814-Geer-_b

Report
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
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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,
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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,
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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.

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