Current Drug Safety - Volume 18, Issue 1, 2023

The history of pharmacovigilance started back 169 years ago with the death of a 15- year-old girl, Hannah greener. However, the Thalidomide incident of 1961 brought a sharp change in the pharmacovigilance process, with adverse drug reaction reporting being systematic, spontaneous, and regulated timely. Therefore, continuous monitoring of marketed drugs was essential to ensure the safety of public health. Any observed adverse drug reaction detected by signals was to be reported by the health profession. Moreover, signal detection became the primary goal of pharmacovigilance based on reported cases. Among various methods used for signal detection, the Spontaneous Reporting System was most widely preferred; although, it had the limitation of "under- reporting”. Gradually, the World Health Organization collaborating centre and “Uppsala Monitoring Centre” were established in 1978 for international monitoring of drugs. The centre was responsible for operating various databases like vigiflow, vigibase, vigilyze, and vigiaccess. Recently, huge data could be generated through spontaneous reporting linked with computational methods, such as Bayesian Framework, E-Synthesis. Furthermore, drug safety surveillance at an early stage prior to the official alerts or regulatory changes was made possible through social media. In addition, India created a National Pharmacovigilance Program, and Schedule Y of the Drug and Cosmetic Act 1945 was reviewed and amended in 2005. The collaboration of Information Technology and Pharmaceutical Company can further enhance the awareness regarding artificial intelligence in pharmacovigilance, which was in its infancy until 2017. Artificial intelligence helps improve the quality and accuracy of information much quickly.

Background: There are various vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, vaccination may lead to some complications. Objective: This study aimed to investigate the complications of transplant recipients who received the Sinopharm COVID-19 vaccine. Methods: This was a retrospective cross-sectional study conducted among 667 transplant recipients (211 liver transplant recipients and 456 kidney transplant recipients) who received the Sinopharm COVID-19 vaccine from March to August 2021 and had medical records in Montaserieh Hospital, affiliated to Mashhad University of Medical Sciences, Mashhad, Iran. The demographic and clinical information, as well as patient's symptoms after each dose of the vaccine, were recorded. Results: Only 16.8% and 13.7% of the patients experienced some symptoms following the first and second doses of the Sinopharm vaccine, respectively. No significant difference was observed between patients younger than 50 years and those aged 50 years and over in terms of the complication rate of the Sinopharm vaccine (P>0.005). Vaccine failure was reported in 10% of the cases; however, the mortality rate due to infection with the Delta variant of COVID-19 in this population was reported to be 0.7%. Conclusion: Based on the obtained results, adverse reactions of the Sinopharm COVID-19 vaccine are generally mild, predictable, and non-life-threatening both in the first and second doses. Vaccine failure was reported in 10% of the cases; however, mortality due to infection with the Delta variant of COVID-19 was reported in less than 1% of the cases.

Aims: To identify the extent and associated factors for patients with prolonged prothrombin time, international normalized ratio (PT-INR), and the dosage modifications were carried out with warfarin. Background: Studies evaluating patients on warfarin with supratherapeutic anticoagulation are limited. It is vital to understand the management strategies for patients receiving warfarin who are bleeding and those with only supratherapeutic PT-INR. Objective: To evaluate the factors associated with supratherapeutic anticoagulation without bleeding with warfarin. Methods: A cross-sectional study was carried out on patients receiving long-term warfarin with at least one PT-INR value > 3.2. Percent time in therapeutic range (TTR) was calculated and National Institute for Health and Care Excellence (NICE) guidelines were adhered to defining anticoagulation control into good (> 65%) and poor (< 65%). Results: One hundred and forty-four patients were recruited. Nearly half of the study population had PT-INR values between 3.2 and 3.9. On average, individuals had at least 4 times PT-INR values in the supratherapeutic range. Elderly patients were observed with a significant trend of supratherapeutic INR. Duration of therapy was significantly correlated with the risk of PT-INR > 4. Lower TTR was observed in patients with frequent PT-INR > 4 and those patients had significantly poor anticoagulation control. Duration of warfarin therapy and HAS-BLED scores were observed to be significant predictors of supratherapeutic INR. Large variations were observed in the modifications of warfarin dose carried out at various supratherapeutic INR values and consequently PTINR values. Conclusion: We observed that the majority of patients with supratherapeutic INR had their INR values between 3.2 and 3.9. Elderly patients, with higher HAS-BLED scores and prolonged duration of warfarin therapy, were observed with an increased risk of supratherapeutic anticoagulation. Careful dosage modifications are needed particularly in high-risk categories as mentioned above.

Background: Nursing students and employees remain the first point of contact in case a patient develops an adverse drug reaction in hospital settings. Thus, it is important for nurses to understand the importance of pharmacovigilance activity and implement the same in their practice. They can also contribute to drug safety by reducing medication errors and adverse drug reaction reporting. Methods: After ethics approval, an observational questionnaire-based study was conducted in 2017 that involved nursing students and nursing employees (N=390) to assess their baseline knowledge, attitude, and practice toward pharmacovigilance. Participants who consented were enrolled and a pre-training survey was conducted. Pharmacovigilance sensitization/ training sessions were conducted in the same year after getting their baseline data. Three years later in 2021, the same questionnaire was distributed to a subset of nursing students and employees (N=299) to analyze any change in their knowledge, attitude, and practice towards the pharmacovigilance activity as a posttest. Pre and post sensitization session questionnaire-based survey data was analyzed to confirm the long-term impact of conducting such pharmacovigilance awareness training. Results: The nurses’ overall performance before and after training in each of the domains of knowledge, attitude and practice were 17.53%, 72.86%, 39.69% in the pretest group, respectively, and post test scores were 30.77%, OR-3.04, p=0.0 (Knowledge), 85.92%, OR-0.14, p=0.0 (Attitude) and 37.21%, OR-0.08, p=0.08 (Practice) in the corresponding domain. Overall, there was a declining trend in the practice domain of the nurses response between the pre-test and post intervention groups however this decline was not statistically significant (p=0.08). Conclusion: Pharmacovigilance awareness training and sensitization programs had an impact on the knowledge and attitude of nurses but there is a need to ensure that it is implemented in clinical practice.

Introduction: This study was designed to evaluate the sustainability of the impact of educational programs provided by pharmacists on the appropriateness of surgical antibiotic prophylaxis and cost-savings in a short time and a long time after the intervention. Methods and Materials: This prospective educational interventional study was conducted in a tertiary referral hospital for surgery in the West of Iran from September 2018 to October 2019. The study was designed in three phases: pre-intervention phase, short term after the intervention, and six months after the intervention. Within a one month course, several educational sessions regarding the appropriate preoperative antibiotic prophylaxis based on the recommendations of the American Society of Health-System Pharmacists guideline (ASHPs) were provided by a clinical pharmacist in an interactive manner for the surgeons. The appropriateness of antibiotic prophylaxis regarding the necessity for surgical antibiotic prophylaxis use (indication), the choice of antibiotic, the timing of antibiotic administration, the route of administration, the dose of antibiotics, and the total duration of antibiotic prophylaxis were evaluated and compared before and after the educational intervention. Additionally, medication-related costs, non-medication-related costs, antibiotic prophylaxis-related costs, and total costs of care were also assessed before and after the educational intervention. Results: Our survey showed that total adherence to the guideline recommendations among surgeons in our center was relatively low, and in 71.8% of procedures, at least in one of the quality indicators, non-adherence to the guideline recommendations was observed. After the educational intervention, a significant improvement in the rationality of antibiotic prophylaxis, in terms of not administrating antibiotic prophylaxis in procedures without indication, appropriate timing of administration, appropriate antibiotic dose, and appropriate duration of antibiotic prophylaxis, especially in the short time after the intervention was observed that ultimately reduced the medication, non-medication, antibiotic prophylaxis related, and total therapeutic costs. Conclusions: Our survey showed that educational interventions provided by pharmacists in an interactive manner could improve guideline recommendations’ adherence among surgeons, particularly in a short time. Thus, continuous education still should be considered an essential element of a multifaceted intervention for improving guideline adherence.

Background: Remarkable and groundbreaking performances of scientists all over the globe have led to the evolution of COVID-19 vaccines, which are extensively viewed as means to control the epidemic. The primary purpose of this research work was to discover the major side effects of the vaccines, mainly in Homo sapiens. Methods: An online survey was conducted in various cities of Haryana, India, using a trial version of QualtricsCoreXM software to prototype 20 questionnaires. Results: In the survey, 200 candidates participated, among which 83.5% had received Covishield and 16.5% had been vaccinated with Covaxin. Overall 65% of respondents have reported side effects. The major side effects reported were fever, tiredness, myalgia, diarrhea, headache, etc. Conclusion: Succeeding the survey related to the effects of COVID-19 vaccine on non-identical Homo sapiens, generally with respect to their perspective regarding the symptoms of vaccine, both the vaccines were found to have mild side effects which could be easily managed.

Background: Temporal lobe epilepsy (TLE) has the highest probability of becoming resistant. One of the causes was Polymorphism in multidrug resistant-1 (MDR1) C3435T. In Dr. Cipto Mangunkusumo Hospital, potential drug-resistant epilepsy prevalence was 84.51%; 66.6% of them used carbamazepine (CBZ) as antiseizure medication. This comparative cross-sectional study aimed to investigate MDR1 C3435T polymorphism and CBZ plasma level (plCBZ) in Indonesian TLE patients. Methods: TLE patient was selected consecutively; divided into drug-responsive (DRV) and drugresistant (DRE) groups. Healthy subjects were included as a control for the gene polymorphism comparison. MDR1 was identified using the restriction fragment length polymorphism PCR technique; C allele at 159 and 57bp while T allele at 216bp. High-performance liquid chromatography was used to determine plCBZ. Results: There were 86 subjects; 61 in the study group and 25 controls. The genotype distribution between them was 0.58 vs 0.42, x²=0.54, p=0.000. In the study group, CBZ within therapeutic doses (dCBZ) had outreached the therapeutic plCBZ and found similar in all genotypes. DRE criteria were found in 37 subjects. Distribution of C and T in DRV was 0.63 vs 0.37, x²=10.4; and DRE 0.55 vs 0.45 x²=6.17 (p=0.019). In Tukey’s multiple comparison post hoc test, CT in DRV had significantly lower dCBZ (330,36 ± 174,91 mg) and plCBZ (7.15 ± 2.64 mcg/mL) compared to all genotypes in DRE. Whereas mean dCBZ was around 800mg and plCBZ outreached the toxic level; TT was the highest. Conclusion: The genotype MDR1 distribution was similar in the normal population and DRE. Therapeutic plCBZ was achieved using the low dose. CT genotype responds to lower dCBZ, while TT genotype outreached the highest toxic plCBZ.

Background: Cefepime is a fourth-generation cephalosporin with a broad spectrum coverage and anti-pseudomonal activity. The safety profile of cefepime was relatively favourable until neurotoxicity was first reported in 1999. Despite cefepime-induced neurotoxicity (CIN), it continues to be a principal part of parenteral treatment for various infections. Objective: The study aimed to determine the incidence and risk factors for CIN compared to other antibiotics. Methods: A retrospective cohort study was conducted involving 738 patients over eight months in Kasturba Medical College and Hospital, Manipal, India. Patients with cefepime were selected as study cohort (SC; n= 496), and other antibiotics were included in the reference cohort (RC; n=242). Results: The results showed that 53 (10.7%) patients developed neurotoxicity in the SC, whereas 12 (5%) patients in the RC. A significant association was found between neurotoxicity and cefepime use (X² =6.641; p=0.01). SC has a 2.29 times increased risk of neurotoxicity than RC (OR: 2.29; 95% CI: 1.2-4.38). Risk estimation showed that renal failure patients had a 5.5 times higher risk for CIN than non-renal failure patients (OR: 5.5; 95% CI: 2.98 - 10.17). CIN symptoms were disorientation (38.5%), loss of consciousness (23.1%), drowsiness (18.5%), etc. The calculated number needed to harm (NNH) for cefepime was 17.2. Conclusion: The study found a higher incidence of CIN compared to other antibiotics-induced neurotoxicity and a harmful association between cefepime use and CIN development. Besides, renal failure is a risk factor for CIN. Therefore, the study warrants the use of cefepime, where no other alternatives are available.

Background: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system(CNS). It is widely accepted that the development and progression of MS result from aberrant activation of potentially encephalitogenic reactive-T cells against CNS antigens. The pathologic roles of both CD4+ (T helper; Th) and CD8+ T cells have been demonstrated in MS lesions. Objective: In the present work, we applied a series of bioinformatics tools to design a dendritic cell (DC)-targeting Tregitope-based multi-epitope vaccine for MS to induce tolerance in pathogenic myelin-specific T cells. Methods: The 3D structure of anti-DEC205 scFv and the remaining part of the vaccine were modeled by ROSIE Antibody server and ITASSER software, respectively. AIDA web server (ab initio domain assembly server) was applied to assemble two parts of the vaccine and build the full construct. Following modeled structure refinement and validation, physicochemical properties, and allergenicity of the vaccine were assessed. In the final step, in silico cloning was done to ensure high-level expression in the desired host. Results: This vaccine consists of three main parts; 1) Anti-DEC205 scFv antibody, 2) multiepitope vaccine part composed of multiple pathogenic CD4+, and CD8+ T cell epitopes originated from multiple known antigens in MS patients, as well as T-regulatory (Treg)-inducing epitopes (Tregitopes), and 3) vasoactive intestinal peptide (VIP). All parts of the final vaccine were joined together with the help of proper linkers. After vaccine construction, the three-D structure, as well as different physicochemical and immunological features of the vaccine were predicted. Finally, in silico gene cloning was also carried out to assure efficient production of protein vaccine in Escherichia coli K12 expression strain. Conclusion: Computational study revealed that this vaccination can regulate MS disease progression and even relapse by harnessing pathogenic T cells.

Background: Lumacaftor/Ivacaftor (LUM/IVA) is an approved combination therapy for cystic fibrosis (CF) patients homozygous for F508del. Objective: This study aimed to detect changes in liver stiffness measurement (LSM) in patients under this treatment. Methods: The study population consisted of CF patients homozygous for F508del, 6 to 11 years old, who had been treated for six months with LUM/IVA. Shear wave elastography (SWE) was performed in all of them, before and 6 months after the commencement of treatment. Results: Thirty-one patients were included in the study. LSM values after treatment were significantly higher than the values before treatment (medians and interquartile ranges of LSM values before and after treatment: 5.6, 5.3-6.3 kPa and, 6.4, 6.0-7.6 kPa, respectively, p<0.001). Conclusion: SWE can detect early changes in LSM in some CF patients treated with LUM/IVA.

Background: Caffeine enhances the efficacy of non-opioid analgesics. Data on the cardiovascular health effects of caffeine intake are controversial, and studies on the cardiovascular effects of medical caffeine use are lacking. Objective: The study aims to explore the cardiovascular effects of an ibuprofen/caffeine combination in comparison to ibuprofen alone. Methods: Secondary analysis of a previously reported bioequivalence study of a single dose of a fixed dose ibuprofen/caffeine combination (400/100 mg) vs. ibuprofen alone in a randomized, cross-over design in 36 healthy volunteers. Plasma catecholamines were analyzed to enhance mechanistic interpretation of the data. Results: After exclusion of 10 protocol violators (pre-dosing intake of caffeine), vital signs were comparable over a 24-h period in the absence and presence of caffeine. Plasma catecholamine levels were also comparable. Conclusion: These data do not support the hypothesis that occasional intake of a small dose of caffeine as part of pain medication imposes a health risk due to vital sign changes. Based on the proven increase in efficacy, the addition of caffeine to non-opioid analgesics such as IBU has a favorable risk/benefit profile for occasional use.

Introduction: COVID-19 vaccine-induced serious adverse reactions are rare. Hypereosinophilia syndrome with myocarditis has not been reported earlier following BBV152 vaccine administration. Case Presentation: A young man without any co-morbidities presented with persistent periorbital swelling along with itchy swelling over fingers, resting tachycardia, and exertional breathlessness following the first dose of an inactivated SARS-CoV-2 vaccine (BBV152, COVAXIN). On investigation, the patient had elevated blood eosinophils (maximum 21.5% with an absolute eosinophil count of 2767/mm³) and myocarditis (Lake Louise Criteria). He was successfully treated with steroids and supportive treatment. Conclusion: This is the first reported case of hyper-eosinophilia syndrome after COVAXIN administration. Prior history of the allergic disease may be a predisposing factor in this case. Hypereosinophilia can present with variable symptoms. In the current case, myocarditis was present with persistent resting tachycardia and dyspnea. Steroid and antiallergic drugs may be successful for the treatment of vaccine-induced hyper-eosinophilia with myocarditis. Increased vigilance is needed for such adverse events.

Background: Prostate cancer (PC) is the most common type of neoplasm in men and the fourth leading cause of mortality in Brazil. The prostate cancer refractory metastatic castration can be treated with abiraterone acetate (AA). Case Presentation: Its use has been associated with increased survival. However, there are also side effects associated with the use of this drug, such as severe electrolyte disturbances. Conclusion: The objective is to report the clinical case of a patient with castration-resistant metastatic prostate cancer who developed ascending flaccid paralysis secondary to severe hypokalemia, probably due to hyperaldosteronism secondary to the use of Abiraterone Acetate, despite the use of Prednisone.

Background: Bipolar disorder is a chronic psychological disorder, and lithium remains the mainstay of therapy. Lithium toxicity can be acute or chronic and the effects may be disabling or life-threatening. The presence of risk factors can increase the chances of lithium toxicity in a patient on long-term lithium therapy. We hereby report a case of chronic lithium toxicity in a patient with a known case of bipolar disorder. Case Presentation: A 44-year-old female patient with a known case of bipolar disorder presented with altered sensorium, seizures, and renal insufficiency. On admission, the patient was severely dehydrated and the serum lithium level was 3.43 mEq/L. Hemodialysis was performed and she improved gradually. Conclusion: Lithium has constantly proven to be beneficial in lowering suicide rates in bipolar disorder patients over the years since its approval. However, its use is limited due to the risk of toxicity. The chances of developing toxicity are higher in patients on long-term lithium therapy. Patients with high risk factors for toxicity should be monitored frequently as the effects of lithium toxicity can be fatal.

Orthopaedic implant removal is considered a sterile procedure, but the current literature suggests it is associated with around a 20% Surgical Site Infection (SSI) rate. The use of antibiotic prophylaxis is still ambiguous and contentious. Taking into consideration this issue we conducted a meta-analysis for the use of antibiotic prophylaxis in orthopaedic implant removal surgery. Objectives: To determine whether or not antibiotic prophylaxis benefits orthopaedic implant removal surgeries. Methods: Electronic and printed sources were searched up to February 2021 for randomised controlled trials (RCTs) using antibiotic prophylaxis and a control group. Data from eligible studies were pooled for the following outcomes: overall, superficial, and deep surgical site infection (SSI). Pooled odds ratios with a 95% confidence interval (CI) were calculated using Mantel Haenszel fixed-effect model preferentially. Results: Two studies, including 766 patients were included in this meta-analysis. Heterogeneity was not statistically significant between the studies. There was no significant difference in the incidence of overall SSI in cefazolin and normal saline (NS) groups (Pooled OR 0.79; 95% CI 0.53- 1.17). In subgroup analysis, antibiotic prophylaxis showed statistically significant improvement for deep SSI (Pooled OR 0.20; 95% CI 0.06-0.70). Conclusion: Overall incidence of SSI is not reduced after the administration of antibiotic prophylaxis one hour before removal of orthopaedic implants.