Mohammad Ishaq Geer*, M. Y. Shah*, Parvaiz A. Koul**, Shafiqa A. Tanki** *Dept. of Pharmaceutical Sciences, University of Kashmir, Srinagar, India **Sher-i-Kashmir Institute of Medical Sciences, Srinagar, India Third International Conference for Improving Use of Medicines, Antalya, Turkey November 14-18, 2011 ABSTRACT PROBLEM STATEMENT: Prior to this study, there was no provision for monitoring drugs for their adverse effects in any of the leading hospitals of Kashmir division of the Jammu and Kashmir state. OBJECTIVES: To assess the prevalence, preventability, category, costs, and severity of drug-related adverse effects in Kashmiri patients at a Srinagar-based tertiary care hospital, Sher-i-Kashmir Institute of Medical Sciences (SKIMS), Srinagar. DESIGN: Prospective, observational, cohort study with follow-up SETTING: All adult Kashmiri patients admitted to internal medicine IPD, presenting to internal medicine OPD, and those visiting the accident and emergency department of SKIMS over a 270-day period were included in the study. STUDY POPULATION: A total of 5482 adult, Kashmiri patients of both sexes were screened and monitored on a daily basis for the occurrence of any ADRs. INTERVENTION: Data was recorded using structured forms and then scrutinized for various assessment parameters by a multidisciplinary medical team comprising of a senior consultant in medicine, a clinical pharmacologist, and a clinical pharmacist. Interventions relating to detection and management of ADRs were undertaken on a case-to-case basis. This study led to the establishment of a full-fledged pharmacovigilance centre and initiation of pharmaceutical care services in the hospital. POLICIES: No hospital drug policy or ADR monitoring policy/framework was available in SKIMS at the time of this study. OUTCOME MEASURES: Causality assessment, severity assessment, preventability assessment, extension of hospital stay, and cost due to ADRs. RESULTS: ADRs account for 6.23% of adult Kashmiri patients visiting a tertiary care hospital, SKIMS, either for referral or hospitalization, with the majority (81.57%) of these ADRs being preventable; 23.68% of patients had mild ADRs, 69.29% had ADRs of moderate severity, and 7.01% had severe ADRs. The 4 classes of drugs most frequently suspected in admissions due to ADRs were anti-infective agents (40.92%) including anti-tubercular drugs (13.15%), steroids (14.03%), anti-coagulants (8.77%), and NSAIDs (7.89%). Increasing age and female gender were identified as risk factors. The organ systems most commonly affected were gastrointestinal (81%), dermatological (43%), central nervous (40%), hematological (34%), metabolic (33%), cardiovascular (22%), urinary (18%), ENT (18%), immunological (11%), and respiratory (10%) systems. The total cost to the hospital due to hospitalization of patients presenting with ADRs over the 9-month period in the internal medicine IPD was found to be USD 22469. CONCLUSIONS: The present work is the maiden pharmacovigilance study conducted on Kashmiri patients, especially at a tertiary care teaching hospital such as SKIMS that has provided baseline information about the prevalence of ADRs and their distribution among different age groups, genders, organ systems affected, and therapeutic classes of medicines. The data collected has paved way for long term and more extensive ADR monitoring on Kashmiri patients and will also be useful in framing policies toward the rational use of drugs. FUNDING SOURCES: Nil INTRODUCTION/BACKGROUND ADRs are a serious cause of mortality and morbidity in humans inflicting huge costs to the nation, healthcare system, hospitals & patients. Clinical trials are not sufficient to detect all ADRs. Complete safety profile of a drug evolves over its lifetime in the market. In India, pharmacovigilance is still in its infancy and is yet to gain the momentum needed to cope up with the demands of a country that is already under the pressure of overpopulation, malnutrition and high disease burden. ADR monitoring & reporting scenario in J&K was grim. No such initiative till this study was launched in 2007. As per govt. figures Jammu and Kashmir state consumes medicines worth Rs. 600 crores annually, out of which medicines worth 400 crores are consumed by people living in Kashmir valley alone. Upon literature search for ADR reports from J&K using various database resources like PubMed, Medline, Toxline, Chemical, Biological and Pharmaceutical Abstracts between 1966 to 2009, reports not exceeding a twodigit figure in number from J&K state could be retrieved. No pharmacovigilance activities were undertaken in any of the leading hospitals like SKIMS, SMHS etc prior to this study. Study was undertaken to provide baseline data that could help launch a fullfledged pharmacovigilance programme at SKIMS. AIM AND OBJECTIVES AIM To assess the prevalence, preventability, category, costs and severity of drug-related adverse effects in Kashmiri patients, admitted in Internal Medicine IPD, presenting to the Internal Medicine OPD and those visiting the Accident and Emergency Department of SKIMS, Srinagar. OBJECTIVES To estimate the incidence and cost of ADRs causing hospital admissions or occurring whilst in hospital at SKIMS, Srinagar. To estimate the no. of ADRs in patients visiting Internal Medicine OPD and Emergency Department of SKIMS. To identify risk factors responsible for an increased frequency or severity of ADRs such as concurrent drugs, disease, age, sex etc. To identify and suggest ways and means for reducing adverse drug reactions in Kashmiri population. To provide a platform and baseline data for launching a full-fledged Pharmacovigilance Programme and Pharmaceutical Care Services at SKIMS, Srinagar. MATERIALS & METHODS STUDY DESIGN: Prospective, observational, cohort study with follow-up SETTING: All adult Kashmiri patients of both sexes admitted to internal medicine IPD, presenting to internal medicine OPD, and those visiting the accident and emergency department of a tertiary care centre, SKIMS over a 270-day period between May 1st, 2006 to July 29th, 2006 (90 days) and December 31st, 2006 to June 28th, 2007 (180 days), were included in the study. STUDY POPULATION: A total of 5482 adult patients of both sexes were screened and monitored on a daily basis for the occurrence of any ADRs. STUDY HOSPITAL: 650-bedded teaching-cum-service referral, tertiary care centre offering primary and secondary care facilities too. INTERVENTION: Data was recorded using structured forms and then scrutinized for various assessment parameters like frequency, severity, preventability, category, cost and necessary interventions were suggested by a multidisciplinary medical team consisting of a senior consultant in medicine, a clinical pharmacologist and a pharmacist. Interventions relating to detection and management of ADRs were undertaken on case-to-case basis. This study led to the establishment of a fullfledged pharmacovigilance centre in the hospital and initiation of Pharmaceutical Care Services at its Internal Medicine Ward. MATERIALS & METHODS DATA COLLECTION: Medication charts, medical records, daily ward rounds, patient interviews, physician assistance POLICIES: No hospital drug policy or ADR monitoring policy/framework was available in SKIMS at the time of this study. Present study was the first of its kind. OUTCOME MEASURES: Causality assessment, severity assessment, preventability assessment, extension of hospital stay, and cost due to ADRs. CAUSALITY ASSESSMENT: Using Naranjo’s Algorithm classified ADRs into Definite, Probable, Possible, Doubtful. PREVENTABILITY/AVOIDABILITY ASSESMENT: Using Hallas (1990) methodology classified ADRs into Definitely Avoidable, Possibly Avoidable and Unavoidable. SEVERITY ASSESMENT: Using Hartwig & Seigel Scale (1992) classified ADRs into mild, moderate, severe, lethal. FINANCIAL IMPLICATIONS: Using Nicholas (1998) methodology cost of ADRs was calculated by the product of total number of admission days of all patients admitted with the ADR and hospital expenditure per day. Cost of excess hospital days was estimated by multiplying the total number of excess days by the reference daily hospital cost. Direct costs of ADRs calculated for the Internal Medicine ward of SKIMS were then used to extrapolate to annual and hospital-wide rates (Lagnaoui, 2000). STATISTICAL ANALYSIS: Using Student’s t-test with a significance level of P<0.001 and the comparisons of proportions were made using Chi (ᵡ2) square test. METHODOLOGY Visited ward on daily basis, participated in ward rounds Causality assessment of ADRs was done as per Naranjo’s algorithm, severity analysis as per modified Hartwig & Seigel Scale, preventability as per Hallas methodology Examined medical records for drugs prescribed, investigations done & ADRs experienced. Patients were interviewed and clinical records analyzed to collect information about the management and outcome of ADRs. Followed up all patients until discharge for arriving at a final conclusion. Wherever reqd. assistance was sought from prescribing physician Type of ADR was determined as per the classification of Wills and Brown RESULTS: TABLE-1: Department-wise break-up of the patients experiencing ADRs Number of patients with Number of patients with Name of the Department ADR/Number of patients ADR/Number of patients visiting the department visiting the hospital IPD 240/3899 (6.15%) 240/5482 (4.37%) OPD 43/556 (7.73%) 43/5482 (0.78%) Emergency 59/1027 (5.74%) 59/5482 (1.07%) 342/5482 (6.23%) 342/5482 (6.23%) Total RESULTS: TABLE-2: Demographic characteristics of the patients Number of patients Characteristics with ADR/Number Number (%) (n = 121) ADR related of patients visiting the hospital ADRs occurring during hospital stay admissions Male 132/3283 (4.02%)* 21 (0.63%)* 111 (3.38%)* Female 210/2199 (9.54%)* 47 (2.13%)* 163 (7.41%)* Adult 187/3985 (4.69%)* 38 (0.95%)* 149 (3.73%)* Elderly(>65yrs) 155/1497 (10.35%)* 30 (2.00%)* 125 (8.35%)* 342/5482 (6.23%) 68 (1.24%) 274 (5.07%) Total *P<0.001 on student’s t-test/chi-square (ᵡ2) test (level=highly significant) RESULTS TABLE-3: Age-wise incidence of ADRs in 5482 admissions Age Group No. of Admissions No. of ADRs Incidence (%; 95% CI) 18 - 38 1748 66* 3.77 39 - 58 2237 121* 5.40 59 - 78 972 89* 9.15 ≥ 79 525 66* 12.57 *P<0.001 on student’s t-test/chi-square (ᵡ2) test (level=highly significant) Classification and assessment of ADRs 300 Number of ADRs 250 200 150 100 50 0 Types of ADverse Drug Reactions RESULTS TABLE-5: VARIOUS CLASSES OF DRUGS WITH FREQUENCY OF CAUSING ADRs Drug Class Fluoroquinolones No. (%) of ADRs 48 (14.03%) Individual Drugs (number) Moxifloxacin (17), Ciprofloxacin (13), Ofloxacin (7), Gatifloxacin (11) Beta-lactam antibiotics 30 (8.77%) Anti-tubercular drugs 45 (13.15%) Other antibiotics 17 (4.97%) Steroids 48 (14.03%) NSAIDs 27 (7.89%) Benzathine-Penicillin (2), Cefadroxil (4), Ceftriaxone (11), Cefixim (2), PiperacillinTazobactum (5), Meropenem (3), Imipenem (3) Rifampin (8), Ethambutol (11) Pyrazinamide (3), Streptomycin (12), Isoniazid (11) Doxycycline (4), Azithromycin (5), Vancomycin (3), Aztreonam (1), Clindamycin (4) Prednisolone (12), Hydrocortisone (11), Betamethasone (9), Dexamethasone (16) Diclofenac (7), Aspirin (6), Serratiopeptidase (11), Ibuprofen (4) RESULTS TABLE-5: VARIOUS CLASSES OF DRUGS WITH FREQUENCY OF CAUSING ADRs Drug Class No. (%) of ADRs Individual Drugs (number) Anti-coagulants 30 (8.77%) Diuretics 12 (3.5%) Anti-hypertensives 12 (3.5%) Drugs used in hypotension Hormones 9 (2.63%) 12 (3.5%) Beta-Blockers 9 (2.63%) Heparin (8) Warfarin (19) Acenocoumarol (3) Furosemide (3) Spiranolactone (3) Bumetanide (2) Amiloride (2) Indapamide (2) Enalapril (9) Amlodipine (3) Dopamine (7) Parathyroid hormone (2) Thyroxine (6) Insulin (4) Atenolol (3) Carvedilol (2) Sotalol (1) Propranolol (3) RESULTS TABLE-5: VARIOUS CLASSES OF DRUGS WITH FREQUENCY OF CAUSING ADRs Drug Class No. (%) of ADRs Individual Drugs (number) Anti-depressants 6 (1.75%) Escitalopram (6) Opioid analgesics 3 (0.87%) Morphine (3) Multi-vitamins 5 (1.46%) Vitamin B1, B6, B12 (5) Anti-histaminics 2 (0.58%) Diphenhydramine (2) Sedatives 2 (0.58%) Diazepam (2) RESULTS TABLE-5: VARIOUS CLASSES OF DRUGS WITH FREQUENCY OF CAUSING ADRs Drug Class No. (%) of ADRs Individual Drugs (number) Phenothiazines 3(0.87%) Trifluperazine (1), Olanzapine (2) Cardiac stimulants 3 (0.87%) Digoxin (3) Anti-epileptics 6 (1.75%) Phenytoin (6) Oral hypoglycemic agents 6(1.75%) Glimepiride (2), Glyburide (4) Haematinics 3(0.87%) Ferrous fumarate(2), Ferrous sulphate (1) Anti-asthmatics 4 (1.16%) Salbutamol (4) RESULTS Most common drugs causing ADRs 20 18 Number of ADRs Caused 16 14 12 10 8 6 4 2 0 RESULTS Most common Adverse Drug Reactions 4 4 4 4 Hyponatremia Eosinophilia Anemia Dyspepsia Itching/Pruritis Cochlear Toxicity Tachycardia Thrombocytopenia Muscle Weakness Hypotension Vomiting Diarrhoea Gastric Bleeding Leucopenia Encephalopathy Hepatotoxicity Hypersensitivity Hypokalemia Skin Rashes Gastritis 5 5 5 5 6 7 8 8 9 10 10 10 11 11 12 20 0 5 10 15 20 25 RESULTS Organ Systems affected by ADRs Gynaecological 1 Opthalmological 4 Hormonal 5 Muscular 7 Skeletal 8 Immunological 11 Respiratory 10 ENT 18 Urinary/Renal 18 CVS 22 Metabolic 33 Hematological 34 CNS 40 Skin 43 Gastrointestinal 81 0 10 20 30 40 50 60 No. of Adverse Drug Reactions 70 80 90 RESULTS Classes of drugs responsible for causing ADRs (numbers indicate percentage) 15.26 Anti-infectives 2.63 Steroids 3.5 40.92 Anti-coagulants NSAIDs 3.5 Diuretics 3.5 Anti-hypertensives Hormones Beta-Blockers 7.89 Others 8.77 14.03 IMPLICATIONS/CONCLUSIONS ADRs continue to represent a considerable burden on our healthcare system, accounting for 6.23% Kashmiri patients visiting a tertiary care hospital like SKIMS, either for referral or hospitalization and a majority (81.57%) of these ADRs were preventable. Rate of incidence of ADR was found to be higher (7.73%) in patients presenting to the OPD clinic of Internal Medicine, followed by 6.15% in patients admitted to the Internal Medicine ward and 5.74% patients visiting the Accident and Emergency Department of SKIMS during the period of study. Out of a total of 342 patients experiencing various kinds of ADRs, 70.17% patients were those admitted to the Internal Medicine ward whereas 12.57% patients were those that presented to the OPD clinic of Internal Medicine and 17.25% patients were those that visited the Accident and Emergency Department of SKIMS during the period of study. It was seen that 81/342 (23.68%) patients had mild ADRs while 237/342 (69.29%) patients had ADRs of moderate severity and 24/342 (7.01%) patients had severe ADRs. Thus a majority of the ADRs detected were of moderate severity. The four classes of drugs most frequently suspected in admissions due to ADRs were anti-infective agents (40.92%) including anti-tubercular drugs (13.15%), steroids (14.03%), anti-coagulants (8.77%) and NSAIDs (7.89%). IMPLICATIONS/CONCLUSIONS The most common drugs related to ADRs were Moxifloxacin (17), Ciprofloxacin (13), Gatifloxacin (11), Ceftriaxone (16), Ethambutol (11), Streptomycin (13), Isoniazid (11), Rifampin (8), Prednisolone (10), Hydrocortisone (8), Betamethasone (14), Dexamethasone (16), Serratiopeptidase (11), Warfarin (19), Heparin (8) and Enalapril (9). Most common adverse drug reactions were gastritis (n=20), skin rashes (n=12), hypokalemia (n=11), hypersensitivity (n=11), hepatotoxicity (n=10), gastric bleeding (n=9), hypotension (n=7), thrombocytopenia (n=5), tachycardia (n=5), cochlear toxicity (n=5), anemia (n=4), diarrhea (n=8), vomiting (n=8), encephalopathy (n=10), leucopenia (n=10), itching/pruritis (n=5), dyspepsia (n=4), muscle weakness (n=6), eosinophilia (n=4) and hyponatremia (n=4). The organ-systems most commonly affected were gastrointestinal (81%), dermatological (43%), central nervous (40%), hematological (34%), metabolic (33%), cardiovascular (22%), urinary (18%), ENT (18%), immunological (11%) and respiratory (10%) systems. The average cost per patient hospitalized with an ADR was INR 3,285/(USD 65$). The total cost to the hospital due to hospitalization of patients presenting with ADRs over the 9 month period in the IPD of General Medicines at SKIMS, Srinagar was found to be INR 11,23,470/(USD 22469). IMPLICATIONS/CONCLUSIONS The number of suspected adverse drug reactions was significantly higher in females as compared to males in all age groups above 18 years of age, and the size of the increased risk was relatively consistent across all the age-bands. Adverse drug reaction recording rates increased further in the age group of 80s and 90s. The highest rate of ADRs in males was recorded in the >79 year age group and in females in the age group of 59-78 years. Considering that 81.57% ADRs were found to be preventable, adequate measures need to be taken to decrease the unnecessary burden of ADRs. Qualified pharmacists too must be involved in the process of achieving drug safety by allowing them to contribute towards the prevention, identification, documentation, and reporting of ADRs. They must be included in the daily ward rounds and assigned suitable duties in areas of Clinical, Hospital and Community Pharmacy. Present study paved way for the establishment of a full-fledged Pharmacovigilance centre in the tertiary care hospital and lead to the initiation of Pharmaceutical Care Services in its Internal Medicine Ward. Authors are thankful to the medical and nursing staff of the study departments at Sher-i-Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir, India for their support and cooperation.