Rajiv Gandhi University of Health Sciences Bangalore, Karnataka.

ANNEXURE-II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

JOHN PRESHANTH KUMAR.P 01 Name of candidate and address S/O PATHI RAJ. M (in block letters) 39/2 kaveri nagar, beml nagar post. Kolar gold feilds..563115

02 Name of institution Al-Ameen College of Pharmacy, Hosur Road, Bangalore- 560027

03 Course of study and subject M. Pharm Pharmacy Practice

04 Date of admission to course 6/06/2007

05 Title of the Topic:

“ To monitor adverse drug reactions under National Pharmacolovigilance programme, Ministry of Family welfare, Govt of India at select hospitals in Bangalore.” 06 BRIEF RESUME OF THE INTENDED WORK 6.1 Need for the study:

Indian scenario: Monitoring of adverse drug reactions started in India about two decades ago (1982). Under the chairmanship of the Drug Controller of India, five centres were established with the idea of starting a monitoring programme nationwide. It consisted of three phases: the first one being monitoring of reactions in the institutes, second one in governmental bodies like CGHS, and the third phase proposed to include general practitioners. A multi-institutional pilot study involving 58,194 cases was done in 1987 under the aegis of Indian Council of Medical Research. Its nodal centre (National Pharmacovigilance Centre) is located in the Department of Pharmacology, All India Institute of Medical Sciences, New Delhi. It is affiliated to WHO collaborating Centre for ADR Monitoring, Uppsala, Sweden. The others are located in PGI (Chandigarh), JIPMER (Pondicherry), KGMC (Lucknow), and Seth GS Medical College (Mumbai) – special centre. It was envisaged to be a collaborative activity of both clinicians and pharmacologists; now in India, the pharmacologists with or without the involvement of clinicians usually do it. Physicians, however, continue to play a meaningful role in the entire monitoring process, as the co-operation of the clinicians is needed to have an access to the patient data and at times in interpretation of the reports of suspected adverse drug reactions. In many other countries, the pharmacists or nurses usually carry it out under supervision 2.3. They are specially recruited for this purpose; physicians and pharmacologists are involved in the interpretation of the collected data or hypothesis testing on the basis of the reports. These workers may involve a panel of the physicians in reviewing all the collected reports. Though the pattern of adverse reactions differs slightly from country to country, adverse reactions to analgesics (mainly, non- steroidal anti-inflammatory drugs) and antibiotics constitute about half of all such reports in India 1. This may be partly due to the fact that these are the most commonly used drugs in therapeutics. ADR monitoring features outside India. A number of studies conducted throughout the world have demonstrated that ADR’s significantly decrease the quality of life,increase hospitalization, prolong hospital stay and increase mortality. A landmark study by Lazarou in 1998 described ADRs to be 4th- 6th largest cause of death in the USA & ADRs are estimated to cause 3-7% of all hospital admissions14 . More than half of the ADR’s are not recognized by the physicians on admission & ADRs may be responsible for death of 15 of 1000 patient’s admitted15. Also the financial cost of ADRs to the healthcare system is also huge. With more new new medicines being approved for marketing more quickly with long-term safety studies by the regulatory authorities & switching of prescription only medicines(POM) to over-the-counter(OTC) to be used more widely by patients for self-medication, the general public is at risk of exposing itself to ADRs. ADRs reported by health professional occur on a voluntary basis. The Joint Commission on Accreditation of Healthcare Organizations (JCAHO) requires hospitals to have written procedures for ADR reporting, evaluating, and monitoring. Typically, the hospital’s pharmacy and therapeutics (P and T) committee reviews monthly summaries of ADRs . The reporting of ADRs occurring in other settings is still unclear. This is the case with ambulatory or community settings. However, the impetus is to devise means in which to capture ADRs in non-traditional arenas.

ADR definitions:  WHO's Definition for ADR: “a response to a medicine which is noxious and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease, or for the modification of physiological function”.  What is important in this definition is that a patient experiences an unwanted and/or harmful (noxious) reaction following drug therapy. Individual factors may play an important role but the key point is that the phenomenon experienced is noxious. An ADR is essentially a “bad” reaction suffered by the patient and differs from “side effect” which is essentially an unexpected therapeutic response – which is related to the pharmacological properties of the drug and may be “good” or “bad”.  FDA defines an adverse drug reaction as "an appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the product." Such reactions are currently reported by use of WHO's Adverse Reaction Terminology, which will eventually become a subset of the International Classification of Diseases.

Classifications of ADRs:

Type of reaction Mnemonics Features

Related to pharmacology (toxic effect or side A: dose related Augmented effect--for example, digoxin toxicity) Unrelated to pharmacology (idiosyncratic for B: non-dose Bizarre example, malignant hyperthermia, or related immunological--for example, penicillin rash) Related to cumulative drug use--for or C: dose and time Continuous or chronic chronic example, NSAID induced renal related failure Apparent only some time after use of drug-- D: delayed effect Delayed for example, thalidomide in first trimester and phocomelia limb defects Apparent only some time after use of drug-- E: Withdrawal Delayed for example, thalidomide in first trimester and phocomelia limb defects Results from the ineffective treatment

(previously excluded from analysis F: Failure of Failure according therapy to WHO definition)

e.g: accelerated hypertension because of inefficient control

Edwards IR, Aronson JK. Adverse drug reactions: definitions, diagnosis and management. Lancet 2000; 356:1255-9.

Based on severity

Severity Description

No antidote or treatment is required; hospitalization is Mild not prolonged

A change in treatment (e.g., modified dosage, addition of a drug), but not necessarily Moderate discontinuation of the drug, is required; hospitalization may be prolonged, or specific treatment may be required

An ADR is potentially life threatening and requires Severe discontinuation of the drug and specific treatment of the ADR An ADR directly or indirectly contributes to a Lethal patient's death

Common Terminology for Adverse Events (CTCAE)

National Cancer Institute,

Grading adverse events

By this grading scale, all adverse events are classified as follows:

0=No adverse event or within normal limits 1=Mild adverse event 2=Moderate adverse event

3=Severe and undesirable adverse event 4=Life-threatening or disabling adverse event

5=Death related to adverse event

Monitoring of adverse drug reactions is an ongoing, ceaseless, and continuing process. Though pharmacovigilance is still in its infancy in India, this is likely to expand in the times to come. This is because, as the newer and newer drugs hit the market, the need for pharmacovigilance grows more than ever before. Therefore, monitoring of the adverse effects of newer drugs particularly of serious nature is mandatory. Physicians should report death due to drugs, lifethreatening complications, hospitalisation (initial orprolonged), disability if significant, persistent, or permanent, congenital anomalies, a reaction which requires medical intervention to prevent damage, such as the administration of N- acetylcysteine following acetaminophen overdose. It is important to remember that most adverse drug reactions would subside once the offending agent is discontinued or dosage reduced; however, many result in permanent damage. The need is to spread awareness about using minimal doses of the drugs, at least in the beginning of the treatment. Who can report? How to report? Whom to report to? These are among the most frequently asked questions by a novice in pharmacovigilance. Health professionals working in the field of delivering the health care (both conventional and unconventional) like physicians,dentists, nurses, pharmacists, can report suspected adverse drug reactions by letter, phone, fax, e-mail, or by personal contact to any of the five adverse drug reaction monitoring centres located across the country. In India, the clinicians working in the tertiary care hospitals usually do the spontaneous monitoring. A recent study from a large tertiary care hospital from north India showed that in most instances, such reports are sent by the nonfaculty postgraduate students (junior doctors)1.There are many problems associated with this kind of monitoring. The most important among them being under-reporting or biased reporting. For that matter, all the suspected ADRs should be reported and lack of the evidence of proof or certainty of causality should not be the reason for not reporting. This is because the reports sent by the clinicians are evaluated in a wider perspective, i.e., with the causality assessment criteria and the detailed assessment is done, with the help of all the available pharmacoepidemiological tools14,15. What can be done to decrease ADRs? The simplest way to prevent most adverse drug reactions is to use the minimum dosages of drugs17. The simple principle of ‘start low and go slow’ should be followed. Dosages should be individualised to the patients and drugs should be tailored to patient’s need and not the vice versa. Health professionals should periodically be educated about adverse reactions and should be encouraged to report the same. Students should be taught principles of drug safety and rational drug use in their undergraduate and postgraduate curriculum. History of drug allergy should be elicited, and renal and hepatic status of the patient should be known before drug use. This is because failure to adjust drug dosages results in adverse drug reactions in cases with renal/hepatic impairment18.

6.2 REVIEW OF LITERATURE A retrospective study was carried out to evaluate the frequency, severity and preventability of Adverse drug reactions (ADRs) in pediatric patients during a six-year period. Data on patient demographic, documented allergies, suspected drugs, American Health Formulary Service drug classification and dosage regimen were collected and categorized by severity, preventability and casuality. The study showed that ADRs resulted in treatment intervention or temporary patient discomfort in >50% of patients. Opoids, Anticonvulsants and Antibiotics were the most common drug classes associated with ADRs and thus strategies targeting these drug classes and intervention during the medication ordering and administration processes may reduce the number of ADRs and possibly the associated costs.1 The impact of ADRs on health care costs were studied and showed that these costs are essentially hospital costs, in particular arising from an increase in length of stay caused by an ADR.It is therefore necessary to implement preventive programmes with different strategies consisting of educational programmes, identifying risks groups, implementing good drug practice and clinical and laboratory monitoring for ADRs.Promoting pharmacoeconomic studies and co- operation between clinicians, medical pharmacologists and pharmacists remains the key factor for preventing ADRs and decreasing their costs.2 A pilot study was carried out to assess the feasibility of, establish the methodology for, conducting a large prospective study to assess the impact of Adverse drug reactions on In-Patients and the National Health Service (NHS). Results showed that almost one-fifth of patients suffered an ADR as an impact and almost two-third of reactions were potentially avoidable and interventions were required in all ADRs, and reactions indirectly contributed to the death of two patients. Methodology tested using this pilot will enable the design of a larger study, which will allow the ADR burden and vulnerability patient groups, to be more accurately characterized.3 A Postal Questionnaire Survey of ADR reporting by hospital pharmacists to the Committee on Safety of Medicines was studied, objectives included how ADR reporting by hospital pharmacists is managed, the education of pharmacy personnel on ADR reporting, the number of ADR reports send to the Committee and also the barriers to reporting. Results concluded that the role played by the pharmacy department in the area of Hospital Pharmacist ADR reporting varied considerably but in most cases was insufficiently developed.4 A Pharmacovigilance study done to monitor ADRs associated with Antihypertensive drugs was conducted in medicine outpatient department by way of one- to -one patient interview by the pharmacist based on a questionnaire (ADR monitoring form) drafted according to World Health Organization (WHO) ADR monitoring guidelines. Calcium Channel Blockers was the prescribed drug category associated with maximum ADRs, followed by Beta-blockers, Angiotensin Converting Enzyme Inhibitor and Diuretics.5 A Prospective, observational study was carried out in the Dermatology outpatient department of a hospital for a period of one year to assess Adverse Cutaneous Drug Reactions (ACDR). The study revealed that the incidence of drug induced adverse skin reactions was 2.6% and urticaria and fixed drug reactions were the most common morphological reaction types. Despite the limitations of spontaneous reporting of ADRs, it can still be considered as an effective tool in Pharmacovigilence.Only if clinicians recognize and foster a culture for reporting such reactions to regulatory authorities drug safety measures can be taken.6

A study was conducted to provide data about the type and incidence of ADRs in a Neurological department and to compare two different methodological approaches to collecting information on ADRs.The two methods used were intensified surveillance of neurological wards by daily ward rounds and computer assisted screening for ADRs by means of pathologic laboratory parameters. But the study showed that by measuring pathologic laboratory parameters majority of ADRs couldn’t be detected in Neurological parameters. 7 The effect of the periodical distribution of a bulletin on drug safety issues and of including yellow cards in prescription pads on the rate of ADR reporting was studied. The study revealed that ADR bulletins elicit a temporal increase of ADR reporting rate and including a yellow card in prescription pads was followed by even greater increase in the reporting rate, possibly because it guarantees that yellow cards are available at the workplace.8 A study was carried out to assess the development of monitoring schedule approach to medication management and also to review and compare the instruments available for monitoring the adverse drug reactions of Antipsycotic medications. The UKU (Udvalg for Kliniska Undersogelser) scale and the West Wales ADR profile showed to assess a broader range of physiological parameters and potential problems than other instruments and such instruments must achieve a balance between clinical gain and practical costs, including the time spent in administration. The study concludes that further work was needed to explore the translation of formalized ADR surveillance programmes into clinical gains and improve outcomes for clients. Materials and methods 7.0 7.1 Source of data Data will be collected from: a) Prescribers written spontaneous ADRs reports encountered across the selected hospitals on prescription charts or case sheets. b) From the “Yellow Forms” (ADR notification forms) provided to all the departments of the study hospitals.

Inclusion criteria  Randomly selected in-patients & out-patients.  All suspected ADRs that conforms WHO’s definition.

Exclusion criteria The ADRs which is reported as a result of : a) Unintended Overdose. b) Intended drug abuse. c) Improper administration. d) Medication errors.

7.2 Method of collection of data:  From the inpatients’ case reports & outpatients’ cards or from the “Yellow forms” issued to all departments for spontaneous ADR reporting where a drug(s) is reported or suspected.  The clinical pharmacist also will participate in ward rounds of the study hospitals & the spontaneous ADR report would be collected voluntarily from the prescribers & residents.  A comprehensive medical history will collected through the medication charts, the patient &/or the attendant would be quizzed orally w.r.t the dose cum administration of the prescribed & suspected drug which would have eventually manifested in the ADR.  The causality assessment of the reported ADR will be done using “Naranjo’s causality assessment scale” & WHO’s probability scale.  Assessment of the severity will be carried out using Hartwig’s scale.

7.3 Duration of study The study will be conducted for a period of 6 months. 7.4 Does the study require any investigation or intervention to be conducted on patients, other humans or animals? The study involves collection of data from the patients medication history, patient’s case sheets, reported Yellow forms duly filled by the prescriber or residents. The study would include investigation of the reported ADR from the primary secondary & tertiary sources. The intervention would constitute an appropriate comment after a thorough search from the sources.

7.5 Has ethical clearance been obtained from your institution in case of 7.5? The protocol has been submitted for ethical committee clearance. Ethical clearance certificate will be submitted to the university as soon as the ethical committee of the study hospital grants them.

8.0 References: 1. Uppal R, Jhaj R, Melhotra S. Adverse drug reactions among inpatients in a north Indian referral hospital. Natl Med J Ind 2000; 13: 16-9. 2. Taylor D, Clark DW, Dovey SM, Tilyard MW. The prescribing and adverse reactions of non-steroidal anti-inflammatory drugs in general practice. A Dunedin study. NZ Med J 1994; 107 (981): 263-6. 3. Singh G, Rosen-Ramey D. NSAIDs induced gastrointestinal complications. J Rheumatol 1999; 56S: 8-16. 4. Frequency and Preventability of Adverse Drug Reactions in Pediatric Patients. Drug Safety Vol27 No11 2004 819-829(11) 5. The cost of adverse drug reactions.Expert Opinion on Pharmacotherapy, Vol4 No 3 March 2003, 319-326(8). 6. Adverse drug reactions in hospital in-patients: a pilot study.Journal of Clinical Pharmacy and Therapeutics.Vol31 Issue4 335 Aug 06 7. A survey of adverse drug reaction reporting by hospital pharmacists to the Committee on Safety of Medicines- the role of pharmacy departments.Int J Pharm Pract 1999;7:167-71. 8. A pharmacovigilence study for monitoring adverse drug reactions with antihypertensive agents at a South Delhi hospital.Int J Pharm Pract Vol 14 No 4 Dec 2006 311-313(3). 9. Adverse cutaneous drug reactions:A one year survey at a dermatology outpatient clinic of a tertiary care hospital. Indian J Pharmacol2006;38:429-431. 10. Detection of Adverse Drug Reactions in a Neurological Department:Comparison Between Intensified Surveillance and a Computer- Assisted Approach.Drug Safety Vol25 No 10 2002 713- 724(12). 11. Stimulating Adverse Drug Reaction Reporting:Effect of a Drug Safety Bulletin and of Including Yellow Cards in Prescription Pads.Drug Safety Vol26 No14 2003 1049-1055(7). 12. Monitoring adverse drug reactions:scales, profiles and checklists.International Nursing Review Vol 51 No 4 Dec 2004 208- 221(14). 13. 10. National Pharmacological Protocol, Ministry of Family Welfare, Govt of India. 14. 15 . Taylor D, Clark DW, Dovey SM, Tilyard MW. The prescribing and adverse reactions of non-steroidal anti-inflammatory drugs in general practice. A Dunedin study. NZ Med J 1994; 107 (981): 263-6. 15. Singh G, Rosen-Ramey D. NSAIDs induced gastrointestinal complications. J Rheumatol 1999; 56S: 8-16. 16. Dhikav V, Gosain R, Gupta SK. Adverse drug reactions in the department of psychiatry: Incidence and preventability (Abstract). Ind J Pharmacol 2001; 33 (1): 70. 17. Polluck BG. Adverse reactions to antidepressants in elderly patients. J Clin Psychiat 1999; 20S: 4-8.

9.0 Signature of the candidate

10.0 Remarks of the Guide

11.0 Guide Mr.Jai Prakash.S.Vastrad Asst.Professor Department ofPharmacy Practice Al-Ameen College of Pharmacy Bangalore-560027.

Signature

12.0 Head of the Department Dr.Shobha Rani R.H Professor and Head Department ofPharmacy Practice Al-Ameen College of Pharmacy Bangalore-560027.

Signature 13.0 Remarks of the Principal Recommended for research

Prof. B.G.Shivananda 14.0 Principal Al-Ameen College of Pharmacy Bangalore-560027.

Signature