Unexpected Adverse Drug Reactions Research Articles

Efficacy and safety of biosimilar trastuzumab (CT-P6) in routine clinical practice in the Republic of Korea: a real-world post-marketing surveillance study

ABSTRACT Background The trastuzumab biosimilar CT-P6 is approved for human epidermal growth factor receptor 2 (HER2)–positive early breast cancer (EBC), metastatic breast cancer (MBC), and metastatic gastric cancer (MGC). The objective of this post-marketing surveillance (PMS) study was to evaluate the real-world safety and effectiveness of CT-P6 in patients with HER2-positive cancers. Research design and methods This open-label, observational, prospective, PMS study collected data via investigator surveys from 35 centers in the Republic of Korea (5 October 2018–4 October 2022). Eligible patients with HER2-positive EBC, MBC, or MGC started CT-P6 treatment during routine clinical practice, followed by 1-year observation. Evaluations included adverse events (AEs), adverse drug reactions (ADRs), and effectiveness. Results Safety was analyzed in 642 patients (494 EBC, 94 MBC, 54 MGC). Overall, 325 (50.6%) patients experienced 1316 AEs, and 550 ADRs occurred in 199 (31.0%) patients. Unexpected ADRs occurred in 62 (9.7%) patients. Unexpected ADRs and ADRs of special interest did not raise any new safety signals. Among trastuzumab-naïve patients, 34/106 (32.1%) with EBC achieved pathological complete response; 30/74 (40.5%) MBC and 24/49 (49.0%) MGC patients achieved complete or partial response. Conclusions In a real-world setting, CT-P6 demonstrated safety and efficacy findings consistent with previous CT-P6 studies.

Profile of adverse drug reactions reported via the Continuum+ platform: Results from three-year regional follow-up

In 2017, the Continuum+ platform was launched to provide a monitoring solution to home-based cancer care patients: AKO@dom monitoring. This platform also offers the follow-up of adverse drug reactions (ADRs) via direct notification to regional centers of pharmacovigilance (RCPVs). According to previous studies, the AKO@dom monitoring has successfully maintained treatment at the maximum effective dosage, managing ADRs and patient satisfaction. However, on the pharmacovigilance side, opinions are more divided. Due to the launch of the AKO@dom-PICTO experimentation in December 2021, in which our RCPV takes part, and to provide more data on pharmacovigilance, we decided to conduct a descriptive analysis of cases reported to our RCPV via the Continuum+ platform between 2019 and 2022. During these three years, we analyzed 1070 events, corresponding to 37patients. Patients were primarily women (74.8%) aged around seventy with breast cancer. The most used drugs were tyrosine kinase inhibitors: palbociclib (29.7%), axitinib (16.2%), and cabozantinib (13.2%). Patients had an average of 8 ADRs, including one serious and/or unexpected ADR. Although the Continuum+ platform makes it possible to considerably limit under-reporting in pharmacovigilance, it has shortcomings. The lack of medical elements and context in notifications is a massive problem for analyzing pharmacovigilance reports. Improved access to the platform's medical information for RCPVs and pharmacovigilance training for healthcare professionals would make Continuum+ a helpful tool in pharmacovigilance.

Novel insights into post-marketing adverse events associated with lenvatinib: A comprehensive analysis utilizing the FAERS database

PurposeThe primary aim of this study was to closely monitor and identify adverse events (AEs) linked to lenvatinib, a pharmacotherapeutic agent employed for the management of renal cell carcinoma, thyroid cancer, and hepatocellular carcinoma. The ultimate goal was to optimize patient safety and provide evidence-based guidance for the appropriate utilization of this medication. MethodsA comprehensive collection and analysis of reports from the FDA Adverse Event Reporting System (FAERS) database was conducted, encompassing the period from the first quarter of 2015 to the first quarter of 2023. Disproportionality analysis, employing robust algorithms including ROR, PRR, BCPNN, and EBGM was employed for effective data mining to quantify signals associated with lenvatinib-related AEs. ResultsAmong the collected reports, a total of 15,193 cases were identified where lenvatinib was the "primary suspected (PS)" drug, resulting in 50,508 lenvatinib-induced AEs. An analysis was conducted to examine the occurrence of lenvatinib-induced adverse drug reactions (ADRs) across 26 organ systems. The findings revealed the presence of expected ADRs, including diarrhea, vomiting, stomatitis, hepatic encephalopathy, decreased appetite, dehydration, decreased weight, and electrolyte imbalances, which were consistent with the information provided in the drug labels. Furthermore, unexpected significant ADRs were observed at the preferred terms (PT) level, such as interstitial lung disease, pneumothorax, hypophysitis, failure to thrive, polycythemia, hypopituitarism, spontaneous pneumothorax, pulmonary cavitation, and limbic encephalitis. These findings indicated the potential occurrence of adverse effects that are currently not documented in the drug instructions. ConclusionsThis study has successfully detected novel and unforeseen signals pertaining to ADRs associated with the administration of lenvatinib, thereby contributing significant insights into the intricate correlation between ADRs and the utilization of lenvatinib. The outcomes of this investigation underscore the utmost significance of continuous monitoring and vigilant surveillance in order to promptly identify and effectively manage AEs, consequently enhancing overall patient safety and well-being in the context of lenvatinib therapy.

New Adverse Drug Reaction Signals from 2017 to 2021-Genuine Alerts or False Alarms?

Spontaneous adverse events reporting systems are used internationally to flag new or unexpected adverse drug reactions (ADRs). Disproportionality analysis is a recognised technique, but false alarms may arise. We aimed to determine whether these new ADR signals had subsequently been followed-up with detailed hypothesis-testing studies. We searched PubMed to identify published studies (years 2017-2021) where the authors reported findings of new ADR signals from disproportionality analyses. We used PubMed and forward citation tracking (Google Scholar) to identify any subsequent confirmatory studies of these ADR signals. We screened 414 titles and abstracts and checked the full-text articles of 57 studies. We found signals for 56 suspected new ADRs from 24 drugs. Google Scholar showed that the ADR studies had been cited a median of seven times (range 0-61). However, none of the suspected new ADRs had undergone detailed evaluation in the citing literature. Similarly, our PubMed search did not find any confirmation studies for the 56 suspected new ADRs. Although many suspected new ADR signals have been identified through disproportionality analysis, most signals have not been further verified as being either genuine ADRs or false alarms. Researchers must focus on follow-up studies for these new signals.

Non-Negative matrix factorization combined with kernel regression for the prediction of adverse drug reaction profiles.

Post-market unexpected Adverse Drug Reactions (ADRs) are associated with significant costs, in both financial burden and human health. Due to the high cost and time required to run clinical trials, there is significant interest in accurate computational methods that can aid in the prediction of ADRs for new drugs. As a machine learning task, ADR prediction is made more challenging due to a high degree of class imbalance and existing methods do not successfully balance the requirement to detect the minority cases (true positives for ADR), as measured by the Area Under the Precision-Recall (AUPR) curve with the ability to separate true positives from true negatives [as measured by the Area Under the Receiver Operating Characteristic (AUROC) curve]. Surprisingly, the performance of most existing methods is worse than a naïve method that attributes ADRs to drugs according to the frequency with which the ADR has been observed over all other drugs. The existing advanced methods applied do not lead to substantial gains in predictive performance. We designed a rigorous evaluation to provide an unbiased estimate of the performance of ADR prediction methods: Nested Cross-Validation and a hold-out set were adopted. Among the existing methods, Kernel Regression (KR) performed best in AUPR but had a disadvantage in AUROC, relative to other methods, including the naïve method. We proposed a novel method that combines non-negative matrix factorization with kernel regression, called VKR. This novel approach matched or exceeded the performance of existing methods, overcoming the weakness of the existing methods. Code and data are available on https://github.com/YezhaoZhong/VKR.

Strong opioids-induced cardiac, neurologic, and respiratory disorders: a real-world study from 2004 to 2023 based on FAERS.

Opioids are mainly used as adjuncts to the induction and maintenance of general anesthesia, postoperative analgesia, and treating moderate to severe cancer pain and chronic pain. However, the hazards of these drugs to various organ organs still need to be further explored. This study used the US FDA Adverse Event Reporting System (FAERS) database to determine whether commonly receiving opioids was higher than the baseline risk for all other medications. FAERS was asked about adverse events (AEs) for the opioids "morphine," "fentanyl," "oxycodone," "hydromorphone," "sufentanil," and "remifentanil" from the first quarter of 2004 (2004Q1) through the second quarter of 2023 (2023Q2). Disproportionality signaling analysis was performed by calculating reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and Empirical Bayesian Geometric Mean (EBGM). AEs with system organ classes (SOCs) of "cardiac disease," "neurologic disease," and "respiratory, thoracic, and mediastinal disease" were then screened. The statistical analysis included 12,819,518 reports in the FAERS database from 2004Q1 to 2023Q2, of which 236,619 AEs were reported as "primary suspect" for the six drugs mentioned above, which were selected as "cardiac disorders," "nervous system disorders," and "respiratory, thoracic and mediastinal disorders." Some AEs identified in this study are consistent with the drug labeling, such as bradycardia, respiratory depression, and somnolence. In addition, some unexpected and significant acute adverse drug reactions (ADRs), such as toxic leukoencephalopathy and coma, may occur. This study identified potential new and unexpected ADRs for opioids, providing valuable evidence for safety studies of opioids.

Unravelling Transplant-Ineligible Newly Diagnosed Multiple Myeloma Treatment in Real-World Practice in Spain. Carinae Study

Introduction: There is little data regarding real-world treatment patterns and outcomes of transplant-ineligible newly diagnosed multiple myeloma patients (TIE-NDMM) in Spain. In recent years, several treatment regimens have been authorized as effective options for TIE-NDMM, providing patients with better outcomes and quality of life, as evidenced in clinical trials (Mateos et al. Lancet 2020). However, the contribution of incorporating these new treatments into the daily therapeutic arsenal has not been widely explored. Methods: Observational, ambispective, multicenter ongoing study on TIE-NDMM patients who started antineoplastic treatment in the context of daily clinical practice in Spanish hospitals. Group A: started treatment with a combination of ≥2 drugs, between Sep/01/2018 and Aug/31/19. Group B: started treatment with daratumumab in combination with bortezomib, melphalan and prednisone (DVMP group), between Sep/01/19 and Nov/30/20. Here, we present the efficacy and safety outcomes obtained in the second interim analysis after ≈24-month study initiation. Results: 117 patients were recruited, and 108 were evaluable for efficacy in this interim analysis (group A n=51; group B n=57). No significant differences were observed in basal clinical and demographics characteristics between groups (table 1): mean age 76.9 years; male (53.7%); cardiopathy 28.7%; renal failure 25%; pulmonary obstructive disease 8.3%; peripheral neuropathy 2.8%; median ECOG PS 1; most common myeloma type was IgG (49.5%); 13.9% had a high-risk cytogenetic profile, defined by one of the following alterations: t(4;14), t(14;16) and del 17p13; plasmacytoma 24.3 %. More than 90% of the patients in group A started treatment with schemes based on bortezomib, lenalidomide, or both. Median follow-up was 36.3 versus 23.3 months for groups A and B, respectively, since the initiation of first-line treatment (p<0,0001). Probably in relation to the different follow-ups, the median PFS for Group A was 32.78 months and not reached for Group B (p=0,1129), figure 1. The progression rate at 18 months was 27.5% and 10.5% for Group A and B respectively (p=0,0238). Rates of ≥VGPR and ≥CR, were 60% and 30% in Group A whilst 75.4% and 33.3% in Group B, table 2. 36.9% of the patients showed adverse drug reactions (ADR) related to the first-line treatment during the prospective period. 10.6% of the reported ADRs were serious with no significant differences between groups. No unexpected ADRs were observed. Additional data will be presented at the Congress. Conclusions: In this interim analysis, a significant clinical benefit has been identified in patients treated with DVMP, with improved PFS indicators vs. other treatment alternatives. Along with the deeper hematological responses observed, we expect this benefit to be consolidated in the final PFS analysis of the Carinae study. These real-world practice data continue to support the choice of daratumumab regimens in frontline TIE-NDMM patients.

DMFDDI: deep multimodal fusion for drug-drug interaction prediction.

Drug combination therapy has gradually become a promising treatment strategy for complex or co-existing diseases. As drug-drug interactions (DDIs) may cause unexpected adverse drug reactions, DDI prediction is an important task in pharmacology and clinical applications. Recently, researchers have proposed several deep learning methods to predict DDIs. However, these methods mainly exploit the chemical or biological features of drugs, which is insufficient and limits the performances of DDI prediction. Here, we propose a new deep multimodal feature fusion framework for DDI prediction, DMFDDI, which fuses drug molecular graph, DDI network and the biochemical similarity features of drugs to predict DDIs. To fully extract drug molecular structure, we introduce an attention-gated graph neural network for capturing the global features of the molecular graph and the local features of each atom. A sparse graph convolution network is introduced to learn the topological structure information of the DDI network. In the multimodal feature fusion module, an attention mechanism is used to efficiently fuse different features. To validate the performance of DMFDDI, we compare it with 10 state-of-the-art methods. The comparison results demonstrate that DMFDDI achieves better performance in DDI prediction. Our method DMFDDI is implemented in Python using the Pytorch machine-learning library, and it is freely available at https://github.com/DHUDEBLab/DMFDDI.git.

Epirubicin and gait apraxia: a real-world data analysis of the FDA Adverse Event Reporting System database.

Introduction: Epirubicin is widely used in many malignancies with good efficacy and tolerability. However, investigations about adverse events (AEs) using real-world information are still insufficient. Methods: We extracted Epirubicin-related reports submitted between the first quarter of 2014 and first quarter of 2023 from FAERS database. Four algorithms were utilized to evaluate whether there was a significant correlation between Epirubicin and AEs. Results: After de-duplicating, a total of 3919 cases were extracted. Among the 3919 cases, we identified 1472 AEs, 253 of which were found to be adverse drug reactions (ADRs) associated with Epirubicin. We analysed the occurrence of Epirubicin-induced ADRs and found several unexpected significant ADRs, such as hepatic artery stenosis, hepatic artery occlusion, intestinal atresia and so on. Interestingly, we found gait apraxia, a neurological condition, was also significantly associated with Epirubicin. To our knowledge, there haven't studies that have reported an association between gait disorders and the usage of epirubicin. Discussion: Our study identified new unexpected significant ADRs related to Epirubicin, providing new perspectives to the clinical use of Epirubicin.

Comparing adverse events of tenecteplase and alteplase: a real-world analysis of the FDA adverse event reporting system (FAERS).

The aim of this study is to monitor, identify, and compare the adverse events (AEs) related to tenecteplase and alteplase, with the objective of exploring the potential safety of tenecteplase for acute ischemic stroke (AIS) and guiding its use to enhance patient safety. In order to evaluate the disproportionality of AEs associated with tenecteplase and alteplase in real-world data, four algorithms (ROR, PRR, BCPNN, EBGM) were utilized as measures to detect signals of AEs related to both drugs. Subsequently, Breslow-Day statistical analysis was applied to compare the RORs of the main system organ classes (SOCs) and key preferred terms (PTs) between tenecteplase and alteplase. A statistical analysis was performed utilizing data gleaned from the Food and Drug Administration Adverse Event Reporting System (FAERS) database, encompassing 19,514,140 case reports from 2004Q1 to 2023Q1. There were 1,004 cases where tenecteplase was reported as the primary suspected (PS) and 2,363 tenecteplase-related adverse drug reactions (ADRs) at the PTs level were identified, the two data of alteplase were 10,945 and 25,266, respectively. The occurrence of drug-induced ADRs was analyzed across 27 organ systems, The analysis revealed several expected ADRs, such as Haemorrhage, Hypersensitivity which were consistent with the two drug-labels. It is of note that the signal strengths of 'death,' 'ventricular fibrillation,' 'cardiogenic shock' and 'pneumonia aspiration' at the PT level were markedly higher for tenecteplase than for alteplase, whereas the signal strength of 'angioedema' at the PT level was significantly higher for alteplase in comparison to tenecteplase. Additionally, unexpected significant ADRs associated with ocular adverse reactions and pneumonia aspiration at the PT level were identified, indicating potential AEs not currently mentioned in the drug instructions. This study identified and compared signals of ADRs associated with tenecteplase and alteplase, although tenecteplase is as effective as alteplase and has advantages such as ease of use and affordability, it cannot replace alteplase in the treatment of AIS until its safety profile is fully recognized. Additionally, previously unreported ocular ADRs and pneumonia were identified, providing valuable insights into the relationship between ADRs and the use of these thrombolytic drugs. These findings underscore the importance of continuous monitoring and effective detection of AEs to ultimately enhance the safety of AIS patients undergoing thrombolytic therapy.

Peripheral Neuropathy Potentially Associated to Poly (ADP-Ribose) Polymerase Inhibitors: An Analysis of the Eudravigilance Database.

Poly (ADP-Ribose) polymerase inhibitors (PARPi) have emerged as a targeted therapy in cancer treatment with promising results in various types of cancer. This work aims to investigate the profile of adverse drug reactions (ADRs) associated with PARPi through the reports provided by the Eudravigilance (EV) database. We also intend to analyze the potential association of peripheral neuropathy to PARPi. Data on individual case safety reports (ICSRs) were obtained by accessing the European spontaneous reporting system via the EV website. A total of 12,762 ICSRs were collected from the EV database. Serious cases of nervous system disorders were analyzed providing strong evidence that peripheral neuropathy was reported in a higher frequency in patients treated with niraparib. Most cases reported a not recovered/not resolved outcome and involved drug withdrawal. However, several studies suggest that PARPi attenuate chemotherapy-induced painful neuropathy. Unexpected ADRs such as peripheral neuropathy may also occur, mostly in patients taking niraparib. Further pharmacovigilance studies should be conducted in this area to clarify with more precision the toxicity profile of these drugs.

A Randomized, Double-Blind, Placebo-Controlled, Bridging Study to Evaluate the Efficacy and Safety of Vibegron in Treating Korean Patients With Overactive Bladder.

Vibegron, a novel, potent β3 agonist, has been approved for clinical use in overactive bladder (OAB) treatment in Japan and the Unites States. We performed a bridging study to investigate the efficacy and safety of a daily 50-mg vibegron (code name JLP-2002) dose in Korean patients with OAB. A multicenter, randomized, double-blind, placebo-controlled study was conducted from September 2020 to August 2021. Adult patients with OAB with a symptom duration of more than 6 months entered a 2-week placebo run-in phase. Eligibility was assessed at the end of this phase and selected patients entered a double-blind treatment phase after 1:1 randomization to either the placebo or vibegron (50 mg) group. The study drug was administered once daily for 12 weeks and follow-up visits were scheduled at weeks 4, 8, and 12. The primary endpoint was the change in mean daily micturition at the end of treatment. The secondary endpoints included changes in OAB symptoms (daily micturition, nocturia, urgency, urgency incontinence, and incontinence episodes, and mean voided volume per micturition) and safety. A constrained longitudinal data model was used for statistical analysis. Patients who took daily vibegron had significant improvements over the placebo group in both primary and secondary endpoints, except for daily nocturia episodes. The proportions of patients with normalized micturition and resolution of urgency incontinence and incontinence episodes were significantly higher in vibegron group than in the placebo. Vibegron also improved the patients' quality of life with higher satisfaction rates. The incidence of adverse events in the vibegron and placebo groups was similar with no serious, unexpected adverse drug reactions. No abnormality in electrocardiographs was observed as well as no significant increase in postvoid residual volume. Once daily vibegron (50 mg) for 12 weeks was effective, safe, and well-tolerated in Korean patients with OAB.

Safety and effectiveness of intra-articular injection of a highly cross-linked hyaluronic acid, LBSA0103 (Synovian): Results from a post-marketing surveillance study in South Korea.

This study aimed to assess the safety and effectiveness of the highly cross-linked hyaluronic acid-LBSA0103-in patients with knee osteoarthritis (OA) as per the prescribing information (PI) in South Korea. A total of 3,140 subjects aged ≥19 years were enrolled in this post-marketing surveillance (PMS) study from 2013 to 2019. The subjects received one or two injections of LBSA0103. The median duration of follow-up was 308 days. Adverse events (AEs), adverse drug reactions (ADRs), and serious AEs (SAEs) were monitored. Effectiveness was evaluated based on an index of effectiveness in accordance with the guidelines established by the Ministry of Food and Drug Safety and using a 100-mm visual analog scale (VAS) for weight-bearing pain. Overall, 250 subjects (7.96%) experienced 292 AEs and of these, unexpected AEs occurred in 114 subjects (3.63% [95% CI: 3.00-4.35]). Injection site pain was the most frequent AE reported by 81 subjects (2.58% [95% confidence intervals (CI): 2.05-3.20]). One hundred subjects experienced 108 ADRs (3.18% [95% CI: 2.60, 3.86]) and 15 unexpected ADRs were experienced by 13 subjects (0.41% [95% CI: 0.22-0.71]). Seventeen subjects experienced 22 SAEs (0.54% [95% CI: 0.32-0.87]) during the entire PMS period, and all were considered "unlikely" related to the study drug. Most AEs were mild in terms of severity and resolved during the study period. LBSA0103 was also effective in relieving symptomatic pain in knee OA patients. The condition in more than 80% of the subjects was considered to be improved when assessed by the investigators. LBSA0103 resulted in a significant reduction in the mean VAS score at 12 weeks after the first and second injections (24.79 (± 20.55) mm and 17.63 (±12.31) mm, respectively; p<0.0001). In conclusion, LBSA0103, used for the treatment of knee OA in a real-world setting, was well tolerated, with an acceptable safety profile and consistent therapeutic effect.

Under-reporting of gastrointestinal bleeding associated with anticoagulant use using the UK Yellow Card Scheme.

The Yellow Card Scheme was created in 1964 to oversee new and existing medicines and medical devices, and act as an early warning system for unexpected adverse drug reactions (ADRs). Under-reporting within the system is a known issue, estimated to be as high as 94% in a 2006 systematic review. Anticoagulants are often prescribed in the UK to prevent stroke in patients with atrial fibrillation but can be associated with gastrointestinal bleeding as a common ADR. The study aimed to investigate the incidence of suspected DOAC-related GI bleeds at a North-West England hospital and explore the volume of these incidents reported through the MHRA Yellow Card Scheme, over a 5-year period. Hospital coding data was used to identify patient records with GI bleeding and cross-referenced with electronic prescribing records for anticoagulant usage. Additionally, pharmacovigilance reporting activity for the Trust was obtained from the MHRA Yellow Card Scheme. For the period investigated, the Trust recorded 12,013 GI bleed related emergency admissions. Of these admissions, 1058 patients were taking a DOAC. During the same time period, a total of 6 DOAC-related pharmacovigilance reports were made by the trust. Utilisation of the Yellow Card System for reporting potential ADR is poor, leading to under-reporting of ADRs.

A real-world data analysis of acetylsalicylic acid in FDA Adverse Event Reporting System (FAERS) database

ABSTRACT Background Acetylsalicylic acid (Aspirin), one of the oldest medicines, is widely used in various clinical fields. However, numerous adverse events (AEs) have been reported. In this study, we aimed to investigate adverse drug reactions (ADRs) of aspirin using real-worlddata from the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. Methods We assessed the disproportionality of aspirin-related AEs by calculating measures such as reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagationneural network (BCPNN), and Gamma-Poisson Shrinker (GPS). Results Out of 7,510,564 casereports in the FAERS database, 18644 reports of aspirin as the ‘primary suspected (PS)’ AEs were recorded. Disproportionality analyses identified 493 aspirin-related preferred terms (PTs) across 25 organ systems. Notably, unexpected significant AEs such as pallor (p=5.66E–33), dependence (p=6.45E–67), and compartment syndrome (p=1.95E–28) were observed, which were not mentioned in the drug’s instructions. Conclusion Our findings align with clinical observations, highlighting potential new and unexpected ADR signals associated with aspirin. Further prospective clinical studies are necessary to confirm and elucidate the relationship between aspirin and these ADRs. This study offers a fresh and unique perspective for studying drug-AEs.

3D graph neural network with few-shot learning for predicting drug–drug interactions in scaffold-based cold start scenario

Understanding drug–drug interactions (DDI) of new drugs is critical for minimizing unexpected adverse drug reactions. The modeling of new drugs is called a cold start scenario. In this scenario, Only a few structural information or physicochemical information about new drug is available. The 3D conformation of drug molecules usually plays a crucial role in chemical properties compared to the 2D structure. 3D graph network with few-shot learning is a promising solution. However, the 3D heterogeneity of drug molecules and the discretization of atomic distributions lead to spatial confusion in few-shot learning. Here, we propose a 3D graph neural network with few-shot learning, Meta3D-DDI, to predict DDI events in cold start scenario. The 3DGNN ensures rotation and translation invariance by calculating atomic pairwise distances, and incorporates 3D structure and distance information in the information aggregation stage. The continuous filter interaction module can continuously simulate the filter to obtain the interaction between the target atom and other atoms. Meta3D-DDI further develops a FSL strategy based on bilevel optimization to transfer meta-knowledge for DDI prediction tasks from existing drugs to new drugs. In addition, the existing cold start setting may cause the scaffold structure information in the training set to leak into the test set. We design scaffold-based cold start scenario to ensure that the drug scaffolds in the training set and test set do not overlap. The extensive experiments demonstrate that our architecture achieves the SOTA performance for DDI prediction under scaffold-based cold start scenario on two real-world datasets. The visual experiment shows that Meta3D-DDI significantly improves the learning for DDI prediction of new drugs. We also demonstrate how Meta3D-DDI can reduce the amount of data required to make meaningful DDI predictions.

The impact of educational interventional session on healthcare providers knowledge about pharmacovigilance at a tertiary Jordanian teaching hospital

ObjectiveA limited number of educational interventions among health care providers and students have been made in Jordan concerning the pharmacovigilance. Therefore, the main aim of this study was to evaluate how an educational workshop affected the understanding of and attitudes toward pharmacovigilance among healthcare students and professionals in a Jordanian institution.MethodsA questionnaire was used before and after an educational event to evaluate the pre- and post-knowledge and perception of pharmacovigilance and reporting of adverse drug reactions (ADRs) among a variety of students and healthcare professionals at Jordan University Hospital.ResultsThe educational workshop was attended by 85 of the 120 invited healthcare professionals and students (a response rate of 70.8%). The majority of respondents were capable of defining ADRs (n = 78, 91.8%) and pharmacovigilance accurately (n = 74, 87.1%) in terms of their prior understanding of the topic. Around 54.1% of the participants (n = 46) knew the definition of type A ADRs while 48.2% of them (n = 41) knew the definition of type B ADRs. Additionally, around 72% of the participants' believed that only serious and unexpected ADRs should be reported (n = 61, 71.8%), also, 43.5% of them (n = 37) believed that ADRs should not be reported until the specific medication that caused it is known. The majority of them (n = 73, 85.9%) agreed that reporting of ADRs was their responsibility. The interventional educational session has significantly and positively impacted participants' perceptions (p value ≤ 0.05). The most reason for not reporting ADRs as stated by the study participants was the lack of information provided by patients (n = 52, 61.2%) and the lack of enough time to report (n = 10, 11.8%).ConclusionParticipants’ perspectives have been greatly and favorably impacted by the interventional educational session. Thus, ongoing efforts and suitable training programs are required to assess the effect of bettering knowledge and perception on the practice of ADRs reporting.

A real-world data analysis of topotecan in the FDA Adverse Event Reporting System (FAERS) database

ABSTRACT Objectives The objective of this study was to monitor and identify adverse events (AEs) associated with topotecan, a medication used for the treatment of solid tumors, in order to improve patient safety and guide medication usage. Methods To assess the disproportionality of topotecan-related AEs in real-world data, four algorithms (ROR, PRR, BCPNN, and EBGM) were employed as measures to detect signals of topotecan-associated AEs. Results A statistical analysis was conducted using data from the FAERS database, encompassing 9,511,161 case reports from 2004Q1 to 2021Q4. Among these reports, 1,896 were identified as primary suspected (PS) AEs related to topotecan, and 155 topotecan-related adverse drug reactions (ADRs) at the preferred terms (PTs) level were selected. The occurrence of topotecan-induced ADRs was analyzed across 23 organ systems. The analysis revealed several expected ADRs, such as anemia, nausea, and vomiting, which were consistent with the drug labels. Additionally, unexpected significant ADRs associated with eye disorders at the system organ class (SOC) level were identified, indicating potential adverse effects not currently mentioned in the drug instructions. Conclusion This study identified new and unexpected signals of adverse drug reactions (ADRs) related to topotecan, providing valuable insights into the relationship between ADRs and topotecan usage. The findings highlight the importance of ongoing monitoring and surveillance to detect and manage AEs effectively, ultimately improving patient safety during topotecan treatment.

Nirmatrelvir/ritonavir (Paxlovid®): French pharmacovigilance survey 2022

Nirmatrelvir/ritonavir (Paxlovid®) is currently one of the few therapeutic options for coronavirus disease 2019 (COVID-19) curative treatment in non-oxygen-requiring adult patients at-high risk of progressing to severe disease. This recently approved boosted antiviral therapy presents a significant risk of drug-drug interactions (DDI). As part of the enhanced surveillance program in France for COVID-19 drugs and vaccines, the French national pharmacovigilance database (BNPV [base nationale de pharmacovigilance]) was queried in order to better characterize the drug safety profile, with a special focus on DDI. The aim of the study was to describe the adverse drug reactions reported through the BNPV. All nirmatrelvir/ritonavir reports validated in the BNPV from the first authorization in France (January, 20th 2022) to December, 3rd 2022 (date of the query) were considered. An analysis of the scientific literature (PubMed®) and from the WHO pharmacovigilance database (Vigibase) was also performed. Over this period (11 months), 228 reports (40% of serious reports) were registered with a sex ratio of 1.9 female/1 male and a mean age of 66 years old. DDI reports account for more than 13% of reports (n=30) and were mainly related to immunosuppressive drugs overexposure (n=16). A total of 10/228 reports with fatal outcomes were reported in complex clinical settings. The main reported unexpected adverse drug reaction (ADRs) were high blood pressure (n=7), confusion (n=5), acute kidney injuries (AKI, n=7) and various skin reactions (n=22). Apart from situations of disease recurrence (not found in this analysis), data from Pubmed® and Vigibase also reported the above-mentioned events of interest. Overall, this analysis shows that nirmatrelvir/ritonavir safety profile was conform to current summary of product characteristics (SmPC). The main concern was the risk of DDI. Therefore, SmPC and expert recommendations should be systematically consulted before initiation of this antiviral, which is particularly indicated in polypharmacy patients. A case-by-case multidisciplinary approach including a clinical pharmacologist is required in these complex situations. Blood pressure elevation, confusion, cutaneous reactions and AKIs were the main unexpected ADRs of interest to follow, but need to be confirmed with a qualitative approach over time and new reports.

Safety signals of albumin-bound paclitaxel: Data mining of the Food and Drug Administration adverse event reporting system.

With the extensive application of paclitaxel for injection (albumin-bound), its adverse reactions have also received increasing attention. This study aims to provide a reference for the safe use of albumin-bound paclitaxel in clinical practice; adverse drug events signals of albumin-bound paclitaxel were reviewed and identified by data mining of the Food and Drug Administration (FDA) adverse event reporting system (FAERS). The reporting odds ratio method was used for the quantitative detection of signals from the data in the FDA public data program (OpenFDA) during 2004-2019 for the albumin-bound paclitaxel. According to the OpenFDA, 1659 adverse events (AEs) were identified for albumin-bound paclitaxel. AEs were mostly observed in females rather than males, aged 45-64 years. AEs involved 17 system organ classes, mainly blood and lymphatic, gastrointestinal, hepatobiliary, respiratory, thoracic, and mediastinal systems, and general AEs. Safety signals were found in 20 unexpected adverse drug reactions which are not listed on drug labels, mainly including macular edema and lymphopenia. Identifying and evaluating albumin-bound paclitaxel-associated AEs signals by mining FAERS may help evaluate the safety profiles of albumin-bound paclitaxel and reduce the risk of medical treatment. In the clinical application of albumin-bound paclitaxel in addition to the adverse reactions mentioned in the drug instructions, lymphocyte changes should be paid close attention to, and eye monitoring should be conducted regularly to avoid drug withdrawal or organ damage caused by adverse reactions.