1. Effets indesirables des médicaments Cours en partie basé sur source documentaire de l’OMS

2. Key Definitions (1) Adverse drug reaction (ADR) (effets indésirables)  A noxious and unintended response to a medicine that occurs at normal therapeutic doses used in humans for prophylaxis, diagnosis, or therapy of disease, or for the modification of physiologic function  The word “effect” is used interchangeably with “reaction.” Side effect (tolérance)  Any unintended effect of a pharmaceutical product occurring at normal therapeutic doses and is related to its pharmacological properties. Such effects may be well-known and even expected and require little or no change in patient management. Serious adverse effect (effets indesirables graves)  Any untoward medical occurrence that occurs at any dose and results in death, requires hospital admission or prolonged hospital stay, results in persistent or significant disability, or is life threatening

3. Key Definitions (2) Adverse drug event  Any untoward medical occurrence that may be present during treatment with a medicine but does not necessarily have a causal relationship with this treatment. Adverse drug events include medication errors and overdoses. Causality  The probability that a particular medicine is responsible for an isolated effect or ADR. Signal  Reported information on a possible causal relationship between and adverse event and a medicine, the relationship being previously unknown or incompletely documented. Usually more than one signal report is required to generate a signal, depending on the seriousness of the event and the quality of the information.

4. Adverse Drug Reactions (1) Patient injury caused by a medicine taken in therapeutic doses  Type A—Exaggerated pharmacological response  Pharmacodynamic (e.g., bronchospasm from beta-blockers)  Toxic (e.g., deafness from aminoglycoside overdose)  Type B—Nonpharmacological, often allergic, response  Medicine-induced diseases (e.g., antibiotic-associated colitis)  Allergic reactions (e.g., penicillin anaphylaxis)  Idiosyncratic reactions (e.g., aplastic anemia with chloramphenicol)

5. Adverse Drug Reactions (2)  Type C—Continuous or long term (time related)  Osteoporosis with oral steroids  Type D—Delayed (lag time)  Teratogenic effects with anticonvulsants or lisinopril  Type E—Ending of use (withdrawal)  Withdrawal syndrome with benzodiazepines  Type F—Failure of efficacy (no response)  Resistance to antimicrobials

6. Determining Medicine Safety: Identifying and Managing ADRs  Premarketing clinical trials  Animal studies, human studies—Phases I, II, III  Cannot identify ADRs with incidence < 1%  Unproven ADRs listing for legal protection of manufacturer  Postmarketing surveillance  Spontaneous reporting  Postmarketing clinical trials—Phase IV  Other methods—observational studies, meta-analysis, case reports  Determining causality  Actions taken to manage new ADRs

7. Determining Medicine Safety: Identifying and Managing ADRs  Premarketing clinical trials  Animal studies, human studies—Phases I, II, III  Cannot identify ADRs with incidence < 1%  Unproven ADRs listing for legal protection of manufacturer  Postmarketing surveillance  Spontaneous reporting  Postmarketing clinical trials—Phase IV  Other methods—observational studies, meta-analysis, case reports  Determining causality  Actions taken to manage new ADRs

8. Postmarketing Surveillance of ADRs: Spontaneous Reports  Best method for detecting new ADRs  Necessary because many ADRs not detected in pre- or postmarketing studies  Initiated by physicians, pharmacists, nurses, patients  Problems include underreporting, inaccurate reporting that may not show causality, and high false positive rates

9. Postmarketing Surveillance of ADRs: Clinical Studies  Postmarketing clinical studies  Done to determine efficacy and safety (Phase IV trials)  Generally poor in detecting ADRs because—  RCTs often insufficient for assessing ADRs, so observational cohort and cases control studies are used  Nonrepresentative patient selection  Narrow medicine indications and dosing structure  Limited concomitant medicine use

10. Postmarketing Surveillance: Other Methods  Observational studies provide limited identification of new ADRs  Large databases in the United States and Europe from national health programs, HMOs, health insurance programs can provide data for case control or cohort studies  Cohort studies useful for assigning causality  Published case reports—provide limited information about ADRs  Meta-analysis of published papers—provide identification of new ADRs by increasing the power of the clinical studies

11. Actions for Newly Discovered ADRs  “Dear Doctor” letters—describe a new safety concern about a particular medicine  Package insert revisions  For significant safety concerns  Manufacturers must change the official labeling and the package insert to reflect the new safety concern  Typically approved by the regulatory authority  Medicine recalls (voluntary and compulsory)  For serious safety concerns  May be voluntary or imposed by the regulatory authority

12. Determining Causality of an ADR  Factors in determining causality  Strength of the association  Consistency of the observed evidence  Temporality of the relationship  ADR that occurs in association with a medicine does not mean the medicine is responsible  Delayed reactions do not rule out the medicine as causing the ADR  Dose-response relationship  Confounding factors

13. Classifying Causality of an ADR  Certain causality—when a clinical event (including laboratory test abnormality) occurs in a plausible time relationship to medicine administration and cannot be explained by concurrent disease or other medicines or chemicals; re-administration of the medicine causes a similar reaction  Probable or likely causality—when a clinical event occurs with a reasonable time sequence to medicine administration and is unlikely to be due to any concurrent disease or other medicine administration  Possible causality—when a clinical event occurs with a reasonable time sequence to medicine administration, but which could be explained by concurrent disease or other medicine administration  Unlikely causality—when a clinical event (including laboratory test abnormality) occurs in temporal relationship to medicine administration that makes a causal relationship improbable, and when other medicines, chemicals, or underlying disease provide plausible explanations

14. Classifying Causality of an ADR: Naranjo Algorithm Total the score to determine the category of the reaction. The categories are defined as follows: Definite>9; Probable 5–8; Possible 1–4; Doubtful 0. Question YesNoDo Not Know Are there previous conclusive reports on this reaction?+100 Did the adverse event appear after the suspected medicine was administered? +20 Did the adverse reaction improve when the medicine was discontinued or a specific antagonist was administered? +100 Did the adverse reaction reappear when the medicine was re- administered? +20 Are there alternate causes (other than the medicine) that could solely have caused the reaction? +20 Was the medicine detected in the blood (or other fluids) in a concentration known to be toxic? +100 Was the reaction more severe when the dose was increased or less severe when the dose was decreased? +100 Did the patient have a similar reaction to the same or similar medicines in any previous exposure? +100 Was the adverse event confirmed by objective evidence?+100

15. Implications for DTC Surveillance of ADRs  Monitoring and managing ADRs requires setting up surveillance systems  Use of local surveillance (tracking and reporting) system run by the DTC  Use of standardized reporting forms  Analysis of reported ADRs to be done by selected DTC committee member  Reporting of serious and recurring ADRs to regulatory authorities and manufacturers

16. Why Pharmacogentics Avoidable Medical Problem 700,000 600,000 500,000 400.000 300.000 200,000 100,000 Heart Cancer Stroke RX Car Accidents 2.2 MILLION severe adverse drug reactions per year PATIENTS ARE AT RISK 100,000 deaths per year By PROPERLY PRESCRIBED MEDICATIONS COST LEADER for Mal-Practice If a patient had “double” or “triple hit” genetic variations, wouldn’t you want to know that prior to their procedure?

18. Date of download: 4/14/2015 Copyright © 2015 American Medical Association. All rights reserved. From: Incidence of Adverse Drug Reactions in Hospitalized Patients: A Meta-analysis of Prospective Studies JAMA. 1998;279(15):1200-1205. doi:10.1001/jama.279.15.1200

19. Date of download: 4/14/2015 Copyright © 2015 American Medical Association. All rights reserved. From: Incidence of Adverse Drug Reactions in Hospitalized Patients: A Meta-analysis of Prospective Studies JAMA. 1998;279(15):1200-1205. doi:10.1001/jama.279.15.1200

20. Date of download: 4/14/2015 Copyright © 2015 American Medical Association. All rights reserved. From: Incidence of Adverse Drug Reactions in Hospitalized Patients: A Meta-analysis of Prospective Studies JAMA. 1998;279(15):1200-1205. doi:10.1001/jama.279.15.1200

21. Resultats Over six months, there were a total of 3695 patient episodes Women experienced significantly more ADRs (n = 308, 17.8%) than men (n = 216, 13.5%); The median age was significantly higher in the ADR group at 72 years compared with 61 years in the non-ADR group. More medical patient episodes (n = 406, 16.0%) than surgical episodes (n = 139, 12.0%) resulted in ADRs. The median length of stay for patient episodes that resulted in an ADR was 20 days compared to 8 days for those episodes without ADRs.

26. Conclusion Effets indesirables doivent etre une preoccupation constante des medecins En partie evitable Nécessité de déclarer ces effets indesirables +++