Drug Safety最新文献

Background: Adverse drug reactions (ADRs) are a key contributor to unplanned hospitalisations, particularly in patients with polypharmacy. Traditional detection methods, such as expert reviews or diagnostic coding, are limited in scalability and sensitivity.

Objective: This study introduces and evaluates a novel scalable method, implied ADR-admissions, that links drug exposures to adverse events using administrative data to improve the detection of plausible drug-related hospitalisations.

Methods: A retrospective cohort study was conducted using linked health data from 123,662 individuals aged ≥ 40 years with polypharmacy in two Scottish health boards. Implied ADR-admissions were defined as emergency hospitalisations with one of 15 adverse events plausibly linked to drug exposure (based on a structured consensus process) within the prior 90 days. Incidence was compared with three existing approaches: adverse event-admissions (regardless of drug exposure), explicit ADR-admissions (explicitly coded as ADRs) and preventable ADR-admissions (with prior medication error). Multivariate logistic regression was used to identify predictors of implied ADR-admissions.

Results: Over 1 year, 2.6% experienced an implied ADR-admission, compared with 5.7% with adverse event-admissions, and 0.4% with explicit ADR-admissions. For gastrointestinal bleeding, the implied ADR-admission incidence was 20 times higher than the preventable ADR-admission incidence. Key predictors for implied ADR-admissions included prior hypokalaemia-related hospitalisation and use of potentially inappropriate medications.

Conclusions: The implied ADR-admission approach has improved specificity relative to broad adverse event definitions while enhancing sensitivity beyond methods that rely solely on explicit ADR codes or pre-specified medication errors. It offers a scalable automated tool for pharmacovigilance, though further validation is needed prior to routine use in medication safety monitoring.

Introduction: Major congenital malformations (MCMs) are a primary outcome of interest in pregnancy safety studies.

Objective: This study aimed to identify and summarize algorithms used to identify MCMs in routinely collected healthcare data sources in the USA, Canada, and Europe by conducting a systematic literature review.

Methods: We developed a search strategy to identify studies containing algorithms for MCMs from January 1, 2010, to April 11, 2025. Search terms included those related to MCMs as an outcome, routinely collected healthcare data, epidemiologic designs likely to incorporate algorithms, and pregnant individuals and/or infants. Study review and data extraction was conducted in duplicate using a standardized data collection form.

Results: Among the initially identified 2242 studies, 974 were selected for full-text review. Of these, 70.3% were excluded, leaving 289 studies. Over half (58.1%) of the included studies were from Europe, predominantly from Nordic countries using national register data (N = 135; 80.4%). Studies using claims (18.0%) or hospital discharge data (16.3%) were also common. Although there was heterogeneity in the timing of MCM assessment, 55.7% of studies collected MCMs through the infant's first year of life. Overall, algorithms varied across data source type and geography in the codes specified, rules, utilization of maternal versus infant records, and coding system. There were 27 (9.3%) validation studies, 70.4% of which were based on claims and/or electronic health record data only. Most had positive predictive values >70%, though this varied according to MCM type or anatomical site.

Conclusion: We provide the first comprehensive systematic literature review of algorithms used to identify MCMs in routinely collected healthcare data, aiding researchers in their ability to generate reliable evidence in pregnancy safety pharmacoepidemiology.

Background: Piperacillin-tazobactam combined with vancomycin is widely employed for broad-spectrum empiric coverage but has been increasingly associated with acute kidney injury (AKI). The comparative renal safety of substituting vancomycin with teicoplanin remains uncertain.

Objective: This meta-analysis aimed to evaluate renal outcomes between piperacillin-tazobactam plus teicoplanin (TZP-TEI) versus piperacillin-tazobactam plus vancomycin (TZP-VAN).

Methods: PubMed, Scopus, and Cochrane Central were searched for studies comparing TZP-TEI versus TZP-VAN in hospitalized patients. The primary outcome was AKI incidence, defined by Kidney disease: Improving global outcomes (KDIGO) or RIFLE (Risk of renal dysfunction, Injury to kidney, Failure or Loss of kidney function, and End-stage kidney disease) criteria. Data were analyzed using Review Manager, with heterogeneity assessed via the I² statistic.

Results: A total of 908 patients were included from five cohort studies, four of which applied propensity-score matching (PSM), with reported ages ranging from 56.8 to 79 years. The TZP-TEI regimen was associated with a significantly reduced rate of AKI compared with TZP-VAN (odds ratio [OR] 0.52; 95% confidence interval [CI] 0.30-0.89; p = 0.02; I² = 51%). No statistically significant differences were observed between groups for AKI recovery (OR 0.68; 95% CI 0.41-1.12; p = 0.13; I² = 0%) or for 30-day all-cause mortality (OR 1.34; 95% CI 0.77-2.32; p = 0.30; I² = 0%). Subgroup analyses stratified by AKI severity (KDIGO stages 1-3 or RIFLE criteria) demonstrated consistent directionality across stages, with no significant differences observed within PSM or non-PSM cohorts.

Conclusion: The TZP-TEI combination was associated with a significantly lower incidence of AKI than was TZP-VAN. Further studies are warranted to validate these findings, optimize teicoplanin dosing within the TZP-TEI combination, and inform therapeutic drug monitoring implementation in high-risk hospitalized patients.

Introduction: At times it is necessary to withdraw drugs after they have been approved because of lack of effectiveness or safety concerns. Health Canada does not keep a list of withdrawn drugs.

Objective: The aim of this study was to generate a list of all drugs approved since 1990 and subsequently withdrawn from the Canadian market for safety or effectiveness reasons until the end of 2024. This list was used to examine trends in the number of withdrawals and the percent of new drugs that are approved but eventually withdrawn.

Methods: A list of withdrawn drugs was developed based on previous published research and supplemented by examining lists of withdrawn drugs in other jurisdictions. The time, in years, was calculated between the date of approval and withdrawal. The reasons for withdrawal came from either Health Canada documents or, if unavailable, from international sources. Withdrawals for commercial reasons were not included in the analysis.

Results: Of the 1094 drugs approved from January 1, 1990, to December 31, 2024, a total of 37 were withdrawn: 32 were new active substances (molecules never marketed before in any form) and five were other types of new drugs. The median time to withdrawal was 3.60 years (interquartile range 2.45-9.50). Approximately 5% of all new active substances approved in a 5-year period were eventually withdrawn over the period 1990-2009. Between 2010 and 2019, the withdrawal rate was < 2%. The most common reasons for withdrawal were cardiac and liver complications.

Conclusion: As a percent of all drugs approved, relatively few drugs are withdrawn, and the number of drug withdrawals as a percent of approvals declined between 2010 and 2019.

Background: Risk management plans (RMPs) are a critical element of pharmacovigilance. However, few studies have examined the quality and type of information included in RMPs, and none has examined the RMPs in the Australian medicines regulatory context.

Objectives: This study aims to characterise safety concerns, particularly missing information listed in the current Australian RMPs for commonly used biologic medicines, and identify additional pharmacovigilance and risk minimisation activities proposed to address identified gaps.

Methods: A descriptive review of RMPs included in the Australian Public Assessment Reports (2009-2024) was performed for 15 biologic medicines approved for use and universally funded in Australia for inflammatory arthropathies, inflammatory bowel diseases and inflammatory skin conditions. We extracted and quantified safety concerns (important identified risks, important potential risks and missing information) from the latest Australian Public Assessment Reports, and further categorised missing information by specific populations and conditions. We then qualitatively described the additional activities proposed.

Results: There were 246 safety concerns listed for the 15 medicines of interest: 85 important identified risks (34.6%), 81 important potential risks (32.9%) and 80 instances of missing information (32.5%). More than half (n = 9, 60%) of the reviewed medicines listed children and adolescents as the most common populations with missing information. Pregnant women (n = 8, 53%) and those with hepatic and renal impairment (n = 7, 47%) were also commonly listed as having missing information. Additional pharmacovigilance activities were proposed for two thirds of the medicines (n = 10, 77%) where missing information was listed. Only one third of the reviewed medicines (n = 5, 33%) had specific proposals or protocols listed in the current Australian Public Assessment Reports to address missing information.

Conclusions: Our study identified important gaps in RMPs for commonly used biologic medicines at the post-market phase. Despite some medicines having an extensive market history, these safety concerns remain unaddressed. Regular monitoring and critical review of RMPs are recommended to prioritise post-market studies and address outstanding safety concerns.

Introduction: Because of the novelty of advanced therapy medicinal products (ATMPs), pro-active risk management is needed post-authorisation; for example, through implementation of additional risk minimisation measures (aRMMs).

Objective: We described which aRMMs were introduced at marketing authorisation (MA) for ATMPs authorised in the European Union (EU), and for what safety concerns.

Methods: We included all ATMPs ever authorised in the EU until December 31, 2023. Data on safety concerns and aRMMs was collected from the European public assessment reports (EPARs) related to initial MA for each ATMP. Safety concerns were categorised using the Medical Dictionary for Regulatory Activities (MedDRA^®) or context of use, where appropriate.

Results: Of the 25 included ATMPs, most (n = 23, 92.0%) were authorised with aRMMs. Of these 23 ATMPs, all (100%) had educational material for healthcare professionals. Additionally, educational material for patients/caregivers was in place for 18 (78.3%) ATMPs and a controlled distribution or controlled access programme for 16 (69.6%). Safety concerns related to 'Long term effects' (n = 23, 92.0%), 'Injury, poisoning and procedural complications' (n = 22, 88.0%), and 'Use in special populations' (e.g., use in pregnancy) (n = 20, 80.0%) were common among all 25 ATMPs. ATMPs often had aRMMs introduced that addressed safety concerns related to 'Injury, poisoning and procedural complications' (n = 19/23; 82.6%), 'General disorders and administration site conditions' (n = 8, 34.8%), and/or 'Immune system disorders' (n = 8, 34.8%).

Conclusion: The majority of ATMPs were authorised with aRMMs. Whilst educational materials were most prevalent, controlled distribution or controlled access programmes were also commonly introduced. For many ATMPs, aRMMs addressed risks related to 'Injury, poisoning and procedural complications'.

Signal management, defined as the set of activities from signal detection to recommendations for action, is conducted using different data sources and leveraging data from spontaneous reporting databases (SRDs), which represent the cornerstone of pharmacovigilance. However, the exponentially increasing generation and availability of real-world data collected in longitudinal healthcare databases (LHDs), along with the rapid evolution of artificial intelligence-based algorithms and other advanced analytical methods, offers a wide range of opportunities to complement SRDs throughout all stages of signal management, especially signal detection. Integrating information derived from SRDs and LHDs may reduce their respective limitations, thus potentially enhancing post-marketing surveillance. The aim of this position statement is to critically evaluate the complementary role of SRDs and LHDs in signal management, exploring the potential benefits and challenges in integrating information coming from these two data sources. Furthermore, we presented successful cases of the interplay between SRDs and LHDs for signal management, along with future opportunities and directions to improve such interplay.

Introduction: The use of incretin-based drugs may be associated with a decreased risk of endometrial cancer among women with type 2 diabetes.

Methods: Using data from the UK Clinical Practice Research Datalink and linked databases, two new-user active comparator cohorts of women with type 2 diabetes who initiated glucagon-like peptide 1 receptor agonists (GLP-1 RAs) or sulfonylureas (cohort 1) and DPP-4 inhibitors or sulfonylureas (cohort 2) were assembled. Propensity score fine stratification weighted Cox proportional hazards models were fitted to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for incident endometrial cancer.

Results: Cohort 1 included 9239 new users of GLP-1 RAs and 80,086 new users of sulfonylureas. The GLP-1 RAs were not associated with a decreased risk of endometrial cancer when compared with sulfonylureas (HR: 1.11, 95% CI: 0.66-1.88). In a duration-response secondary analysis, use of GLP-1 RAs for more than two years was associated with an increased risk of endometrial cancer (HR: 2.47, 95% CI: 1.37-4.43) when compared to sulfonylureas When analysed by drug type, exenatide was associated with an elevated risk when compared to sulfonylureas (HR: 2.26, 95% CI:1.06-4.82). Cohort 2 included 42,486 new users of DPP-4 inhibitors and 79,353 new users of sulfonylureas. DPP-4 inhibitors were not associated with a decreased risk of endometrial cancer compared with sulfonylureas (HR: 1.00, 95% CI: 0.76-1.32). In a duration-response secondary analysis, use of DPP-4 inhibitors for more than two years was associated with an increased risk of endometrial cancer (HR: 1.63, 95% CI: 1.14-2.33) when compared to sulfonylureas.

Conclusions: In this population-based study, the use of GLP-1 RAs and DPP-4 inhibitors was not associated with a decreased risk of endometrial cancer when compared with the use of sulfonylureas among women with type 2 diabetes.

Introduction: Ensuring medication safety during pregnancy is crucial for protecting maternal and fetal health. However, fragmented data sources and the lack of comprehensive databases present substantial barriers to effective pharmacovigilance. The Japan Drug Information Institute in Pregnancy (JDIIP) database, which contains data on drug treatment counseling for pregnant women, is expected to help address the lack of comprehensive databases for pregnancy pharmacovigilance (PregPV).

Objective: We evaluated the quality and utility of the JDIIP database for PregPV activities, particularly its ability to consolidate and utilize drug-exposure data among pregnant women in Japan.

Methods: To assess the quality and utility of the JDIIP database for PregPV, we examined its alignment with 48 core data elements (CDEs) considered critical for PregPV, as recently proposed by a European Union consortium through the ConcePTION Project. We performed a detailed mapping of each CDE definition-including maternal lifestyle factors, drug exposure, and pregnancy outcomes-against the corresponding data elements captured in the JDIIP database.

Results: The JDIIP database either directly collected or could derive 38 of the 48 specific items (79%) recommended by the ConcePTION Project. At the category level, the JDIIP database aligned closely with the CDE requirements for database management details, pregnancy details, maternal medical history, pregnancy medication exposure, live/stillborn birth outcomes, and malformation details, achieving coverage of over 80% of the necessary variables in each category. Some categories, such as maternal medical conditions arising during pregnancy and infant complications within the first year of life, showed less alignment, with coverage rates below 50%. Although the JDIIP database provides comprehensive coverage of critical pharmacovigilance elements, data collection for specific variables and categories that better align with the CDE framework can be enhanced to improve alignment with the CDE framework and strengthen pharmacovigilance capabilities.

Conclusions: Our findings highlight the potential of the JDIIP database as a valuable resource for advancing PregPV research. Although the collection of certain maternal and infant data elements could be improved, the substantial alignment of the database with established CDEs positions it as a promising tool for advancing PregPV initiatives in Japan.