2. Dr. Reneega Gangadhar Professor & Head Dept of Pharmacology Govt. T.D Medical college Alappuzha Pharmacovigilance

3. Focus of Presentation What is Pharmacovigilance and related terminologies? Why Pharmacovigilance? How to monitor and report ADR?

4. PHARMACOVIGILANCE Pharmacovigilance is the same as ‘ drug safety monitoring’/ ‘ADR monitoring’ Pharmakon-drug ; vigilare –to keep alert

5. PHARMACOVIGILANCE The science and activities relating to detection assessment understanding prevention of adverse effects or any other possible drug related problems (WHO, 2002)

6. Includes ADR monitoring of herbals traditional and complementary medicines blood products biologicals medical devices vaccines Pharmacovigilance

7. Need for Pharmacovigilance The thalidomide incidence in the 1960 resulted in major outcry http://www.fda.gov/oc/history/history

8. Need for Pharmacovigilance  Unreliability of pre-clinical studies – Tests in animals are insufficient to detect safety

9. Need for Pharmacovigilance  Limitations of pre-marketing phases of clinical trial Exposure limited to few individuals- rare, serious & unusual ADRs are not detected Exposure to drug is often short- delayed effects of drugs are not available

10. Need for Pharmacovigilance  Limitations of pre-marketing phases of clinical trial  Special groups not represented - pregnant women, children, elderly  Effects of concomitant diseases & multiple medications are not studied  Drug interactions are often not available

11. The Impact of ADRs on Public Health ADRs are the 4th – 6th largest cause for mortality in the USA JAMA, 1998, 279 (15) 1000-5 ADRs were responsible for around 6.5% of all acute hospital admissions and at least 5,000 deaths per year BMJ 2004;329;15-19 Some countries spend up to 15 – 20% of their hospital budget dealing with drug complications Pharmacoeconomics,1999, 15(5). 445-458 Direct cost of managing drug-related morbidity & mortality in ambulatory setting≈ USD$76.6 billion per year J Nurs Care Qual 2003; 18(3): 175-181

12. AETIOLOGY Of ADRs IN INDIA Genetic :50% slow acetylators 1-3% slow oxidizers Nutritional :40-70% iron deficient 50% malnourished Disease :typhoid, malaria Medication :10-57% self medication use of alternate systems Multiethnic population

13. ADVERSE DRUG REACTION It is any undesirable or unintended consequence of drug administration at doses normally used in man

14. ADVERSE DRUG REACTION Excludes: √ therapeutic failures √ overdose & drug abuse √ noncompliance √ medication errors

15. Different Types of ADRs Type of reaction MnemonicFeaturesExamples A: Dose relatedAugmentedCommon, Related to ph.Action, Predictable, Low mortality Digoxin toxicity,. TCA- anti- cholinergic B: Non-dose related BizarreUncommon, Not related to ph.Action, Unpredictable, High mortality Idiosyncratic reaction Hypersensitivity reactions C: Dose related and time related ChronicUncommonSteroid- suppress HPA axis D: Time relatedDelayedUncommon, Dose related, After the use Teratogenesis,Carcinogenesis, Tardive dyskinesia E: WithdrawalEnd of useUncommon, After withdrawalMI- β blocker withdrawal F: Failure of therapy FailureCommon, Dose related, Caused by drug interaction Rifampin with OCP - Contraceptive failure

16. Adverse Event (AE): is an adverse outcome that occurs while a patient is taking a drug, but not necessarily attributable to it

17. Adverse Event (AE) can be.. Undesirable physical signs and symptoms Abnormal laboratory values Changes in vital signs, or on an electrocardiogram An increase in the frequency or intensity (worsening) of a condition or illness Complications from a surgery or procedure

18. What is the difference between AE and ADR? AE event: does NOT imply Causality ADR: an adverse drug reaction is an adverse event with a causal link to a drug.

19. Serious Adverse Reactions Death Life-threatening (immediate risk of death from the reaction e.g. anaphylactic shock (not allergic reaction) Hospitalisation (initial or prolonged)

20. Serious Adverse Reactions Congenital anomaly or birth defect Required intervention to prevent permanent impairment or damage Disability /incapacity eg. amputation of leg

21. Serious Reaction vs Severe Reaction Serious based upon event outcome Severity describes the intensity of the event e.g. mild, moderate, severe eg. A severe headache may not be serious, but a mild stroke resulting in disability is serious.

22. Unexpected Adverse Drug Reaction ICH E6 1.60 The nature or severity of reaction is not consistent with product information or characteristics of the drug

23. Frequency of adverse drug reactions Very common >= 1/10 Common (frequent) > = 1/100 and < 1/10 Uncommon >= 1/1000 and < 1/100 (infrequent) Rare >= 1/10000 and < 1/1000 Very rare < 1/10000

24. Pattern of Drug Withdrawals Top 7 safety reasons were: Hepatic: 26.2% Haematological: 10.5% Cardiovascular: 8.7% Dermatological: 6.3% Carcinogenic Issues: 6.3% Renal: 4.8%

25. Drug Withdrawals 1997-2006 Troglitazone Fenfuramine Astemizole Cisapride Cerivastatin Rofecoxib Valdecoxib Ximelagatrin 1997 1998 2000 2001 2004 2005 2006

26. WHAT TO REPORT? All suspected drug related adverse events, including herbal, traditional or alternative remedies Insignificant or common adverse reactions All adverse events suspected to have been caused by new drugs and ‘Drugs of current interest’ All suspected drug interactions Serious adverse reactions

27. Who can report? Doctors Nurses Dentists Pharmacists

28. WHERE TO REPORT ? PvPI Headquarters, CDSCO link – vigiflow for data entry Dept of Pharmacology, TDMCA

30. How to Report?

31. A. Patient Information 1. Patient identifier/ initials_________ (In confidence). 2. Age at time of event:or Date of birth: 3. Sex: Male /Female 4. Weight_____ Kgs

32. 5. Date of reaction started (dd/mm/yy): 6. Date of recovery (dd/mm/yy): 7. Describe reaction or problem B. Suspected adverse reaction

33. C. Suspected medications 8. Name (brand and / or generic name) Manufacturer (If known) Batch No. (If known) Exp. Date (If known) Dose used Route used Frequency Therapy dates (if unknown, give duration) Date started Date stopped

34. 9. Reaction abated after drug stopped or dose reduced Yes No Unknown NA Reduced dose 1. 2. 3. 4.

35. 10.Reaction reappeared after reintroduction Yes No Unknown NA If reintroduced, dose 1. 2. 3. 4.

36. 11.Concomitant medical products and therapy dates including self medication and herbal remedies (exclude those used to treat reaction).

37. 12. Relevant tests/ laboratory data, (including dates)

38. 13.Other relevant history, including pre- existing medical conditions(e.g., allergies, race, pregnancy, smoking, alcohol use, hepatic/renal dysfunction, etc.)

39. Death (dd/mm/yy)____ Life threatening Hospitalization-initial or prolonged Disability Congenital anomaly Required intervention to prevent permanent impairment / damage Other (specify)____ 14. Seriousness of the reaction

40. Fatal Continuing Recovering Recovered Unknown Other (specify)____________ 15. Outcomes

41. 16. Name and Professional Address: _______________________________________ ___________________________________ Pin code: ______________ E-mail: _______ Cell No. / Tel. No. with STD Code________ Specialty: __________ Signature: 17. Occupation 18. Date of this report D. Reporter

42. You’re not certain the product caused adverse reaction You don’t have all the details although point nos. 1, 5,7, 8, 11, 15, 16 & 18 are essentially required. Report even if:

43. 1. Patient identifier/initials 5. Date of reaction started 7. Describe reaction or problem 8. Name of drug 11. Concomitant medication 15. Outcome 16. Name of reporter 18. Date of report Essential information for ADR report

44. Confidentiality The patient’s identity is held in strict confidence Submission of a report does not constitute an admission that medical personnel or manufacturer of the product caused or contributed to the reaction.

45. SAE Reporting - INDIA If investigator identifies an ADR Inform Sponsor (24h) Ethics committee (7 days) Regulators (i.e. DCGI) 14 calendar days

46. You can reduce the suffering and save thousands of patients lives by doing one thing : Report suspected adverse drug reactions / events Conclusions