PATTERN, CAUSALITY ASSESSMENT AND SEVERITY OF SUSPECTED ADVERSE DRUG REACTIONS REPORTED AT TERTIARY CARE TEACHING HOSPITAL

PATTERN, CAUSALITY ASSESSMENT AND SEVERITY OF SUSPECTED ADVERSE DRUG REACTIONS REPORTED AT TERTIARY CARE TEACHING HOSPITAL

Shukla, P. Barot * and D. J. Dave

Department of Pharmacology, GMERS Medical College, Himmatnagar, Gujarat, India.

ABSTRACT: Background: Present study was conducted to evaluate pattern, causal association and severity of suspected Adverse Drug Reactions (ADRs) at a tertiary care teaching hospital in western India. Materials & Method: Spontaneous collection of suspected ADRs was done over a period of one year. Demographic data, suspected drug group/s, causal association, severity & preventability scale from the reported ADRs were analysed. Results: 150 suspected ADR reports were collected. Adult patients (14-50 years) experienced 109 (72.66 %) ADRs followed by elderly patients (>50 years) experienced 29 (19.33%) ADRs and paediatric patients (<14 years) experienced 12(8%) ADRs. On the causality scale 62.67% were probable ADRs and on severity scale 63% were moderately severe ADRs. According to MeDRA classification of ADR, Skin and subcutaneous tissue disorders were most common (47.67%), followed by Gastrointestinal disorders (23 %) and Nervous system disorders (13.95%). ADRs were most commonly seen due to antimicrobial drugs (44.3%) followed by Non steroidal anti-inflammatory drugs (NSAIDs) (17.8%). Conclusion: Our study findings showed underreporting in spontaneous ADR reporting system. Continuous efforts through training, sensitization & awareness programmes of all the stakeholders of health care system should be done to improve ADR reporting.

Keywords: Suspected ADR, Antimicrobials, Causal association, Spontaneous reporting

INTRODUCTION: The incidence of adverse drug reaction (ADR) has been raised drastically because of mushrooming of new drugs that occurred in health care practice, especially in last decade ¹. According to WHO, ADR is any response to a drug that is noxious and unintended, and that occurs at doses used in man for the prophylaxis, diagnosis or therapy of disease or for modification of physiological function ².

While Pharmacovigilance encompasses science and activities related to detecting, assessing, understanding and preventing adverse effects or any other drug-related problem ³. Drug therapy can act as a double-edged sword in the management of ailments. Rational drug use can make a remarkable improvement in morbidity and mortality. In contrast, irrational drug usage, polypharmacy and drug interactions are major responsible factors for adverse drug reactions, increased in-hospital stay, and a remarkable increase in the cost of therapy.

Pharmacovigilance aims to foster rational drug therapy to maximize the health care outcome through early detection, treatment, prevention of adverse drug reactions and associated health care burden. ADR is a major concern for the patient too, and it has been found that it is the core reason for the reduction in patient compliance. If ADR has been effectively communicated before therapy, there will be a definite improvement in patient compliance ⁴. Further to this, the data collected by ADR reporting will be very useful for the future decision of the therapeutic status of the drug as well as the selection of drug treatment for health illnesses ⁵.

Pharmacovigilance's official functioning has been initiated in India through “Pharmacovigilance Programme of India” (PvPI) by Govt. of India in 2010. The headquarter of this program was shifted to Indian Pharmacopoeia Commission (IPC) in 2011 as a national coordinating center (NCC) in Ghaziabad ¹. There is an improvement in the reporting of ADRs because of tireless efforts of national coordinating center and peripheral ADR monitoring centres ⁶. It was also reflected in the reporting number. In 2020-21, the total number of ADR reporting was 52, 810 ⁷. These data were effectively evaluated and utilized by NCC, and recommendations were made to the Central Drug Standard & Control Organization (CDSCO) for the necessary regulatory measures. Even though the graph of the ADR reporting is on an increasing trend year by year, the actual percentage of ADR reporting is far from the expected (only 1% Vs expected 5-6%) ^{8, 9}.

Amidst many measures, the most important measure is to enhance the awareness of health care professionals about the importance of ADR reporting. This will improve the outcome of therapy and reduce the health care-associated economic burden to society. Considering all these, the present study evaluated the pattern, causal association, and severity of suspected adverse drug reactions (ADRs) in western India's tertiary care teaching hospital.

METHODS: This research work was conducted after the approval (IAEC no-19/2019; dated 25/10/2019) of the institutional ethics committee, GMERS medical college, Gandhinagar, Gujarat, India. Suspected ADRs were collected over one year through spontaneous reporting from all the clinical specialties of tertiary care teaching hospitals. All the spontaneously reported suspected ADRs (N=150) by health care professionals (including intern doctors) in the outpatient department (OPD) as well as in patient department (IPD) were evaluated.

Data of spontaneously reported ADRs were collected from health care professionals, and they were carefully evaluated. Demographic details of patients, duration & details of suspected adverse reaction, suspected agent(s) along with indications for which they were prescribed, other co-prescribed agents, self-medications, laboratory parameters, de-challenge, re-challenge and the outcome were reported in suspected ADR reporting form.

MeDRA (Medical Dictionary for Regulatory Activities) coding system was utilized for system organ classification of suspected adverse drug reactions ¹⁰. The causal association was done by using Naranjo’s causality assessment scale ¹¹. According to this scale, ADRs were classified into definite (if score >9), probable (score in between 5-8), possible (score in between 1-4), and doubtful (if 0 or less than it). Modified Hartwig and Siegel scales were used to assess the severity of suspected ADRs ¹². Based on this scale, suspected ADRs were categorized into mild, moderate, and severe based on the duration of hospitalization, the requirement of change in the medication and if any disability occurred or not due to ADR. Data was entered in Microsoft Excel version 2010 and the results were analyzed using descriptive statistics. Results were presented in table, pie chart and bar diagram. Throughout the research, confidentiality of study participants was maintained.

RESULTS AND DISCUSSION: Pharma-covigilance programme of India (PvPI) has monitored adverse drug reactions across the country since 2010, and total 395 adverse drug reaction monitoring centers (AMCs) have been recognized in India ¹³. Although most health care professionals are sensitized about Pharma-covigilance, the practice of spontaneous ADR reporting is highly underrated.

For the present study, total 150 ADR forms were evaluated. The analysis of ADR forms revealed that patients aged 14 to 50 years experienced 109 (72.66 %) ADRs, elderly patients (>50 years age) experienced 19.33 %, and pediatric patients (< 14 years age) experienced 8% ADRs. Concerning patient gender, 51% of female experienced ADR. Age is one of the important risk factors for the occurrence of ADR¹⁴. Previous studies showed that high incidence of ADR reporting in paediatric and old age patients may be due to age-related changes in pharmacokinetics and pharmacodynamics of drugs.

In contrast, we have found the maximum number of ADR reported in adult patients. This finding can be attributed to the age-related changes in pharmacokinetic and pharmacodynamic of drug responses, co-morbid conditions, and polypharmacy ^15-17.

Our study also showed that the female gender reported more ADRs than males, similar to other studies. An increased number of drugs prescribed to females is a possible explanation.

Other probable factors include differences in weight, body mass index, fat composition, and hormonal changes in different phases (menstruation, pregnancy, lactation, menopause) ¹⁸.

System Organ Class Analysis: According to MeDRA classification of ADR, as shown in Table 1, skin and subcutaneous tissue disorders were the most affected system with 47.67% of all ADRs reported, followed by Gastrointestinal disorders (23 %), nervous system disorders (13.95 %) and General disorders and administration site conditions (5.81 %). Similar findings were observed by Jung IY et al. Dermatitis was the most common preferred term (16.28 %), followed by vomiting (11.63%) and pruritus (10. 47 %). Patients are more cautious about skin-related issues, leading to frequent hospital visits ¹⁹.

TABLE 1: CLASSIFICATION OF ADR ACCORDING TO MEDRA

Causality and severity assessment

The Causality assessment, according to Naranjo’s algorithm, is shown in Fig. 1, 62.67 % ADRs were classified as ‘probable’ and 36.67 % ADRs as ‘possible.

FIG. 1: CAUSALITY ASSESSMENT OF REPORTED ADR ACCORDING TO NARANJO’S SCALE

FIG. 2: SEVERITY ASSESSMENT OF REPORTED ADR ACCORDING TO MODIFIED HARTWIG AND SIEGEL SCALE

Main reason for probable category being common is health care professionals who confirmed first for any cause of ADR and responsible drug for ADR clinically along with laboratory parameters, and then they sent us ADR information ²⁸. The severity assessment according to modified Hartwig and Siegel scale as shown in Fig. 2, with majority being classified as moderate (62.66 %) followed by mild (36 %) and severe (0.67 %) adverse drug reactions. This result is in line with several other studies ²⁵.

Drug Class Analysis: Antimicrobials were the most common group of drugs responsible for ADR reports (82, 44.3%) followed by analgesics (33, 17.8%) and drugs acting on the central nervous system fulfilled (40, 21.62 %) of ADR reports Fig. 3.

FIG. 3: DRUG ANALYSIS (185 DRUGS/150 ADR FORMS)

Table 2 shows antimicrobials involved in ADR. Out of 82 antimicrobial agents, drug groups are fluoroquinolones (27,14.6%) and  nitroimidazoles (14, 7.6%) were two classes most commonly implicated in reports followed by cephalosporins (13, 7%), penicillins (9, 4.9%), antitubercular drugs (8,4.3%), antimalarial drugs (4,2.2%) cotrimoxazole (2, 1.1%), macrolides (2, 1.1%) & antifungal agents (2, 1.1%). The other group of drugs represented fewer than 3 % of ADR. Out of 63 suspected ADRs due to 82 antimicrobial agents, 52 (63.41%) belonged to dermatology while 16 (19.51%) belonged to the gastrointestinal system. Amidst these 63 suspected ADRs, the male to female ratio was 1.03%. The range of duration of suspected ADRs due to antimicrobials was less than one day to 10 days.

TABLE 2: ANTIMICROBIALS INVOLVED IN ADVERSE DRUG REACTIONS

In the present study, antimicrobials were the most commonly reported group responsible for the occurrence of suspected ADRs. In one study conducted at an Indian tertiary care hospital, antimicrobials were responsible for 40.9% of ADRs and an Australian tertiary center reported that antimicrobials were related to 25% of ADRs ^19-21. It is likely that Antimicrobial agents are the most commonly prescribed medication worldwide, and their usage is continuously increasing ^22-24.

Among all antimicrobials, fluoroquinolones were top reported drug group, followed by nitroimidazole and cephalosporins, as they were the most prescribed antimicrobial agents at our hospital. NSAIDs were the second most responsible for ADRs because conventional usage is a popular prescription pattern all over India ²⁸.

Jung IY et al. 2017 reported that fluoroquinolones were the second most frequent cause of ADRs among antimicrobials, accounting for 16% of cases ¹⁹. Two studies found that third-generation cephalosporins were more responsible compared to other generations cephalosporins ^{29, 30}. In the present study, ceftriaxone was the only cephalosporin responsible for the occurrence of ADRs. It has been suggested that there is no other available cephalosporin in hospitalized patients in the present institute.

We reported approximately 12 to 13 suspected ADR forms per month. Hence, the total numbers of reported suspected ADR forms were 150 in a span of one year. This result suggests that the ADR reporting rate is low in this study, while dikshit et al. and Jose et al show that the average ADR reporting is 28 and 34 per month, respectively ^{31, 32}. Low ADR reporting may be due to overburdened or inattention toward ADR reporting by doctors and nursing staff. Negligence towards mild and common ADRs to report and lack of guidelines also contribute to under-reporting ADRs. Due to limited manpower and the absence of a database of drug prescriptions, it was impossible to find out the actual incidence of ADRs to drugs as there was no denominator. The authors observed only frequently responsible drugs for ADRs. They also could not apply the preventability of ADR. Despite some limitations in the study, data obtained from this research will be useful for clinicians regarding proper drug selection and limiting the unnecessary use of AMA and NSAIDs. It also reflects the need to carefully measure safety, monitoring, preventability, and treatment of adverse drug reactions of drugs ³³. The pattern of ADRs reported in our hospital provides data of ADRs due to frequent drugs used at our hospital. It will be helpful to clinicians for optimum and safe use of these drugs. Hence, continuous efforts are required for the safety assessment of drugs.

CONCLUSION: Insignificant ADR reporting observed in the spontaneous ADR reporting system is a major concern. Continuous efforts like training, sensitization, and collaboration of health care professionals are required for up-gradation in ADR reporting.

ACKNOWLEDGEMENT: We are thankful to the Dean, GMERS Medical College, and the Medical Superintendent, GMERS General Hospital, Gandhinagar, for their kind support for the conduct of the study.

Funding: None

CONFLICTS OF INTEREST: None declared.

REFERENCES:

1. Venkatasubbaiah M, Reddy PD and Satyanarayana SV: Analysis and reporting of adverse drug reactions at a tertiary care teaching hospital. Alexandria Journal of Medicine 2018; 54(4): 597-603.
2. Sherfa A, Haile D, Yihune M and Sako S: Incidence and predictors of Adverse Drug Reaction (ADR) among adult HIV positive patients on anti-retroviral treatment in Arba Minch town public health facilities, southern Ethiopia: a retrospective cohort study. PLoS One 2021; 16(5): 0251763.
3. Jose J, Al Rubaie MH, Al Ramimmy H and Varughese SS: Pharmacovigilance: Basic concepts and an overview of the system in Oman. Sultan Qaboos University Medical Journal 2021; 21(2): 161.
4. World Health Organization policy on Safety of Medicines in Public Health Programmes: Pharmacovigilance an essential tool (2006). Available at http://www. who.int/medicines/areas/quality_safety/safety_efficacy/Pharmacovigilance_B.pdf?ua=1, (Accessed 02 June 2021).
5. Alomar M, Tawfiq AM, Hassan N and Palaian S: Post marketing surveillance of suspected adverse drug reactions through spontaneous reporting: Current status, challenges and the future. Therapeutic Advances in Drug Safety 2020; 11: 2042098620938595.
6. Kalaiselvan V, Srivastava S, Singh A and Gupta SK: Pharmacovigilance in India: present scenario and future challenges. Drug Safety 2019; 42(3): 339-46.
7. Ghaziabad: Indian Pharmacopoeia Commission performance report on Pharmacovigilance Programme of India (PvPI) Updates (2021). Available at:https://ipc.gov.in/mandates/pvpi/pvpi-updates/8-category-en/646-annual-performance-report [Accessed on August 2021]
8. Patel KJ, Panchasara AK, Barvaliya MJ and Tripathi CB: Analysis of spontaneously reported adverse drug reactions to pharmacovigilance cell of a tertiary care hospital. International Journal of Basic & Clinical Pharmacology 2018; 7(8): 1551.
9. Hennessy S and Strom B: PDUFA Reauthorization — Drug Safety's Golden Moment of Opportunity. The New England Journal of Medicine 2007; 356: 1703-4.
10. Introductory Guide MedDRA Version 23.0 March 2020,000417. Available at: http://www.who.int/https://admin.new.meddra.org/sites/default/files/guidance/file/intguide_%2023_0_English.pdf [Last accessed on May 2021]
11. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I and Roberts EA: Method for estimating the probability of adverse drug reactions. Clinical Pharmacology & Therapeutics 1981; 80: 289-95.
12. Hartwig SC, Siegel J and Schneider PJ: Preventability and severity assessment in reporting adverse drug reactions. American J of Hospital Pharmacy 1992; 49: 2229-32.
13. Pharmacovigilance Programme of India (PvPI) and Advantages of Enrolment as Adverse Drug Reaction Monitoring Centre (AMC) under PvPI (Annexure-I). Available at: https://pci.nic.in/pdf/14-190_circular_16082021.pdf [Last accessed on August 2021]
14. Wang N, Chen Y, Ren B, Xiang Y, Zhao N, Zhan X and Feng B: A cross-sectional study: comparison of public perceptions of adverse drug reaction reporting and monitoring in eastern and western China. Brihanmumbai Municipal Corporation Health Services Research 2022; 22(1): 1-1.
15. Mehta P, Rathore U, Naveen R, Chatterjee R, Agarwal V, Aggarwal R and Gupta L: Prevalent Drug Usage Practices in Adults and Children With Idiopathic Inflammatory Myopathies: Registry-Based Analysis From the MyoCite Cohort. J of Clinical Rheumatology 2022; 28(2): 89-96.
16. Yadesa TM, Kitutu FE, Tamukong R and Alele PE: Predictors of hospital-acquired adverse drug reactions: a cohort of Ugandan older adults. Brihanmumbai Municipal Corporation 2022; 22(1): 1-1.
17. Won SH, Suh SY, Yim E and Ahn HY: Risk Factors Related to Serious Adverse Drug Reactions Reported through Electronic Submission during Hospitalization in Elderly Patients. Kore J of Fam Med 2022; 43(2): 125-31.
18. De Vries ST: Sex differences in adverse drug reactions reported to the National Pharmacovigilance Centre in the Netherlands: An explorative observational study. British Journal of Clinical Pharmacology 2019; 85(7): 1507–1515.
19. Jung IY, Kim JJ, Lee SJ and Kim J: Antibiotic-Related Adverse Drug Reactions at a Tertiary Care Hospital in South Korea. Biomed Research Inter 2017; 4304973.
20. Geer M, Koul P, Tanki S and Shah M: Frequency, types, severity, preventability and costs of Adverse Drug Reactions at a tertiary care hospital. J of Pharmacological and Toxicological Methods 2016; 81: 323–34.
21. Costa MJ, Herdeiro MT, Polónia JJ, Ribeiro-Vaz I, Botelho C, Castro E and Cernadas J: Type B adverse drug reactions reported by an immunoallergology department. Pharmacy Practice (Granada) 2018; 16(1).
22. Iftikhar S, Sarwar MR, Saqib A and Sarfraz M: Causality and preventability assessment of adverse drug reactions and adverse drug events of antibiotics among hospitalized patients: A multicenter, cross-sectional study in Lahore, Pakistan. PloS One 2018; 13(6): 0199456.
23. Miranda-Novales MG, Flores-Moreno K, López-Vidal Y, Rodríguez-Álvarez M, Solórzano-Santos F, Soto-Hernández JL and Ponce de León-Rosales S: Antimicrobial resistance and antibiotic consumption in Mexican hospitals. Salud Públ de México 2022; 62: 42-9.
24. Zumaya-Estrada FA, Ponce-de-León-Garduño A, Ortiz-Brizuela E, Tinoco-Favila JC, Cornejo-Juárez P, Vilar-Compte D, Sassoé-González A, Saturno-Hernandez PJ and Alpuche-Aranda CM: Point Prevalence Survey of Antimicrobial Use in Four Tertiary Care Hospitals in Mexico. Infection and Drug Resistance 2021; 14: 4553.
25. Joseph SG and Badyal DK: Spontaneous adverse drug reaction monitoring in a tertiary care hospital in Northern India. JK Science 2016; 18(2): 103.
26. Klein EY, Van Boeckel TP and Martinez EM: Global increase and geographic convergence in antibiotic consumption between 2000 and 2015. Proceeding of National Academy of Sciences of the Unites States of America 2018; 115(15): 3463–70.
27. Dadgostar P: Antimicrobial resistance: implications and costs. Infection and Drug Resistance 2019; 12: 3903.
28. Mendes D, Oliveira AR, Alves C and Batel Marques F: Spontaneous reports of hypersensitivity adverse drug reactions in Portugal: A retrospective analysis. Expert Opinion on Drug Safety 2020; 19(6):763-9.
29. Agrawal M, Singh P and Joshi U: Antimicrobials associated adverse drug reaction profiling: a four years retrospective study (Pharmacovigilance study). Alexandria Journal of Medicine 2021; 57(1): 177-87.
30. Karaismailoglu B, Saltoglu N, Balkan II, Mete B, Tabak F and Ozturk R: A prospective pharmacovigilance study in the infectious diseases unit of a tertiary care hospital. The J of Inf in Developing Countries 2019; 13(07): 649-55.
31. Dikshit RK, Desai C and Desai MK: The pleasures and the pains of running a pharmacovigilance center. Indian journal of Pharmacology 2008; 40: 31-34.
32. Jose J and Rao PG: The pattern of adverse drug reactions which was notified by spontaneous reporting in an Indian tertiary care teaching hospital. Pharmacological Research 2006; 54: 226–33.
33. Elena Lopez-Gonzalez and Maria T: Determinants of under-reporting of adverse drug reactions. Drug safety 2009; 32:19- 31.
    

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    How to cite this article:

    Shukla A, Barot P and Dave D: Pattern, causality assessment and severity of suspected adverse drug reactions reported at tertiary care teaching Hospital. Int J Pharm Sci & Res 2022; 13(12): 5001-06. doi: 10.13040/IJPSR.0975-8232.13(12).5001-06.

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