As known “No drug is absolutely free from side effects” in clinical practice. Adverse Drug Reaction (ADR), by World Health Organization (WHO) definition, is “a response to a medicinal product which is noxious, unintended and which occurs at doses normally used in man for prophylaxis, diagnosis or therapy of diseases or for the restoration, correction or modification of physiological function”. Pharmacovigilance (PV) is the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other possible drug-related problems. To enhance patient care and patient safety is the primary aim of pharmacovigilance (Hamidet al., 2022; The Importance of Pharmacovigilance, 2002).

Need of systemic collection of adverse events and thus safety monitoring of drugs in post-marketing setup has been derived from past catastrophes. The first safety concern was raised in 1848 after death of a girl from England following administration of chloroform for anaesthesia for removal of an infected toenail. Thalidomide tragedy with its presence in 46 countries where thousands of children were born with limb deformities demanded a systemic approach for monitoring of post-marketing adverse events (The Importance of Pharmacovigilance, 2002). Unexpected Adverse Drug Reactions (ADRs) are mostly not identified prior to approval of drugs by regulators resulting in increased morbidity and mortality. Pharmacovigilance analysis allows collecting real-world drug safety information. This information is crucial for determining benefit-risk profile of a drug and thus building trust on drug therapies (Garashiet al., 2022).

WHO initiated Programme for International Drug Monitoring (PIDM) in 1968 with a goal to identify rare Adverse Reactions. Over the time, scope of PIDM was expanded to promote PV at country level and collaborate internationally for drug safety monitoring (Olsson, 1998). India joined as a member country to WHO PIDM in 1998 with unsuccessful attempt. Later, National Programme of Pharmacovigilance was launched in 2005 and was renamed to Pharmacovigilance Programme of India (PvPI) in 2010 (Kalaiselvanet al., 2019). PvPI is continuously working hard creating awareness on ADR reporting among the Indian population and to build trust among patients and healthcare professionals with respect to medicines safety. Drug-related morbidity and mortality are reported in studies conducted in Indian tertiary care hospitals. ADRs are a significant concern in tertiary care hospitals, with a prevalence of 28.3% (Raikaret al., 2023). Despite of this fact and PvPI tremendous efforts to establish ADR reporting culture, rate of ADR reporting is less than 1% in India whereas worldwide, it is 5% (Shuklaet al., 2024; Kalaiselvanet al., 2016; Singhet al., 2023). Lack of time, knowledge and attitude of Health Care Professionals (HCPs) towards ADR reporting responsibility are prime factors for under-reporting in India (Rajuet al., 2022; Kumaret al., 2023). HCPs from both private and public hospitals, teaching institutions and pharmaceutical companies are key-players for ADR surveillance and thus for establishment of culture of drug safety (Olssonet al., 2015; Bansodet al., 2020).

The objective of this study was to identify, analyse and understand characteristics of ADRs arise during clinical practice at Parul Sevashram-a tertiary care teaching hospital and thus to contribute in preventing reoccurrence of ADRs. Parul Sevashram is the NABH (National Accreditation Board for Hospitals and Healthcare Providers) accredited multispecialty hospital providing advanced treatments and procedures for wellbeing of the patients in Waghodia region of Vadodara, Gujarat, India. This present study also contributes towards increasing awareness and improving culture of ADR reporting among hospital staff and intern students.

This prospective, non-interventional, observational study was carried out from July 2022 to December 2023 at general medicine department. Study was initiated after obtaining Institutional ethics committee permission (Reference No. PUIECHR/PIMSR/00/081734/4915).

Patients or their guardian who provided consent voluntarily for collection of their treatment and safety data and developed ADR were included in this study.

• ADR associated with use of alternative system of medicines like Ayurveda, Homeopathy, Unani, etc.
• Adverse event developed following vaccine/immunization.
• Adverse drug events due to medical devices.

Patients were included after obtaining their consents. Patients and their guardian were explained about ADR and were encouraged to report and HCPs were informed for reporting of observed ADR. Data were collected by interviewing patients or their guardian and/or reviewing their case records. Any untoward event was labelled as ADR. Data on Patient’s demographics, medical history, prescription medicine and ADR and its outcome were collected on Central Drug Standard Control Organization (CDSCO) ADR reporting form (Central Drug Standard Control Organization (CDSCO), 2022) and then transferred to structured datasheet for further analysis. Data were kept confidential at all levels of handling. Confirmed ADR were submitted to respective unit for reporting to PvPI. Analysis of ADR was performed at Preferred Term (PT) level of the Medical Dictionary for Regulatory Activities (MedDRA) terminology (Medical Ddictionary for Rregulatory Aactivities (MedDRA), 2023). ADR were analysed for the demographic profile of patients, system organ class and causative drugs on the drug substance level, ADR outcome and causality assessment. The seriousness was assessed following standard criteria given by the PvPI and following Important Medical Event (IME) list (Indian Pharmacopoeia Commission (IPC), 2019; EudraVigilance ExpertWorking Group (EV-EWG), 2015). The causality was assessed following World Health Organization Uppsala Monitoring Centre (WHO-UMC) system for standardised case causality assessment (The use of the WHO-UMC system for standardised case causality assessment, 2020). Treating physician’s opinion was considered as final for ADR consideration and related assessment.

The study used descriptive statistics and the values were expressed in absolute numbers and percentages as appropriate with the help of Microsoft Excel.

Total of 125 ADRs were reported among 91 patients during study duration at the study site.

Sex-distribution showed more ADR were reported in female patients (N=55, 60.44%) than in male patients (N=36, N=39.56%).

Overall mean age was 41.66±20.54 years. The age group in the range of 18-65 years with mean age of 45.62 years was most commonly involved in ADR reporting (N=67, 73.63%) followed by below 18 years age group with mean age of 9.37 years (N=16, 17.58%) and above 65 years age group with mean age of 73.36 years (N=8, 8.79%).

Outpatient department cases were in predominance (N=54, 59.34%) compared to inpatient department cases (N=37, 40.6%).

Out of 91 patients, 53 patients (58.24%) reported to have presence of other illness along with treating diseases for which suspect drug was prescribed. Most observed co-morbidity was hypertension (16.98%) followed by renal disorder (13.21%) and hyperchlorhydria (9.43%) and diabetes mellitus (9.43%) among 53 patients who reported comorbidity.

Majority of the patients (N=44, 48.35%) were reported use of other medications concomitantly with suspect drug experienced ADRs. Twenty-four patients (26.37%) were not receiving any concomitant medication and administration of concomitant medication was unknown for 23 patients (25.27%). Out of 44 patients who were on polypharmacy, pantoprazole was found most frequently taken concomitant medication (25%), followed by aspirin and multivitamins each of them accounting 20.45% and ondansetron (18.8%). Analysis of patient demographics was presented in Table 1.

Outof 20 noteddrugclasses, highestnumberof ADRswerereported from the antibiotics class (N=36, 28.8%). This was followed by analgesics (N=15, 12.0%) and then equal number of ADRs from antithrombotic agents and antineoplastic agents (N=12, 9.6%). Detailed list of causative drugs is shown in Table 2. The highest observed drug-ADR pair was spironolactone-Gynecomastia (N=4), followed by polymyxin-acute kidney injury (N=3) and ceftriaxone-eye swelling (N=3).

ADRs were spanning among nineteen SOCs as detailed in Table 3. In our study, general disorders and administration site conditions and skin and subcutaneous tissue disorders were found most frequently affected SOCs recording 19 (15.2%) ADRs. These were followed by SOC gastrointestinal disorders (N=18, 14.4%) and then nervous system disorders (N=14, 11.2%).

As depicted in Table 4, majority of the ADRs were non-serious (N=82, 65.6%) in nature. There were 43 (34.4%) serious ADRs, out of which one (0.80%) was resulted into death, four (3.20%) were life-threatening, 23 (18.40%) were resulted into hospitalization or prolong hospitalization and 15 (12%) were found to be important medical events.

According to WHO-UMC causality scale, association of 63 ADRs (50.4%) were probable to suspect drugs, 61 ADRs (48.8%) were possible and one (0.8%) ADR was unlikely.

Suspect drug withdrawal was noted (dechallenge) in most of the cases (N=70, 76.92%). Treatment with suspect drug was continued in 15 (16.48%) cases and suspect drug was continued at reduced dose in six cases (6.59%). Information on re-challenge was lacking as it was not performed. Among 91 patients, complete recovery was noted in 46 (50.55%) cases and 20 (21.98%) patients were recovering during study period. One case (1.10%) was resulted into fatal outcome; two (2.20%) patients did not recover during study period, while outcome of 22 (24.18%) cases was unknown. Positive dechallenge was observed among 56 (61.54%) patients, who were recovered or under recovery stage upon withdrawal of suspected drug. Case outcome and action with suspect drug were demonstrated in Table 4.

Underreporting of ADRs in India remains a challenge in achieving goal of PvPI towards patient and drug safety. On the other hand, a robust PV system is a need since India is developing as a hub for global clinical studies (Singhet al., 2023). Limitation of underreporting can be minimized by educating health care professionals periodically, developing and maintaining a culture of ADR reporting and reiterating goals of PvPI within organization (Singhet al., 2023; Rajuet al., 2022). Studies on evaluation of knowledge, attitude and practice of pharmacovigilance conducted in various parts of India suggested rate of spontaneous ADR reporting by patients and health-care professionals is low and there is a great need to improve perception for the reporting (The use of the WHO-UMC system for standardised case causality assessment, 2020; Sidhuet al., 2023; Panneerselvamet al., 2022).

By means of this study, we contributed to overcome limitation of underreporting and analyse the profile of ADR occurring at Parul Sevashram extensively. In our study we coded all ADRs with standardised terminology using MedDRA and thus introduced the culture of MedDRA for analysis in the institute. The study results were compared with prospective studies conducted in various parts of India to behold ADR pattern among them. Comparison of prospective study results conducted in various parts of India has been demonstrated in Table 5.

In our study, we found more ADR occurrences in females (60.44%) than males (39.56%) which are in concordance to prospective studies carried out by Raju S et al., Singh P. et al., and Vohra A et al. In contrary, significant number of male patients with severe ADR incidence was reported in the prospective studies carried out by Chhabra M et al., from north India while incidence of ADRs was found similar in males and females by Venkatasubbaiah M et al., from south India. Many drugs manifested elevated blood concentrations and longer eliminations times in women and this sex-biased pharmacokinetics attribute higher ADR incidence in women than men (Zucker and Prendergast, 2020).

In this study, population was classified mainly into three age-groups: paediatric (0-17 years), adult (18-65 years) and geriatrics (>65 years) and adults were found with highest ADR incidence (73.63%). Similar results are also discovered in northern India study (81.48%) conducted by Vohra A et al. Six age-groups were stratified by Raju S et al., with highest ADR recorded from 31-45 years age-group and four age-groups were used by Singh P et al., with highest recorded ADR from 31-60 years age-group as depicted in Table 5. However, older adults (>65 years) are found with more ADR occurrences than younger adults (19-65 years) in study carried out by Dubrall D et al., using ADR database of the German Federal Institute for Drugs and Medical Devices (BfArM).

ADR characteristics found in our study are similar to studies from southern (Rajuet al., 2022), east-central (Singhet al., 2017) and northern India (Vohraet al., 2023). The drug mostly associated with ADR was found to be antibiotics class (Rajuet al., 2022; Singhet al., 2017; Vohraet al., 2023). and a large number of ADRs were observed from dermatological body system class (Rajuet al., 2022; Singhet al., 2017). Vohra A et al. noted highest ADR incidences from Gastro-intestinal followed by dermatology (Vohraet al., 2023). Several other studies across India (Raikaret al., 2023; Kumaret al., 2023; Bansodet al., 2020) also have analogous observation. It is because most of the drugs are capable to cause cutaneous ADRs whereas antibiotics, antiepileptics, antineoplastics, NSAIDs are commonly implicated class of drugs causing cutaneous ADRs (Bettuzziet al., 2024). ADR like Stevens-Johnson syndrome reported in this study is a serious type of cutaneous reaction, mostly drug induced and can be life threatening if timely detection and management are not done and leads to economic burden (Hazinet al., 2008). Therefore, health care professionals should thoroughly review and understand medical history of the patient for any drug allergy. ADRs from general disorders and administration site conditions system organ class was also equally distributed in current study.

Preponderance of non-serious ADRs was noted as demonstrated in Table 5. One death was observed in this study though it was not directly attributed to ADR but due to co-morbidity. Incidence of fatal ADRs was less than 1% in other Indian studies also (Rajuet al., 2022; Venkatasubbaiahet al., 2018). Recovery has been reported in majority cases in our study similar to southern India study (Rajuet al., 2022) suggesting capabilities of Indian health care system in managing the outcome well. Discontinuation of suspect drug was found as a common pattern in ADR management in this study and other Indian studies (Rajuet al., 2022; Singhet al., 2017).

Causality assessment is an important parameter of ADR analysis to measure degree of likelihood. In pharmacovigilance, adverse reactions are rarely specific for the drug, diagnostic tests are usually absent and rechallenge is rarely ethically justified. WHO-UMC causality assessment offers assessment based on clinical-pharmacological aspects of the case history and the quality of the documentation and hence it is widely acceptable for real-life case reports (The use of the WHO-UMC system for standardised case causality assessment, 2020). Therefore, we choose WHO-UMC causality assessment for our study over other algorithms which are too specific for general use for spontaneous reporting system. In present study, little more than 50% ADR were found probably associated with suspect drug. Similar result was also found in studies from southern India (Rajuet al., 2022), east-central India (Singhet al., 2017) and northern India (Vohraet al., 2023) which reported 66%, 67.24% and 55.6% ADR probably related to suspect drug respectively. Through this comparison, we have tried to provide insights on characteristics of ADR originated from various regions for health care professionals practicing in diversified culture of India.

The pharmacovigilance study conducted at Parul Sevashram Hospital represents a pioneering effort using standardized MedDRA coding for Adverse Drug Reactions (ADR), ensuring consistent reporting and information exchange among healthcare professionals, regulators, academics and organizations. This study provided valuable insights into ADR analysis, offering a comprehensive understanding of the ADR profile specific to our hospital. It underscored increased awareness and reporting of ADRs within our institution, particularly noting antibiotics as the primary contributors to ADRs in Indian healthcare settings. The widespread use of antibiotics poses a significant risk of antimicrobial resistance, carrying substantial economic implications.

Although the study did not identify any signals for serious conditions like Stevens-Johnson syndrome among patients receiving ceftriaxone, it emphasized the importance of monitoring and reviewing medical histories to detect drug hypersensitivity effectively. However, the study also highlighted challenges such as inadequate vigilance and time constraints among healthcare providers at tertiary care centers, leading to underreporting and compromising the quality of ADR data in India’s pharmacovigilance system.

Notably, the study did not report any cases of medication errors, overdoses, abuses, misuses, or occupational exposures during its duration. To enhance ADR reporting, the study recommends periodic awareness sessions focusing on ADR reporting protocols, maternal and fetal exposures and other specialized scenarios. It advocates for more extensive observational studies in India to address these gaps, as such situations are often overlooked in controlled clinical trial environments.

Overall, this pharmacovigilance study serves as a critical tool to raise awareness among the Indian population, address underreporting issues and support the PvPI mission of enhancing patient safety.

The authors acknowledge the support received from medical director and hospital staff of Parul Sevashram and Department of Pharmacology.