Therapeutic Advances in Drug Safety最新文献

Metformin is a cornerstone medication and first-line therapy for type 2 diabetes mellitus (T2DM), with a well-established safety profile and widespread use over many years. Its most common adverse effects are gastrointestinal in nature. However, the drug carries a rare but serious risk of lactic acidosis. Recognized risk factors for metformin-associated lactic acidosis (MALA) include renal or hepatic impairment, excessive alcohol consumption, poorly controlled diabetes, ketosis, prolonged fasting, and conditions predisposing to hypoxia. This paper presents a case of MALA in a 75-year-old patient with T2DM and schizophrenia who lacked any typical risk factors. This case underscores the importance of maintaining a high index of suspicion for this potentially fatal complication in all patients taking metformin. Early recognition and prompt intervention are critical to improving clinical outcomes.

Background: Drug-related problems (DRPs) are a significant concern in hospitalized patients. In Ethiopia, DRPs occur at a rate of 9.2 per 100 admissions and 9.4 per 1,000 patient days; however, pediatric-specific data are limited.

Objective: This study assessed the magnitude, types, and predictors of DRPs and evaluated the acceptability of pharmacist-led interventions in pediatric intensive care units (PICUs) in Northwest Ethiopia.

Design: A multicenter prospective interventional study.

Methods: All pediatric patients admitted to the PICU during the study period were consecutively enrolled. The study was conducted from January 1, 2025 to March 31, 2025 across four specialized hospitals, resulting in a total of 394 participants. DRPs were identified through medical record reviews, caregiver interviews, and direct bedside assessment by a clinical pharmacist. Each DRP was classified according to the Pharmaceutical Care Network Europe (PCNE) classification system version 8.01. Binary logistic regression was performed to identify independent predictors of DRPs.

Results: Of the patients, 251 (63.7%) experienced at least one DRP, with 522 DRPs identified (mean 1.3 ± 0.8 per patient). The dominant domains were treatment effectiveness (54.6%) and treatment safety (30.3%), and 97.7% were deemed preventable. Drug and dose selection were the main causes (46.0% and 43.8%, respectively). Independent predictors included age 29 days-1 year (AOR = 2.2, 95% CI: 1.0-4.8), polypharmacy (⩾5 medications; AOR = 1.7, 95% CI: 1.0-2.8), multiple prescribers (AOR = 1.8, 95% CI: 1.1-2.9), prolonged ICU stay (⩾10 days; AOR = 2.4, 95%CI: 1.2-4.7), circulatory system disease (AOR = 3.5, 95% CI: 1.4-9.0), the use of anti-infectives (AOR = 5.0, 95% CI: 2.0-13.7), and antiepileptics medications (AOR = 2.1, 95% CI: 1.0-4.3) were independent predictors of DRPs.

Conclusion: DRPs were common in PICU but predominantly preventable. Despite a modest mean number of DRPs per patient, the type and causes identified indicate opportunities for optimizing medication use. Younger age, polypharmacy, multiple prescribers, prolonged PICU stays, circulatory system disease, and specific drug classes were independent predictors. The high acceptance and effectiveness of pharmacist-led interventions underscore their crucial role in improving medication safety and optimizing pharmacotherapy in resource-limited intensive care settings.

Background: Adverse drug reactions (ADRs) are a leading cause of morbidity and mortality worldwide. Despite advances in pharmacovigilance, population-level evidence on long-term trends and disparities in ADR-related mortality in the United States remains limited.

Objectives: This study aimed to characterize national temporal trends and demographic, geographic, and drug-class disparities in ADR-related mortality.

Design: Population-based, cross-sectional analysis of US death certificate data using age-adjusted mortality rates (AAMRs) and log-linear estimated annual percentage changes (EAPCs) to assess temporal trends.

Methods: ADR-related deaths were identified using International Classification of Diseases, Tenth Revision (ICD-10) codes Y40-Y59. AAMRs and EAPCs were calculated to assess temporal trends. Frontier analysis evaluated the relationship between AAMR and the Socio-Demographic Index (SDI) across states, and the leading drug categories contributing to ADR-related deaths were identified.

Results: A total of 8425 ADR-related deaths were recorded over the study period. The national AAMR increased from 0.086 per 100,000 in 1999 to 0.140 in 2020 (EAPC: 1.49). Men, older adults, Black individuals, and rural residents experienced disproportionately high AAMRs. The West and Midwest regions exhibited steeper increases than other regions. Frontier analysis identified high-SDI states performing comparatively better. Among specific drug classes, anticoagulants were the leading contributors to ADR-related deaths, followed by immunosuppressive agents, antineoplastic drugs, and opioids.

Conclusion: ADR-related mortality in the United States rose steadily, with pronounced disparities by sex, age, race, geography, and rurality. These findings should be interpreted with caution, given the observational study design and reliance on death certificate-based data.

Background: While recipient cytochrome P450 (CYP) genetic polymorphisms are established modulators of tacrolimus (TAC) pharmacokinetics, the combined effects of donor-derived hepatic and recipient intestinal CYP3A4/5 and CYP2C19 genotypes during voriconazole (VRC)-mediated CYP3A inhibition remain inadequately elucidated in liver transplantation.

Objectives: This study evaluated the impact of donor and recipient CYP3A4/5 and CYP2C19 polymorphisms on TAC pharmacokinetics during VRC co-therapy in liver transplant recipients.

Design: A retrospective study was conducted on 139 liver transplant patients receiving TAC-based immunosuppressive therapy at the First Affiliated Hospital of Sun Yat-sen University from December 2016 to June 2025.

Methods: The liver transplant recipients were stratified into a VRC co-therapy group (n = 33) and a non-VRC control group (n = 106). TAC dose-corrected trough concentrations (C₀/D) were analyzed in relation to donor and recipient genotypes of CYP3A4*1G (rs2242480), CYP3A5*3 (rs776746), CYP2C19*2 (rs4244285), and CYP2C19*3 (rs4986893).

Results: During VRC co-therapy, dual donor-recipient CYP3A4*1G CC carriers exhibited a 73% increase in TAC C₀/D compared with TT/TC genotypes (6.83 vs 3.95, p = 0.0031). Recipients grafted from CYP3A5 non-expresser donors exhibited 34% higher TAC C₀/D than those from CYP3A5 expressers (6.35 vs 4.75, p = 0.0196). Recipient CYP2C19 poor metabolizers demonstrated 36% elevated TAC C₀/D compared to extensive or intermediate metabolizers (6.47 vs 4.76, p = 0.0401). The magnitude of TAC-VRC interaction was modulated by both donor and recipient genotypes. Comparing with the control group, VRC co-therapy increased TAC C₀/D by 3.80- and 2.75-fold increases in CYP3A5 expresser and non-expresser recipients, respectively, and by 3.44- and 3.53-fold in recipients grafted from CYP3A5 expresser and non-expresser donors, respectively. Post-VRC discontinuation, TAC C₀/D remained significantly elevated for 5 days before returning to baseline level by day 6 (p < 0.0001).

Conclusion: In summary, Donor and recipient CYP3A4/5 and CYP2C19 genotypes jointly influence TAC pharmacokinetics during VRC co-therapy. Genotype-guided dosing strategies integrating both donor and recipient genotypes may improve TAC dosing precision. TAC dose reinstatement may be deferred until day six following VRC discontinuation to avoid overexposure.

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.