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1 SSPP3 Adverse Drug Reactions (ADR) Monitoring & Reporting in India with Local Analysis Abstract: Adverse drug reactions (ADR) are importan t causes of deaths and hospitalization worldwide. ADR affects the patient’s compliance to treatments and may affect their trust in healthcare system. India has developed a platform for ADR monitoring & reporting since 1982, but despite of having wide population, the reporting rate of ADR’s is nowhere near to other small European countries. Collection of adverse events helps to generate information regarding any new adverse event , its severity and frequency associated with a drug . This may further lead to change in the reference safety information (contraindications, warnings, and precautions , use in special population) and depending upon its risk- benefit analysis, may also be responsible for withdrawal of a drug from the market. Because of lack of the intention or awareness the stakeholders of medical field do not report ADR’s, t hat is why t here are many drugs which are banned in other countries for their serious adverse effects but continue to be on the list of bestseller s in India. Thus, it is extremely important to increase awareness among health -care professionals regarding diagnosis, prev ention, and reporting of adverse drug events. Keywords: Adverse drug reactions monitoring, Pharmacovigilance, PvPI, Drug safety. World Health Organization (WHO) defines that adverse drug reactions (ADRs) are noxious and unwanted effects produced by the drug. Adverse effects may be local, i.e. limited to a certain location, or systemic, where a medication has caused adverse effects throughout the systemic circulation. Ironically, ADRs are still one of the leading causes of deaths in the World , after major disorders and accidents. The most common examples of drug s that produce ADRs include Paracetamol and Nimesulide (hepatotoxic effects); skin rashes due to Sulphonamides etc. [1] Causes of ADR: a) Polypharmacy b) Patient non- compliance c) New drugs in market d) Negligence e) Lack of systematic approach for ADR monitoring Types of ADRs: 1. Excessive pharmacological effects: Most common and major cause of ADR. It is related to the pharmacological action of drug. It is dose dependent and the level of severity increases with increase in dose. Its occurrence can be limited by slow intr oduction of low dosages. Predictable by the pharmacological mechanisms, e.g., dry mouth with tricyclic antidepressants and respiratory depression with opoids. 2. Secondary pharmacological effects: It is rare, not related to pharmacologic action of drug, also unrelated to the dose, unpredictable, mechanisms are unknown. It can be fatal resulting in high mortality, e.g. aplastic anaemia caused by chloramphenicol, neuroleptic malignant hyperthermia caused by some general anaesthetics and antipsychotics. 3. Idiosyncr asy: Idiosyncratic ADRs are unpredictable and difficult to prevent, if risk factors for occurrence are unknown. Idiosyncratic ADRs2 SSPP3 do not occur in most patients, may be unrelated to both the dose and the pharmacology of the drug, and can be potentially life-threatening. They include the most serious and dangerous ADRs known: lupus, bone marrow toxicity (aplastic anemia), hepatitis and Stevens -Johnson syndrome 4. Allergic reactions : Allergic reactions represent one third of adverse drug reactions. They are considered rare but with high morbimortality. Type B reactions include symptoms of intolerance to drugs, idiosyncratic reactions and allergic reactions. 5. Withdrawal effects: Withdrawal reactions which are uncommon and occur soon after the withdrawal. Management includes reintroducing the drug and withdrawing it slowly. Occurs typically with the depressant drugs, e.g., hypertension and restlessness in opiates; insomnia and anx iety with benzodiazapenes [2]. Need for ADR monitoring in India: Adverse drug events are estimated to be the fourth to sixth larges t cause of death in the USA. As against this, in India, drug adverse effects are responsible for only 3.4% of the hospital admissions and 1.8% of deaths [3]. These figures are disproportionate with the c ountry’s populations and indicate high underreporting of adverse events . That is why the ADR monitoring and reporting should be of immense importance to stakeholders. 1. It is difficult to draw parallels between toxicity in animal models and potential risks to man. 2. Type B Adverse reactions having frequency less than 0.5 to 1% are missed [4] . 3. Population variation: ADR may differ on account of genetics, environmental/dietary factors, disease patterns and drugs used. 4. Nutritional status: In rural areas over 50% children’s are malnourished, which may affect incidence of ADR [5]. 5. Use of traditions medicines along with modern drugs may lead to ADR. 6. 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. 7. Another important drawback of clinical trials is that they can only report adverse reactions that appear within the finite duration of trial. Delayed reactions would be missed [6] . ADR Monitoring : The aims of ADR monitoring involve detecting unknown safety problems at earlier stage and increases in their frequencies, identifying and quantifying risk factors, and preventing patients from being affected unnecessarily. ADR Monitoring involves: i. Collecting the ADR data ii. Assessing the causality between drugs and suspected reactions, and iii. Reporting ADRs to Pharmacovigilance centres or ADR regulating authorities [7] . Methods of detecting ADR Monitoring: 1. Spontaneous case reports: It is the common met hod of arousing suspicion about drug related disease. The prescriber reports the suspected drug reaction either in medical journal or manufacturer of drug [8]. 2. Vital statistics and record linkage studies: The details of cause of death or of hospitalizati on are routinely collected and analyzed . It gives early warning of an epidemic of drug related disease. Record3 SSPP3 linkage studies may be used to great effect in the search for drug -induced disease. 3. Cohort studies: The ‘cohort’ means indentifying a group of recipients of drug of interest and observing them. This type of study is used for short term clinical trial of new drug. This method is of great value for detecting ADR due to excessive pharmacological effects. 4. Case – Control studies: It involves the comparison of group of patients with a disease which is thought to be due to a drug (‘Case’) with a group of patients who do not have the disease (‘Control’). The drug histories of the ‘cases’ & ‘controls’ are obtained and compared. These studies can be conduc ted rapidly and efficiently at relatively low cost. ADR Reporting and Documentation in India: Monitoring of adverse drug reactions started in India about two decades ago (1982). Today a standard platform for ADR reporting is established. 1. Indian Pharmacopoeia Commission (IPC) is functioning as National Coordination Centre (NCC) for Pharmacovigilance Programme of India (PvPI) since 15th April 2011 under the aegis of Ministry of Health & Family Welfare, Government of India. 2. The major functions of NCC are to collect, collate and analyze Adverse Drug Reactions data to arrive at an inference to recommend regulatory interventions to Central Drugs Standard Control Organization (CDSCO), besides communicating risks to healthcare professionals and the public through PvPI Newsletters. 3. To collect the ADRs from patients over 170+ ADRs monitoring centers (AMCs) are set up under NCC. 4. The rationale for setting up the AMCs is to make it possible to identify rare ADRs that could not be found through clinical trial programmes [9]. 5. NCC provides the logistic support and manpower to AMCs for their smooth functioning and reporting the ADRs. 6. All healthcare professionals (clinicians, dentists, pharmacists, nurses) and patient/consumers can report ADRs to NCC or AMCs. 7. ADRs can be also reported via PvPI helpline number (18001803024) on weekdays from 9:00 am to 5:30 pm. The mobile Android application for ADR reporting has also been made available to the public [10]. 8. The submitted ADR report does not have any legal implication on the reporters. The patients’ identity are held in strict confidence and protected to the fullest extent. AMC ’s in Maharashtra: Mumbai , Pune , Nagpur , Ambejogai , Miraj , Latur 9. Minimum valid criteria to ADR report includes, patient identifier, e.g., initials, age or date of birth, gender, reporter details (name, profession, institution, contact details), name of suspected medicinal product (s) include drug name (brand or generic name), manufacturer, batch no/lot no, expiry date, dose used, route used, frequency, dates of therapy started and stopped, and indication of use, report de -challenge (drug withdrawn) and re -challenge (re administered of4 SSPP3 drug after adverse drug reaction) an d details of the suspected adverse drug reaction. 10. Report form also contain concomitant medication (drugs which are used or given at the same time as suspected drug), outcome of the events (recovered, not recovered or recovering). Doctors (Interns, House officers), nurses, pharmacist and residents also need to be more actively involved in reporting ADRs. 11. All types of suspected ADRs irrespective of whether they are known or unknown, serious or non serious and solicited (clinical study) or unsolicited (spont aneous). In addition, the reporting ADRs due to lacking of efficacy, overdose, antibiotic resistance and suspected pharmaceutical defects (spurious and adulterated drugs) is recommended [11]. Table 1. Drug banned in 2011 after reporting of severe life threatening ADRs [12] . Name of drug Reasons Cisapride Risk of cardiac arrhythmias Phenylpropanolamine Risk of stroke Nimesulide (Below age 13) Life threatening hepatotoxic effects Sibutramine Increased cardiovascular risks Tegaserod Increased risk of heart attack Negligence related to ADR reporting in India: India is the world’s third -largest medicine market. It stands to scientific reason that these drugs will have side effects. Yet, in 2013, India reported no more than 2% of globally occurring adverse drug reactions (ADRs) [14]. India has become a dumping ground for banned drugs. Thanks to a virtually “absent” adverse drug reaction mechanism in the country, drugs like Cisapride, Furazolidone , Phenylpropanolamine Analgin , Cisapride , Nimesulide and Piperazine, have been banned, withdrawn or marketed under restrictions in North America, Europe and many Asian countries , continues to be sold in India and are among the bestsellers in India. According to a report of the WHO, there has not been a single instance of adverse drug reaction reported against any drug in the country. The business of production of these discarded drugs is booming in India. Some of the most common ones include a) Nise (Dr Reddy’s), Nimulid (Panacea Biotech) that are discarded f or reported liver damage, b) Vicks Action 500 from the stable of Procter and Gamble is discarded for increasing chances of brain hemorrhage. c) Anti -depressant drug Droperol (produced by Triokka) has been discarded for irregular heartbeats in patients. d) Anti -diarrheal drug Furoxone (from the house of Glaxo) was withdrawn from the market after reports of cancer in some patients, who were administered the drug [15]. Current Need of Awareness : Given below are some suggestions to address these problems: 0500010000 15000 No. of ADR Reporting's 2015 2016 India US Fig 1. Comparison of No. ADR reporting between India and US [16 ,17]5 SSPP3 22.33% 52.77% 24.90% (i) Awareness programmes, symposia and workshops for practitioners and healthcare workers should be arranged; (ii) The syllabus for doctors, pharmacists and nurses can be modified to make them aware of this issue; (iii) The national programme should involve the pharmaceutical industry; (iv) The policy on periodic safety update reports should be strictly implemented and (v) In hospi tals ADR drop -boxes in wards, daily enquiries, e -mail alerts and thank -you letters can increase the chances of reporting. Such procedures can increase the knowledge of ADRs, and decrease the mortality and morbidity of millions of people in India. The role of pharmacist related to ADR’s : A multifaceted approach is required for safety of medicine regulation in the Indian market. A useful first step is to establish transparency, which is not apparent presently. The pharmacist can play a very imp ortant role in drug safety. Hence every state drug control officer should strictly abide by the Drug and Cosmetic Act 1940, which mandates every pharmacy to have a pharmacist at all times during business hours. Pharmacist can educate assistant pharmacists as well as patients visiting the pharmacy by writing labels in easy and understandable language, patient counseling, providing leaflets and stick posters about certain ADRs related to the obtained medications and advice to report ADRs to pharmacists or other healthcare professionals [ 18] . Our Local Analysis: As a responsible Citizen and future pharmacists, we did some local analysis of following hospitals in Chopda. 1. Hartalkar Hospital; 2. Patil Multispeciality Hospital; 3. Sanjog Hospital; 4. Malti Hos pital; 5. Civil hospital 6.Kamal Hospital We asked them following 7 questions: 1. Have you noticed any adverse drug reactions in your hospital ? 2. If yes, what type of ADR s? 3. W hat is name of the responsible drug? 3. Are these ADRs common with that particular drug? 4. After noticing ADRs, what do you do? 5. Any deaths because of ADR? 6. Have you reported any ADRs? 7. How to report ADRs? Different ADRs observed in Chopda were related to extrapyrim idal affects like Stiffening of neck, Severe vomiting, Hypertension, Gastric bleeding, Vomiting with blood etc. Here major question was to test knowledge related to ADR reporting. We got the answers which are depicted by following figure. Fig. 2. Awareness about PvPI, AMCs and Android App in Chopda Conclusion: Rational use of drugs includes right drug, right dose, and right time with the right patient could improve the quality of the public. Both healthcare professionals and Don’t Know No Yes6 SSPP3 non-healthcar e professionals should aware about Pharmacovigilance programme. In India, the Pharmacovigilance programme is facing difficulties. Drugs are sold without prescriptions in many medical shops; hence it is difficult to trace the use of these medicines. Several preparations containing allopathic drugs are sold as herbal medicines. Also, the Pharmacovigil ance centers are in shortage of money as well as staff. References: 1. Rehan HS, Vasudev K, Tripathi CD (2002) Adverse drug reaction monitoring: knowledge, attitude and practices of medical students and prescribers. Natl Med J India 15(1):24–25. 2. A.V. Ya dav, Book of Hospital and Clinical Pharmacy, Nirali Prakashan 3. Apte AA. Reporting of adverse events for marketed drugs: Need for strengthening safety database. Perspect Clin Res 2016; 7:111- 4. 4. Vikas D., Sindhu S., Anand KS, Adverse Drug Reaction Monitoring In India, Clin Pharmacology, JIACM 2004; 5(1): 27 -33 5. Kshirsagar NS, Karande S, Potkar CN, Adverse drug reaction monitoring in India. The Journal of the Association of Physicians of India 41(6):374- 6 6. Viveknandan K., System of adverse drug reactions reporting: What, where, how, and whom to report?, Indian J Crit Care Med. 2015 Sep; 19(9): 564–566. 7. Bhosale V., Adverse Drug Reaction Monitoring, Current Science, Vol. 101, No. 8, 25 October 2011. 8. Adhikari A., Evalu ation of Adverse Drug Reactions in Tertiary Care Hospital of Kolkata, West Bengal, India , J Young Pharm, 2017;9(3):311- 314. 9. Kalaiselvan V., Current Status of Adverse Drug Reactions Monitoring Centres under Pharmacovigilance Programme of India, Indian Journal of Pharmacy Practice, Vol 7, Issue 3, Jul –Sep, 2014, 21- 24. 10. Kavya HB, Recent Development of Pharmacovigilance System in India , J Pharma Care Health Sys 2018, Vol 5(2): 193. 11. Sahu RK, Yadav R, Prasad P, Roy A, Chandrakar S. Adverse drug react ions monitoring: prospects and impending challenges for pharmacovigilance. SpringerPlus. 2014;3:695. doi:10.1186/2193- 1801-3- 695. 12. 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