Therapeutic Advances in Drug Safety最新文献

Postmarketing surveillance is critical for confirming the safety profile of vaccines following regulatory approval. This article contributes to the ongoing discussion on safety surveillance strategies for seasonal influenza vaccines in Europe. We examine the implementation of enhanced passive safety surveillance (EPSS) for seasonal influenza vaccines from season 2015/16 through season 2023/24, as conducted by a Marketing Authorization Holder in accordance with European Medicines Agency guidelines. We describe the evolution of data collection methods of EPSS studies conducted across nine seasons in Finland, United Kingdom, Republic of Ireland, Denmark, and Germany with different influenza vaccine formulations. Exposure data were prospectively collected in vaccination cards at the time of vaccination, while safety data collection evolved from telephone calls to electronic reporting systems. The use of an electronic system in recent seasons facilitated adverse drug reaction reporting by the vaccinees and improved real-time monitoring and accurate data collection. Operational challenges included country and site selection constraints and difficulty achieving target sample sizes and age group representation within short recruitment windows. Reporting rates varied across seasons, countries, and vaccine formulations, potentially influenced by factors such as vaccine reactogenicity, population demographics, and reporting behaviors. Future perspectives suggest the need for a unified Europe-wide safety surveillance system to enhance collaboration among regulatory bodies, public health agencies, and vaccine manufacturers, ultimately contributing to a more robust and reliable safety framework for influenza vaccines.

Background: Lenalidomide is an immunomodulatory agent thought to inhibit the growth of del(5q) haematopoietic progenitors in myelodysplastic syndromes (MDS) that was approved for use in Europe for certain forms of these conditions in 2013.

Objectives: This study aimed to identify the distribution of lenalidomide treatment and safety outcomes in patients with MDS in Europe among those treated within (on-label) and outside (off-label) of the European Commission-approved indication.

Design: This observational, retrospective study of prospectively collected disease registry data (13 June 2013 to 1 May 2023) summarised lenalidomide treatment patterns and safety outcomes by on- and off-label treatment in 11 European countries.

Methods: Safety outcomes included progression to acute myeloid leukaemia (AML), second primary malignancies (SPMs), adverse events (AEs) and all-cause mortality. Hazard ratios (HRs) and 95% CI were reported for progression to AML comparing on- to off-label treatment.

Results: Among 523 qualifying patients, more were prescribed lenalidomide off-label (n = 345) than on-label (n = 157); label status was unknown in 21 patients prescribed lenalidomide. Progression to AML occurred in 10.2% of on-label patients and 13.0% of off-label patients (HR: 0.9; 95% CI: 0.4, 1.7). Solid tumours were the most common SPM (7.0% on-label, 1.7% off-label). Neutropenia (38.9% on-label, 33.3% off-label) and thrombocytopenia (36.9% on-label, 28.1% off-label) were the most common AEs. Death occurred in 53 on-label and 75 off-label patients. The most common causes of death were unknown (19.1% on-label, 4.3% off-label) or due to AML (3.2% on-label, 6.1% off-label).

Conclusion: Analysis of real-world registry data indicated that off-label lenalidomide use in patients treated for MDS was common. Across the registries studied, the overall incidence of safety events of lenalidomide in patients with MDS was consistent in both on-label and off-label use, highlighting the importance of researching off-label use of lenalidomide in MDS.

Trial registration: This study was registered with the EU Post-Authorisation Studies (PAS) Register: EUPAS22604.

Background: Intestinal obstruction is a severe abdominal condition that can be triggered by various medications; however, the drugs most strongly and frequently linked to this adverse event (AE) remain insufficiently defined in the current medical literature.

Objectives: This study sought to systematically identify and evaluate medications most strongly and consistently associated with intestinal obstruction by analyzing real-world evidence from a large pharmacovigilance database.

Design: We conducted a retrospective, observational pharmacovigilance study.

Methods: Reports submitted to the U.S. FDA Adverse Event Reporting System (FAERS) between January 2004 and June 2024 were analyzed. Disproportionality analyses using the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Empirical Bayesian Geometric Mean, and Information Component were conducted to identify significant safety signals associated with drug-induced intestinal obstruction.

Results: Among 21,433,114 AE reports, 60,814 (0.28%) involved intestinal obstruction. Humira (10,356 cases) was the most frequently reported drug, followed by Remicade (2223 cases), Avastin (1580 cases), Vedolizumab (1385 cases), Clozaril (1229 cases), and Accutane (1088 cases). Disproportionality analysis revealed that the top five drugs with the highest ROR and PRR were Accutane, Teduglutide, Lonsurf, Avastin, and Lynparza. Among the top 50 drugs, 47 lacked clear labeling in their drug packaging.

Conclusion: Our findings, derived from FAERS signal detection, identify drug-event pairs that warrant further clinical evaluation. These results should not be interpreted as evidence of causality. The high volume of reports associated with certain drugs may reflect usage patterns, underlying disease conditions, or reporting behaviors. Caution should be exercised in clinical translation.

Background: Prescribing errors are a significant cause of preventable harm in healthcare, particularly in low- and middle-income countries where system-level safeguards are often lacking. However, data on their prevalence and predictors in Ghana's primary healthcare facilities remain limited.

Objectives: To determine the prevalence, types and predictors of prescribing errors in a primary-level health facility in a peri-urban municipality in Ghana.

Design: Retrospective analytical cross-sectional study.

Methods: We analysed data from the hospital's pre-existing prescribing error incident reporting database, which contains errors identified by pharmacists and documented during routine care between June 2021 and June 2024. Prescribing errors were classified using a structured tool based on the National Coordinating Council for Medication Error Reporting and Prevention (NCC MERP) guidelines. Logistic regression analysis was conducted to identify predictors of prescribing errors, with statistical significance set at p < 0.05.

Results: The prevalence of prescribing errors was 1.92% (95% CI: 1.71-2.13). The most common errors were frequency (27.8%), commission (26.2%) and dose errors (25.2%). Dose errors were more frequent among nurse prescribers (odds ratio (OR) = 3.02; p = 0.022) and less common in patients aged 41-65 years (OR = 0.24; p < 0.001). Commission errors were higher among doctors (OR = 2.79; p = 0.001), while frequency errors were less likely with doctors (OR = 0.28; p = 0.006). Incorrect drug selection occurred more often among nurse prescribers (OR = 6.35; p = 0.012) and non-insured patients (OR = 6.05; p = 0.006).

Conclusion: Although prescribing errors were relatively infrequent, they were significantly influenced by prescriber type, patient age and health insurance status. These findings highlight the importance of continuous prescriber training, enhanced pharmacist participation in the medication-use process and the establishment of robust prescription monitoring systems to strengthen medication safety and optimize patient outcomes.

Background: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors differ in cardiovascular (CV) safety. Ribociclib has been associated with a higher risk of CV adverse events compared to palbociclib and abemaciclib.

Objectives: We examined patterns of CDK4/6 inhibitor selection among patients with breast cancer who had pre-existing cardiovascular disease (CVD) or cardiometabolic conditions (hypertension, hyperlipidemia, or diabetes).

Design: We conducted a retrospective cohort study.

Methods: Using 2017-2021 Merative MarketScan claims, we identified women ⩾18 years with breast cancer who initiated a first CDK4/6 inhibitor. The outcome was the type of CDK4/6 inhibitor. Primary factors were preexisting CVD and cardiometabolic risk factors measured in the prior 12 months. Multinomial logistic regression estimated unadjusted and adjusted odds of initiating palbociclib or abemaciclib versus ribociclib.

Results: Among 5002 initiators (palbociclib n = 3734; ribociclib n = 328; abemaciclib n = 940), no risk factor significantly affected drug choice in unadjusted analyses; hypertension showed a non-significant trend toward lower initiation of palbociclib (odds ratio (OR) 0.94; 95% confidence interval (CI) = 0.75-1.18) and abemaciclib (OR 0.78; 95% CI = 0.60-1.00). After controlling for additional variables, hypertension was associated with 33% lower odds of initiating palbociclib (adjusted odds ratio (AOR) 0.67; 95% CI = 0.51-0.87) and 40% lower odds of initiating abemaciclib (AOR 0.60; 95% CI = 0.45-0.81) relative to ribociclib. Pre-existing CVD, hyperlipidemia, and diabetes were not associated with CDK4/6 inhibitor selection.

Conclusion: Despite its potential higher risk of CV adverse events, ribociclib is more frequently prescribed to patients with breast cancer who have hypertension. Incorporating CV risk prediction into CDK4/6 inhibitor selection could help prevent costly CV complications.

Background: Tourniquet-related responses are a frequent clinical challenge during foot and ankle surgery under peripheral nerve block. Pharmacologic sedation and analgesia represent a common approach. Ciprofol, a novel intravenous sedative, remains underexplored in this surgical context.

Objective: This study aimed to evaluate the impact of ciprofol-assisted sedation on tourniquet-related responses in patients undergoing foot and ankle surgery.

Design: In total, 240 patients scheduled for foot and ankle procedures under peripheral nerve block with the use of a high thigh tourniquet were enrolled and randomized to undergo ciprofol (Group C) or propofol (Group P) sedation.

Methods: In Group C, ciprofol was administered at an initial rate of 0.5 mg/(kg·h), with maintenance doses ranging from 0.5 to 2 mg/(kg·h) to maintain a BIS (bispectral index) between 65 and 80. Group P received an initial infusion of propofol at 2 mg/(kg·h), with maintenance between 2 and 8 mg/(kg·h). Primary outcomes included the incidence of intraoperative rescue analgesia and body movement. Secondary outcomes encompassed hemodynamic fluctuations, anesthesia success rate, injection-related discomfort, respiratory depression, blood pressure abnormalities, postoperative complications, and long-term complications.

Results: There were no significant differences between groups in terms of the need for rescue analgesia or body movement during surgery. However, patients in the ciprofol group experienced significantly lower rates of injection pain and intraoperative hypotension relative to the propofol group (p < 0.05). No significant differences were found in postoperative adverse effects or long-term complications. In addition, both anesthesia completion rates and physician/patient satisfaction scores were similar between the two groups.

Conclusion: BIS-guided sedation with ciprofol during foot and ankle surgery provides equivalent control of tourniquet-related responses compared to propofol. However, ciprofol demonstrates superior intraoperative hemodynamic stability and a more favorable safety profile, including reduced adverse event rates.

Trial registration: http://www.chictr.org.cn; ChiCTR2400083924; May 7, 2024.

Background: Medication harm is a significant healthcare challenge in hospitalised adult patients. Machine learning (ML) approaches offer the potential to improve prediction accuracy for medication harm by capturing complex relationships among clinical risk factors that traditional statistical models may not detect.

Objective: To develop and evaluate ML models for predicting medication harm in hospitalised adult patients.

Design: ML study involving secondary use of a prospectively collected hospital cohort dataset.

Methods: This study used data from 279 adult patients admitted to general medical and geriatric wards of a tertiary hospital, among whom 40 experienced 51 medication harm events. Eight ML models were trained and evaluated for identifying patients at risk of medication harm. Medication harm cases were identified through detailed chart reviews, trigger tools, voluntary incident reporting, and International Classification of Diseases version 10 discharge coding. Data were pre-processed with missing values imputed using median imputation. Ten predictive features were selected using recursive feature elimination and clinical expert opinion. Models were trained using stratified 10-fold cross-validation with an 80/20 train-test split. Class imbalance was addressed using an oversampling approach.

Results: A random forest model demonstrated the highest performance, achieving an area under the receiver operating characteristic curve of 0.76, precision of 0.50, recall of 0.62, F1 score of 0.54, accuracy of 0.86, specificity of 0.90, and an area under the precision-recall curve of 0.47. Predictive features of importance included length of stay, depression, dementia, insulin use, number of medications (⩾15), age (⩾65), opioid use, and antibiotic use.

Conclusion: This study highlights the potential of ML models to predict medication harm, enabling early identification of high-risk patients for preventive interventions. Interdisciplinary collaboration is essential in developing robust, clinically relevant models that can be used to improve patient safety.

Background: In tissue regenerative trials, investigators operate in the intersection of routine clinical care and research. Often, clinical trials are the only option to introduce innovative treatments to disadvantaged populations in safety-net hospitals (SNHs). It is necessary to maintain a balance between efficient study conduct and patient safety. Social determinants play a role in medication adherence in clinical trials and chronic disease management that may increase risks if not managed correctly.

Objectives: We aimed to assess the safety of patients in tissue regenerative clinical trials while examining underlying causes to develop proactive risk mitigation strategies for high-risk patients.

Design: A single-center, retrospective study was conducted for clinical trials with tissue regenerative products for chronic wounds at an SNH.

Methods: Data obtained from 186 subjects were analyzed retrospectively for correlation between social determinants of health and adverse events by using Spearman correlation and Kruskal-Wallis tests.

Results: Wound healing was achieved in 41.94% of patients who received investigational products. Overall, the diabetic foot ulcer group was noted to have a higher prevalence of serious adverse events (SAEs; 22.8% of enrolled subjects) and adverse events (78.3% of enrolled subjects) as compared to the venous stasis ulcer group, with 12.4% of SAEs and 71.0% adverse events observed in the study population. Kruskal-Wallis test demonstrated statistically significant correlation between polypharmacy (⩾5 drugs) and a higher number of adverse events (p = 0.0016). A Spearman correlation test showed that a higher number of comorbidities was associated with a higher number of adverse events (p = 0.0007).

Conclusion: These findings in polypharmacy and comorbidities being associated with a higher number of adverse events highlighted the importance of safety monitoring of patients with high disease burden in clinical trials. Understanding the frequency/types of adverse events can provide important insights for those conducting trials in a particular indication. In addition, monitoring can help to address social determinants that contribute to higher numbers of adverse events, and proactively address disease burden with appropriate medical management to minimize risks in tissue regenerative clinical trials.

Background: Potentially inappropriate medications (PIMs) are common among older adults with chronic diseases and are linked to adverse outcomes, including hospitalization. Evidence on PIM prevalence and its clinical impact in Ethiopia is limited. This study assessed the prevalence of PIM use and its association with hospitalization among older adults in the Amhara Region, Ethiopia.

Objectives: To determine the prevalence of PIM use and identify factors associated with PIM exposure and hospitalization in older adults with chronic diseases.

Design: Multicenter prospective cohort study.

Methods: Between May 1 and November 30, 2024, 1700 adults aged ⩾60 years were enrolled from five comprehensive specialized hospitals in the Amhara region. PIM use was assessed using the 2023 American Geriatrics Society Beers criteria. Sociodemographic, clinical, medication, and hospitalization data were collected via structured interviews and medical chart reviews. Multivariable logistic regression identified factors independently associated with PIM use and hospitalization.

Results: PIM use was identified in 41.1% of participants. Exposure to PIMs significantly increased the risk of hospitalization (adjusted odds ratio (AOR) = 3.70, 95% confidence interval (CI): 2.25-4.95, p = 0.023). Independent predictors of PIM use included khat chewing (AOR = 1.95), cor pulmonale (AOR = 2.28), degenerative diseases (AOR = 3.20), Charlson Comorbidity Index >4 (AOR = 4.50), prolonged chronic illness (AOR = 3.07), benzodiazepine use (AOR = 1.80), and concurrent benzodiazepine-opioid use (AOR = 4.02). Regular medication reviews were protective, reducing the risk of PIM use (AOR = 0.55).

Conclusion: PIM use is highly prevalent among older adults with chronic diseases in the Amhara Region and is associated with increased hospitalization risk. Systematic medication reviews and improved prescribing practices are essential to enhance medication safety and reduce preventable hospital admissions.