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1 IOP1 Adverse Drug Events: Monitoring and Reporting Abstract : It is well known that all drugs carry the potential to produce both desirable and undesirable effects. No drug is absolutely safe under all circumstances of use or in all patien ts and adverse drug events may occur even if a drug is correctly selected and dosed. The main responsibility of any drug regulatory authority is to ensure the quality, efficacy, and safety of all marketed products. The first two criteria can be established through data obtained from in vitro testing to ensure compliance with acceptable standards and data obtained from animal studies, preclinical and clinic al trials involving humans. Pre-marketing clinical trials do not have the statistical power to detect rare adverse drug even ts (ADEs) nor do they have significant follow -up to identify delayed ADEs. An Adverse Drug Event (ADE) is harm associated with any dose of a drug, whether the dose is “normally used in man” or not. An Adverse Drug Reaction (ADR) is a subtype of an ADE. The se adverse effects cause concern both to the physician and the patient, which increases costs of medical treatment, morbidity and mortality. Thus, it becomes challengeable for physician, health care providers, WHO and pharmaceutical industries to resolve t he associated problem of ADRs. In view of this, Pharmacovigilance plays a significant role in prevention of adverse effects or any other drug ‐related problems. Keywords : Drug regulatory authority, Adverse Drug Event, Adverse drug Reaction , quality, efficacy and safety. Introduction: Medicines are one of the most essential components in the health care system. This indisputable fact makes rational selection, procurement, distribution, and use of medicines of paramount importance in health care. Worldwide, numerous numbers of drugs are being released into the market every day with incomplete knowledge as to their safety levels when used by wide variety of population category other than the one studied in the limited clinical trials making safety of medicines as one important concern. ADR monitoring is an important part of post marketing surveillance which helps in generating data on safety of medi cations. Main Aim to ADRs Monitoring is to the Promoting rational use of drugs, Safe use of Medicine, Improving patient care, improving public health. An Adverse Drug Event (ADE) is harm associated with any dose of a drug, whether the dose is “normally use d in man” or not. Some ADEs arise as a result of an error and are considered preventable. Others arise from ADRs, where the medication is used in a proper manner and are considered non -preventable ADEs . ADEs can happen anywhere: in hospitals, long -term car e settings, and outpatient settings. The2 IOP1 good news is that large majority of ADEs are preventable. Reducing ADEs is expected to result in safer and higher quality health care services, reduced health care costs, more informed and engaged consumers, and improved health outcomes. An Adverse Drug Reaction (ADR) is a subtype of an ADE (i.e., all ADRs are ADEs, but not vice versa) and by definition, drug- induced harm occurring with appropriate use of medication (i.e., not caused by an error). It is a well-known fact that no drug is completely free from side effects. Before executing any new drug in the market, its clinical trial and safety database are validated for the safety profile of the drug. In various countries, whether developed or developing, the issue of ADRs is accepted to effortlessly and thus it becomes a prime duty to develop awareness among patients about ADRs. There are a bunch of examples of drugs, which have been detached as well as outlawed from the European market owing to reported adverse eff ects of drugs. Rosiglitazone holds the first position in the market; other well- known drugs including terfenadine, cisapride, phenylpropanolamine, rofecoxib, cerivastatin, gatifloxacin, cisapride, sibutramine and tegaserod were withdrawn because of their a dverse reactions. For every drug in the market, the adverse events, if any, should be inspected in detail, and the facts should be conveyed to the people or public for elucidation of the information. Reasons for high number of ADEs: There are several reasons why the number of adverse drug events is so high. These include: 1) T he number of dru gs prescribed are high 2) T he ever-increasing number of new drugs in the market 3 ) The lack of a formal system for monitoring adverse drug reactions. Need for ADEs mo nitoring: One of the most frequently asked questions in Pharmacovigilance is: What is the need to monitor the adverse events to drugs, if their safety profiles have already been studied adequately before their commercial release? The answer is simple: To m ake the drugs safer. The next obvious question would be: How would drug monitoring for adverse events make the drugs safer, when, according to the general perception, safety is something that is inherent in the physiochemical properties of the drug molecul es under consideration? This is because in the formal evaluation of the drug by clinical trials, many of the drug issues related to the safety are inadequately studied. In addition, the formal therapeutic trials are conducted in carefully controlled condit ions; in highly selected and limited number of patients, so that the exact safety profile of the drug in the real life situations is not known. Children, pregnant women, and elderly are not included in clinical trials for ethical reasons. Therefore, the safety of the drug in these cases remains unknown until its release. Another important drawback of clinical trials is that they can3 IOP1 only report adverse reactions that appear within the finite duration of trial. Delayed reactions would be missed. ADEs monito ring involves: (i) Collecting the ADE data (ii) A ssessing the causality between drugs and suspected re actions, and (iii) R eporting ADE s to Pharmacovigilance centres . • Collecting data on adverse drug reactions A number of methods are employed to identify pr eviously unknown detrimental outcomes attributable to the use of medications. The initial step of identifying ADE s can be performed actively or passively. Active surveillance includes reviewing medical records or interviewing patients and/or physicians in a sample of healthcare centres called sentinel sites. A follow -up questionnaire can then be sent to each prescribing physician or the patient at specified intervals to obtain information. The passive methods comprise spontaneous reports and case series of similar reports. A spontaneous report is an unsolicited communication by healthcare professionals (doctors , nurses and pharmacists) to a company, regulatory authority or an organization (e.g. WHO regional centres ) that describes one or more ADE s in a patient who was given one or more medicinal products. T hese reports play a major role in the identification of safety signals once a drug is marketed. For instance, temafloxacin, a fluoroquinolone antibiotic, was withdrawn within six months of its introduction because of the association between its use and haemolytic anaemia in healthy individuals. • Assessing causality between drugs and suspected reactions To establish the relationship between a drug and adverse events(s), causality assessment is important. The re is no gold standard for this assessment. Some of the widely used algorithms and scales include Naranjo’s scale, WHO probability sc ale, European ABO system etc. The categorization of causal relationships between a drug and the suspected adverse reactions varies with the scale adopted. The WHO scale categorizes the causality relationships into certain, probable, possible, unassessible/unclassifiable, unlikely, and conditional/unclassifiable . In general, the following four aspects are to be considered while attributing a clinical adverse event to a drug: (i) temporal time relationship between the suspected reaction and the drug (ii) dechallenge (cessation of drug); (iii) rechal lenge (reintroduction of drug) (iv) likelihood of other possible causes. • Reportin g adverse drug events The National Pharmacovigilance Programme (NPP) encourages the reporting of all suspected drug -related adverse events . Any adverse reactions if noticed should be reported as soon as possible . The various ADE regulatory authorities are: Committee on Safety of Medicine, Adverse Drug Reactions4 IOP1 Advisory Committee, Med Watch and Vaccine Adverse Event Reporting System. The WHO –Uppsala Monitoring Committee (UMC) international database in Sweden maintains all information on ADRs. In India, NPP comprises one National Pharmacovigilance Centre located at the Central Drugs Standard Control Organization (CDSCO), in New Delhi, two zonal centres (All India Institute of Medical Sciences, New Delhi for north and east, and King Edward Memorial Hospital, M umbai for south and west), five regional centres (Department of Pharmacology, JIPMER Pondicherry, TN Medical College, Mumbai, IGMC Nagpur, Lady Harding Medical College, New Delhi and NRS Medical College, Kolkata) and 24 peripheral centres (including some m edical colleges and hospitals approved by the Medical Council of India, private hospitals, public health programmes and autonomous institutes). The ADR form is available at any pharmacovigilance centre. The completed form should be sent to the peripheral pharmacovigilance centre. The information provided is handled in strict confidence. The peripheral centre forwards the submitted form to the regional centre where causality analysis is carried out, after which it is sent to the zonal centre. The data are st atistically analysed and forwarded to WHO–UMC. Table 1.: Procedure for reporting ADEs : Elements in Necessary Others ADR r eporting information What should be reported Adverse events of the drug , suspected drug’s details , patient’s information Medicat ions overdose, pharmaceutical defect, drug interactions Who can report medical practition ers , doctors, nurses, pharmacists, clinical officers and other health care providers Manufacturers, all government and private hospital’s health center When it can be reported Any adverse reactions if noticed should be reported as soon as possible – How to report Through completely filled yellow card form – Where it can be reported Fully filled Yellow Card should be submitted to any Pharmacovigilance center -5 IOP1 Conclusion : The simplest way to pr event most adverse drug event s is to use the minimum dosages of drugs. The simple principle of ‘start low and go slow’ should be followed. Health professionals should periodically be educated about adverse events an d should be encouraged to report the same. Moni toring of adverse drug events 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. Physicians should report death due to drugs, lifethreatening complications, hospitalisation (initial or prolonged), disability if significant, persistent, or permanent, congenital anomalies etc. Continuing medical education programmes for physicians and other health professionals should be conducted to make them aware of the methodologies and other technical aspects of the drug monitoring process. References: 1. Dr Ozayr Mahomed, Moodley and C.C. Jinabhai, Adverse Events Monitoring And Reporting Guidelines . 2. Guideline for Adverse Drug Events Monitoring (Pharmacovigilance) Third Edition Food, Medicine and Healthcare Administrati on and Control Authority of Ethiopia. 3. 4. Vikas Dhikav*, Sindhu Singh**, KS Anand***, Adverse Drug Reaction Monitoring In India, Clinical Pharmacology, JIACM 2004; 5(1): 27-33. 5. Aeries N (1995) Consumer reporting of ADRs. WHO Drug Information 14:211–215 6.…/the -yellow -card -scheme – guidance- for-healthcare . 7. Gholasni K, Shalvani G. Factors associated with preventability, predictability and severity of adverse drug reactions. Ann Pharmacother 1999; 33: 236- 40. 8. VA Center for Medication Safety And VHA Pharmacy Benefits Management S trategic Healthcare Group and the Medical Advisory Panel November 2006, Adverse Drug Events, Adverse Drug Reactions and Medication Errors Frequently Asked Questions . 9. ASHP Guidelines on Adverse Drug Reaction Mo nitoring and Reporting . 10. World Health Organization. International Drug Monitoring: The Role of National Centers , Geneva.