergic But Doctor, Pharmacist... I don t tolerate I react.... WS SIG-MI Barcelona October

5 ADRs - Classification Type A reactions: pharmacological ADR - related to the pharmacological actions of the drug - predictable, dose-related - low mortality - usually identified before drug is marketed Examples: Toxicity or overdose Secondary pharmacological effect Drug interaction ADRs - Classification Predisposing factors to type A reactions - drug formulation - drug dose - multiple drug therapy (drug-drug interactions) - gender: females >> males - age: altered pharmacokinetics altered pharmacodynamic sensitivity - underlying disease - genetic polymorphism WS SIG-MI Barcelona October

6 ADRs - Classification Type B reactions: - uncommon, unpredictable, non-dose-related, mostly NOT detected during clinical trials - not related to the pharmacological actions of the drug - high mortality Idiosyncratic reactions ADRs - Classification Comparison Type A and Type B Parameter Type A Reaction Type B Reaction Predictable Yes No Dose related Yes No Incidence High Low Frequency Regular Rare Morbidity High Low Mortality Low High Treatment Dose reduction Stop WS SIG-MI Barcelona October

7 Can I only buy the side effects of this cough syrup? ADRs - Importance account for 2-6% of all hospital admissions occur in 10-20% of hospital inpatients cause death: in 0.1% medical inpatients in 0.01% surgical inpatients Manasse HR. Am J Health Sys Pharm 1989 Lazarou J. JAMA 1998 WS SIG-MI Barcelona October

8 Terminology & overlap (1) Nebeker J.R. et al. Ann Intern Med. 2004;140: Terminology & overlap (2) Otero M.J. & Dominguez-Gil A. Farmacia Hospitalaria Med. 2000;24: WS SIG-MI Barcelona October

9 Terminology & overlap (3) Morimoto T. et al. Qual Saf Health Care. 2004;13: ADVERSE DRUG REACTIONS Importance affect patient quality of life cause patients to lose confidence in health care providers and may lead to medication non-adherence may mimic disease (unnecessary investigations and delay in treatment) increase cost of patient care BURDEN ON HEALTH CARE BUDGET WS SIG-MI Barcelona October

10 19 ADVERSE DRUG REACTIONS Diagnosis Timing dose-related reaction interacting drug previous exposure WS SIG-MI Barcelona October

11 ADVERSE DRUG REACTIONS Diagnosis pattern recognition background frequency ADVERSE DRUG REACTIONS Diagnosis 3 key questions 1. Can the drug cause the ADR? 2. Has the drug caused the ADR? 3. Will the drug cause the ADR? Also How likely is it that this drug is the cause of this problem in this specific patient? Making a differential diagnosis needs full access to all available data. WS SIG-MI Barcelona October

12 ADVERSE DRUG REACTIONS Diagnosis- Causality Challenging Discrepancies between evaluators Usage of standardized case causality assessment Algorithms and evaluation scales WHO-UMC system & Naranjo scale BUT Limitations too ADVERSE DRUG REACTIONS Advantages & limitations of standardized case causality assessment What it CAN do Decrease disagreement between assessors Classify relationship likelihood Mark individual case reports Improvement of scientific evaluations; educational What it CANNOT do Give accurate quantitative measurement of relationship likelihood Distinguish valid from invalid cases Prove the connection between drug and event Quantify the contributions of a drug to the development of an ADR Change uncertainty into certainty WS SIG-MI Barcelona October

13 WHO The Uppsala Monitoring Centre 25 WHO-UMC Causality Categories WHO-UMC WS SIG-MI Barcelona October

14 Naranjo ADR Probability Scale To assess the adverse drug reaction, please answer the following questionnaire and give the pertinent score. Yes No Do Not Know Score 1. Are there previous conclusive reports on this reaction? 2. Did the adverse event appear after the suspected drug was administered? 3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered? 4. Did the adverse reactions appear when the drug was readministered? 5. Are there alternative causes (other than the drug) that could on their own have caused the reaction? 6. Did the reaction reappear when a placebo was given? 7. Was the drug detected in the blood (or other fluids) in concentrations known to be toxic? 8. Was the reaction more severe when the dose was increased, or less severe when the dose was decreased? 9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure? 10. Was the adverse event confirmed by any objective evidence? Total Score Total Score ADR Probability Classification Naranjo CA. Clin Pharmacol Ther 1981;30: Highly Probable 5-8 Probable 1-4 Possible 0 Doubtful ADVERSE DRUG REACTIONS Diagnosis Use of Algorithm The Naranjo Algorithm 10 Questions with scoring system -1, 0, +1 and +2 Score of 9-10 definitely ADR 5-8 probable ADR 1-4 possible ADR < 1 doubtful Naranjo CA. Clin Pharmacol Ther 1981 WS SIG-MI Barcelona October

15 Outline of this session Introduction & definitions Practical clinical guidance, sources of information & causality assessment Case studies in small groups Feedback from the groups What is happening at European level? Current status & Conclusions Causality Assessment Practice in small groups Causality assessment using 1. Naranjo Scale 2. WHO-UMC system Also consider for each case Likely causes? Action to be taken? Investigations needed? Management? Further assessment? WS SIG-MI Barcelona October

16 Case 1 - Male, 56 years, 92 kg, BMI 32 - Medical conditions DM type 2 Dyslipidemia Hypertension Case 1 Current home medication Metformin 500 mg TID Atorvastatin 40 mg HS Valsartan/Amlodipine 160/5 32 WS SIG-MI Barcelona October

17 Case 1 - Admitted for minor elective surgery - Medication at Hospital Home medication + ranitidine 150 mg po BID heparin 5000 units SubQ 33 Case 1 Platelet count (normal range x10 9 /L) - Day Day Day WS SIG-MI Barcelona October

18 Case 1 Does ranitidine cause thrombocytopenia? Naranjo Score? WHO-UMC system? Action plan? 35 Ranitidine and thrombocytopenia Score? To assess the adverse drug reaction, please answer the following questionnaire and give the pertinent score. Yes No Do Not Know Score 1. Are there previous conclusive reports on this reaction? 2. Did the adverse event appear after the suspected drug was administered? 3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered? 4. Did the adverse reactions appear when the drug was readministered? 5. Are there alternative causes (other than the drug) that could on their own have caused the reaction? 6. Did the reaction reappear when a placebo was given? 7. Was the drug detected in the blood (or other fluids) in concentrations known to be toxic? 8. Was the reaction more severe when the dose was increased, or less severe when the dose was decreased? 9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure? 10. Was the adverse event confirmed by any objective evidence? Total Score Total Score ADR Probability Classification 9 Highly Probable 5-8 Probable 1-4 Possible 0 Doubtful 36 WS SIG-MI Barcelona October

19 WHO-UMC Causality for ranitidine and thrombocytopenia WHO-UMC Case 1 Are there any other reasons for thrombocytopenia in this patient? 38 WS SIG-MI Barcelona October

20 Heparin and thrombocytopenia Score? To assess the adverse drug reaction, please answer the following questionnaire and give the pertinent score. Yes No Do Not Know Score 1. Are there previous conclusive reports on this reaction? 2. Did the adverse event appear after the suspected drug was administered? 3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered? 4. Did the adverse reactions appear when the drug was readministered? 5. Are there alternative causes (other than the drug) that could on their own have caused the reaction? 6. Did the reaction reappear when a placebo was given? 7. Was the drug detected in the blood (or other fluids) in concentrations known to be toxic? 8. Was the reaction more severe when the dose was increased, or less severe when the dose was decreased? 9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure? 10. Was the adverse event confirmed by any objective evidence? Total Score Total Score ADR Probability Classification 9 Highly Probable 5-8 Probable 1-4 Possible 0 Doubtful 39 WHO-UMC Causality for heparin and thrombocytopenia WHO-UMC WS SIG-MI Barcelona October

21 Case 2, 80 years, 65 kg medical conditions: reflux gastric ulcer osteoporosis hypertension atrial fibrillation (paroxysmal) depressed Case 2 Morning Breakfast Lunch Dinner Bedtime spironolactone 50 mg bisoprolol 5 mg bisoprolol 5 mg Amlodipine 5 mg Aspirin 80 mg alendronate 70 mg (weekly) omeprazole 20 mg escitalopram 10 mg WS SIG-MI Barcelona October

22 Case 2 Hospitalisation for: decrease of general health confusion agitation sodium level: 116 meq/l Case 2 - Qs Likely causes? Action(s) to be taken? Investigations needed? Management? Further assessment? WS SIG-MI Barcelona October

23 Likely causes Case 2 - Aws Hyponatremia Drug induced? escitalopram + spironolactone Other? SIADH Case 2 - Aws Action(s) to be taken Dechallenge escitalopram (temporally) stop spironolactone? Rechallenge? WS SIG-MI Barcelona October

24 Case 2 - Aws Investigations needed Lab values electrolytes: Na, K, Blood pressure Mini-mental state Case 2 - Aws Management Infusion: 0.9% NaCl SLOWLY! 40 meq/l KCl (lab result: 3.2 meq/l) Liquid restriction WS SIG-MI Barcelona October

25 Case 2 - Aws Further assessment & follow-up Electrolyte balance Blood pressure control Assess need for antidepressive medication no (S)SRI/(S)NRI Case 4, 24 years, 85 kg, 164 cm Medical conditions: chronic: diabetes type 1 obesity hypertension acute pelvic inflammatory disease penicillin allergy WS SIG-MI Barcelona October

26 Case 4 Medication taken at home NovoRapid (insulin aspart): 8h: 30 E / 12h: 30 E / 18h: 40 E Lantus (insulin glargine): 23h: 42 E NovoRapid ramipril 8h: 5 mg Case 4 Medication received in the hospital ciprofloxacin IV 400 mg/200 ml 8h: 30 E / 12h: 30 E / 18h: 40 E paracetamol IV 1 g Complaints burning sensation erythema multiforme WS SIG-MI Barcelona October

27 Case 4 - Qs Likely causes? Action(s) to be taken? Investigations needed? Management? Further assessment? Likely causes Case 4 - Aws ADR on ciprofloxacin Preventable? penicillin allergy? infusion time: advised: 60 min here: 30 min medication error WS SIG-MI Barcelona October

28 Case 4 - Aws Action(s) to be taken Dechallenge stop ciprofloxacin IV Rechallenge? possible with correct infusion rate nevertheless, chosen to give ciprofloxacin orally Case 4 - Aws Investigations needed None Management Oral antihistaminic WS SIG-MI Barcelona October

29 Case 4 - Aws Further assessment & follow-up Erythema vanished after 45 minutes Patient recovered completely followed by hospital discharge few days later Outline of this session Introduction & definitions Practical clinical guidance, sources of information & causality assessment Case studies in small groups Feedback from the groups What is happening at the European level? Conclusions & take home messages WS SIG-MI Barcelona October

30 ADVERSE DRUG REACTIONS ADVERSE DRUG REACTIONS WS SIG-MI Barcelona October

31 ADVERSE DRUG REACTIONS ADVERSE DRUG REACTIONS WS SIG-MI Barcelona October

32 ADVERSE DRUG REACTIONS WS SIG-MI Barcelona October

33 Outline of this session Introduction & definitions Practical clinical guidance, sources of information & causality assessment Case studies in small groups Feedback from the groups What is happening at European level? Current status & Conclusions ADRs - Definition Any noxious, unintended, and undesired effect of a drug that occurs at doses used in man for prevention, diagnosis, or treatment of disease, or modification of physiological function Any unwanted effect WHO, 1966 WS SIG-MI Barcelona October

34 What triggered the WHO in 1966? 67 Softenon tragedy Thalidomide (Contergan, Softenon ) launched by Grünenthal in 1957 & marketed in 47 countries (not in US) used as samples on 20,000 US patients sold until 1961 for insomnolence & morning sickness during pregnancy 10 to 20,000 babies with deformities (phocomelia) 68 WS SIG-MI Barcelona October

35 Softenon tragedy 1 SEP 2012 apologies from Grünenthal for not trying to reach out to victims for over 50 years 5000 to 6000 sufferers are still alive Victims criticize the company for not compensating them and for ignoring the red flags Too little too late 69 Adverse Drug Reactions Applying Theory to Clinical Practice Do causality scales solve all problems? Remember What it CAN do What it CANNOT do limitations too Decrease disagreement between assessors Classify relationship likelihood Mark individual case reports Improvement of scientific evaluations; educational Give accurate quantitative measurement of relationship likelihood Distinguish valid from invalid cases Prove the connection between drug and event Quantify the contributions of a drug to the development of an ADR Change uncertainty into certainty WS SIG-MI Barcelona October

36 Method: 6 assessors 2 pharmacists 2 physicians 2 nurses - Assessed 200 ADR reports for causality using Naranjo ADR Probability Scale Venulet algorithm WHO causality term assessment criteria - Assessment of agreement between 1. assessors using the same algorithms 2. algorithms for the same assessor WS SIG-MI Barcelona October

37 Results: Majority of the causality assessments resulted in probable or possible Physician and pharmacist assessment was more likely to result in definite or certain causality assessments than nurse assessment, when using the Naranjo and WHO algorithms. Use of the Venulet algorithm resulted in a higher number of unlikely or unrelated assessments than the other two methods. Results: cont d The inter-assessor agreement measured was no greater than fair (weighted kappa = 0.31) for any comparison between raters, and for three comparisons, inter-assessor agreement was less than that expected by chance. Conversely, the weighted observed proportion of agreement, Po (w), was good (>0.6) for all assessments. Intra-assessor agreement between scales was highest for the Naranjo algorithm versus the WHO algorithm, with substantial (weighted kappa = 0.61) agreement between assessments made by pharmacist 1. The mean Po (w) for intra-assessor agreement was WS SIG-MI Barcelona October

38 Conclusions: 1. Comparability between assessors was found to be fair or less for the ADR causality assessment methods examined. 2. The most consistent results were produced by the application of the Naranjo algorithm and the least consistent was the Venulet algorithm. 3. It is likely that the clinical experience of the assessor influences how the assessment methods are applied. 4. The high level of disagreement in the results produced using the assessment scales in this study question the robustness of causality assessments. Adverse Drug Reactions Applying Theory to Clinical Practice Problems with different scales Problems of reproducibility and validity No single method is universally accepted Different causality categories are adopted in each method Categories are assessed using different criteria Assessment methods are also not entirely devoid of individual judgments, therefore inter-rater reliability can be low In conclusion, there is still no method universally accepted for causality assessment of ADRs Agbabiaka TB, Drug Saf. 2008;31(1): WS SIG-MI Barcelona October

39 Adverse Drug Reactions Applying Theory to Clinical Practice So, what did we do this afternoon? BUT with the growing rate of new pharmaceuticals Early recognition of potential ADRs is critical Reporting of ADRs is an essential part of healthcare practice We cannot allow another Softenon tragedy ADRs Useful Websites & References WS SIG-MI Barcelona October

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