Therapeutic Advances in Drug Safety最新文献

Background: Patients with low body weight (LBW) often exhibit altered pharmacokinetics (PK) in renal clearance and total body water. These changes complicate β-lactam antibiotic dosing, potentially resulting in suboptimal efficacy or increased toxicity.

Objectives: To evaluate the attainment of PK/pharmacodynamic (PD) targets, the prevalence of subtherapeutic and supratherapeutic concentrations, and the incidence of neurotoxicity among LBW patients treated with piperacillin/tazobactam (TZP), cefepime (FEP), and meropenem (MEM).

Design: A prospective observational study conducted at a tertiary hospital from January 2020 to December 2022.

Methods: Adult patients with a body mass index ⩽18.5 kg/m² who received TZP, FEP, or MEM were included. Trough serum concentrations were analyzed for PK/PD targets: 100% time above minimum inhibitory concentration (100% fT > MIC) and 100% time above four times MIC (100% fT > 4MIC). Neurotoxicity was assessed using standardized criteria. Statistical analyses identified factors associated with concentration variability and adverse outcomes.

Results: Seventy-two patients were included: 29 received TZP, 23 FEP, and 20 MEM. Achievement of the 100% fT > MIC target was comparable across all antibiotics (~70%), but 100% fT > 4 MIC attainment was significantly higher for FEP (47.8%) than for TZP (10.3%) and MEM (30%) (p = 0.01). Supratherapeutic concentrations were observed in 34.8% of FEP users compared to 3.4% and 5% for TZP and MEM, respectively (p = 0.002). Neurotoxicity occurred in 13% of FEP patients but was not reported in TZP or MEM groups (p = 0.04). Subtherapeutic concentrations were noted in approximately 30% of patients across all groups.

Conclusion: PK changes complicate β-lactam antibiotic dosing, resulting in frequent failure to achieve PK/PD targets. FEP demonstrated a particularly high risk of supratherapeutic concentrations and neurotoxicity. Therapeutic drug monitoring is crucial to optimize dosing and improve safety in this population.

Hospital pharmacies play a unique role in healthcare by regularly compounding drug products (DPs) in response to hospital demands and practices, for example, drug shortages, to cater to frail and vulnerable patients with infectious, chronic or nutrition-related conditions. Drugs are compounded in precise concentrations for extended durations, sometimes involving complex formulations. A significant challenge in this context is the off-label use of short-term plastic primary packaging for long-term storage of compounded DPs, which could be due to a lack of awareness, financial constraints and inadequate regulation. Without proper risk assessments, such packaging can release potentially harmful leachable compounds, posing a serious threat to patient safety. Evaluating hospital pharmacy compounding procedures to mitigate this risk is essential. While off-label drug use is a well-known concept in hospitals, off-label use of plastic primary packaging is an entirely different practice. In both the United States and Europe, healthcare professionals, including pharmacists, are allowed to use medical devices, including primary packaging, in ways that are not explicitly approved by regulators based on their clinical judgement and best practices, taking into account the patient's best interest. However, this off-label use could bring about unique risks and challenges, especially in the highly controlled environment of hospital pharmacy compounding, where patient safety is crucial. Therefore, the current review explores the historical context and the current landscape of hospital pharmacies, investigates the potential root causes of container closure integrity issues in pharmaceutical compounding, discusses the materials of construction as well as their physical-chemical properties influencing their roles in most popular primary packaging and finally presents expert opinions aimed at identifying long-term solutions to the existing challenges regarding their off-label uses in hospital pharmacy compounding.

Background: Current guidelines recommend the use of only on a limited basis in patients with normal or minimal structural heart disease. The CAST study, the only randomized controlled trials, showed increased mortality from long-term flecainide use in post-myocardial infarction (MI) patients with reduced left ventricular ejection fraction (LVEF). However, many later studies have revealed its safety when used in other structural heart diseases.

Objectives: This study investigates the incidence of ventricular tachycardia (VT) or ventricular fibrillation (VF) VT/VF in patients with structural heart disease compared to those with a normal heart when using flecainide.

Methods: We retrospectively recruited patients who had received at least one dose of flecainide in the past 5 years. Baseline characteristics, indications for flecainide use, and echocardiography results were reviewed. After 1 year, we evaluated the incidence of ventricular arrhythmias and all-cause mortality.

Results: After screening, 447 patients had received at least one dose of flecainide, and 336 patients were included in the study. Forty-seven patients (14%) had structural heart disease as defined by our protocols. Left ventricular hypertrophy (LVH) and impaired LVEF accounted for 28% and 25% of cases, respectively. There were five patients with coronary artery disease (CAD). After 1 year, ventricular arrhythmias occurred in two patients (4.7%) in the structural heart group; these patients had also experienced arrhythmias before receiving flecainide. In the non-structural heart group, ventricular arrhythmias were detected in three patients (1.1%). In multivariate analysis, structural heart disease was not associated with an increased incidence of ventricular arrhythmias (OR = 4.8 (0.6-38.44), p = 0.139).

Conclusion: Our study showed that no patients died due to ventricular arrhythmia, and the incidence of VT/VF was not increased in patients with structural heart disease. A prospective study is needed to further evaluate the safety of flecainide in patients with structural heart disease other than ischemic heart disease.

In 2019, intranasal esketamine gained approval as a promising therapy for those individuals grappling with treatment-resistant depression. Both clinical trials and real-world studies have underscored its efficacy in alleviating and remitting depressive symptoms, with sustained benefits observed for nearly 4.5 years. As the S-enantiomer of ketamine, esketamine's dosing guidelines and strict medical supervision stem from prior research on ketamine's use in depression and history as a recreational drug. Despite initial concerns, long-term clinical studies have not documented instances of abuse, misuse, addiction or withdrawal, and the same was found in case reports or subsamples of high-risk populations with comorbidities such as substance use disorder or alcohol use disorder. Esketamine has proven to be safe and well tolerated without fostering new-onset substance use in vulnerable groups. Real-world studies reinforced these observations, reporting no adverse events (AEs) related to pharmacological interactions of esketamine with any other substance, and no new-onset drug or alcohol misuse, craving, misuse or diversion of use. Reports of esketamine craving remain rare, with only one case report documented in 2022. Most drug-related AEs reported in pharmacovigilance databases are those identified in the product's technical data sheet and with known reported frequency. More importantly, no register of illicit acquisition of esketamine or its tampering for obtaining ketamine or other altered products was found in our search. Overall, our review confirms esketamine's safety across diverse patient populations, reassuring its responsible use and the scarcity of reports of abuse or misuse since its introduction to the market.

The overlap of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) and Stevens-Johnson syndrome (SJS) caused by antituberculosis drugs represents an extremely rare event. This situation can manifest between 2 and 8 weeks after the first exposure to the medication. The overlap of these conditions can lead to atypical clinical manifestations, thus complicating the early diagnosis and the implementation of early treatment. This report describes the case of a patient who developed the DRESS/SJS overlap 35 days after starting antituberculosis treatment. The patient experienced severe skin and systemic involvement, a situation that required her admission and monitoring in the intensive care unit. From our experience with this case, we conclude the importance of an accurate and timely diagnosis using validated scoring systems such as RegiSCAR to confirm the clinical diagnosis of DRESS/SJS and ALDEN to assess the likelihood of drug causality. Timely intervention with corticosteroids plays a key role in moderating the exaggerated immune response, helping to alleviate dermatological symptoms and prevent long-term organ damage. In addition, the availability of safe therapeutic alternatives for tuberculosis treatment allows for more effective and safer management in these patients.

Background: Reporting serious adverse events (SAEs) is crucial to reduce or avoid toxicities that can lead to major consequences for patient's health due to treatments tested in clinical trials. Its exhaustiveness is often inadequate, and we observe discrepancies between data published by pharmacovigilance organizations and clinical databases.

Objectives: While the process of reconciliation aims at reducing these differences, it remains a very time-consuming and imprecise task. We propose a tool to automate this process.

Design: We have developed and tested Reconciliaid, an application that compares the SAEs of the databases of clinical trials collected according to a standard inspired by the Clinical Data Interchange Standards Consortium, and of pharmacovigilance collected according to the international standards ICH-E2B (R3). It generates a reconciliation file that indicates precisely what information does not coincide in the two databases to facilitate the identification of inconsistencies.

Methods: Reconciliaid was tested to create 13 reconciliation files, containing 290 SAEs. We inspected these files to determine their ability in identifying the inconsistencies and compared the manual and semi-automated reconciliation time. Four users answered the System Usability Scale (SUS) to measure its usability.

Results: The application identified all variables of interest in all reconciliations. Different formats and libraries were automatically harmonized, allowing a perfect identification of inconsistencies for all variables. The matching of the same SAE in the two databases was correct in 97.2% of the reconciliations. Reconciliaid is six times faster than the manual approach for senior data managers (range = 3-24 times). A novice data manager performed three reconciliations 4.8 faster with the help of Reconciliaid than manually (29 min vs 134 min) and with fewer mistakes. Mean SUS score was 92.5.

Conclusion: Reconciliaid has a high level of usability, can increase the quality of reconciliation, and reduces considerably the reconciliation time, allowing to increase the frequency of reconciliation processes and to focus resources on patient safety and medical assessment.

Background: The majority of patients with alcohol use disorder (AUD) regularly take medication. Alcohol interacts negatively with many commonly prescribed drugs. However, little is known about the characteristics and frequency of potential alcohol-medication and drug-drug interactions in patients with AUD.

Objectives: This study aimed to determine the prevalence and characteristics of drug interactions in patients with AUD during withdrawal therapy on an addiction-specific ward.

Design: Retrospective cohort study.

Methods: Medication charts were analyzed and screened for potential alcohol-medication and drug-drug interactions. For the screening of potential alcohol-medication interactions, the drugs.com classification was utilized and potential drug-drug interactions were identified using the mediQ electronic interaction program.

Results: In our study, almost two-thirds (66.3%; 1089/1643) of all patient cases were prescribed at least one drug that could potentially interact with alcohol. Four percent of all alcohol-medication interactions were classified as severe, 91.8% as moderate, and 4.3% as mild. Drug classes commonly involved in serious interactions with alcohol were analgesics and drugs used in diabetes. A total of 811 potential drug-drug interactions were identified, of which 3.3% were classified as severe and 96.5% as moderate. Psychoanaleptics (ATC N06) and psycholeptics (ATC N05) were most frequently associated with moderate to severe interactions.

Conclusion: Potential alcohol-medication and drug-drug interactions are common in hospitalized patients with AUD. Improvements in the quality of prescribing should focus on the use of psychotropic drugs.

Background: Gilteritinib and midostaurin are FLT3 inhibitors that have made significant progress in the treatment of acute myeloid leukemia. However, their real-world safety profile in a large sample population is incomplete.

Objectives: We aimed to provide a pharmacovigilance study of the adverse events (AEs) associated with gilteritinib and midostaurin through the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database.

Design: A retrospective analysis of the FAERS database was conducted by disproportionality analyses.

Methods: We conducted disproportionality analyses to identify drug-AE associations, including the reporting odds ratio and the Bayesian confidence propagation neural network. A signal was detected if both methods achieved statistical significance.

Results: There were 1887 and 2091 case reports for gilteritinib and midostaurin, respectively. We have separately retained significant disproportionality AEs across two algorithms, with a total of 53 AEs for gilteritinib and 46 for midostaurin. The common AEs observed with gilteritinib included febrile neutropenia, pyrexia, anemia, and thrombocytopenia. Similarly, the prevalent AEs associated with midostaurin were nausea, vomiting, diarrhea, pyrexia, and febrile neutropenia. The common AEs of both drugs are consistent with previous clinical trials. Notably, we also revealed unexpected significant AEs for both drugs. For gilteritinib, 29 positive signals for AEs not mentioned in its instructions were identified, such as cerebral hemorrhage, tumor lysis syndrome, and interstitial lung disease. Midostaurin exhibited 24 positive signals for AEs not listed in its instructions, including neutropenic colitis, neutropenic sepsis, and septic shock.

Conclusion: This study highlights the need for continued monitoring and evaluation of these drugs in clinical practice, as it first reveals their AEs in a large real-world sample population. Some AEs are generally consistent with the instructions and previous studies, but some unexpected AEs are detected for each drug. Due to the limitations of the spontaneous report database, such as including potential underreporting, overreporting, lack of causal relationship, unable to calculate incidence, and other confounding factors, more pharmacoepidemiology studies are needed to validate our findings.

Background: Medication safety is crucial in clinical care. Although many hospitals have implemented prospective prescription review systems to manage medication use, the impact of these systems on pediatric patients is not yet fully understood.

Objectives: We explore the characteristics and economic impacts of pediatric prospective prescription review and identify factors influencing intervention success rates.

Design: This study adopted a cross-sectional design.

Methods: Prospective prescription review tasks were compared in the outpatient of our hospital between 2021 and 2023 to assess medication rationalization rates and cost variability. Data were collected using the PASS PharmReview system, including patient information, medication indications, prescribing physicians, intervention pharmacists, prescription rationality rate, and medication costs. SPSS 26.0 software was used to compare changes in medication rationality and medication costs between the initial (2021) and stable (2023) periods and to analyze factors affecting intervention success during the stable period by the logistic regression model.

Results: The study included 11,533,807 prospective prescription review tasks. The medication rationalization rate increased from 92.0% to 95.7% (p < 0.05) between the initial (n = 5,392,551) and stabilization periods (n = 6,141,256). Outpatient medication costs per capita decreased by 3.2%, from ¥320.7 to ¥310.5. Factors influencing intervention success included the following: the greater age is negatively associated with success(p < 0.001, odds ratio (OR) = 0.98); internal medicine demonstrates a superior intervention success rate compared to the surgical department (p < 0.001, OR = 1.37); higher physician titles were associated with lower success rates (p < 0.001, OR = 0.59); and success increased with pharmacists of higher educational levels (p < 0.001, OR = 1.18).

Conclusion: Implementing a prospective prescription review system in pediatric outpatient settings improves medication rationality and reduces errors and costs, with intervention success influenced by patient age, department, physician titles, and the educational level of pharmacists.

Background: Clarithromycin is a widely used antibiotic, but its safety profile, particularly in different age groups, remains inadequately explored.

Objectives: This study aims to characterize and illustrate the features of clarithromycin-related adverse events (AEs) across different age groups using the FDA Adverse Event Reporting System (FAERS) database, providing a reference for the clinical detection, prevention, and management of AEs in various age groups.

Design: A disproportionality analysis was performed using data from the FAERS database. The study included all AE reports related to clarithromycin, stratified by age groups.

Methods: Disproportionality analysis was conducted using reporting odds ratio, proportional reporting ratio, Bayesian confidence propagation neural network, and multiple gamma Poisson shrinkers. Statistical analyses included descriptive statistics and Chi-square tests.

Results: A total of 7319 reports of clarithromycin AEs were retrieved from the FAERS database. Vomiting, diarrhea, drug interactions, and drug interactions were reported most frequently in the age groups 0-17, 18-44, 45-64, and ⩾65 years, respectively. Abnormal product taste, taste disorder, and medication errors related to drug interactions specified in the package insert were the strongest signals in the age groups 0-17, 18-44, 45-64, and ⩾65 years, respectively. A total of 41 Preferred Terms signals were not explicitly included in the clarithromycin package insert and were mainly associated with psychiatric disorders, skin and subcutaneous tissue disorders, and gastrointestinal disorders, among others. Specific signals for age differences were identified, with 18 signals being age-specific, including 3 in children and 15 in elderly individuals.

Conclusion: The safety profile of clarithromycin varies across age groups. In children, it is mainly associated with vomiting, hypersensitivity, and dyspnea, while in adults, psychiatric AEs are more common. In the elderly, clarithromycin should be used cautiously, with attention to drug interactions.