ADVERSE DRUG REACTION MONITORING IN A TERTIARY CARE HOSPITAL: A PRELIMINARY APPROACH TO ENHANCE REPORTING

ADVERSE DRUG REACTION MONITORING IN A TERTIARY CARE HOSPITAL: A PRELIMINARY APPROACH TO ENHANCE REPORTING

Aswathi Elisabeth Philip, A. S. Ezhilarasi, V. R. Gautham, Mancy Jose Mattam, Babu Narayanan, Aarthi Prakasam and S. Ramalakshmi *

Department of Pharmacy Practice, K. K. College of Pharmacy, Chennai, Tamil Nadu, India.

ABSTRACT: Background: Adverse drug reaction (ADR) evaluation and monitoring is key for safe medication use. This study aimed to initiate, enhance reporting and support the Pharmacovigilance program of India. Methodology: This prospective observational study on the evaluation of adverse drug reactions was carried out for 6 months with the approval of ethics committee. Using standard tools, data was collected in the Standard suspected ADR reporting form and assessed for causality, severity, and preventability. Complete data were collected until the discharge of the patient. Results: A total of 31 cases were recorded with 33 ADRs. The incidence of ADRs was predominant among the elderly (38.7%). ADRs were more prevalent in females (54.83%) than males. Hypertension was the commonly observed  co-morbidity among the patients enrolled in the study. The most common suspected drug class was antibiotics (48.48%) followed by anti-hypertensive agents (12.12%). Type B adverse reactions were predominant (69.69%) with a higher incidence of cutaneous manifestations (51.61%). On Causality assessment using the WHO-UMC scale, the majority of the ADRs were Probable (83.87 %) and 6.45% were possible. Most of the ADRs were moderate (87.09%) in severity (Hartwig’s scale), and the majority of ADRs were not Preventable (96.77%). Conclusion: This study provides a database of ADRs, which will help the healthcare professionals for optimum and safe use of the drugs.

Keywords: Pharmacovigilance, Adverse drug reaction, Causality assessment, Severity assessment, Preventability assessment

INTRODUCTION: The World Health Organization (WHO) defines pharmacovigilance (PV) as the science and activities relating to detecting, understanding, and prevention of adverse effects or any other drug-related problems ¹. Medication safety monitoring is an essential element of healthcare system for high quality medical care.

In view of it, nationwide Pharmacovigilance program of India (PvPI) was launched by the Ministry of Health and Family Welfare (MoHFW) in the year 2010. Indian Pharmacopeia Commission (IPC) under the MoHFW has been functioning as the National Coordination Centre (NCC) for PvPI since April 2011.Since then; PvPI regularly recommends the drug regulatory authorities and suggests the health care professionals (HCPs) towards safe use of the drugs.

Scenario of Reporting ADR in Hospitals: Three hundred and eleven ADR monitoring centers (AMCs) are established in various medical institutions/hospitals across India to monitor and collect ADR reports under NCC-PvPI ². Spontaneous reporting of ADRs is considered as the foundation of post-marketing drug safety surveillance ³. The main function of spontaneous reporting is to detect early signals of new, rare, and serious ADRs. Under reporting of ADR’s is a common problem in Indian PV system. There is an inadequate nationwide awareness and poor knowledge about PV among health care professionals ⁴.

Lack of knowledge of where and how ADRs should be reported also affects reporting. The reason for poor reporting includes no financial incentives, legal aspects, apprehension that the serious ADRs are already documented when a drug is introduced into the market and that a single report would make no difference, ignorance (that only serious ADRs are to be reported) and lack of time or overload ⁵.

Strategies Undertaken to Improve Reporting of ADR in Hospitals: The major drawback observed in India was poor reporting of ADRs. However, there is an improvement in reporting of ADR after regular training sessions and awareness programs conducted by IPC. A single countrywide specific reporting form should not only be used by the National Pharmacovigilance Centers but also by all registered hospitals, teaching hospitals, Primary health care centers, drug information centers, and pharmacies throughout India.

The Under reporting issues are resolved due to accessible reporting facilities like toll-free dial numbers, messages, mail, ADR forms with vernacular languages and outsourcing of PV activity by different multinational companies with awareness among the healthcare sector and public ^{6, 7}. In light of supporting PVPI, this study was undertaken to initiate and enhance ADR reporting in the hospital.

MATERIALS & METHODS: This prospective observational study was carried out at Vijaya Hospital for 6 months (March-August 2019), after getting approval from the Institutional Ethics Committee (IEC-VCMR)– EC/LTR/2019/049(F) of Vijaya Hospital. All inpatients greater than 18 years of age, of either sex with ADR, were enrolled with written informed consent. Outpatients, patients on chemotherapy, Pediatrics, History of drug abuse, Drug poisoning (intentional and unintentional), Materialistic reactions, and Reaction due to blood and its products were excluded from the study.

Complete data were collected from the case sheets individually, both by visiting the patients or by going through case sheets and consulting the treating clinicians. The data on demographics (age, sex, weight) details, co-morbidities, past and present medication, medical history, newly diagnosed disease, drug treatment regimens and all the lab parameters were collected.

Causality Assessment: Causality assessment (CA) is a method of evaluating the relationship between drugs exposed and reported adverse drug reactions. Causality assessment of ADRs was carried out by using the WHO-UMC scale ⁸. Several criteria, as given below, were used to assess and categorize the identified ADRs in patients

• Time relationship between drug use and the adverse reaction.
• Absence of other competing causes.
• Response to drug on withdrawal or dose reduction (de-challenge).
• Response to drug on re-administration (re-challenge).

The ADRs were classified into Certain, Probable, Possible, Unlikely, Conditional (unclassified), and Unassessable.

Severity Assessment Scale - Hartwig’s Scale: Seriousness of an ADR is related to its life-threatening nature. It defined as any untoward reaction to the medicinal product that may require inpatient hospitalization or may result in prolongation of existing hospitalization, or death. Hartwig’s Severity Assessment Scale was used to evaluate the seriousness of reported ADR based on their life-threatening nature and were classified as Mild (level 1, level 2), Moderate (level 3, level 4), Severe (level 5, level 6, level 7) ⁹.

Preventability Scale - Schumock and Thornton: Modified Schumock and Thornton scale were used to identify the preventability of ADR, thereby improving drug use.

The preventability of the ADR was classified as Definitely Preventable, Probably Preventable, and not Preventable ¹⁰. A regular follow-up of the patients until discharge was carried out.

The identified ADRs were documented in the Indian Pharmacopoeia Commission (IPC version 1.2) documentation form and were reported to the nearest Pharmacovigilance center. All the data collected was entered in Microsoft Excel. Descriptive data analysis was carried out and represented as percentage and frequency.

RESULTS: A total of 33 ADRs in 31 patients were recorded and assessed for 6 months. Among 31 patients, the incidence of ADRs was predominant among the elderly, i.e., > 60 years of age (38.70 %.) Adverse drug reaction observed with respect to age is depicted in Fig. 1.

FIG. 1:  AGE-WISE DISTRIBUTION OF THE STUDY POPULATION

Within the study population, female patients (54.83%) developed more ADR than Male (45.16%). Varied Comorbid condition is a risk factor for causing ADR. The distribution of co-morbidity among the study population is presented in Table 1.

TABLE 1: COMORBIDITIES AMONG THE STUDY POPULATION

Polypharmacy adds on to the risk of causing ADRs. Among the study population, most patients had less than 5 medications (74.19%).

The distribution of concurrent medications with the suspected drug is depicted in Fig. 2.

FIG. 2: NUMBER OF MEDICATIONS PRESCRIBED AMONG THE STUDY POPULATION

The ADRs were commonly observed in the department of general medicine (54.83%), followed by critical care (25.80%) and surgery (19.35%). Of the total (n=33) reactions observed, Type B ADR (69.69%) was predominant followed by Type A (21.21%).

FIG. 3: CLASS OF THE DRUG INVOLVED WITH ADR

Incidences of Type C, D, and F were 3.03% each. Antibiotics were the major class of drug causing ADR, followed by other drug classes as shown in Fig. 3. The distribution of various organs affected is depicted in Fig. 4.

Incidence of ADR was high in a patient receiving drug via the Intravenous route of administration (50%) followed by Oral (40.62%), Intradermal (6.25%), and nebulization (3.125%), Cutaneous Manifestations (n=16) was the commonly observed Adverse Drug Reaction followed by SJS (n=2) and Numbness (n=2).

The drugs involved in these reactions are depicted in Table 2.

FIG. 4: ORGAN / SYSTEM AFFECTED BY ADR

TABLE 2: SPECTRUM OF REACTIONS AND THE DRUGS INVOLVED

Abnormal laboratory values were observed in 7 patients following drug administration. Hyperkalemia was observed with Aldactone-telmisartan, spironolactone (n=2), Hypernatremia with Amlodipine + indapamide (n=1), Elevated liver enzymes with ATT, warfarin (n=1), Elevated blood sugar with Methylprednisolone sodium succinate (n=1) and decreased BP with levosimendon (n=1).

Causality assessment of ADRs using the WHO-UMC scale indicated that most of the ADRs were probable, as illustrated in Fig. 5.

FIG. 5: CAUSALITY ASSESSMENT BASED ON (WHO-UMC SCALE)

The severity assessment of the ADRs indicated 85.29% as moderate, and 14,7% were mild. No severe cases were found during the study period. On the assessment of preventability, most of the ADRs that occurred were not Preventable (96.77%), followed by probably Preventable (3.22%), and none of ADRs were Preventable. About 75.75% of the patients with ADRs were managed by giving specific treatment, 12.12% required supportive care, and 12.12% required drug withdrawal. The fate of the suspected drug is shown in Table 3.

TABLE 3: FATE OF SUSPECTED DRUGS

Upon follow-up of these patients, the outcome of the ADR was good, as 67.74% of the patients recovered from the ADR, 29.03% of the patients were recovering, and 3.22% does not recover because of obesity. The duration of recovery from ADRs is represented in Fig. 6.

FIG. 6: DURATION INVOLVED FOR RECOVERY FROM THE ADR

DISCUSSION: This study identified and reported ADR among inpatients from various departments of a tertiary care hospital for 6 months. Age is a very important factor that affects the occurrence of ADRs. In our study, ADR incidence was predominant among the Elderly (38.7%). It is widely acknowledged that elderly patients are mainly at risk for ADRs ^11-13, primarily due to increased chronic disease, polypharmacy (concomitant prescription of five or more drugs), and age-related physiological changes affecting the pharmacokinetics and pharmacodynamics of drugs. ADR incidences were more common among females (17(54.83%) than males. Interpretations of Global post-marketing surveillance data on spontaneous reports from individual case reports indicate that women, from puberty and onwards and especially in their reproductive years, report more ADRs than men ¹⁴.

The difference in susceptibility pattern of   ADRs between male and female is due to the physiological characteristics, such as weight, intestinal transit velocity and fat percentage, and genetic/metabolic and hormonal differences ¹⁵. Concomitant patient’s disease may also influence susceptibility to ADRs. The commonly observed co-morbidities in our study population were HTN (32.25%), Type 2 DM (19.35%), Respiratory Disorder (12.9%), and CAD (19.67%). The was similar to a prospective cohort study done by Peter U Bassi et al., 16 wherein 36% were hypertensive, 2.2% hypertensive with diabetes, 4.4% were diabetic, and 4.3% were asthmatic. Hypertension and diabetes are some of the factors responsible for causing drug-disease interaction ¹⁷. Taking several drugs, whether prescription or over-the-counter, contributes to the risk of having an ADR. ADRs may occur due to drug interaction, synergism, and additive effect. Our study observed polypharmacy (>5 medications in a prescription) in only 8 patients. In a study by Marisa Rosimeire Ribeiro et al., higher number of medications used during their hospital stay showed a 10% increase in the rate of an overall adverse event indicating a positive correlation between the number of concomitant medications and ADR ¹⁸.

Alcohol affects the metabolism of many drugs, and it facilitates the development of ADRs. Smoking also affects the metabolic process by affecting liver enzymes acting as a potent inducer of the hepatic cytochrome P-450 (CYP) isoenzymes 1A1, 1A2, and, possibly, 2E1¹⁹. In our study, two patients were alcoholics, and one was a chronic smoker. Drug-independent cross-reactive antigens can induce sensitizations, manifesting as a drug allergy. The Frequent drugs involved were with sulfa antibiotics and β-lactams ²⁰. Among the 31 patients, 3 patients had a history of allergies to Diclofenac, Sulpha drugs & Penicillin, respectively. About 69.65% of the ADRs were Type B (69.649%), and one was Type F (telmisartan, aldactone), Type C (Amlodipine induced gingival hypertrophy) each. These findings were consistent with other studies that reported an increased incidence of Type B cutaneous manifestations ^{21, 22}.

The adverse reaction can occur with any class of drugs. According to a study, the most troublesome class of drug contributing to Adverse Drug Reactions was antibiotics ²³. In our study, antibiotics (48.48%) were the most common class of drugs causing ADRs. A study by S. M. Shareef et al., also showed a similar pattern. It is because of the routine practice of these drug groups for prophylactic or curative therapy ²⁴. In India, Cutaneous adverse drug reactions account for 2–5% of all inpatients and a common manifestation of allergic and non-allergic hypersensitivity ¹⁸. In our study, cutaneous manifestations (51.61%) were prevalent, with a very low chance of prevention.

A study done by Pankaj Daulat et al. showed that 26% of the suspected ADRs reported during the study period were skin rashes with swelling ²⁵.

Causality assessment is essential to confirm whether the reaction is because of the drug alone or other pre-disposing factors. Causality assessment was carried out using WHO-UMC scale, which showed a majority of the ADRs as Probable 26 (83.87 %) and (6.45%) were possible. Our study was consistent with a prospective observational study done by Meena Shrivastava et al., which revealed that among 1475 ADRs, most of the ADRs belonged to probable (55.89%)followed by possible categories ²⁶. Among the suspected drug-causing ADR, about 93.75% of the patients were de-challenged with the drug, and 6.25% were re-challenged. Re-challenging in these cases was done based on the risk-benefit ratio. This was consistent with an observational study conducted by S.M. Shareef et al. ²⁴ where 58.02% of the patients were de-challenged, and 38.80 were re-challenged.

Assessment of Severity is also essential to take action against the drug continuation. Most of the study population's ADRs were moderate 27 (87.09%). A study by Jamunarani R et al. reported moderate ADRs (66.7%), and no severe ADRs were found ²⁷.

Assessment of Preventability helps In improving rational drug use. About 96.77% of the ADRs were not preventable. A prospective spontaneous reporting study by M. Shamma et al., conducted in India, also reported that the incidence of ADRs was definitely preventable (55.10%) ²⁸.

Altering a dosage regimen or withdrawing a medicine suspected of causing an ADR are common methods of managing ADRs in practice ²⁹. About 75.75% of patients with ADRs were managed with a specific treatment, mainly antihistamine and steroids, 12.12% of patients required supportive care treatment, followed by withdrawal of the drug (12.12%). Among the 33 ADRs, de-challenge of the suspected drug with specific treatment was given in 62.50% of the patients, de-challenge alone in 28.12%, and 3.125% were substituted with the same class of drug (diuretics- Dytor Plus was substituted with Dytor). This was consistent with the observational study by Jayanthi C R et al., were the suspected drug was withdrawn, and medical treatment was given ³⁰. Among the study population, 67.74% of the patients recovered and managed well. This was consistent with a study by Meda Venkatasubbaiah et al., which also reported a good outcome as most of the patients (67.74%) recovered after the drug withdrawal and/or with the treatment of ADRs ³¹.

As the majority of the patients (48.38%) had less severe hypersensitivity reactions, the duration of recovery was less than one day, and this was consistent with Brahadeesh Mayathevar et al., which also reported improvement within 2-7 days (47.92%), indicating good recovery ^{32, 33}.

CONCLUSION: Adverse reactions are a major inevitable risk factor associated with modern medicines. Identification, treatment, prevention, and reporting not only improve the patient's quality of life but will decrease hospitalization of patients due to ADR and the cost. With continuous awareness and motivation, reporting culture can be Improved  through well organized and dedicated pharmacovigilance system in the hospital. Due to constraints in data collection and the short study period, this study was limited to inpatients. This study also affirms further research on possible intervention strategies to reduce ADR burdens among all patients.

ACKNOWLEDGEMENT: We are thankful to Dr. Shahjahan, O. M, Clinical Pharmacologist, Vijaya Hospital, for his clinical input during data collection.

CONFLICTS OF INTEREST: Authors declare no conflict of interest.

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    How to cite this article:

    Philip AE, Ezhilarasi AS, Rgautham V, Mattam MJ, Narayanan B, Prakasam A and Ramalakshmi S: Adverse drug reaction monitoring in a tertiary care hospital: a preliminary approach to enhance reporting. Int J Pharm Sci & Res 2022; 13(7): 2787-93. doi: 10.13040/IJPSR.0975-8232.13(7).2787-93.

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