The document outlines a pharmacovigilance workshop, including definitions of pharmacovigilance, the need for monitoring drug safety post-approval, and the pharmacovigilance system process of collecting, evaluating and taking action on adverse drug reactions. The workshop introduction discusses educational activities in Croatia to increase healthcare professional reporting of adverse reactions.

1. Pharmacovigilance Workshop

2. Outline What is Pharmacovigilance? Need for Pharmacovigilance? The concept of Pharmacovigilance system Pharmacovigilance in Croatia Introduction to Workshop Workshop

3. What is Pharmacovigilance? pharmakon (Greek) = medicinal substance vigilia (Latin) = to keep watch Science and activities relating to the detection, assessment, understanding and prevention of adverse effects and any other medicine-related problem (WHO) Includes clinical development and postmarketing surveillance OBJECTIVES

4. Objectives of Pharmacovigilance Long term monitoring of drug-safety in order to: Identify previously unknown hazards Evaluate changes in benefits and risks Provide optimal information to users Take action to promote safer use Monitor impact of action taken

5. Need for Pharmacovigilance ? ? ? ? ? ?

6. From test tube to the market – PRECLINICAL RESEARCH SYNTHESIS CANDIDATES SAFETY, TOLERABILITY & PHARMACOKINETICS Toxicity testing , reproductive toxicology, carcinogenicity, genotoxicity, toxicokinetics DRUG SCREENING activity & selectivity = Pharmacological profile

7. From test tube to the market – CLINICAL RESEARCH PHASE I PHASE III PHASE II “ First-in-Man Trial” Pharmacokinetics Metabolism Pharmacology Safety (early effectiveness) 20-80 HEALTHY VOLUNTEERS Preliminary data on efficacy for a particular indication(s) Short-term Adverse Drug Reactions Dose range SEVERAL HUNDRED PATIENTS WITH DISEASES OR CONDITION SEVERAL HUNDRED TO THOUSAND PATIENTS Efficacy and safety for overall benefit-risk assessment Product information APPROVAL

8. ? Limitations of Clinical Study Data ? Variable (compliance?) Fixed Dose Flexible; less information Rigorous; more information Conditions Usually present Avoided Concomitant medication and illness All Pregnant, children, elderly excluded Population Years Weeks Duration Thousands to millions Hundreds (rarely thousands) Number of patients Clinical Practice Clinical trials

9. Drug Safety Information Formulation (STRUCTURE ACTIVITY RELATIONSHIP) Preclinical studies (TOXICOLOGY, PHARMACOLOGY, PHARMACOKINETICS) Clinical studies (IDENTIFICATION OF ADRs, CHARACTERISATION, CAUSALITY, FREQUENCY, MANAGING) Pre marketing RARE ADRs? CHRONIC USE? DELAYED ADRs? INTERACTIONS? CHILDREN/ELDERLY?

10. From test tube to the market – CLINICAL RESEARCH PHASE I PHASE III PHASE II “ First-in-Man Trial” Pharmacokinetics Metabolism Pharmacology Safety (early effectiveness) 20-80 HEALTHY VOLUNTEERS Preliminary data on efficacy for a particular indication(s) Short-term Adverse Drug Reactions Dose range SEVERAL HUNDRED PATIENTS WITH DISEASES OR CONDITION SEVERAL HUNDRED TO THOUSAND PATIENTS Efficacy and safety for overall benefit-risk assessment Product information APPROVAL POSTMARKETING SURVEILLANCE

11. Postmarketing surveillance Additional data on safety and efficacy that could not be collected through Phase I-III

12. Postmarketing surveillance TOOLS FOR COLLECTION Spontaneous reporting unsolicited communication by Healthcare professional or Consumer to a company, regulatory authority or other organisation Post-Authorisation Safety Studies (Phase IV): Interventional (Clinical Trial) Non-interventional (observational) Medicinal product is prescribed in the usual manner in accordance with the terms of the Marketing Authorisation Registries, Named-patient use programmes, Surveys of patients and Healthcare Providers…

13. Withdrawals from the market as a result of spontaneous reporting 1998 1997 Serious hepatotoxic effect bromfenac 1998 1985 Fatal cardiac arrythmias terfenadine 1992 1992 Haemolytic anemia temafloxacin 1991 1987 Excessive mortality encainide 1982 1982 Onycholysis, renal, liver, bone marrow toxicity benoxaprofen 1975 1970 Blindness practolol Year of withdrawal Year of approval Reason for withdrawal INN

14. Need for Pharmacovigilance ! ! ! ! ! !

15. Histor ical Background Thalidomide 1960 marketed in 46 countries (hypnotic, prevention of nausea in pregnancy) Heavily promoted 1960 first reports of deformed infants (phoecomelia) tot. more than 20 000 cases

16. Histor ical Background Direct result of thalidomide: USA : 1962 amendment to Federal Food, drug & Cosmetic Act-required both safety & efficacy da t a EU : EC Directive 65/65 UK: 1964 Yellow card scheme WHO : 1968 Programme for International Drug Monitoring

17. The WHO set up its International Drug Monitoring Programme after the thalidomide disaster Since 1978 the Programme has been carried out by the Uppsala Monitoring Centre (UMC) in Sweden responsible for the collection of data about adverse drug reactions from around the world, especially from countries that are members of the WHO, and the generation of signals of drugs which might possibly have problematic side-effects

18. 82 Official Member Countries 17 Associate Member Countries WHO Database  3.7 million reports (2006)

19. The Concept of Pharmacovigilance System

20. Pharmacovigilance – concerned parties Competent Authorities (National Agencies, European Medicines Agency) Healthcare Professionals: Voluntary reporting or Mandatory reporting WHO Pharmaceutical Industry (Marketing Authorisation Holder & Sponsor of Clinical Trials) Patients: Complain or Complain & Report

21. Collect Identify Evaluate Take action INDIVIDUAL REPORTS

22. Reporting forms CIOMS I form Developed by CIOMS working group in 1990 (Council for International Organizations for Medical Sciences =industry+regulators) Standard form for reporting ADRs by the pharmaceutical industry

23. Reporting forms National reporting forms Every country with a developed Pharmacovigilance system has its own form Based on the CIOMS I reporting form Adjusted to the national legal requirements & praxis

24. Minimum information for a valid report Identifiable source (Healthcare professional) Identifiable patient Suspected product Suspected reaction

25. What needs to be collected? Adverse Drug Reactions Outcome of a use of a medicinal product during pregnancy Adverse reactions during breastfeeding Paediatric data Data from compassionate/named-patient use Lack of efficacy Suspected transmission of infectious agents Overdose, abuse and misuse Medication errors

26. Healthcare Professionals AGENCY National ADR Database MAH - PhV Qualified Person Individual answer to the reporter (Croatia, New Zealand…) WHO-UMC Database EudraVigilance - Database Marketing Authorisation Holder (through sales representatives) MAH -Central Office Information about the ADRs and other important information about the safety profile of the drug The Agency sends new Report forms Prepaid envelope for ADRs reporting Part of continuos medical education European Medicines Agency How is it collected?

27. Collect PSUR Identify Evaluate Take action INDIVIDUAL REPORTS

28. A regulatory document prepared by the Marketing Authorisation Holder & submitted to the Agency Worldwide post-authorisation safety experience includes information on ALL ADRs collected irrespective of the reporting country Includes scientific evaluation of the risk-benefit balance EU requirements: first 2 years after authorisation  every 6 months next 2 years  once a year after that  every 3 years PSUR PERIODIC SAFETY UPDATE REPORT

29. Collect SIGNAL DETECTION PSURs Identify Evaluate Take action INDIVIDUAL REPORTS

30. Signal Detection Today: Large & Complex computerised systems Signal: new, previously unknown safety information

31. Collect SIGNAL DETECTION PSURs Identify Evaluate Take action INDIVIDUAL REPORTS CLINICAL EVALUATION REGULATORY ACTION INFORMATION TO HEALTHCARE PROFESSIONALS AND THE PUBLIC

32. Regulatory actions on the basis of ADR reports Changes in the Summary of Product Characteristics (SPC) and Patient Information Leaflets (PIL) in the part which is dealing with the product safety

33. Product Information Summary of the Product Characteristics (SPC) basis of information for Healthcare Professionals on how to use the medicinal product safely and effectively Patient Information Leaflet (PIL) drawn up in accordance with the SPC

34. Summary of the Product Characteristics (SPC) 1. NAME OF THE MEDICINAL PRODUCT 2. QUALITATIVE AND QUANTITATIVE COMPOSITION 3. PHARMACEUTICAL FORM 4. CLINICAL PARTICULARS 4.1 Therapeutic indications 4.2 Posology and method of administration 4.3 Contraindications 4.4 Special warnings and precautions for use 4.5 Interaction with other medicinal products and other forms of interaction 4.6 Pregnancy and lactation 4.7 Effects on ability to drive and use machines 4.8 Undesirable effects 4.9 Overdose 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties 5.2 Pharmacokinetic properties 5.3 Preclinical safety data 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients 6.2 Incompatibilities 6.3 Shelf life 6.4 Special precautions for storage 6.5 Nature and contents of container 6.6 Special precautions for disposal and other handling 7. MARKETING AUTHORISATION HOLDER 8. MARKETING AUTHORISATION NUMBER(S) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 10. DATE OF REVISION OF THE TEXT LEGAL CATEGORY

35. Regulatory actions on the basis of ADR reports Changes in the Summary of Product Characteristics (SPC) and Patient Information Leaflets (PIL) in the part which is dealing with the product safety Changes in classification: From Over the counter to Prescription only Medicine From renewable prescription to non-renewable Special medical prescription Restricted prescription Marketing Authorisation withdrawal Batch recall based on clustering of ADRs

36. Information to Healthcare Professionals and the Public In addition to the information provided in Product Information when there are new important safety findings, withdrawals, suspensions, revocations… Tools: Direct Healthcare Professional Communication  “Dear Doctor Letters” Web Newsletters Publications

37. Pharmacovigilance in Croatia

39. Agency for Medicinal Products and Medical Devices, Ksaverska cesta 4, Zagreb tel. 01/ 46 93 830; fax. 01/ 46 73 275

40. Pharmacovigilance Unit ADR report assessment (expectedness, seriousness and causality assessment) Individual answer to the reporters Entering ADR reports into the Agency’s Database PSUR assessment Safety news monitoring Web-site regularly updated with Pharmacovigilance news C ollaboration with Public Relations Office (newspapers, radio, TV) Education of Healthcare Professionals & Industry

41. Educational activities Workshop about the role of physicians and pharmacists in adverse reaction reporting and pharmacovigilance system in Croatia: Over 1200 participants in 10 different cities free of charge recognised as a part of continuing education by the Croatian health - care professionals chambers

42. Educational activities

43. Educational activities - results Number of reports increased N ew reporters Better quality of reports Healthcare professionals recognise the Agency as a reliable source of information

44. Educational activities - results Percentage of reports received from pharmacists increased

46. Introduction to the Workshop

47. What is an Adverse Reaction? A reaction to a drug which is harmful and unintended and which occurs at doses normally used in man for the prophylaxis, diagnosis or treatment of disease or the modification of physiological function Adverse reaction vs Adverse event Adverse event: time relationship with drug + causal relationship with drug -

48. Types of Adverse Reactions Type A (augmented) P harmacological mechanism Excess of desired pharmacology ( β -blockers, antidiabetics, diuretics…) Unwanted but documented pharmacology ( antihistaminics, Ca-chanel blockers, NSAID s ) Type B (bizarre) Specific, characteristic reactions S usceptible individuals only Anaphylaxis/anaphylactoid, cytotoxic, immune complex, cell mediated, unknown

49. Types of Adverse Reactions Type C (chronic) Due to repeated insult by the drug T i me relationship variable Mechanism uncertain Type D (delayed) Take time to develop Carcinogenesis, teratogenesis

50. Types of Adverse Reactions Type E after termination of therapy symptoms of abstinence rebound phenomena Type F ( failure ) therapeutic failure inefficacy (vaccines, contraceptives)

51. Serious adverse reaction Fatal Life threatening Disabling or incapacitating Results in, or prolongs hospitalisation Is a co n genital anomaly/birth defect In medical judgement may jeopardise the patient

52. Unexpected Adverse Reaction Not mentioned in the S ummary of P roduct C haracteristics (SPC) – any adverse drug reaction whose nature, severity or outcome is inconsistent with information in the SPC

53. Causality Assessment Definite/certain Probable Possible Causality unclear (unlikely) None  Adverse Drug Event! Uncertain/unknown Un-assessable Adverse Drug Reaction!

54. Definite/certain Very close time relationship Single suspected drug Positive de-challenge and re-challenge No other likely cause + DE-CHALLENGE=when the drug is stopped the reaction resolves + RE-CHALLENGE=the reaction reappears when the drug is restarted

55. Probable Close time relationship Single suspected drug Positive de-challenge N o other likely cause

56. Possible Plausible time relationship Single or multiple suspected drugs Not recovered, or needed therapy Other possible medical explanation, but not likely

57. Causality unclear (unlikely) Implausible time relationship Implausible biological association Single or multiple suspected drugs Not recover ed , or needed therapy Other likely cause(s)

58. WHO causality classification Probable Unlikely Unlikely Possible No data on dechallenge Possible Possible Dechallenge Probable No Dechallenge i rechallenge Certain Other factors Time relationship

59. Time for exercise!

60. Case 1 43 year–old man had been taking Painomore tablets 200 mg (ibuprofen) occasionally for headache for the past 5 years. On 15.10.2005. he is coming to your pharmacy and asking for another analgetic because he was hospitalised a week ago after developing difficulty with breathing and severe pruritus and rash on his hands, back and abdomen after taking Painomore . Previously, on one occasion, he also developed a rash after taking Painomore but the symptom lasted for 6 hours and resolved spontaneously, so he didn’t visit his doctor. The second time he had terrible headache and he didn't have anything else at home. He is not taking any other medicine.

61. Painomore tablets 200 mg Summary of the product characteristics: 4.8 Adverse drug reactions: Hypersensitivity: Hypersensitivity reactions have been reported following treatment with ibuprofen. These may consist of (a) non-specific allergic reaction and anaphylaxis, (b) respiratory tract reactivity comprising asthma, aggravated asthma, bronchospasm or dyspnoea, or (c) assorted skin disorders, including rashes of various types, pruritus, urticaria, purpura, angioedema and, less commonly, bullous dermatoses (including epidermal necrolysis and erythema multiforme).

62. 1. Suspected drug is: 2. What are the symptoms of adverse drug reaction? 3. Is this ADR serious? 4. If yes, why? 5. Is this reaction expected? 6. Drug-reaction causality assessment: certain probable possible unlikely not related 7. What advice you would give to the patient?

63. Case 2 74 year–old woman, asks you for advice because she is feeling sad and depressed since her husband died 6 months ago. You recommend her to take an OTC herbal antidepressant Proactive tablets (St. John's Worth) two times a day. Two months after she comes to your pharmacy to buy a 3rd box of Proactive . In a short conversation you find out that she is feeling better, but that three weeks ago a mild dizziness appeared. Patient is not especially worried about this symptom because she attributes it to her age. She didn’t contact her doctor yet. She is also taking acetylsalicylic acid tablets 100 mg.

64. Proactive Summary of the product characteristics : 4.8. Adverse drug reactions: very rare: nausea, rash, weakness or agitation

65. 1. Suspected drug is: 2. What are the symptoms of adverse drug reaction? 3. Is this ADR serious? 4. If yes, why? 5. Is this reaction expected? 6. Drug-reaction causality assessment: certain probable possible unlikely not related 7. What advice you would give to the patient?