Daridorexant, as the first Dual Orexin Receptor Antagonist (DORA) marketed in Europe, offers a novel therapeutic approach to insomnia. However, data regarding its real-world safety are scarce. Thus, the aim of this study was to assess its safety profile using a large-scale pharma-covigilance database. Daridorexant-related Adverse Drug Reaction (ADR) reports from the FDA Adverse Event Reporting System were scrutinized, and ADRs were selected using reporting odds ratio (ROR) as a measure of disproportionality. Frequencies of events related to daridorexant were compared to all other drugs (reference group, RG1) and only to other DORAs (RG2). Only significant disproportionalities to both RGs were evaluated in-depth. A total of 845 dari-dorexant-related reports were selected; nightmares (n = 146; Dari vs. RG1: ROR = 113.74; 95%CI[95.13, 136]; Dari vs. RG2: ROR = 2.35; 95CI%[1.93, 2.85]), depression (n = 22; Dari vs. RG1: 2.13; [1.39, 3.25]; Dari vs. RG2: ROR = 2.31; 95CI%[1.45, 3.67]), and hangover (n = 20; Dari vs. RG1: ROR = 127.92; 95CI%[81.98, 199.62]; Dari vs. RG2: 3.38; [2.04, 5.61]) were considered as safety signals. These data provide valuable insights into the real-world safety profile of dari-dorexant, supporting the existence of safety signals related to nightmares, depression, and hang-over.

Abstract: Our research analyzed the characteristics of phase IV clinical trials in oncology using data from the ClinicalTrials.gov registry. The included trials were conducted between January 2013 and December 2022 and were examined for key characteristics, including outcome measures, interventions, sample sizes, and study design, different cancer types, and geographic regions. Our analysis included 368 phase IV oncology studies. We found that 50% of these studies aimed to examine both safety and efficacy, while 43.5% only reported efficacy outcome measures, and 6.5% only described safety outcome measures. Only 16.9% of studies were powered to detect adverse events with a frequency of 1 in 100. Targeted therapies accounted for the majority of included studies (53.5%), with breast (32.91%) and hematological cancers (25.82%) being the most frequently investigated malignancies. Most phase IV oncology studies lacked sufficient power to detect rare adverse events due to their small sample sizes and instead focused on effectiveness. To ensure that there is no gap in drug safety data collection and detection of rare adverse events due to limited phase IV clinical trials, there is a significant need for additional education and participations by both health care providers and patients in spontaneous reporting processes.

This post-hoc analysis of an Italian active pharmacovigilance study describes pharmacological differences of ADEs leading to emergency department (ED) visit and hospitalization in women and men. During the study period (January 2007 – December 2018), 61,855 reports of ADE leading to ED visit were collected. Overall, 30.6% of ADEs resulted in hospitalization (30% in women and 31% in men). Multivariate logistic regression showed that, among women, drug classes significantly associated with an increased risk of hospitalization were heparins (ROR 1.41, CI 1.13-176), antidepressants (ROR 1.12, CI 1.03-1.23) and antidiabetics (ROR 1.13, CI 1.02-1.24). Among men only vitamin K antagonists (ROR 1.28, CI 1.09-1.50), opioids (ROR 1.30, CI 1.06-1.60) and digitalis glycosides (ROR 1.32, CI 1.09-1.59) were associated with a higher risk of hospitalization. Overall, older age, multiple suspected drugs and the presence of comorbidi-ties were significantly associated with a higher risk of hospitalization. A significantly reduced risk of hospitalization was observed in both women and men experiencing and adverse event following immunization (ROR 0.36, CI 0.27-0.48 and 0.83, 0.42-0.74, respectively) compared to drugs. Results obtained from this real-world analysis highlight important aspects of drug safety between sexes.

Background: There are anecdotal reports on reversible QTc prolongation during therapeutic hypothermia (TH) for moderate to severe neonatal encephalopathy after asphyxia. As the QTc interval is a relevant biomarker to assess safety during medication development, a structured search and review on published neonatal QTc values to generate reference values is warranted to facilate medication development in this specific population. Methods: A structured search and literature assessment (PubMed, Embase, Google Scholar) with ‘Newborn/Infant, QT and hypothermia’ was conducted (October 2021). Retrieved individual values were converted to QTc (Bazett) over postnatal age (day 1-7). Results: We retrieved 94 QTc intervals [during TH (n=50, until day 3) or subsequent normothermia (n=44, day 4-7)] in 33 neonates from 6 publications. The median (range) of QTc intervals during TH was 508 (430-678), and 410 (317-540) ms afterwards (difference 98 ms, or +28 ms/°C decrease). Four additional cohorts (without individual QTc intervals) confirmed the pattern and magnitude of the effect of body temperature on the QTc interval. Conclusions: We added a relevant non-maturational covariate (TH, °C dependent) and generated reference values for the QTc interval in this specific neonatal subpopulation. This knowledge on QTc during TH should be considered and integrated in neonatal medication development.

Introduction Pharmacovigilance may detect safety issues after marketing of medications, and this can result in regulatory action such as direct healthcare professional communications (DHPC). DHPC can be effective in changing prescribing behaviour, however the extent to which prescribers vary in their response to DHPC is unknown. This study aims to explore changes in prescribing and prescribing variation among GP practices following a DHPC on the safety of mirabegron, a medication to treat overactive bladder (OAB). Methods This is an interrupted time series study of English GP practices from 2014-2017. NHS Digital provided monthly statistics on aggregate practice-level prescribing and practice characteristics (practice staff and registered patient profiles, Quality & Outcomes Framework indicators, and deprivation of the practice area). The primary outcome was monthly mirabegron items as a percentage of all OAB drug items. The exposure was a DHPC issued by the European Medicines Agency in September 2015. Variation between practices in mirabegron prescribing before and after the DHPC was assessed using the systematic component of variation (SCV). Multilevel segmented regression with random effects quantified the change in level and trend of prescribing after the DHPC. Practice characteristics were assessed for their association with a reduction in prescribing following the DHPC. Results This study included 7,408 practices. During September 2015, 88.9% of practices prescribed mirabegron and mirabegron composed a mean of 8.2% (SD 6.8) of OAB items. Variation between practices was classified as very high and the median SCV did not change significantly (p=0.11) in the 6 months after the September 2015 DHPC (12.4) compared to before (11.6). Before the DHPC, there was a monthly trend of 0.294 (95%CI, 0.287, 0.301) percentage points increase in mirabegron percentage. There was no significant change in the month immediately after the DHPC (-0.023, 95% CI -0.105 to 0.058) however there was a significant reduction in trend (-0.036, 95% CI -0.049 to -0.023). Higher numbers of registered patients and patients aged ≥65 years, and practice area deprivation were associated with having a significant decrease in level and slope of mirabegron prescribing post-DHPC. Conclusion Variation in mirabegron prescribing was high over the study period and did not change substantively following the DHPC. There was no immediate prescribing change post-DHPC, although the monthly growth did slow. Knowledge of the degree of variation in and determinants of response to safety communications may allow those that do not change prescribing to be provided with additional supports.

QTc interval measurement is a widely used screening tool to assess the risk of cardiac diseases, arrhythmias, and is a useful biomarker for pharmacovigilance. However, interpretation of QTc is difficult in neonates due to hemodynamic maturational changes and uncertainties on reference values. To describe trends in QTc values throughout infancy (1 year of life), and to explore the impact of (non)-maturational changes and medicines exposure, a structured systematic review (PROSPERO CRD42022302296) was performed. In term neonates, a decrease was observed over the first week of life, whereafter values increased until two months of age, followed by a progressive decrease until six months. A similar pattern, with longer QTc values was observed in preterms. QTc is influenced by cord clamping, hemodynamic changes, therapeutic hypothermia, illnesses and sleep, not by sex. Cisapride, domperidone and doxapram result in QTc prolongation in neo-nates. Further research in this age category is needed to improve primary screening practices, earlier detection of risk factors and precision pharmacovigilance.

Objectives: The aim of this study was to assess the knowledge, attitude and practice of healthcare professionals regarding adverse drug reaction [ADR] monitoring and pharmacovigilance [PV] in India. Materials and Methods: It was a questionnaire based cross sectional observational study. Data was collected with the help of data collection Google form that included the demographics and twenty two survey based questions. Data were analysed by using Microsoft Excel sheet, further analysed for results, including frequency, percentage, mean and standard deviation. Result: The questionnaire was filled by two hundred ten healthcare professionals in which 52.9 % were male and 47.10% of female. Most of the respondents were pharm d students (50.47%). Out of the total 91.4% responded to the definition of pharmacovigilance correctly. 87.6% participants said all ADR should be reported. 86.20% participants think Pharmacovigilance should be taught in detail to healthcare professionals. Most of the respondents (43.8%) always informed the patients about ADR while prescribing the medicines. Conclusion: Study revealed most of the participants have good knowledge about ADR and pharmacovigilance. Difficult to decide whether ADR occur or not and extra work load being major factors responsible for under reporting.

Cannabidiol, is the first cannabis-derived drug approved for the treatment of Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and Tuberous Sclerosis Complex (TSC). The current study performed a descriptive analysis followed by a disproportionality analysis of potential adverse events caused by CBD extracted from the database VigiBase®. Further, biological plausibility of the association between CBD and the serotonin 5-HT1A receptor, as possible cause of adverse events was analyzed and discussed. Data were extracted from VigiBase® database using VigiLyze® signal detection and signal management tool. Adverse events in VigiBase® reports were coded using MedDRA, version 19 of Preferred Terms (PTs). Data were uploaded into SPSS software and analyzed via disproportionality analysis. Statistically significant disproportionality signals for CBD were found for “weight decreased” 5.19 (95% CI: 4.54 - 5.70), “hypophagia” 3.68 (95% CI: 3.22 - 5.27), and “insomnia” 1.6 (95% CI: 1.40 - 1.83). Positive IC025 values were found for “weight decreased” (2.2), “hypophagia” (1.3), and “insomnia” (0.5), indicating a surplus of reported cases. CBD’s interactions with 5-HT1A serotonin receptors may offer a potential biological explanation for the occurrence of insomnia in patients. It is noteworthy that the risk profiles mentioned in the prescribing information for CBD as antiepileptic agent by regulatory agencies showed disparities specifically related to the adverse event “insomnia”.

Although marketing authorization holders (MAHs) are involved in monitoring medication safety, it was unclear how they experience their role and current monitoring activities in pregnancy. Therefore, a qualitative study using online focus groups with MAHs and the Belgian umbrella organisation of MAHs was conducted in June-July 2021. In total, 38 representatives of nine organisations participated. Overall, participants reported multiple difficulties with data collection, including underreporting, collection of incomplete information and loss to follow-up. The limited number of high-quality data collected, the unknown denominator and the lack of comparator data complicate MAHs’ data processing activities, preventing them to timely provide evidence in the pregnancy label. Three ‘conflicts’ inherent to the specific position of MAHs were identified explaining the difficulties they experience, i.e., 1) mistrust from patients and healthcare professionals (HCPs); 2) MAHs’ legal obligations and regulatory framework; 3) MAHs’ position outside the healthcare context. To overcome these barriers, MAHs suggested that data registration should occur in close collaboration with patients and HCPs, organized within the healthcare context and performed by using a user-friendly system. In conclusion, the reported difficulties and underlying conflicts of MAHs highlight the need for more effective, collaborative data collection strategies to generate new evidence on this topic.

(1) Background: Antimicrobial resistance (AMR) requires urgent multidisciplinary solutions, and Pharmacovigilance (PV) has the potential to strengthen current antimicrobial stewardship (AMS) strategies. This study aimed to characterise AMR-relevant adverse drug reaction (ADR) reports submitted to The Netherlands Pharmacovigilance Centre (Lareb); (2) Methods: We carried out a descriptive analysis of ADR reports submitted to Lareb, coded with AMR-relevant MedDRA Preferred Terms (PTs).; (3) Results: Between 1998 and Jan 2019, 252 AMR-relevant ADR reports were submitted to Lareb. The most frequent antibiotics were tobramycin (n=89; 35%), colistin (n=30; 11,9%), ciprofloxacin (n=16; 6,35%), doxycycline (n=14; 5,5%) and aztreonam (n=12; 4,76%). The most frequently used PTs were drug ineffective (n=71; 28%), pathogen resistance (n=14; 5%) and drug resistance (n=13; 13%). A total of 119 reports (74%) suggested use-related issues. Watch antibiotics were in 54% of the reports and Reserve antibiotics were in 19%. In the Watch group, “Off label use” and “Product use in unapproved indication” were the most frequent PTs and majority of reports on Reserve antibiotics were coded as “Off label”. (4) Conclusions: Addressing AMR using the PV methods will provide an opportunity for PV expansion and could encourage further investment in both in AMS programs and PV systems.

This study proposes an innovative pharmacovigilance approach, VIGI-4, leveraging ChatGPT Teams Pro version. Our method involves aggregating data from all phase 4 studies published in February 2024 to identify adverse reactions. These results are categorized by disease state alphabetically, demonstrating the method's capacity to generate structured and easily navigable outputs. The results section is tailored to exemplify the valuable, actionable insights attainable through our workflow. This research emphasizes the game-changing potential of integrating advanced technologies such as ChatGPT into pharmacovigilance, signaling a new era in safeguarding drug safety.

Exposure to vaccine lipid nanoparticles, mRNA, adenoviral DNA, and or Spike protein from one of the approved Covid-19 vaccines, or through secondary exposure, as through blood transfusion, is a potential source of harm. Blood reactions are an acknowledged side-effect of Covid-19 vaccination, not limited to hemolysis, paroxysmal nocturnal hemoglobinuria, chronic cold agglutinin disease, immune thrombocytopenia, haemophagocytosis, hemophagocytic lymphohistiocytosis, and many other blood related conditions. The observation of adverse events has motivated investigation into the cardiovascular mechanisms of harm by Covid-19 vaccines, and the biodistribution of vaccine contents. Biodistribution may not be limited to the body of the vaccine recipient, as a growing body of evidence demonstrates the possibility of secondary exposure to vaccine particles. These can be via bodily fluids and include the following routes of exposure: blood transfusion, organ transplantation, breastfeeding, and possibly other means. As covid-19 vaccines are associated with an increased risk of stroke, the persistence of vaccine artifacts in the blood presents a possible threat to a recipient of a blood donation from a vaccinated donor who suffered from vaccine induced thrombosis or thrombocytopenia. (VITT) We assess the feasibility and significance of these risks through an overview of the case report literature of blood disorders in vaccinated individuals, pharmacovigilance reports from the US Vaccine Adverse Events Reporting System (VAERS) and a meta-analysis of the available literature on organ transplants from vaccinated organ donors. Our analysis establishes biological mechanistic plausibility, a coherent safety signal in pharmacovigilance databases for secondary vaccine contents exposure (for the cases of blood transfusion and breastfeeding) and also an elevated level of adverse events in organ transplants from VITT-deceased donors, echoing increases in organ transplantation related complications seen in national statistics for some countries. Secondary exposure to vaccine artifacts is a potential explanation for some of the cases put forth, and requires a deeper investigation.

Background: This study assessed the nephrotoxicity of oral BRAF inhibitors (BRAFi), regorafenib (REG) and encorafenib (ENC), in metastatic colorectal cancer (mCRC), through an analysis of re-ports from the US Food and Drug Administration's Adverse Event Reporting System (FAERS) da-tabase. Methods: A descriptive and disproportional analyses were performed for all reports with ENC and REG as the primary suspect. Results: A total of 379 reports had at least one renal ADR, mainly related to REG (93.1%). Potential safety signals for REG particularly included chromaturia (n = 44; ROR = 12.00, CI 95% = 8.92-16.16; IC = 2.36, IC025-IC075 = 2.06-2.66), hydronephrosis (10; 8.70, 4.67-16.19; 1.85, 1.23-2.47), nephrotic syn-drome (7; 5.73, 2.73-12.03; 1.47, 0.73-2.21), renal impairment (53; 4.16, 3.17-5.45; 1.39, 1.12-1.66), dys-uria (19; 3.06, 1.95-4.81; 1.06, 0.61-1.52), renal failure (38; 1.66, 1.20-2.28; 0.49, 0.17-0.81), and acute kidney injury (AKI) (43; 1.46, 1.08-1.97; 0.37, 0.07-0.67). For ENC, consistent disproportionalities were observed for AKI (n = 11; ROR = 3.79, CI 95% = 2.09-6.90; IC = 1.32, IC025-IC075 = 0.72-1.91) and dysuria (4; 6.50, 2.43-17.39; 1.86, 0.88-2.85). Conclusions: These findings highlighted some not extensively reported renal ADRs that required further investigations to better characterize the safety profile of BRAFi in patients with mCRC.

Background. To determine the effectiveness and safety of meropenem in routine clinical practice, in terms of clinical and microbiological response. Methods. A real-world, observational, descriptive, longitudinal study with daily monitoring of clinical history records was conducted on all patients who were medically prescribed meropenem during a period between October 2015 and March 2016 at a university hospital in Bucaramanga (Colombia). Results. The study evaluated 84 patients with an average age of 63.2 years, mostly older adults with multiple comorbidities, of whom 54.8% were men. A positive clinical or microbiological response was obtained in 98.8% of the patients. At the end of the treatments, significant improvements in dysthermia (0% vs 29% at the beginning, p = 0.000), tachycardia (13% vs 47%, p = 0.049) and leukocytosis (39% vs 15% at the beginning, p = 0.008) were evidenced. The improvement in the indicator that combines all the SIRS criteria was also significant (p = 0.000). The treatment was well tolerated, although we identified some non-serious and expected adverse reactions. Conclusions. Generic meropenem proved to be effective and well tolerated for different types of infection in routine clinical practice. The results are consistent with the findings of the clinical studies with the innovator drug.

Recent media reports commented about a possible antidiabetics’ misuse issue related to molecules promoted as a weight-loss treatment in non-obese people. We evaluated here available pharmacovigilance misuse/abuse signals related to semaglutide, a glucagon-like peptide-1 (GLP-1) analogue, in comparison to other GLP-1 receptor agonists (albiglutide; dulaglutide; exenatide; liraglutide; lixisenatide; tirzepatide) and the phentermine-topiramate combination. To that aim, we analysed the Food and Drug Administration-FDA Adverse Events Reporting System (FAERS) dataset, performing a descriptive analysis of adverse event reports (AER) and calculating related pharmacovigilance measures, including the reporting odds ratio (ROR) and the proportional reporting ratio (PRR). During January 2018-December 2022, a total of 31,542 AER involving the selected molecules were submitted to FAERS; most involved dulaglutide (n=11,858; 37.6%) and semaglutide (n=8,249; 26.1%). In comparing semaglutide vs the remaining nolecules, the AER ‘drug abuse’, ‘drug withdrawal syndrome’, ‘prescription drug used without a prescription’ and ‘intentional product use issue’ respective PRR values were 4.05, 4.05, 3.60 and 1.80 (all<0.01). The same comparisons of semaglutide vs the phentermine-topiramate combination were not associated with any significant differences. To the best of our knowledge, this is the first study documenting the misusing/abusing potential of semaglutide in comparison with other GLP1 analogues and the phentermine-topiramate combination. Current findings will need to be confirmed by further empirical investigations to fully understand the safety profile of those molecules.

Recent media reports commented about a possible antidiabetics’ misuse issue related to molecules promoted as a weight-loss treatment in non-obese people. We here evaluated available pharmacovigilance misuse/abuse signals related to semaglutide, a glucagon-like peptide-1 (GLP-1) analogue, in comparison to other GLP-1 receptor agonists (albiglutide; dulaglutide; exenatide; liraglutide; lixisenatide; tirzepatide) and the phentermine-topiramate combination. To that aim, we analysed the Food and Drug Administration-FDA Adverse Events Reporting System (FAERS) dataset, performing a descriptive analysis of adverse event reports (AER) and calculating related pharmacovigilance measures, including the reporting odds ratio (ROR) and the proportional reporting ratio (PRR). During January 2018-December 2022, a total of 31,542 AER involving the selected molecules were submitted to FAERS; most involved dulaglutide (n=11,858; 37.6%) and semaglutide (n=8,249; 26.1%). In comparing semaglutide vs the remaining antidiabetics, the AER ‘drug abuse’, ‘drug withdrawal syndrome’, ‘prescription drug used without a prescription’ and ‘intentional product use issue’ respective PRR values were 4.05, 4.05, 3.60 and 1.80 (all<0.01). The same comparisons of semaglutide vs the phentermine-topiramate combination were not associated with any significant differences. To our best, this is the first study documenting the misusing/abusing potential of semaglutide in comparison with other novel antidiabetics and the phentermine-topiramate combination. Current findings will need to be confirmed by further empirical investigations to fully understand the safety profile of those molecules.

This study evaluates the incidence and characteristics of adverse events (AEs) following the second COVID-19 booster dose, leveraging Taiwan's distinctive approach of extending booster vaccinations to all citizens, unlike the targeted high-risk group strategies in other countries. Utilizing data from Taipei Veterans General Hospital's Vaccine Adverse Event Reporting System (VAERS) from October 27, 2022, to January 19, 2023, the research examines AEs in 441 out of 1711 second booster recipients, considering factors like age, vaccine brands, and booster combinations. The findings reveal incidence rates (IR) of 25.6% (95% CI: 21.1-30.8) after the first booster and 24.9% (95% CI: 20.5-30.0) after the second, mostly non-serious, with those having AEs post-first booster 5 times more likely to report them again (Incidence rat rato, 5.02, P&lt;0.001). Significantly, switching from the mRNA1273 vaccine to another brand reduced AE risk by 18%. The study underscores that AEs are more repetitive than cumulative with additional booster doses, advocating for personalized vaccination strategies based on individual medical histories and previous vaccine reactions. These insights are valuable for healthcare providers in discussing potential AEs with patients, thereby improving vaccine compliance and public trust, and for policymakers in planning future booster vaccination strategies.

We tested the possibility of using “adverse events count” (AEC) as a drug-risk indicator and side-effect severity indicator. Data from 3938 adverse event (AE) reports for COVID-19 vaccines (Comirnaty, Moderna, Vaxzevria, and Janssen) and 6869 AE reports for other medicines were collected from the Bulgarian Drug Agency database (01.01.2018–31.03.2022). AEC was modeled with zero-adjusted negative binomial (ZANBI) and zero-adjusted Poisson inverse Gaussian (ZAPIG) regression models, which account for zero absence and overdispersion. The models’ fit was checked with residual diagnostic plots and parametric correspondence to normality. Explanatory variables were: age, sex, sequence number (order of submission), severity of AE, and vaccine type. Average AEC was higher in severe vs. non-severe AE, and in females vs. males; it decreased with age and was lower in Comirnaty than other vaccines. Variability of AEC for COVID-19 data decreased with sequence number in severe AE and increased in non-severe AE. Full ZANBI models had greater sensitivity than parametric ZANBI or ZAPIG models. Results showed correlation between AEC and AE severity, suggesting AEC as a simple and reliable measure of drug-risk and side-effect severity for clinicians and regulators, especially for COVID-19 vaccines.