DOI 10.1515/jbcpp-2012-0077 J Basic Clin Physiol Pharmacol 2014; 25(1): 125–130
Ambili Remesh*, Aswathy Balan and Angela Gnanadurai
A cross-sectional study of surveillance of adverse drug reactions in inpatient departments of a tertiary care hospital Abstract Background: Pharmacovigilance plays an imperative role in providing information about adverse drug reactions (ADRs) and drug safety in a hospital. Hence, it was considered worthwhile to study the surveillance of ADRs in inpatient departments (IPD). Our study aims to evaluate the frequency, type, characteristics, causality, and severity and avoidability of ADRs in the IPDs. Methods: This prospective observational study was done in the IPDs of a 550-bed tertiary care hospital in South India during the period April to September 2012. All the patients had experienced at least one suspected ADR after hospitalization and drug treatment; patients who are hospitalized due to suspected ADR(s) in the last 6 months were assessed after obtaining permission from the Institutional Research and Ethics Committee. All the ADRs were recorded on the appropriate, prescribed form for reporting ADRs designed by the Central Drugs Standard Control Organization. Results: A total of 147 ADRs were reported with the use of 96 drugs used by 91 IPD patients. The maximum number of ADRs reported in our study was with antipsychotic drugs and the maximum number of patients reported rashes (n = 30) followed by extrapyramidal symptoms (n = 17). Causality assessment by the WHO scale and Naranjo’s algorithm showed 48 and 59 ADRs possibly related to drugs, respectively. Of this, 45 patients with ADR had moderate severity and 41 patients with ADRs were not preventable. Conclusions: The maximum number of ADRs reported in our study was with antipsychotic drugs and the most common ADR reported was rashes. Most of the ADRs reported had a possible causality, were moderate in severity, and were not preventable. The majority of patients had recovered from the ADRs. Keywords: adverse drug reactions; antimicrobial/antipsychotic drugs; inpatient wards; pharmacovigilance. *Corresponding author: Dr. Ambili Remesh, Associate Professor, Pharmacology and Therapeutics, Dr. Somervell Memorial CSI Medical College, Trivandrum, Kerala, India, Phone: +91-9497011358, E-mail: [email protected]
Aswathy Balan and Angela Gnanadurai: Dr. Somervell Memorial CSI Medical College, Trivandrum, Kerala, India
Introduction Studies directed for safer use of medications appear mandatory to prevent adverse drug reactions (ADRs) and to achieve rational therapeutic practices. This activity requires collective and coordinated efforts from all the healthcare professionals such as doctors, nurses, and pharmacists [1]. It is also the responsibility of the pharmaceutical industry and governmental agencies to ensure this via multiphase clinical trials and drug safety and efficacy laws such as the Food, Drug and Cosmetic act before the approval of the drug [2, 3]. Pharmacovigilance is the surveillance of unwanted effects of drugs and other drugrelated activities even after free marketing of the drug [3]. Pharmacovigilance plays an important role in providing information about ADRs in the general population to promote the rational use of medicines. Spontaneous reporting of ADRs has contributed significantly to the success of pharmacovigilance. The role of health professionals, in this regard, to ADR databases is vital and has encouraged ongoing ascertainment of the benefit-risk ratio of drugs and has also contributed to the signal detection of unsuspected and unusual ADRs previously undetected during the initial evaluation of a drug [4]. Pharmacogenomics is the branch of pharmacology that deals with the molecular study of genetic factors that determine drug efficacy and toxicity [5]. Various genetic tests can accurately predict those most at risk for certain ADRs [6]. Pharmacovigilance needs teamwork and the participation of healthcare professionals is the vital force of this program. Although the benefits of spontaneous reporting are enormous, underreporting remains a major drawback, and as per estimate, only 6%–10% of all ADRs are reported [7, 8]. This is a serious issue hampering the dynamics of pharmacovigilance program. For a better and safe use of drugs, establishing standard approaches and active reporting of suspected ADRs by all healthcare professionals should be facilitated. The key objective of this
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126 Remesh et al.: Surveillance of drugs in a tertiary care hospital study is to evaluate the frequency, type, characteristics, causality, and severity and to avoid the ability of ADRs in the inpatient departments (IPDs).
Materials and methods This prospective observational study was done in the IPDs of a 550bed tertiary care hospital in South India during the period April to September 2012. All the patients had experienced at least one suspected ADR after hospitalization and drug treatment in the IPDs; patients who are hospitalized due to suspected ADR(s) in the IPD, who are on modern medicine (only), irrespective of age and gender, were included in the study. The exclusion criteria were patients on alternative systems of medicines, unconscious/mentally retarded patients, and patients in the intensive care unit. The study was approved by the Institute of Research and Human Ethics Committee and project protocol was in accordance with the Declaration of Helsinki. Prior permission was obtained from the medical superintendent of the hospital. This study was done prospectively for a period of 6 months. The subjects were inpatients who developed a minimum of one suspected ADR during their hospital stay and drug treatment and all the patients who are hospitalized due to suspected ADRs in the IPDs were also evaluated irrespective of age and gender. The ADRs were reported mainly by intensive monitoring and spontaneous reporting. All the ADRs, including both the observed and volunteered ones, were recorded on the appropriate, prescribed form for reporting ADRs designed by the Central Drugs Standard Control Organization’s National Pharmacovigilance Programme [9, 10]. When an ADR was suspected, the data from the patient profile sheet such as demographic details, medication details including prescription drugs, and recently ceased medications were collected. All the relevant details of suspected ADRs such as onset of reaction, duration of reaction, suspected drug, abation of reaction after stoppage of the drug, whether physician reintroduced the drug, and any reactions that reoccurred were noted. The medication charts of the patients who were admitted with adverse reactions were also reviewed and the complete patient and drug history were collected. For each ADR, the following information has to be recorded in individual adverse event reporting forms, including the type of adverse event, serious or nonserious, date and time of onset, resolution of reactions, severity, outcome of ADR, further details of the ADR if any, other drugs used, dose, route, and period. The collected reports were entered into statistical package Microsoft Excel and analyzed further for demographic details, causality, severity, and preventability. The classification of ADRs was done on the basis of anatomical and therapeutic classification system. For the analysis, standard scales [10–13] are used, and the details of which are provided below. The causality of ADRs was assessed using the Naranjo’s algorithmic scale [10] and the WHO-UMC system [11]. According to Naranjo’s causality assessment scale, ADRs were classified into definite, probable, possible, and unlikely. WHO causality assessment is based on the dechallenge/rechallenge information of drugs and the temporal association of the adverse event to the suspected drug [11]. The severity was assessed using the modified Hartwig and Siegel severity assessment scale [12]. ADR was classified as mild, moderate, or severe by this scale. It is assessed based on whether the treatment
of the patient is affected by ADR, any treatment is required for ADR, the prolongation of hospital stay by ADR; whether ADR is the reason for admission; or whether it causes permanent harm or death of the patient [12]. The preventability was assessed by the definitions stated by modified the Schumock and Thornton scale, which was developed in 1991 [13]. It gives an overview whether ADR is preventable definitely, probably, or not.
Results A total of 91 patients admitted in the last 6 months to the IPD reported ADRs. There were more females (n = 51) than males (n = 40) reporting ADRs. The age range was 4–83 years in female and 1–68 years in males. The maximum number of ADRs reported was of drugs given by the oral route (n = 76) followed by parenteral route (n = 9) then topical (n = 5) and inhalational (n = 1) routes. Most of the ADRs reported were from the IPD of psychiatry (n = 30) followed by the IPD of the medicine department (n = 15). Some other IPDs that reported ADRs were dermatology (n = 8), orthopedics (n = 4), surgery (n = 3), neurology (n = 2), and pediatrics (n = 2). There was one ADR reported from the IPD of obstetrics and gynecology and radiodiagnosis. A total of 147 ADRs were reported with the use of 96 drugs used by IPD patients. The types of ADR reported are tabulated in Table 1. The maximum number of patients reported rashes (n = 30) followed by extrapyramidal symptoms (n = 17). Other ADRs that were reported frequently were itching (n = 14), erythema (n = 10), and tremors (n = 10) (Table 1). The number of ADR reported by IPD patients with the intake of 96 drugs are tabulated in Table 2. Maximum ADRs were reported with the use of antipsychotic drugs (maximum being with risperidone) followed by use of antimicrobial agents, nonsteroidal anti-inflammatory drugs (NSAIDs), and antiepileptic and cardiovascular drugs (Table 2). ADRs were abated after withdrawal of the drug in 37 (40%) patients and after altering the dose of the drug in 18 (20%) patients. The management also included alternate drug therapy and other symptomatic and supportive treatment.
WHO causality assessment of suspected ADRs Causality assessment was done using both WHO and Naranjo’s scales. The WHO causality assessment of suspected ADRs showed that, of a total of 91 patients, 48 ADRs were possible and 38 were classified as probable. One ADR was classified as unlikely and four ADRs were certainly related to drugs (Figure 1).
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Remesh et al.: Surveillance of drugs in a tertiary care hospital 127 Table 1 Type of reactions observed from reported ADRs. Types of reactions
Number of ADR
Rashes Itching Erythema Hirsuitism Fixed drug eruptions Pigmentation Oral ulcer Anaphylaxis
Types of reactions
25 14 10 2 2 1 1 1
Number of ADR
Extrapyramidal symptomsa Tremors Decreased sleep Irritation Fever Aggressive, agitation Shivering Nystagmus
17 10 8 5 2 2 2 1
Types of reactions
Number of ADR
Vomiting Abdominal pain Diarrhea Oral erosion Water retention Weight gain Palpitation Others
6 5 3 2 4 3 2 19
Class of drug (n)/name of drug
Numbers
Parkinsonism, akathesia, dystonia, and tardive dyskinesia.
a
Table 2 Classification of drugs associated with ADRs. Class of drug (n)/ name of drug
Numbers
Antipsychotics Risperidone Olanzapine Quetiapine Chlorpromazine Fluphenazine Clozapine Haloperidol Antiepileptics Phenytoin Carbamazepine Sodium valproate Mood stabilizers Lithium Antidepressants Mirtazipine Benzodiazepine Clonazepam
(28) 16 5 2 2 1 1 1 (6) 2 2 2 (1) 1 (1) 1 (1) 1
(19) 6 5 4 1 1 1 1 (14) 5 4 4 1 (1) 1 (5) 4 1
38
40
24
Males
14 1 0 1
(8) 2 2 1 1 1 1 (3) 1 1 1 (6) 1 2 1 2 (3) 1 1 1
ss es
ifi U na
nc la ss
na l/U
0 0 0
C
on
di
tio
Pr
0 0 0
ed
el y ik nl U
ke ly bl
e/
Li
si bl e
0
ob a
C er
ta
in
0
Females
.
20
/..
26
si bl e
22
4 4
Cardiovascular drugs Digoxin Losartan Ramipril Amlodipine Prazosin Hydrochlorothiazide Endocrine drugs Metformin Neomercazole L-Thyroxine Topical Dimethicone Corticosteroids Ferocox ear drop Povidone-iodine Others Disulfiram, Omnipaque dye Vitamin K
The assessment done using Naranjo’s scale revealed that, of 91 patients, 59 ADRs were possible and 29 were classified as probable. One ADR was classified as unlikely and two ADRs were definitely related to drugs (Figure 2).
Total
30
Numbers
Causality assessment by Naranjo’s scale
Po s
Number of ADRs
Antimicrobials Ampicillin Ciprofloxacin Cephalosporins Amoxicillin Piperacillin Gentamicin Albendazole NSAIDs Paracetamol Aceclofenac Diclofenac Ketorolac Muscle relaxant Chloroxazone Bronchodilators Salbutamol Aminophylline
48
50
10
Class of drug (n)/ name of drug
Figure 1 WHO causality assessment of suspected ADRs.
Severity assessment by the modified Hartwig and Siegel scale The severity of reported ADRs was done with the modified Hartwig and Siegel scale. The severity assessment showed that 42 were mild, 45 ADRs were classified as moderate,
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128 Remesh et al.: Surveillance of drugs in a tertiary care hospital
60
59
45
Total
40
32 27
30
Males
29
Females 18
20
11
10 0
2 Possible
Probable
2
0
Definite
1
1
0
Unlikely
Outcome of ADRs The outcome attributed to ADRs of 90 patients were noted and depicted in Table 3. The unlikely reaction is excluded. No fatal case was reported. A total of 54 patients had recovered from ADRs, and 21 were recovering (not yet recovered). Six patients were continuing ADR in spite of management, whereas, in six patients with ADR, the outcome was unknown. Three patients reported to have 45
40 Number of ADRs
35
Total
25 20
Males
22 23
Females
17
15 10
3
5 0
Mild
Moderate
19
20
0
3
Severe
0
0
17
15
14
15
11 8
5 Preventable
Probably preventable
Not preventable
Figure 4 Preventablity of ADRs as per modified Schumock and Thornton criteria.
Serial number
The preventability of ADRs was determined with the modified Schumock and Thornton criteria. Of the total 91 patients who reported ADRs, 19 were preventable, 31 ADRs were classified as probably preventable, and 41 were classified as not preventable (Figure 4).
25
25
26
Table 3 Outcomes of ADRs.
Preventability assessment by modified Schumock and Thornton criteria
30
30
0
and 3 ADRs were classified as severe. There were no lethal effects observed or produced (Figure 3).
42
31 Females
10
Figure 2 Naranjo’s causality assessment.
45
Males
35 Number of ADRs
Number of ADRs
50
41
Total
40
0
Lethal
Figure 3 Severity of ADRs as per the modified Hartwig and Siegel scale.
1 2 3 4 5 6
Outcome
Fatal (mortality) Recovered from ADR Recovering from ADR Continuing with ADR Unknown Others (morbidity)
Number of ADR 0 54 21 6 6 3
Sex distribution Males
Females
0 22 10 6 4 3
0 32 11 0 2 0
other outcomes specified by disability and permanent impairment.
Discussion ADRs account for a significant number of fatalities each year, occurring frequently and globally [14]. ADRs have a high prevalence rate causing 3%–6% of hospital admission at any age and increase up to 24% in the elderly, are ranked fifth among all causes of death, and represent 5%– 10% of hospital costs [14]. Thus, tracking ADRs is mandatory by the regulatory agencies. In the present study, we evaluated the causality, severity, and preventability of ADRs in the IPDs. The maximum number of ADRs reported was with antipsychotic drugs, especially risperidone, followed by antimicrobials. The most common ADR reported was rashes followed by extrapyramidal symptoms. Most of the ADRs reported had a possible causality, were moderate in severity, and were not preventable. The majority of patients had recovered from the ADRs.
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Remesh et al.: Surveillance of drugs in a tertiary care hospital 129
The results of our study are in agreement with a prospective, spontaneous, reporting study conducted over a period of 6 months by clinical pharmacists, where the majority of ADRs reported were possibly drug related and were moderate in severity [15]. Our study differs from this study because most of the ADRs reported were probably preventable, whereas in our study they were not preventable. Another prospective, observational study of adult patients carried out over a 6-week period to assess the economic burden from the hospital perspective observed that the majority of patients who reported an ADR had mild severity, a probable causality, and were possibly avoidable and is different from our study, where majority had a moderate severity, possible causality, and were not preventable. The most common ADR reported in this study was rashes, which is similar to our study, but majority of ADRs were associated with the use of antimicrobials and NSAIDs [16]. A prospective observational study for a period of 1 year on adverse cutaneous drug reaction in the dermatology outpatient clinic was done to analyze the clinical pattern causality, severity, and preventability and observed that the majority of ADRs reported were of moderate severity— which is in accordance with our study. However, this study observed that the majority of ADRs had probable causality and were preventable, which differentiates it from our study. The majority of ADRs reported were from antimicrobial drugs and NSAIDs [17]. There are certain limitations for our study. The study was conducted on IPD patients
only and duration was only 6 months. Also, spontaneous reporting of ADRs was less.
Conclusions In conclusion, the maximum number of ADRs reported in our study was with antipsychotic drugs, especially risperidone, followed by antimicrobials. The most common ADR reported was rashes followed by extrapyramidal symptoms. Most of the ADRs reported had a possible causality, were moderate in severity, and were not preventable. The majority of patients had recovered from the ADRs. Acknowledgments: The authors gratefully acknowledge the Dr. Somervell Memorial CSI Medical College (Trivandrum, Kerala, India) for providing the necessary facilities to this research work. Conflict of interest statement Authors’ conflict of interest disclosure: The authors stated that there are no conflicts of interest regarding the publication of this article. Research funding: None declared. Employment or leadership: None declared. Honorarium: None declared. Received December 6, 2012; accepted May 15, 2013; previously published online June 11, 2013
References 1. Kulkarni C. Need to be ‘vigilant’ about pharmacovigilance studies. J Med Sci Res 2007;2:11–2. 2. McClure DL. Improving drug safety active surveillance systems should be paramount. Pharm Med 2009;23:127–30. 3. Sharma HL, Sharma KK. Drug discovery and clinical evaluation of new drugs. Principles of Pharmacology. Paras 2011;2:94–105. 4. Oshikoya KA, Awobusuyi JO. Perceptions of doctors to adverse drug reaction reporting in a teaching hospital in Lagos, Nigeria. BMC Clin Pharmacol 2009;9:14. DOI:10.1186/1472-6904-9-14. 5. Katsung BG. Basic principles introduction. Basic and clinical pharmacology. Lange 2009;10:1–13. 6. Rang HP, Dale MM, Ritter JM, Flower R, Henderson G. Pharmacogenetics, pharmacogenomics and personalized medicine. Rang and Dales pharmacology. Churchill Livingstone: Elsevier, 2012: pp. 132–7. 7. Smith CC, Bennett PM, Pearce HM, Harrison PI, Reynolds DJ, Aronson JK, et al. Adverse drug reaction in a hospital general medical unit meriting notification to the Committee on Safety of Medicines. Br J Clin Pharmacol 1996;42:423–9.
8. Lopez-Gonzalez E, Herdeiro MT, Figueiras A. Determinants of under-reporting of adverse drug reactions: a systematic review. Drug Saf 2009;32:19–31. 9. Suspected ADR Reporting Form [Internet], India. Available at http://cdsco.nic.in/ADR_form_PvPI.pdf. Accessed on Jan 22 2012. 10. Naranjo CA, Busto U, Sellers EM. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239–45. 11. The use of the WHO-UMC system for standardised case causality assessment, Uppsala, Sweden. Available at http://www. who-umc.org/Graphics/24734.pdf. Accessed on Jan 22 2012. 12. Hartwig SC, Siegel J, Schneider PJ. Preventability and severity assessment in reporting adverse drug reactions. Am J Hosp Pharm 1992;49:2229–32. 13. Schumock GT, Thornton JP. Focusing on the preventability of adverse drug reactions. Hosp Pharm 1992;27:538. 14. Oshikoya KA, Chukwura H, Njokanma OF, Senbanjo IO, Ojo I. Incidence and cost estimate of treating pediatric adverse drug reactions in Lagos, Nigeria. Sao Paulo Med J 2011;129:153–64.
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130 Remesh et al.: Surveillance of drugs in a tertiary care hospital 15. Palanisamy S, Kumaran KS, Rajasekaran A. A study on assessment, monitoring and reporting of adverse drug reactions in Indian hospital. Asian J Pharm Clin Res 2011;4:112–6. 16. Patel KJ, Kedia MS, Bajpai D, Mehta SS, Kshirsagar NA, Gogtay NJ. Evaluation of the prevalence and economic burden of adverse drug reactions presenting to the medical emergency
department of a tertiary referral centre: a prospective study. BMC Clin Pharmacol 2007;7:8. DOI:10.1186/1472-6904-7-8. 17. Brahma DK, Sangma KA, Lynrah KG. Adverse cutaneous drug reactions: a one year survey at dermatology outpatient clinic in a tertiary care hospital. Int J Pharma World Res 2012;3:1–9.
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Ambili Remesh*, Aswathy Balan and Angela Gnanadurai
A cross-sectional study of surveillance of adverse drug reactions in inpatient departments of a tertiary care hospital Abstract Background: Pharmacovigilance plays an imperative role in providing information about adverse drug reactions (ADRs) and drug safety in a hospital. Hence, it was considered worthwhile to study the surveillance of ADRs in inpatient departments (IPD). Our study aims to evaluate the frequency, type, characteristics, causality, and severity and avoidability of ADRs in the IPDs. Methods: This prospective observational study was done in the IPDs of a 550-bed tertiary care hospital in South India during the period April to September 2012. All the patients had experienced at least one suspected ADR after hospitalization and drug treatment; patients who are hospitalized due to suspected ADR(s) in the last 6 months were assessed after obtaining permission from the Institutional Research and Ethics Committee. All the ADRs were recorded on the appropriate, prescribed form for reporting ADRs designed by the Central Drugs Standard Control Organization. Results: A total of 147 ADRs were reported with the use of 96 drugs used by 91 IPD patients. The maximum number of ADRs reported in our study was with antipsychotic drugs and the maximum number of patients reported rashes (n = 30) followed by extrapyramidal symptoms (n = 17). Causality assessment by the WHO scale and Naranjo’s algorithm showed 48 and 59 ADRs possibly related to drugs, respectively. Of this, 45 patients with ADR had moderate severity and 41 patients with ADRs were not preventable. Conclusions: The maximum number of ADRs reported in our study was with antipsychotic drugs and the most common ADR reported was rashes. Most of the ADRs reported had a possible causality, were moderate in severity, and were not preventable. The majority of patients had recovered from the ADRs. Keywords: adverse drug reactions; antimicrobial/antipsychotic drugs; inpatient wards; pharmacovigilance. *Corresponding author: Dr. Ambili Remesh, Associate Professor, Pharmacology and Therapeutics, Dr. Somervell Memorial CSI Medical College, Trivandrum, Kerala, India, Phone: +91-9497011358, E-mail: [email protected]
Aswathy Balan and Angela Gnanadurai: Dr. Somervell Memorial CSI Medical College, Trivandrum, Kerala, India
Introduction Studies directed for safer use of medications appear mandatory to prevent adverse drug reactions (ADRs) and to achieve rational therapeutic practices. This activity requires collective and coordinated efforts from all the healthcare professionals such as doctors, nurses, and pharmacists [1]. It is also the responsibility of the pharmaceutical industry and governmental agencies to ensure this via multiphase clinical trials and drug safety and efficacy laws such as the Food, Drug and Cosmetic act before the approval of the drug [2, 3]. Pharmacovigilance is the surveillance of unwanted effects of drugs and other drugrelated activities even after free marketing of the drug [3]. Pharmacovigilance plays an important role in providing information about ADRs in the general population to promote the rational use of medicines. Spontaneous reporting of ADRs has contributed significantly to the success of pharmacovigilance. The role of health professionals, in this regard, to ADR databases is vital and has encouraged ongoing ascertainment of the benefit-risk ratio of drugs and has also contributed to the signal detection of unsuspected and unusual ADRs previously undetected during the initial evaluation of a drug [4]. Pharmacogenomics is the branch of pharmacology that deals with the molecular study of genetic factors that determine drug efficacy and toxicity [5]. Various genetic tests can accurately predict those most at risk for certain ADRs [6]. Pharmacovigilance needs teamwork and the participation of healthcare professionals is the vital force of this program. Although the benefits of spontaneous reporting are enormous, underreporting remains a major drawback, and as per estimate, only 6%–10% of all ADRs are reported [7, 8]. This is a serious issue hampering the dynamics of pharmacovigilance program. For a better and safe use of drugs, establishing standard approaches and active reporting of suspected ADRs by all healthcare professionals should be facilitated. The key objective of this
Brought to you by | Lulea University of Technology Authenticated Download Date | 1/13/16 10:03 AM
126 Remesh et al.: Surveillance of drugs in a tertiary care hospital study is to evaluate the frequency, type, characteristics, causality, and severity and to avoid the ability of ADRs in the inpatient departments (IPDs).
Materials and methods This prospective observational study was done in the IPDs of a 550bed tertiary care hospital in South India during the period April to September 2012. All the patients had experienced at least one suspected ADR after hospitalization and drug treatment in the IPDs; patients who are hospitalized due to suspected ADR(s) in the IPD, who are on modern medicine (only), irrespective of age and gender, were included in the study. The exclusion criteria were patients on alternative systems of medicines, unconscious/mentally retarded patients, and patients in the intensive care unit. The study was approved by the Institute of Research and Human Ethics Committee and project protocol was in accordance with the Declaration of Helsinki. Prior permission was obtained from the medical superintendent of the hospital. This study was done prospectively for a period of 6 months. The subjects were inpatients who developed a minimum of one suspected ADR during their hospital stay and drug treatment and all the patients who are hospitalized due to suspected ADRs in the IPDs were also evaluated irrespective of age and gender. The ADRs were reported mainly by intensive monitoring and spontaneous reporting. All the ADRs, including both the observed and volunteered ones, were recorded on the appropriate, prescribed form for reporting ADRs designed by the Central Drugs Standard Control Organization’s National Pharmacovigilance Programme [9, 10]. When an ADR was suspected, the data from the patient profile sheet such as demographic details, medication details including prescription drugs, and recently ceased medications were collected. All the relevant details of suspected ADRs such as onset of reaction, duration of reaction, suspected drug, abation of reaction after stoppage of the drug, whether physician reintroduced the drug, and any reactions that reoccurred were noted. The medication charts of the patients who were admitted with adverse reactions were also reviewed and the complete patient and drug history were collected. For each ADR, the following information has to be recorded in individual adverse event reporting forms, including the type of adverse event, serious or nonserious, date and time of onset, resolution of reactions, severity, outcome of ADR, further details of the ADR if any, other drugs used, dose, route, and period. The collected reports were entered into statistical package Microsoft Excel and analyzed further for demographic details, causality, severity, and preventability. The classification of ADRs was done on the basis of anatomical and therapeutic classification system. For the analysis, standard scales [10–13] are used, and the details of which are provided below. The causality of ADRs was assessed using the Naranjo’s algorithmic scale [10] and the WHO-UMC system [11]. According to Naranjo’s causality assessment scale, ADRs were classified into definite, probable, possible, and unlikely. WHO causality assessment is based on the dechallenge/rechallenge information of drugs and the temporal association of the adverse event to the suspected drug [11]. The severity was assessed using the modified Hartwig and Siegel severity assessment scale [12]. ADR was classified as mild, moderate, or severe by this scale. It is assessed based on whether the treatment
of the patient is affected by ADR, any treatment is required for ADR, the prolongation of hospital stay by ADR; whether ADR is the reason for admission; or whether it causes permanent harm or death of the patient [12]. The preventability was assessed by the definitions stated by modified the Schumock and Thornton scale, which was developed in 1991 [13]. It gives an overview whether ADR is preventable definitely, probably, or not.
Results A total of 91 patients admitted in the last 6 months to the IPD reported ADRs. There were more females (n = 51) than males (n = 40) reporting ADRs. The age range was 4–83 years in female and 1–68 years in males. The maximum number of ADRs reported was of drugs given by the oral route (n = 76) followed by parenteral route (n = 9) then topical (n = 5) and inhalational (n = 1) routes. Most of the ADRs reported were from the IPD of psychiatry (n = 30) followed by the IPD of the medicine department (n = 15). Some other IPDs that reported ADRs were dermatology (n = 8), orthopedics (n = 4), surgery (n = 3), neurology (n = 2), and pediatrics (n = 2). There was one ADR reported from the IPD of obstetrics and gynecology and radiodiagnosis. A total of 147 ADRs were reported with the use of 96 drugs used by IPD patients. The types of ADR reported are tabulated in Table 1. The maximum number of patients reported rashes (n = 30) followed by extrapyramidal symptoms (n = 17). Other ADRs that were reported frequently were itching (n = 14), erythema (n = 10), and tremors (n = 10) (Table 1). The number of ADR reported by IPD patients with the intake of 96 drugs are tabulated in Table 2. Maximum ADRs were reported with the use of antipsychotic drugs (maximum being with risperidone) followed by use of antimicrobial agents, nonsteroidal anti-inflammatory drugs (NSAIDs), and antiepileptic and cardiovascular drugs (Table 2). ADRs were abated after withdrawal of the drug in 37 (40%) patients and after altering the dose of the drug in 18 (20%) patients. The management also included alternate drug therapy and other symptomatic and supportive treatment.
WHO causality assessment of suspected ADRs Causality assessment was done using both WHO and Naranjo’s scales. The WHO causality assessment of suspected ADRs showed that, of a total of 91 patients, 48 ADRs were possible and 38 were classified as probable. One ADR was classified as unlikely and four ADRs were certainly related to drugs (Figure 1).
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Remesh et al.: Surveillance of drugs in a tertiary care hospital 127 Table 1 Type of reactions observed from reported ADRs. Types of reactions
Number of ADR
Rashes Itching Erythema Hirsuitism Fixed drug eruptions Pigmentation Oral ulcer Anaphylaxis
Types of reactions
25 14 10 2 2 1 1 1
Number of ADR
Extrapyramidal symptomsa Tremors Decreased sleep Irritation Fever Aggressive, agitation Shivering Nystagmus
17 10 8 5 2 2 2 1
Types of reactions
Number of ADR
Vomiting Abdominal pain Diarrhea Oral erosion Water retention Weight gain Palpitation Others
6 5 3 2 4 3 2 19
Class of drug (n)/name of drug
Numbers
Parkinsonism, akathesia, dystonia, and tardive dyskinesia.
a
Table 2 Classification of drugs associated with ADRs. Class of drug (n)/ name of drug
Numbers
Antipsychotics Risperidone Olanzapine Quetiapine Chlorpromazine Fluphenazine Clozapine Haloperidol Antiepileptics Phenytoin Carbamazepine Sodium valproate Mood stabilizers Lithium Antidepressants Mirtazipine Benzodiazepine Clonazepam
(28) 16 5 2 2 1 1 1 (6) 2 2 2 (1) 1 (1) 1 (1) 1
(19) 6 5 4 1 1 1 1 (14) 5 4 4 1 (1) 1 (5) 4 1
38
40
24
Males
14 1 0 1
(8) 2 2 1 1 1 1 (3) 1 1 1 (6) 1 2 1 2 (3) 1 1 1
ss es
ifi U na
nc la ss
na l/U
0 0 0
C
on
di
tio
Pr
0 0 0
ed
el y ik nl U
ke ly bl
e/
Li
si bl e
0
ob a
C er
ta
in
0
Females
.
20
/..
26
si bl e
22
4 4
Cardiovascular drugs Digoxin Losartan Ramipril Amlodipine Prazosin Hydrochlorothiazide Endocrine drugs Metformin Neomercazole L-Thyroxine Topical Dimethicone Corticosteroids Ferocox ear drop Povidone-iodine Others Disulfiram, Omnipaque dye Vitamin K
The assessment done using Naranjo’s scale revealed that, of 91 patients, 59 ADRs were possible and 29 were classified as probable. One ADR was classified as unlikely and two ADRs were definitely related to drugs (Figure 2).
Total
30
Numbers
Causality assessment by Naranjo’s scale
Po s
Number of ADRs
Antimicrobials Ampicillin Ciprofloxacin Cephalosporins Amoxicillin Piperacillin Gentamicin Albendazole NSAIDs Paracetamol Aceclofenac Diclofenac Ketorolac Muscle relaxant Chloroxazone Bronchodilators Salbutamol Aminophylline
48
50
10
Class of drug (n)/ name of drug
Figure 1 WHO causality assessment of suspected ADRs.
Severity assessment by the modified Hartwig and Siegel scale The severity of reported ADRs was done with the modified Hartwig and Siegel scale. The severity assessment showed that 42 were mild, 45 ADRs were classified as moderate,
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128 Remesh et al.: Surveillance of drugs in a tertiary care hospital
60
59
45
Total
40
32 27
30
Males
29
Females 18
20
11
10 0
2 Possible
Probable
2
0
Definite
1
1
0
Unlikely
Outcome of ADRs The outcome attributed to ADRs of 90 patients were noted and depicted in Table 3. The unlikely reaction is excluded. No fatal case was reported. A total of 54 patients had recovered from ADRs, and 21 were recovering (not yet recovered). Six patients were continuing ADR in spite of management, whereas, in six patients with ADR, the outcome was unknown. Three patients reported to have 45
40 Number of ADRs
35
Total
25 20
Males
22 23
Females
17
15 10
3
5 0
Mild
Moderate
19
20
0
3
Severe
0
0
17
15
14
15
11 8
5 Preventable
Probably preventable
Not preventable
Figure 4 Preventablity of ADRs as per modified Schumock and Thornton criteria.
Serial number
The preventability of ADRs was determined with the modified Schumock and Thornton criteria. Of the total 91 patients who reported ADRs, 19 were preventable, 31 ADRs were classified as probably preventable, and 41 were classified as not preventable (Figure 4).
25
25
26
Table 3 Outcomes of ADRs.
Preventability assessment by modified Schumock and Thornton criteria
30
30
0
and 3 ADRs were classified as severe. There were no lethal effects observed or produced (Figure 3).
42
31 Females
10
Figure 2 Naranjo’s causality assessment.
45
Males
35 Number of ADRs
Number of ADRs
50
41
Total
40
0
Lethal
Figure 3 Severity of ADRs as per the modified Hartwig and Siegel scale.
1 2 3 4 5 6
Outcome
Fatal (mortality) Recovered from ADR Recovering from ADR Continuing with ADR Unknown Others (morbidity)
Number of ADR 0 54 21 6 6 3
Sex distribution Males
Females
0 22 10 6 4 3
0 32 11 0 2 0
other outcomes specified by disability and permanent impairment.
Discussion ADRs account for a significant number of fatalities each year, occurring frequently and globally [14]. ADRs have a high prevalence rate causing 3%–6% of hospital admission at any age and increase up to 24% in the elderly, are ranked fifth among all causes of death, and represent 5%– 10% of hospital costs [14]. Thus, tracking ADRs is mandatory by the regulatory agencies. In the present study, we evaluated the causality, severity, and preventability of ADRs in the IPDs. The maximum number of ADRs reported was with antipsychotic drugs, especially risperidone, followed by antimicrobials. The most common ADR reported was rashes followed by extrapyramidal symptoms. Most of the ADRs reported had a possible causality, were moderate in severity, and were not preventable. The majority of patients had recovered from the ADRs.
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Remesh et al.: Surveillance of drugs in a tertiary care hospital 129
The results of our study are in agreement with a prospective, spontaneous, reporting study conducted over a period of 6 months by clinical pharmacists, where the majority of ADRs reported were possibly drug related and were moderate in severity [15]. Our study differs from this study because most of the ADRs reported were probably preventable, whereas in our study they were not preventable. Another prospective, observational study of adult patients carried out over a 6-week period to assess the economic burden from the hospital perspective observed that the majority of patients who reported an ADR had mild severity, a probable causality, and were possibly avoidable and is different from our study, where majority had a moderate severity, possible causality, and were not preventable. The most common ADR reported in this study was rashes, which is similar to our study, but majority of ADRs were associated with the use of antimicrobials and NSAIDs [16]. A prospective observational study for a period of 1 year on adverse cutaneous drug reaction in the dermatology outpatient clinic was done to analyze the clinical pattern causality, severity, and preventability and observed that the majority of ADRs reported were of moderate severity— which is in accordance with our study. However, this study observed that the majority of ADRs had probable causality and were preventable, which differentiates it from our study. The majority of ADRs reported were from antimicrobial drugs and NSAIDs [17]. There are certain limitations for our study. The study was conducted on IPD patients
only and duration was only 6 months. Also, spontaneous reporting of ADRs was less.
Conclusions In conclusion, the maximum number of ADRs reported in our study was with antipsychotic drugs, especially risperidone, followed by antimicrobials. The most common ADR reported was rashes followed by extrapyramidal symptoms. Most of the ADRs reported had a possible causality, were moderate in severity, and were not preventable. The majority of patients had recovered from the ADRs. Acknowledgments: The authors gratefully acknowledge the Dr. Somervell Memorial CSI Medical College (Trivandrum, Kerala, India) for providing the necessary facilities to this research work. Conflict of interest statement Authors’ conflict of interest disclosure: The authors stated that there are no conflicts of interest regarding the publication of this article. Research funding: None declared. Employment or leadership: None declared. Honorarium: None declared. Received December 6, 2012; accepted May 15, 2013; previously published online June 11, 2013
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