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1. Pharmacovigilance Presented By, Mr.V.P.Patil Asst. Professor Institute of Pharmaceutical Education , Boradi 1

2. Contents Introduction Definitions History Aims Of Pharmacovigilance Need Of Pharmacovigilance Classification of Adverse drug reaction Methods & Softwares of Pharmacovigilance Reporting of ADR Centers Current Scenario Role of Pharmacist 2

3. Introduction 1,2 No drug is completely safe Drugs may contribute to 5 –10% of all hospital admissions 10 –20% of all inpatients may suffer a serious ADR in hospital ADRs 4 th to 6 th leading cause of deaths in USA ADRs may contribute 5 –10% of hospital costs. Therefore………… the monitoring of the adverse effects of drugs is an important component of good medical practice 3

4. Pharmacovigilance Pharmakon(Greek) Vigilare(Lation) Drug To keep awake or alert, to keep watch 4

5. Definitions 1-3 According to WHO… Pharmacovigilance is The science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem. Or Pharmacovigilance is the pharmacological science relating to the detection, assessment, understanding& prevention of adverse effects, particularly long term & short term side effects of medicine. 5

6. Or Pharmacovigilance is the science & activities relating to the detection, assessment ,understanding & prevention of adverse effects or any other possible drug related problems. 6

7. History 1,2 Year Event 1848 The Lancet starts collecting notifications of side effects after a death caused by anaesthesia 1906 US Federal Food and Drug Act requires that pharmaceuticals be “pure” and “free of any contamination” 1937 USA: 107 lethal cases after diethylenglycol was mistakenly used to solubilise sulphanilamide 1952 France: 100 lethal cases after diethyl tin diodide was mistakenly used in a skin preparation 1961 Thalidomide disaster 7

8. 1968 WHO pilot research project for international drug monitoring 1971 WHO meeting 1984 International society of pharmacoepidemiology 1992 European society of pharmacovigilance 2002 WHO pharmacovigilance 2004 National pharmacovigilance advisory committee (NHAC) with DGHS as chairman and drug controller general of India as member secretary Thalidomide disaster 8

9. Aims of Pharmacovigilance 2 To improve patient care and safety To improve public health and safety To contribute to the assessment of benefit, harm, effectiveness and risk of medicines To promote understanding, education and clinical training 9

10. WHY PV IS NEEDED 2,8 10

11. Registration of New Chemical Entities was very much dependant on the status of products in the reference countries Changes to product information was mainly industry driven Few pre-clinical studies conducted in the region and hardly any Phase IV studies Adverse drug reaction reporting was very minimal and mainly involved reports submitted by health care professionals 11

12. Most reports were for known reactions involving older drugs which were used in government-run hospitals Signal detection not possible as there were too few reports Only able to detect some quality defects of generics which manifested as ADRs Pharmacovigilance was mainly about getting ADR reports and submitting them to WHO No significant regulatory changes made based on these reports 12

13. Reason 1: Humanitarian concern – Insufficient evidence of safety from clinical trials Animal experiments Phase 1 – 3 studies prior to marketing authorization 13

14. Drug Development 14

15. Limitations of phase 1 -3 clinical trials Limited size: no more than 5000 and often as little as 500 volunteers Narrow population: age and sex specific Narrow indications: only the specific disease studied Short duration: often no longer than a few weeks 15

16. Examples of product recalls due to toxicity Year Medicine 1965 Thalidomide 1975 Practolol 1970 Clioquinol 1982 Benoxaprofen 1997 Terfenadine 2004 Rofecoxib 2007 Veralipride Examples of serious and unexpected adverse events leading to withdrawal of medicine Phocomelia Sclerosing peritonitis Sub acute nephropathy Nephrotoxicity, cholestatic jaundice Torsade de pointes Cardiovascular effects Anxiety, depression, movement disorders 16

17. Reason 2 Medicines are supposed to save lives Dying from a disease is sometimes unavoidable; dying from a medicine is unacceptable 17

18. UK: US: It has been suggested that ADRs may cause 5700 deaths per year in UK . ADRs were 4 th -6 th commonest cause of death in the US in 1994 18

19. Reason 3 ADRs are expensive !! 6.5% of admissions are due to ADRs Seven 800-bed hospitals are occupied by ADR patients Cost £446 million per annum 19

20. Reason 4: Promoting rational use of medicines and adherence Reason 5: Ensuring public confidence 20

21. Reason 6: Ethics: To know of something that is harmful to another person who does not know, and not telling, is unethical 21

22. TERMS: 3,6,7 Side effect: Any unintended effect of a pharmaceutical product occuring at doses normally used in man is related to the pharmacological properties of the drug. Adverse event: Any untoward medical occurrence that may present during treatment with a pharmaceutical product but which does not necessarily have a causal relationship with this treatment. Unexpected Adverse drug Reaction: An adverse reaction, the nature of which is not consistent with domestic labelling or market authorization or expected from characteristics of drug. 22

23. Serious Adverse Drug Reaction: A serious event or reaction is any toward medical occurrence that at any dose: Result in Death Requires inpatient hospitalization or prolongation of existing Hospitalization Results in persistent or significant disability Is life threatening. Drug Interaction: A drug interaction is a situation in which the effects of drug are altered by prior or concurrent administration of another drug. 23

24. Medication error: M edication errors are mishaps that occur during prescribing, transcribing, dispensing, administering, adherence, or monitoring a drug. Examples of medication errors include misreading or miswriting a prescription. 24

25. Signal Reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously. Usually more than a single report is required to generate a signal, depending upon the seriousness of the event and the quality of the information 25

26. Adverse drug reaction: According to WHO………. An Adverse Drug Reaction is obnoxious, unintended response to drugs, which occurs at doses normally used in man for prophylaxis, diagnosis or the therapy of diseases or altered physiological functions. According to FDA……… An Adverse Drug Reaction is any undesired experience associated with the use of drug, whether or not considered drug related, and includes any side effect, injury, toxicity or sensitivity reaction or significant failure of expected pharmacological action. 26

27. Classification: 6,7 Adverse drug reaction are mainly classified in to 2 types: 1.Type-A.( Augmented Adverse Drug Reactions) 2.Type-B.(Bizarre Adverse Drug Reactions ) Other types: Chronic effects Delayed effects End of treatment effects 27

28. TYPE- A TYPE-B Predictable Unpredictable Usually dose dependent Rarely dose dependent High Morbidity Low Morbidity Low Mortality High Mortality Response to dose reduction Response to drug withdrawal 28

29. Other types: Chronic effects : Adverse effects only occur during prolonged treatment and not with single doses. Delayed effect: Adverse effect that occur from remote treatment ,either in the children of treated patients or in patients themselves years after treatment . End of treatment effects: Adverse effects that occur when the treatment is stopped, especially when it stopped suddenly. 29

30. TYPES EXAMPLES Type-A Hypoglycemia due to insulin injection Hemorrhage due to anticoagulants. Type-B Anaphylaxis due to penicillin Bone marrow suppression by chloramphenicol Chronic effects Colonic dysfunction due to laxative Delayed effects Cancer in those treated with alkylating agents for Hodgkin's disease. End of treatment effects Seizure when anticonvulsants such as phenytoin is stopped 30

31. Who are the partners? Government Industry Hospitals and academia Medical and pharmaceutical associations Poisons information centers Health professionals Patients Consumers Media WHO 31

32. Methods of PV 4,11 There are 6 methods are used in pharmacovigilance …… Passive surveillance Stimulated Reporting Active surveillance Comparative observational studies Targeted clinical investigations Descriptive studies 32

33. Softwares Of Pharmacovigilance 12 This helps the patients, the doctors and the manufacturers in the medical world. PV Works : Records report safety data keeping track of adverse event reporting. Flexible data entry, risk management , safety system assessment, evaluation and submission of regulatory reports are some of its important features. PV Works (Vet) : Support veterinary pharmacovigilance business and technical processes meeting the necessary safety standards. Data entry, reporting, audit trail are some of its main features. 33

34. How effective is pharmacovigilance software? Pharmacovigilance software minimizes the risk of adverse events (ADR) by using genetic profiles. It makes accurate determinations as to whether a product is safe or not. It determines the benefit-risk ratio quickly. It overcomes the challenges that small firms face as far as limited financial and personnel resources are concerned. Pharmacovigilance software helps maintain regulatory compliance and improve operational efficiency. Global information can be easily shared by means of this software. 34

35. Reporting 5,9 35

36. WHAT TO REPORT? SERIOUS ADRS A serious adverse event (experience) or reaction is any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization of prolongation of existing hospitalization, is a congenital anomaly/birth defect. 36

37. Adverse Reactions: Possible Causes Intrinsic factors of the drug Pharmacological Idiosyncratic Carcinogenicity, Mutagenicity Teratogenicity Extrinsic factors Adulterants Contamination Underlying medical conditions Interactions Wrong usage 37

38. WHAT SHOULD BE REPORTED New drugs Report all suspected reactions including minor ones For established or well known drugs All serious, unexpected, unusual ADRs Change in frequency of a given reaction ADRs to generics not seen with innovator products ADRs to traditional medicines 38

39. All suspected drug-drug, drug-food, drug-food supplement interactions ADRs associated with drug withdrawals ADRs due to medication errors eg. vincristine given IT ADRs due to lack of efficacy or suspected pharmaceutical defects 39

40. Where to report? Patient Health Professional Regional Centre Manufacturer Hospital DTC National Centre 40

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42. Who can report:   Any health care professional (Doctors including Dentists, Nurses and Pharmacists).   Where to report:   After completing, please return this form to the same Pharmacovigilance centre from where you received. 42

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44. What to Report : You can report suspected side effects of any medicine or herbal remedy, whether it was prescribed by your doctor or bought without a prescription. You can report side effects that have happened: To you personally To your child How to report: Use the online yellow card at www.yellowcard.go.uk . Ask your Pharmacist for a yellow card. Call yellow card hotline on 0808 100 3352 44

45. After sending yellow card report MHRA( Medicine & Health care products Regulatory Agency) will acknowledge each card it receives. All reports are entered on to database, then staff analyze to look the relationship between medicine & side effects. 45

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47. OUTCOME OF PV DHCP Letter (Direct health care professional communication)– product holders Product Alerts – National Health Authorities Media statements - National Health Authorities/Pharmacovigilance Centres Newsletters – National Pharmacovigilance Centres and WHO Feedback to reporters – National Pharmacovigilance Centres 47

48. Centers 8,11 48

49. WHO PROGRAMME FOR INTERNATIONAL DRUG MONITORING Started 1968 Located in Uppsala, Sweden Collaborating centre for maintaining global ADR database - Vigibase 49

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51. Roles of WHO Collaborating Centre Identify early warning signals of serious adverse reactions to medicines Evaluate the hazard Undertake research into the mechanisms of action to aid the development of safer and more effective medicines 51

52. ANALYSIS OF REPORTING RATE (n=3068) 10 38 40 150 216 263 233 400 530 603 875 792 787 1000 1063 1665 2363 2543 3068 500 1000 1500 2000 2500 3000 3500 1987 1988 1989 1991 1992 1993 1994 1995 1996 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 Year No. of Reports 52

53. TEN DRUGS WITH THE MOST REPORTED ADRs NO 2002 2003 2004 2005 2006 2007 1 CO – TRIMOXAZOLE (47) ALLOPURINOL (33) ALLOPURINOL (37) CAPTOPRIL (52) TRADITIONAL MEDICINE (68) PERINDOPRIL (97) 2 CARBAMAZEPINE (32) CLOXACILLIN (30) PARACETAMOL (29) ALLOPURINOL (51) DICLOFENAC (65) ALLOPURINOL (75) 3 CLOXACILLIN (31) MEFENAMIC ACID (25) CARBAMAZEPINE (29) CLOXACILLIN (50) CARBAMAZEPINE (62) CLOXACILLIN (71) 4 AMOXYCILLIN (28) DICLOFENAC (24) NIFEDIPINE (28) DICLOFENAC (44) NIFEDIPINE (58) DICLOFENAC (71) 5 ALLOPURINOL (22) CHLOROTHIAZIDE (22) CO – TRIMOXAZOLE (28) NIFEDIPINE (44) ALLOPURINOL (57) METFORMIN (69) 6 TRADITIONAL MEDICINE (22) CARBAMAZEPINE (19) ERYTHROMYCIN (23) METFORMIN (39) PERINDOPRIL (57) ASPIRIN (67) 7 ALENDRONATE (19) TRADITIONAL MEDICINE (18) AMOXYCILLIN (23) PARACETAMOL (38) CO – TRIMOXAZOLE (55) TICLOPIDINE (50) 8 DICLOFENAC (19) AMOXYCILLIN (18) MEFENAMIC ACID (21) CO – TRIMOXAZOLE (37) ASPIRIN (41) RIFAMPICIN (46) 9 ISOSORBIDE DINITRATE (18) PENICILLIN G SODIUM (15) ASPIRIN (19) ATENOLOL (37) ERYTHROMYCIN (40) PHENYTOIN (44) 10 LOVASTATIN (13) VANCOMYCIN (15) CLOXACILLIN (18) CEFUROXIME (36) PHENYTOIN (39) AMOXYCILLIN (43) 53

54. National Pharmacovigilance Centre CDSCO( Central Drug Standard Control Organization) has initiated a well structured national Pharmacovigilance Programme. It was officially inaugurated by the Honorable Health Minister Dr. Anbumani Ramdas on 23 nov,2004 at new delhi. Composition: Under Programme…… 24 peripheral centre 5 Regional centre 2 Zonal centre 54

55. NPC at CDSCO It shall…… Monitor the ADR of Medicines in order to identify previously unexpected ADR. Review periodic safety update reports submitted by pharmaceutical companies. Maintain Contacts with international regulatory bodies working in pharmacovigilance . Assess the regulatory information relating to safety. Provide information to end users through ADR news, bulletins, drug alerts & seminars. 55

56. CURRENT SCENARIO Increased awareness and interest amongst doctors and pharmacists to report ADRS as they have seen some benefit in reporting Increasing number of clinical trials being conducted especially in Singapore, Thailand and Malaysia GCP training for investigators served to increase awareness of SAE and ADR reporting amongst health care professionals and the industry 56

57. More hospitals and companies using on-line reporting system – less hassle than submitting hard copy reports Increasing involvement by hospital pharmacists in pharmacovigilance – during clinical ward rounds and when counseling patients 57

58. SO….WHAT IS OUR ROLE? SEND NOT ONLY QUANTITY BUT…. QUALITY REPORTS 58

59. Monitor clinical status of patients Identify the correct ADRs not side effects Get more information Investigate at hospital level Help doctors to fill-up the forms Keep patient’s record if more information needed 59

60. References Ron Mann & Elizabeth Andrews, Text book of Pharmacovigilance, John Wiley & sons., Ltd.,2002,pg.no: 4 to 9 www.pharmacovigilance.co.in www.who-ac.in www.sciencedirect.com Dr. H.P.Tipnis & Bajaj, Text book of Clinical Pharmacy, 1 st ed.,july-2003.,p.no:299-311 Pratibha Nand & R.K.Khar , Hospital & Clinical Pharmacy.,1 st (reprint)ed.,2004-05.,p.no:160-168 www.niehs.nih.gov 60

61. 8) www.CDSCO.nic.in 9) www.yellowcard.gov.uk 10) www.tga.gov.com 11) www.pharmainfo.net 12) www.genengnews.com 13) www.articlebase.com 61

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