Pharmaco vigilance for BAMS according to NCISM
- 1. PHARMACOVIGILANCE AND PHARMACOVIGILANCE OF AYURVEDIC DRUGS
- 2. Pharmacovigilance Greek: Pharmakon – drug; and Latin : Vigilare- to be awake or alert, to keep watch.
- 3. Pharmacovigilance Definition “Pharmacovigilance” is the science and activities relating to detection, assessment, understanding and prevention of adverse effects of drugs or any other possible drug related problems.
- 4. History of Pharmacovigilance 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 solubilize sulphanilamides 1952 France: 100 lethal cases after diethylin diodide was mistakenly used in a skin preparation History of Pharmacovigilance
- 5. • 1959 - 61 Reports of foetal abnormalities in relation with the use of a new sleep inducing drug thalidomide (biggest number in Germany) History of Pharmacovigilance • 1959 - 61 Reports of foetal abnormalities in relation with the use of a new sleep inducing drug thalidomide (biggest number in Germany)
- 6. Lesson from the Thalidomide catastrophe •Not all, drugs good in animals are good for humans (thalidomide was safe in pregnant rats …) •Even very dangerous drugs can be valuable if safety measures could be followed (thalidomide is effective in treatment of leprosy type II reactions, erythema nodosum leprosum)
- 7. History of Pharmacovigilance •1962 USA revised law requiring to prove safety and efficacy before issuing marketing authorisation. •1964 UK starts “yellow cards” system. •1967 WHO’s International Drug Monitoring Programme.
- 8. Introduction: The world wide consumption of drugs as well as herbal medicines is enormous So that selecting the adverse drug reactions is becoming important in view of Safety. Hence pharmacovigilance system is becoming increasingly importance Given because of growing use of herbal products and herbal medicines. Since ages Ayurveda , siddha and unani systems are being practised in India.Now in this era of globalization certain concerns are raised with regular to their Safety. Ayurveda has catagorised toxic plants separately and for their use special Processing is essential .There is wide spread misconception that all drugs of “natural” origin are “safe” there is also a common belief that long term use of a medicine based on tradition assures both safety and efficacy. so lets know about pharmacovigilance for the better Assessment of drug use and safety.
- 9. Why Pharmacovigilance ? Adverse Drug reactions are among the top ten causes of drug mortality. Lazarou j et al., 1998 Hospitalization attributed to ADRs account for 2.4 & 6.4 % of all hospital admission in the western world. Hooft et al., 2008 Drug related morbidity and mortality expenses exceeded US$ 177.4 billion in USA in 2000 Ernst & Grizzle, 2001
- 10. Contd….. • The information collected during the pre-marketing phase of a drug is inevitably incomplete with regard to possible adverse reactions. • Tests in animals are insufficiently predictive of human safety . – At the time of approval, clinical trial data are available on limited numbers of patients treated for relatively short periods, the conditions of use differ from those in clinical practice and the duration of trials is limited .
- 11. Contd… – Information about • Rare but serious adverse reactions, – Chronic toxicity, – Use in special groups (children, the elderly or pregnant women) – Drug interactions is often incomplete or not available. • Once a product is marketed, large numbers of patients may be exposed to, including: – Patients with co-morbid illnesses, – Patients using concomitant medications, – Patients with chronic exposure.
- 12. AIMS OF PHARMACOVIGILANCE The rational and safe use of drugs The assessment and communication of the risks and benefits of drugs in the market Educating and updating knowledge of patients.
- 13. Aims Of Pharmacovigilance • Early detection of hitherto unknown adverse reactions and interactions • Detection of increase in frequency of known adverse reactions • Identification of risk factors and possible mechanisms underlying adverse reactions • Estimation of quantitative aspects of benefit / risk analysis and dissemination of information needed to improve prescription and regulation of drugs.
- 14. Terms • Adverse Event (AE) – any untoward medical occurrence that may present during treatment with a pharmaceutical product but which does not necessarily have a casual relationship with this treatment • Adverse Drug Reaction (ADR) – a response to a drug which is noxious and unintended, and which occurs at doses normally used in man. • Serious Adverse Event (SAE) – AE that is either life- threatening, fatal, cause of prolong hospital admission, cause persistent disability or concern misuse or dependence
- 15. Contd… • Serious Adverse Drug Reaction (SADR) – ADR where SAE conditions of severity applies • Unexpected Adverse Drug Reaction (UADR) – an adverse reaction, the nature or severity of which is not consistent with market authorization, or expected from the characteristics of the drug.
- 16. Contd….. • Signal – reported information on a possible relationship between an adverse event and a drug, 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
- 17. Expected and Unexpected Events • Expected are those adverse events that were observed during clinical trials or post-approval observations and are mentioned in Summary of Product Characteristics (SPC) • An adverse reaction,the nature or severity of which is not consistent with domestic labelling or market authorization,or expected from characteristics of the drug.
- 18. Types of Adverse Reactions (Rawlins and Thompson Classification) • Type A Effects (“Augmented”) • Due to pharmacological effects • A dose related – may often be avoided by using doses which are appropriate to the individual patient • A common, can be experimentally reproduced, known before marketing • Example: hypnotic effect after H2 antihistaminics
- 19. Types of Adverse Reactions (Rawlins and Thompson Classification) • Type B Effects (“Bizzard”, idiosyncratic reactions) • Generally rare and unpredictable • Little or no dose relationship, not related to drug pharmacodynamics • Occur in predisposed, intolerant patients – can be explained by rare genetic polymorphism, allergic reactions • Example: Penicilline allergies
- 20. Types of Adverse Reactions (Rawlins and Thompson Classification) Type C Effects (“Continuous”) • Adverse reactions after long term therapy • There is often no suggestive time relationship and the connection may be very difficult to prove. The use of a drug increases the frequency of “spontaneous” disease • Example: carcinogenesis
- 21. Types of Adverse Reactions (Rawlins and Thompson Classification) Type D Effects (“Delayed”) • Adverse effect may be presented years after a drug was used • Example: Vagina cancer of daughters when their mother was treated by diethylstilbestrol Type E Effects (“Ending”) • Absence of drug after withdrawal – rebound effect • Example: corticosteroids in asthma treatment
- 22. Classification of Adverse Events based on its severity • Mild – no changes in therapy are needed • Moderate – change of therapy is desired but the events are not life-threatening or causing disability • Serious – is either life-threatening, fatal, cause of prolong hospital admission, cause persistent disability
- 23. Classification of Adverse Events Adverse events can be roughly classified on base of its underlying mechanism, although this classification is not unambiguous and there are disputable cases to which category an event can be attributed • Intolerance – lower then usual dose produce anticipated response • Idiosyncratic (“unusual”) response – determined by genetic alteration, producing response that is not anticipated • Allergy – response modulated by immune system • Pseudoallergy – reaction similar to allergy but not mediated by immune system
- 24. What to Report – WHO recommendations • Every single problem related to the use of a drug, because probably nobody else is collecting such information • All suspected adverse reactions • ADRs associated with radiology contrast media, vaccines, diagnostics, drugs used in traditional medicine, herbal remedies, cosmetics, medical devices and equipment • Lack of efficacy and suspected pharmaceutical defects • Counterfeit pharmaceuticals • Development of resistance
- 25. Contd… All adverse reactions suspected to have been caused by ASU drugs alone or along with any other drugs. All suspected drug interactions. Reactions to any other drugs which are suspected of significantly affecting a patient's management, including reactions suspected of causing. • Death • Life – threatening (real risk of dying) • Hospitalisation (initial or prolonged) • Disability (significant, persistent or permanent) • Congenital anomaly • Required intervention to prevent permanent impairment or damage
- 26. Who Should Report Safety Data • Physicians • Pharmacists • Pharmaceutical companies qualified persons – (Pharmacovigilence/Regulatory manager) • Investigational products (clinical trials) – Post-approval reporting – Individual Case Safety Report (ICSR), Periodic Safety Update Report (PSUR) • In many countries patients are encouraged (but not obligated) to report side effects
- 27. WHAT HAPPENS TO THE INFORMATION SUBMITTED ? • The information in the form shall be handled in confidentiality. Peripheral Pharmacovigilance Centres shall forward the form to the respective Regional Pharmacovigilance Centres who will carry out the causality analysis. This information shall be forwarded to the National Pharmacovigilance Resource Centre. The data will be statistically analysed and forwarded to the Dept. of AYUSH, Govt. of India
- 28. Information Flow Peripheral Centre (Collection) Regional Centre (Causality Analysis) Zonal Centre (Statistical Analysis) National Centre (Advisory Committee on review of data may suggest regulatory intervention) WHO Uppsala Monitoring Centre
- 29. Reporting Form • The patient: age, sex and brief medical history. • Adverse event: description, results of investigations and tests, start date, course and outcome • Suspected Drugs: name, dose, route, start/stop dates, indication for use, batch number
- 30. Reporting Form • All other drugs (including self medication): names, dose, routes, start/stop dates. • Risk factors: impaired renal function, previous exposure to suspected drug, previous allergies. Social drug use. • Name and address of reporter
- 31. Withdrawn Drugs (in the US, since 2000) Drug Year Reason Lumiracoxib 2008 Hepatotoxicity Aprotinin 2008 Kidney and cardiovascular toxicity Tegaserod 2007 Cardiovascular ischemic events Ximelagatran 2006 Hepatotoxicity Valdecoxib 2005 Dermatology adverse events Pemoline 2005 Hepatotoxicity Rofecoxib 2004 Thrombotic cardiovascular events Levomethadyl 2003 Fatal Arrhytmia Rapacuronium 2001 Risk of fatal bronchospasm Cerivastatin 2001 Rhabdomyolosis Trovafloxacin 2001 Hepatotoxicity Amineptine 2000 Hepatotoxicity, dermatological side effects, abuse potential Cisapride 2000 Cardiac arrhythmias Troglitazone 2000 Hepatotoxicity • Other drugs were restricted in use to exclude some patient populations or indications - Alosetron • Some drugs were withdrawned and reintroduced after further studies or special safety measures – Natalizumab withdrawn in 2005 and reintroduced in 2006
- 32. Importance of pharmacovigilance • Complete safety data (especially for unexpected and serious adverse events) can only be captured through pharmacovigilance • It cannot be captured through clinical trials which are conducted in an “artificial environment.” – In clinical trials • patients are not taking any other medications • do not have concomitant diseases • are taking the drug short-term (during the duration of the trials only) and • are not part of vulnerable groups (e.g., children, pregnant women, elderly, etc.)
- 33. Importance of pharmacovigilance Cannot extrapolate data from developed countries: • Type of drug use is different – Do not use the co-formulated ARVs – Minimally use anti-TB, anti-malarial and anti-diarrhoeal drugs • Patient genotype, phenotype, social and economic conditions are markedly distinct – Large number of malnourished patients – Patients with concomitant diseases – High rates of illiteracy and poverty, increases likelihood of inappropriate use by pregnant women, breast feeding mothers, young children, elderly – Large number of patients using herbal and other traditional medicines
- 34. Importance of pharmacovigilance We are accelerating the use of new drugs in new environments, which are mostly devoid of pharmacovigilance activities • Faster scale up of public health programs due to availability of new funding from major donors such as the Global Fund, World Bank, PEPFAR, PMI, etc • New drugs are reaching developing countries in greater numbers and more quickly because of new funding from several donors, including the Bill and Melinda Gates Foundation
- 36. What is Pharmacovigilance ? All drugs are dangerous, some may also be use full. N Moore, BMJ,2005,330, 539-40 C. S., Su.- 1:124
- 44. Objective of Ayurveda Preservation, Promotion & Maintenance of Health. Treatment of Diseases. It specifies that, Ayurveda deals with the Health Promotive, Preventive, & Curative aspects of life in a most comprehensive way.
- 45. To Fulfill These Objectives: Ancient seers tried innumerable laudable measures • Ayurveda uses drugs of different sources; Herbal, Animal, Mineral / Metal, Marine etc. after a certain modifications • The long history of their usage for different therapeutic purposes is the ultimate proof for their Safe, Efficacious, Non – Toxic & beneficial effects.
- 46. Mile Stones for the National Pharmacovigilance Programme for ASU Drugs: The e-version of the ADR reporting format “AVTAR”, Coimbatore, will be available on the official websites of AYUSH, IPGT & RA & all other National Institutes of AYUSH.
- 47. Tuberous root of Pueraria tuberosa DC Tuberous root of Ipomea digitata Linn. Development of gynacomastasia with deep pigmentation of areola in a patient treated with Pruraria tuberosa DC Adverse effects Gynecomastia (66.7% in GR.I and 16.7% in GRIII patients) erectile difficulties and loss of desire in 100% patients were reported Acharya RN,(2004) Clinico-Pharmacognostical Standardization of Vidari, Souvenir, International seminar on Plant based medicines,25-27 , Oct., 2004, Org. by National Institute of Ayurveda, Jaipur, India.
- 48. VIDARI • Development of gynecomastia can be either due to high estrogen levels, in hepatotoxic conditions, renal failure etc (Harold, 1980). • Here in the present series LFT value indicates the non hepatotoxic effect and at some time high estrogenic effect , which is also confirmatory with earlier reports. (Shukla S, 1993)
- 49. Drug Interactions of Guggul With Hypolipidemic drugs: Potentiates • Cholesterol - and triglyceride-lowering effects • Lowers the dose or eliminates need • Reduces likelihood of side-effects. *Satyavati GV, et al. Experimental studies on the hypocholesterolemic effect of commiphora mukul. Indian J Med Res 1969;57(10):1950-62. *Nityanand S, et al. Clinical trials with gugulipid. A new hypolipidaemic agent. J Assoc Physicians India 1989;37(5):323-8. *Satyavati GV, et al. Guggulipid: a promising hypolipidemic agent from gum guggul (commiphora wightii). Econ Med Plant Res 1991;5:48-82.
- 50. Guggul + Anticoagulant Drugs: Aspirin; warfarin; coumadin; or plavix Potentiates The effects of Prothrombin time.
- 51. GUGGULU With Thyroid medications: Stimulates the thyroid gland May alter the dosing requirement of thyroid medications *Tripathi YB, et al. Thyroid stimulatory action of (Z)- guggulsterone: mechanism of action. Planta Med 1988;54(4):271-7. *Panda S, Kar A. Guggulu (commiphora mukul) induces triiodothyronine production: possible involvement of lipid peroxidation. Life Sci 1999;65(12):PL137-41.
- 52. Reduction: Gum Guggul may reduces absorption of PROPANOLOL Calcium channel blockers (e.g. diltiazem) if taken concurrently. *Dalvi SS, et al. Effects of gugulipid on bioavailability of diltiazem and propranolol. J Assoc Physicians India 1994;42(6):454-5.
- 53. Pharmacovigilance Centre at Annamalai University
- 54. Centers For ADR Monitoring 1-AIIMS, New Delhi. 2-WHO special center at Mumbai (KEM). 3-JLN Hospital, Aligarh Muslim University, Aligarh. These centers were to report ADRs to the Drug Regulatory Authority of India.
- 55. NATIONAL PHARMACOVIGILANCE PROGRAMME OF INDIA • Drugs Controller General of India (DCG - I) & Central Drugs Standard Control Organization (CDSCO) initiative in 2005 • National Pharmacovigilance Advisory Board • National Pharmacovigilance Centre, CDSCO • Zonal, Regional & Peripheral Pharmacovigilance Centers across different parts of the country
- 56. Considering the significance of the problem, IPGT & RA, Jamnagar, Gujarat, took active initiation. 1st Workshop during December 2007 at IPGT & RA, Gujarat Ayurved University, Jamnagar under the sponsorship of WHO Country Office, India In the closing Ceremony- Shri S.K. Chaddha Ex. Director, AYUSH, Announced IPGT & RA as a National PV Centre PHARMACOVIGILANCE PROGRAMME FOR ‘ASU’ DRUGS
- 57. Consultative Committee Meeting at AYUSH, New Delhi, 29th & 30th of August 08 under the sponsorship of WHO, India Office PROTOCOL HAS BEEN FINALIZED
- 58. LAUNCHING OF THE PROGRAMME at New Delhi, 29th September 08
- 59. Finally, Dept. of AYUSH declared Institute For Post Graduate Teaching & Research in Ayurveda, Jamnagar (I.P.G.T.&R.A.) As A National Pharmacovigilance Resource Centre (NPRC) For ‘ASU’ Drugs.
- 60. DURING THE FIRST PHASE • Eight : RPCs (Regional Pharmacovigilance Centre) & • Thirty: PPCs (Peripheral Pharmacovigilance Centre) Which are the nodal agencies for implementing this programme.
- 61. • Administrative heads of National Institutes • Regulatory authorities • Technical persons shall have responsibility of monitoring and regulating administrative and financial aspects related to the programme. National Pharmacovigilance Consultative Committee
- 62. DISCUSSION Ayurvedic drugs are safe due to their natural origin is a popular conception , but it is true to an extent that many are used as food and deserves the classification. Generally recognized as safe GRAS. References in ayurvedic classics is possible adverse reactions to certain ayurvedic medicines alert us accepting this concept as universal, however. This is particularly true if medicines are not prepared properly, or preconditions for their administration are not respected by both doctor and patient which will increase the possibility of an ADR occuring. Charaka Sutra Sthana 26 warns that substances contrary to deha dhatus will be antagonistic (virodha) towards them. Such antagonism may from properties, combination, processing,place, time , dose,etc or natural compositions.
- 63. In Ayurveda diet is as important as medicine. The texts states that an ailment can be cured by following proper diet. In this context Charaka lists dietary incompatibilities between particular food stuffs. o Fish and milk o Honey and ghee in equal quanties. o Hot water after taking bhallataka. o Kampillaka cooked with buttermilk.
- 64. CONCLUSION: On the basis of the above, we conclude that there is a need for a post marketing surveillance program to observe quality, safety and efficacy of ayurvedic drugs , which is now available in the form of National Pharmacovigilence programme for ASU drugs. The success of pharmacovigilence lies in its ability to prevent the adverse reactions on the basis of information received. This will be possible only when the physicians are vitally allert ot the onset or offset of any ADRs. They need to prioritize their contributions to make the pharmacovigilence program for ayurvedic medicines a success.
- 65. You can reduce the suffering and save thousands of patient’s lives by doing one thing: Report suspected adverse drug reactions.