Drug Safety[JOURNAL]
Sun
200 papers
Implementation Aspects of a Medicines Shortage Policy Tool: Evidence from Australia's Serious Scarcity Substitution Instruments.
Janetzki J, Kalisch-Ellett L, Pratt N … +1 more , Kemp-Casey A
Drug Saf · 2026 Jul · PMID 42393456 · Publisher ↗
BACKGROUND: Medication shortages are a considerable and ongoing issue in healthcare, disrupting consumer access to medicines. Since 2021, Australia's national medicines regulator has issued Serious Scarcity Substitution...
BACKGROUND: Medication shortages are a considerable and ongoing issue in healthcare, disrupting consumer access to medicines. Since 2021, Australia's national medicines regulator has issued Serious Scarcity Substitution Instruments (SSSIs), allowing pharmacists to substitute a specific therapeutically equivalent strength and/or formulation of a medicine without prior approval from a prescriber. The impact of SSSIs on utilisation of medicines has not been investigated. OBJECTIVE: To determine whether SSSIs are effective in addressing medicine shortages and meeting patients' needs. METHODS: This retrospective cohort study used aggregated pharmacy claims to examine the utilisation of 12 medicines, which had an SSSI. We calculated the percentage change in defined daily doses dispensed per 1000 population per day in the 11 months after SSSI implementation, compared with the previous 2 years. A percentage change of less than 20% was used to indicate success. RESULTS: Following medicine shortages, utilisation fell for 10 of the 12 medicines examined. For eight of these medicines (amoxicillin, cefalexin, estradiol, fluoxetine, insulin degludec with insulin aspart, isosorbide mononitrate, vigabatrin, and warfarin) decreases in utilisation were minimised to < 20%. On average, SSSIs where all permitted substitute products were scarce (e.g., abatacept) were associated with larger decreases in use (between - 22 and - 68%) than those for which none or only some of the substitutes were in shortage (between - 45 and + 7%, respectively). CONCLUSIONS: While product shortages led to decreases in medicines consumption, SSSIs appeared to be successful in limiting decreases. However, SSSIs were less likely to be successful when many of the permitted substitute products were also scarce.
Availability and Communication of Risk Management Strategies for Pregnancy Category X Medicines across Australian Medicine Information Sources.
Mayer H, Stasinopoulos J, Simpson B … +2 more , Gehlert J, Grzeskowiak LE
Drug Saf · 2026 Jul · PMID 42384309 · Publisher ↗
BACKGROUND: Category X medicines are those which have such a high risk of causing foetal harm that they are contraindicated in pregnancy. When used in reproductive age women, risk management strategies are warranted to r...
BACKGROUND: Category X medicines are those which have such a high risk of causing foetal harm that they are contraindicated in pregnancy. When used in reproductive age women, risk management strategies are warranted to reduce unintended pregnancy exposure. OBJECTIVE: To identify documentation of pregnancy risk management strategies for Category X medicines across Australian medicine information sources. METHOD: The TGA Prescribing Medicines in Pregnancy Database (PMPD) was searched to identify Category X medicines licensed for indications relevant to reproductive age women. For each Category X medicine included in this evaluation, regulatory documents (Product Information [PI] and Consumer Medicine Information [CMI]) and corresponding monographs/chapters in clinical resources (Australian Medicines Handbook [AMH] and Therapeutic Guidelines [TG]) were reviewed for boxed warnings relating to pregnancy risks, pregnancy testing and contraception recommendations, and formal pregnancy prevention programs. RESULTS: Thirty-nine Category X medicines were retrieved through the TGA PMPD, 19 of which met the inclusion criteria. Boxed warnings documenting pregnancy risks were present for 47% (9/19) of medicines. Pregnancy testing and contraception recommendations appeared in most PIs and CMIs (89%, 17/19), as well as in 15 of 17 (88%) medicines listed in the AMH, but were only present for one of 12 (8%) medicines listed in the TG. Structured pregnancy prevention programs exist for only 16% (3/19) of medicines. CONCLUSIONS: Pregnancy risk management strategies for Category X medicines are inconsistently employed across Australian medicine information sources. Improving the quality and consistency of pregnancy risk management strategies is necessary to avoid harms from inadvertent exposure during pregnancy.
The Bidirectionality of Lawyer Reporting Bias in Disproportionality Analysis.
Hauben M, Harpaz R
Drug Saf · 2026 Jul · PMID 42384308 · Publisher ↗
Abstract loading — click title to view on PubMed.
Safety of Biologic and Targeted Synthetic Disease-Modifying Antirheumatic Drugs in Rheumatoid Arthritis: A Longitudinal Analysis.
Peng K, Yan VKC, Chan SCW … +6 more , Shin JY, Lai EC, Pratt NL, Chan EWY, Lau CS, Li X
Drug Saf · 2026 Jun · PMID 42360669 · Publisher ↗
BACKGROUND: Biologic and targeted synthetic disease-modifying antirheumatic drugs effectively manage rheumatoid arthritis but are associated with varying risks of adverse events. OBJECTIVE: Comparing the risk of key clin...
BACKGROUND: Biologic and targeted synthetic disease-modifying antirheumatic drugs effectively manage rheumatoid arthritis but are associated with varying risks of adverse events. OBJECTIVE: Comparing the risk of key clinical events across biologic and targeted synthetic disease-modifying antirheumatic drugs to guide safer prescribing behavior. METHODS: A population-based cohort study analysed patients with rheumatoid arthritis initiated on one of 12 biologic and targeted synthetic disease-modifying antirheumatic drugs (2009-22) in Hong Kong, with adverse events assessed over 5 years, including major adverse cardiovascular events, infections, malignancies, diabetes mellitus, depression, hospitalisation and all-cause mortality. Marginal structural models with inverse probability weighting addressed time-varying confounding and selection bias. Death was treated as a competing risk, and Bonferroni correction accounted for multiple comparisons. RESULTS: Among 2697 patients with rheumatoid arthritis (4276 treatment episodes), the estimated 5-year cumulative probability of adverse events were broadly comparable across biologic and targeted synthetic disease-modifying antirheumatic drugs: with hospitalisation that ranged from 0.48 (95% confidence interval 0.271, 0.636) for baricitinib to 0.726 (0.665, 0.785) for tocilizumab; mortality from 0.028 (0.002, 0.049) for adalimumab to 0.07 (0.03, 0.118) for abatacept; major adverse cardiovascular events from 0.025 (0.004, 0.046) for golimumab and 0.025 (0.007, 0.046) for adalimumab to 0.072 (0.035, 0.107) for abatacept; infection from 0.213 (0.15, 0.265) for etanercept to 0.389 (0.17, 0.664) for rituximab; malignancy from 0.012 (0, 0.028) for abatacept to 0.116 (0, 0.309) for baricitinib; diabetes from 0.018 (0.003, 0.03) for etanercept to 0.079 (0.015, 0.152) for golimumab; depression from 0 (no events recorded) for baricitinib to 0.029 (0, 0.09) for rituximab; and gastritis from 0.041 (0, 0.078) for baricitinib to 0.114 (0.075, 0.157) for tofacitinib. Risks were compared with etanercept to estimate risk differences, which is the most frequently prescribed agent in Hong Kong with a well-documented safety profile. Tocilizumab was associated with a higher hospitalisation risk (risk difference 0.205; 95% confidence interval 0.104, 0.299) and tofacitinib was associated with a higher gastritis risk (risk difference 0.055; 95% confidence interval 0.001, 0.105). CONCLUSIONS: This study demonstrates broadly similar safety profiles among Biologic and targeted synthetic disease-modifying antirheumatic drugs after rigorous adjustment, alleviating concerns about severe adverse events. These findings provide clinicians with evidence to make informed treatment decisions for patients with rheumatoid arthritis.
Developing a Hierarchical Algorithm to Identify Pregnancies and Determine Gestational Age from Nationwide Linked Health Data in Taiwan.
Hsieh MH, Chang ZC, Lin CW … +3 more , Li BM, Lai EC, Huang WT
Drug Saf · 2026 Jun · PMID 42323503 · Publisher ↗
BACKGROUND: Administrative health data are vital for investigating medication safety during pregnancy. In Taiwan, while the National Health Insurance Research Database (NHIRD) and Birth Certificate Application (BCA) capt...
BACKGROUND: Administrative health data are vital for investigating medication safety during pregnancy. In Taiwan, while the National Health Insurance Research Database (NHIRD) and Birth Certificate Application (BCA) capture pregnancy data, no standardized approach exists for integrating these sources to identify episodes and assign gestational age (GA). This study aimed to develop a hierarchical pregnancy-identification algorithm tailored to Taiwan's linked claims and birth registry data. METHODS: We adapted an ICD-10-CM/PCS-based algorithm to the Taiwanese coding environment, incorporating clinician input, local billing practices, and birth registry information. The algorithm refines pregnancy outcome classification, estimates pregnancy start dates, and assigns GA. As a proof of concept, we applied the final algorithm to 2016-2022 data to summarize outcome distributions. RESULTS: We developed a seven-step hierarchical algorithm that uses claims codes to classify pregnancy outcomes, groups records into episodes using spacing rules, assigns pregnancy start dates from ordered prenatal services, validates and refines GA via linkage to the BCA database, determines the number of pregnancies and fetuses, and checks the plausibility of GA and inter-pregnancy intervals. A total of 1,696,229 pregnancies contributed by 1,169,779 women were identified; outcome distributions (69.3% live birth, 16.3% spontaneous abortion, 5.7% elective abortion, 6.0% ectopic pregnancy, 1.4% delivery with unknown outcome, 1.1% stillbirth, 0.2% trophoblastic and other abnormal products of conception) were consistent with national statistics and prior literature. CONCLUSIONS: This hierarchical algorithm provides a transparent, reproducible framework for identifying pregnancies and estimating GA in Taiwan. It establishes a critical foundation for future real-world studies of medication safety during pregnancy.
Safety and Effectiveness of Direct Oral Anticoagulants Versus Low-Molecular-Weight Heparin for Cancer-Associated Thrombosis: A Systematic Review and Meta-analysis.
Kang W, Lam BPY, Lau RTL … +15 more , Li STH, Wu K, Wei Y, Yang Y, Lee KJ, Huang C, Yan VKC, Yiu HHE, Lee SF, Helali AE, Lee VHF, Chan SL, Hui RYM, Lam KO, Chan EW
Drug Saf · 2026 Jun · PMID 42295501 · Publisher ↗
BACKGROUND: Cancer-associated thrombosis is a condition associated with high mortality rates, yet limited evidence exists regarding the safety and effectiveness of low-molecular-weight heparin (LMWH) and direct oral anti...
BACKGROUND: Cancer-associated thrombosis is a condition associated with high mortality rates, yet limited evidence exists regarding the safety and effectiveness of low-molecular-weight heparin (LMWH) and direct oral anticoagulants (DOACs), focusing on a fixed follow-up period based on clinical practice guideline recommendations. OBJECTIVE: This study aimed to compare the safety and effectiveness of DOACs versus LMWH in patients with cancer-associated thrombosis over a 6-month follow-up period. METHODS: PubMed, Embase, and Cochrane Library databases were systematically searched up to 30 June, 2025. Recurrent venous thromboembolism, major bleeding, and all-cause mortality were pooled using a random-effects meta-analysis. RESULTS: Seven randomized controlled trials and 28 cohort studies were included in our systematic review. After applying the criteria for a 6-month follow-up period, five randomized controlled trials and 16 cohort studies with 49,824 patients were analyzed in the meta-analysis. In randomized controlled trials, DOACs showed a lower incidence of venous thromboembolism recurrence (relative risk [RR] 0.66, 95% confidence interval [CI] 0.49-0.87) compared with LMWH, with a non-significant increase in major bleeding (RR 1.28, 95% CI 0.87-1.88) and no significant difference in all-cause mortality (RR 1.00, 95% CI 0.86-1.18). Cohort studies demonstrated a lower incidence of venous thromboembolism recurrence (RR 0.69, 95% CI 0.62-0.76) with DOACs, a non-significant reduction in major bleeding (RR 0.85, 95% CI 0.68-1.07), and a lower risk of all-cause mortality (RR 0.47, 95% CI 0.31-0.72). CONCLUSIONS: In patients with cancer-associated thrombosis, DOACs demonstrated a decrease in recurrent venous thromboembolism without increasing the risk of all-cause mortality. A non-significant increase in the risk of major bleeding was recorded in randomized controlled trials, but not in cohort studies. DOACs may provide greater effectiveness for cancer-associated thrombosis compared with LMWH.
Analytic Misjudgment of Drug Safety Evidence and Causality: From the Prosecutor's Fallacy and Simpson's Paradox to Artificial Intelligence.
Hammad TA, Rochon J
Drug Saf · 2026 Jun · PMID 42283795 · Publisher ↗
Drug safety assessment, particularly in the post-marketing setting, is especially vulnerable to analytic misjudgment because it relies on heterogeneous evidence streams, incomplete data, infrequent events, and decisions...
Drug safety assessment, particularly in the post-marketing setting, is especially vulnerable to analytic misjudgment because it relies on heterogeneous evidence streams, incomplete data, infrequent events, and decisions made under substantial uncertainty. Recurring sources of error include misinterpretation of conditional probabilities, conflation of association with causation, inappropriate denominator and comparator selection, inadequate consideration of background incidence and confounding, aggregation artifacts such as Simpson's paradox, and overinterpretation of exploratory findings arising from multiplicity or repeated testing. Misjudgment may be further amplified by spontaneous reporting data that lack explicit exposure denominators and are susceptible to reporting bias, by fragile or incomplete meta-analyses, and by premature regulatory or public responses to weak or incompletely contextualized signals. Using selected real-world case studies and conceptual examples, this narrative review illustrates how such errors arise and propagate across clinical, regulatory, and public domains, and how they can materially influence causality assessment and decision making. The paper also discusses how artificial intelligence (AI), if implemented without transparency, bias assessment, and clinical oversight, may amplify rather than reduce these vulnerabilities. Greater analytic discipline, clearer communication of uncertainty, triangulation across evidence streams, and careful governance of emerging AI-enabled tools are needed to support more reliable drug safety evaluation.
A Large Language Model for Extracting Post-marketing Adverse Drug Events from Clinical Notes in the Electronic Health Record.
Ludwig D, Wang M, Buchanan J … +1 more , Trinh T
Drug Saf · 2026 Jun · PMID 42283794 · Publisher ↗
BACKGROUND: Clinical notes contain a vast amount of potentially useful information about adverse drug event (ADE) signals that never reach pharmacovigilance databases. Traditional rule-based or sentence-level models ofte...
BACKGROUND: Clinical notes contain a vast amount of potentially useful information about adverse drug event (ADE) signals that never reach pharmacovigilance databases. Traditional rule-based or sentence-level models often miss subtle causal cues and generate excess false positives. OBJECTIVE: To build a large language model (LLM) pipeline that reads entire electronic health record (EHR) notes, identifies drug-event pairs with a "reasonable possibility" of causation, and infers other important properties of each ADR, such whether the event is "serious" or "unlabeled". METHODS: We adopted a two-pass workflow using model "OpenAI o1": Pass 1 screens each note for ADEs; Pass 2 adds 20 structured fields. A diverse sample of 372 deidentified notes from physicians and pharmacists at the University of California, San Francisco (UCSF), from 31 specialty/setting cells, yielded 191 ADEs. One medical expert reviewed each ADE for validity, seriousness, and label status. Another expert created a gold standard manually curated ADE set on 100 of the 372 ADEs to give us a percent "recall" estimate. A third expert met with the first expert to arrive at a consensus on the validity of LLM ADEs validated by the first expert but not found in the gold standard ADEs, giving us a estimate of "accuracy". RESULTS: Of 191 ADEs, 180 were true positives (94.2% precision) with 84.1% recall (F1 = 88.9%). Seriousness was correct in 100% and label status in 93.9% of cases. Medical Dictionary for Regulatory Activities (MedDRA) lowest level term (LLT) coding was correct in 92.5% of valid ADEs; errors were mostly non-existent LLTs. Of all valid ADEs, 12.2% met FDA "serious" criteria, 15.0% were unlabeled, and 8.9% were "failure of efficacy." On the first pass, 84.9% of notes contained no ADEs, keeping inference costs to USD $0.18 per note and $0.35 per validated ADE. The model inferred some ADEs not mentioned by physicians, e.g., tacrolimus-associated hypomagnesemia. CONCLUSIONS: While the LLM evaluated in this study is not perfect, it can transform free-text EHR notes into ADEs with 94% accuracy, and such data, when statistically analyzed in aggregate, can lead to new safety signals of potential drug side effects. Integrated with platforms like Sentinel in the USA, or Darwin EU, in the European Union, this approach could rapidly surface rare, serious, and unlabeled ADEs for further regulatory analysis.
Assessing the Risk of Adverse Maternal and Infant Outcomes Following Prenatal Modafinil Exposure: A French Nationwide Cohort Study.
Kaplan S, de Nascimento J, Contini A
Drug Saf · 2026 Jun · PMID 42274903 · Publisher ↗
BACKGROUND AND OBJECTIVES: Concerns about modafinil and armodafinil use in pregnancy emerged from animal reproductive toxicity and limited human data, including a US registry suggesting increased risk of major congenital...
BACKGROUND AND OBJECTIVES: Concerns about modafinil and armodafinil use in pregnancy emerged from animal reproductive toxicity and limited human data, including a US registry suggesting increased risk of major congenital malformations (MCMs). Subsequent studies have reported conflicting findings. This study aimed to evaluate the risk of MCMs and other adverse pregnancy outcomes following prenatal modafinil exposure in the French population. METHODS: This retrospective cohort study identified pregnancies during 2012-2019 using the French national health database (SNDS). Pregnancies exposed and unexposed to modafinil were identified and propensity score matched (1:4 ratio). Outcomes assessed included MCMs, spontaneous abortion, stillbirth, elective termination, preterm birth, low birth weight, and growth restriction. Prevalence and prevalence ratios (PRs) were calculated and adjusted risk ratios (RR) were estimated using Poisson regression models. RESULTS: A total of 786 modafinil-exposed pregnancies were matched to 3144 unexposed pregnancies. The prevalence of MCMs among first-trimester modafinil-exposed pregnancies was 4.2%, compared with 3.3% in unexposed pregnancies (PR 1.26; 95% CI 0.77-2.04). After adjustment for potential confounding factors, no statistically significant increase in MCM risk was observed (RR 1.32, 95% CI 0.81-2.15). Most other pregnancy and birth outcomes showed no significant differences. However, elective terminations were 32% more frequent in the exposed group (PR 1.32; 95% CI 1.14-1.51). DISCUSSION: This large, population-based study found no increased risk of MCMs or most adverse pregnancy outcomes following modafinil exposure. The elevated rate of elective terminations may reflect clinical decisions influenced by underlying maternal conditions such as narcolepsy. While these findings do not indicate an increased risk of MCM, caution remains warranted regarding modafinil use during pregnancy.
Gabapentin and Pregabalin Use in First Trimester of Pregnancy and Risk of Specific Congenital Anomalies: An IMI ConcePTION European Case-Malformed Control Study.
Beau AB, Castro EC, Benevent J … +19 more , Beslay M, Barrachina-Bonet L, Bergman JEH, Cavero-Carbonell C, Coi A, Dolk H, Garne E, Gatt M, Hoareau J, Hond ED, Latos-Bielenska A, Lelong N, O'Mahony M, Moisset X, Morris J, Neville AJ, Sichitiu J, Loane M, Damase-Michel C
Drug Saf · 2026 Jun · PMID 42230530 · Publisher ↗
INTRODUCTION AND OBJECTIVE: Given the increasing use of gabapentinoids and ongoing safety concerns, we assessed the association between first-trimester exposure to gabapentin and pregabalin and the risk of specific conge...
INTRODUCTION AND OBJECTIVE: Given the increasing use of gabapentinoids and ongoing safety concerns, we assessed the association between first-trimester exposure to gabapentin and pregabalin and the risk of specific congenital anomalies (CAs) in the offspring. METHODS: Using EUROmediCAT data, we conducted a case-malformed control study based on 170,126 registrants with major CAs from livebirths, fetal deaths (≥20 weeks), and terminations of pregnancy for fetal anomaly in nine European countries (2000-2020), covering 10.6 million births. We compared gabapentinoid use in registrants with a specific CA with those among other registrants with non-genetic CA (main control group) and among registrants with a genetic condition (secondary control group). We estimated odds ratios (OR) and 95% confidence intervals (CI), adjusting for registry, birth year, and maternal age. Analyses included specific subgroups of CA with ≥3 exposed registrants. RESULTS: First-trimester gabapentinoid exposure was identified in 37 registrants, with most registered in the Valencian region (Spain) (37.8%), EFEMERIS (France) (13.5%) and three other registries (8.1% each). Over 60% of the exposures were observed during 2015-2020. Seven out of 91 EUROCAT subgroups had ≥3 exposed registrants: congenital heart defects, ventricular septal defects, severe congenital heart defects, limb anomalies, urinary anomalies, genital anomalies, and hypospadias. A significantly higher proportion of exposure (0.4‰, 12 exposed cases) was observed among cases with ventricular septal defect compared with registrants in the non-genetic control group (0.2‰, 17 exposed cases), with an adjusted OR of 2.5 (95% CI 1.1-5.3); and the adjusted OR was elevated but non-significant compared with the registrants in the genetic group (2.3; 95% CI 0.8-6.9). CONCLUSIONS: We observed an association between first trimester exposure to gabapentinoids and ventricular septal defect, the most common cardiac anomaly, although this finding is based on only 37 exposed registrants. While our findings align with some previous studies suggesting teratogenic risks associated with gabapentinoids, they also reveal the challenges of studying rare exposures and rare outcomes.
Global Perspective on the Evolution and Future of Pharmacovigilance: Deliverables from the 24th Annual Meeting of the International Society of Pharmacovigilance Celebrating 25 Years of Excellence.
Elhawary MA, Edwards B, Rostom H … +19 more , Pal SN, Sarinic VM, Bahri P, McCarthy D, Nambasa VP, Härmark L, Bate A, Chandler R, Tuccori M, Alharbi F, Fouda M, Ogar C, Beckmann J, Pandit J, Alkhakany M, Saad C, Younus MM, Edwards IR, Aimer O
Drug Saf · 2026 Jul · PMID 42228333 · Publisher ↗
Abstract loading — click title to view on PubMed.
Incidence of Naloxone-Use Before and After Implementing Opioid Safety Measures for Patients Hospitalised on General Wards in a Swiss University Hospital.
Jungo A, Dongre K, Halbeisen D … +6 more , Schneider T, Chettata S, Gygli N, Bilici M, Meier CR, Leuppi-Taegtmeyer AB
Drug Saf · 2026 Jun · PMID 42228332 · Publisher ↗
BACKGROUND: Opioids are high-risk medications that in overdose can lead to severe life-threatening or fatal adverse drug events. Inadvertent overdose is often the cause of opioid intoxication in hospitals. We introduced...
BACKGROUND: Opioids are high-risk medications that in overdose can lead to severe life-threatening or fatal adverse drug events. Inadvertent overdose is often the cause of opioid intoxication in hospitals. We introduced digital weight-based as-needed morphine and hydromorphone order sets at our hospital in November 2020 to prevent such adverse events. Naloxone given to reverse life-threatening opioid intoxication (LTOI) is a marker for these events in patient records. AIM: The main aim was to ascertain the incidence of opioid-treated patients requiring naloxone for the management of LTOI on general wards before and after implementation of the order sets. METHODS: This investigator-driven, retrospective, observational, single-centre cohort study investigated naloxone administrations for LTOIs per 1000 opioid-treated patients, and per 1000 inpatients on general wards between 2019 and 2024 at the University Hospital Basel (USB). Prescription data and electronic hospital records were reviewed. RESULTS: During the study period, a total of 78,438 patient cases received prescription opioids, of which 149 required naloxone for LTOIs. The incidence of naloxone-treated LTOIs per 1000 opioid treated patients was 3.21 prior to the introduction of the order sets and declined to 1.46 four years later (55% reduction, p = 0.002). There were 181,314 inpatients during the study period. The incidence of naloxone per 1000 inpatients was 1.14 before and 0.64 four years after the introduction of the order sets (44% reduction, p = 0.023). CONCLUSION: We observed a significant reduction in the incidence of naloxone use for LTOI following the introduction of digital order sets for as-required morphine and hydromorphone indicating their effect to help promote safe opioid use and to improve patient safety in our hospital.
Theoretical Framework and Key Considerations for Time-to-Onset Analysis in Spontaneous Reporting Systems.
Noguchi Y, Ino Y, Yokoyama S … +2 more , Tachi T, Yoshimura T
Drug Saf · 2026 May · PMID 42118500 · Publisher ↗
Spontaneous reporting databases play a central role in pharmacovigilance for monitoring the safety of drugs and vaccines. Conventional statistical signal detection has relied primarily on disproportionality analyses base...
Spontaneous reporting databases play a central role in pharmacovigilance for monitoring the safety of drugs and vaccines. Conventional statistical signal detection has relied primarily on disproportionality analyses based on reporting frequencies, whereas information on the timing of adverse event onset has not been fully exploited. Time to onset (TTO), defined as the interval between the initiation of drug administration and the occurrence of an adverse event, provides complementary information that captures temporal patterns of event manifestation beyond simple occurrence counts. This review summarizes the definition, calculation, characteristics, and limitations of TTO analyses in spontaneous reporting databases and provides an overview of statistical signal detection methods incorporating TTO information. In particular, nonparametric distribution-comparison approaches, such as the Kolmogorov-Smirnov and Anderson-Darling tests, are well suited to spontaneous reporting data, in which the underlying population and exposure size are unknown. These methods enable the detection of abnormalities in the temporal structure of adverse event onset that may not be identifiable through frequency-based analyses alone. Furthermore, disproportionality analysis and TTO-based approaches are not competing methods but complementary strategies that capture different dimensions of safety signals-reporting frequency and temporal patterns-and their combined use may improve both sensitivity and interpretability of signal detection. The review also discusses survival analysis-based methods and Weibull modeling for TTO data, outlining their theoretical background and applications while emphasizing their inherent limitations when applied to spontaneous reporting systems. Because of reporting bias, incomplete time information, and the absence of non-event cases, such methods should not be used to estimate population-level risks or to infer causality. In conclusion, TTO analyses using spontaneous reporting databases should be positioned as exploratory tools for characterizing onset patterns, generating hypotheses, and informing the design of subsequent epidemiological and safety studies, rather than as a direct basis for clinical or regulatory decision making.
Assessing Natural Health Product-Drug Interactions and Coding Feasibility: Analysis of a New Zealand General Population Dataset from an Online Market Research Panel.
Lee EL, Ogle F, Nagra J … +3 more , Ye SS, Harrison J, Barnes J
Drug Saf · 2026 May · PMID 42105017 · Publisher ↗
INTRODUCTION: Natural health products (NHPs) include complementary/alternative medicines, dietary supplements, nutraceuticals, and traditional medicines. Natural health products are often self-prescribed and used alongsi...
INTRODUCTION: Natural health products (NHPs) include complementary/alternative medicines, dietary supplements, nutraceuticals, and traditional medicines. Natural health products are often self-prescribed and used alongside conventional medicines, raising safety concerns. AIMS: This study aims to explore NHP-conventional medicine (NHP-drug) combinations used by respondents in New Zealand (NZ), identify those with the potential to cause NHP-drug interactions, and assesses the feasibility of coding NHPs using the WHODrug dictionary. METHODS: A dataset from a pilot study on NHP use in NZ was analysed. Data on NHP and conventional medicine use were descriptively analysed. Where possible, specific product ingredient lists were verified. Two coders independently assigned WHODrug Global codes to each NHP and conventional medicine. Fleiss' Kappa measured inter-coder agreement. RESULTS: Of 992 participants, 381 (38.4%) were current NHP users, reporting 1-18 NHPs. Among them, 271 (71.1%) used conventional medicines concurrently. Natural health product-drug combinations with potential interactions were found with fish oil, coenzyme Q10, turmeric, and glucosamine. An interaction involving fish oil and warfarin was rated as 'may result in significant hazard.' One-third (33.1%) of NHPs could not be coded using WHODrug. Codability agreement was higher for conventional medicines (93.7%) than for NHPs (63.5%). Fleiss' Kappa indicated moderate agreement for NHPs (κ = 0.576) and very good agreement for conventional medicines (κ = 0.911). CONCLUSION: Substantial concurrent NHP-drug use was identified, including combinations with potential adverse reactions. A larger, nationally representative dataset on NHP exposures in NZ is needed. Current challenges in coding NHPs highlight the need for standardised, comprehensive coding tools in future research for comprehensive analysis.
Current Challenges in Monitoring the Safety and Utilisation of the Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RAs): A UK Perspective.
Davies M, Härmark L
Drug Saf · 2026 May · PMID 42086849 · Publisher ↗
Abstract loading — click title to view on PubMed.
Educational Interventions Affecting Medication Error Reporting by Healthcare Professionals in Secondary and Tertiary Care: A Systematic Review and Narrative Synthesis.
Monshi MM, Jalal Z, Aston J … +2 more , Pontefract SK, Cox AR
Drug Saf · 2026 May · PMID 42065841 · Publisher ↗
BACKGROUND: Many healthcare systems are striving to improve patient safety, as medication errors are a significant cause of avoidable morbidity and mortality. This systematic review aims to quantitatively and qualitative...
BACKGROUND: Many healthcare systems are striving to improve patient safety, as medication errors are a significant cause of avoidable morbidity and mortality. This systematic review aims to quantitatively and qualitatively assess the impact of educational interventions on medication error reporting. METHODS: A systematic review of the literature was conducted from database inception to December 2024 across EMBASE (Ovid), MEDLINE (Ovid) and PsycINFO (Ovid). Any study examining educational strategies affecting medication error reporting in secondary and tertiary care settings in the English language was included, except for cross-sectional studies. Search terms included healthcare professionals, educational interventions, medication error reporting, and secondary and tertiary healthcare. Two independent reviewers screened titles, abstracts, full-text studies, extracted the data and undertook quality assessment using the Risk of Bias in Non-Randomised Studies of Interventions (ROBINS-I) tool to assess the risk of bias in the included studies. Finally, data were synthesised as a narrative review to summarise all educational interventions. RESULTS: The systematic search led to 3649 titles. Fourteen studies were eligible for inclusion. Most of the studies were non-randomised experimental studies and assessed the medication error reporting quantitatively, but not qualitatively. The studies reported improvements in medication error reporting rates, nurses' overall reporting competence, and healthcare professionals' form completion skills following educational interventions. CONCLUSION: A better understanding of educational intervention methods, rationales, time frames, frequency, and effective co-interventions may improve medication error reporting. Combining education with other interventions had positive outcomes related to medication error reporting compared with education alone. Educational interventions improved the quantity and some quality measures of medication error reporting.
Pharmacovigilance Regulatory Requirements for the Natural Health Products (NHPs) Industry in World Health Organization-Defined High Health Expenditure Countries (2020): A Scoping Review.
Lim XY, Ram S, Scahill S … +1 more , Barnes J
Drug Saf · 2026 Apr · PMID 42050312 · Publisher ↗
BACKGROUND: Pharmacovigilance is the science and practice of safety monitoring for medicines-related problems; it is also applicable to a broader scope of health products, including natural health products (NHPs). The NH...
BACKGROUND: Pharmacovigilance is the science and practice of safety monitoring for medicines-related problems; it is also applicable to a broader scope of health products, including natural health products (NHPs). The NHPs industry is a key stakeholder in pharmacovigilance for NHPs, but academic review of regulatory requirements concerning pharmacovigilance for the NHPs industry is limited. OBJECTIVES: To map, describe and compare regulatory requirements for the NHPs industry regarding pharmacovigilance for NHPs in selected international jurisdictions. METHODS: The top 30 countries/regions from the World Health Organization's (WHO) list of nations with the highest Current Health Expenditure in 2020 were identified. For these countries/regions, publicly accessible regulatory instruments describing pharmacovigilance requirements for the NHPs industry, available in English on official governmental websites and selected secondary resources, were sought. RESULTS: Regulatory documents from 12 countries/regions (Australia, Brazil, Canada, China, India, Japan, Republic of Korea, South Africa, Switzerland, UK, USA and the EU) were included. Definitions of NHPs vary across jurisdictions, while regulatory frameworks most clearly diverge between single medicine-based systems that include NHPs, and those that apply separate medicine- and food-based primary legislation to different NHP categories. Most included jurisdictions require the NHPs industry (i.e., product sponsors, market authorisation holders, registration/license holders, manufacturers) to report serious adverse drug reactions (ADRs) within 15 days of becoming aware of such reports. However, requirements for submitting foreign ADR reports, periodic safety update reports, conducting literature screening, and employing a Qualified Person for Pharmacovigilance differ. In jurisdictions that apply separate medicine- and food-based primary legislation to different NHP categories, pharmacovigilance requirements for the industry correspondingly vary. There are usually fewer (or no) requirements for products regulated as food compared with those included under medicine-based regulations. CONCLUSIONS: Pharmacovigilance regulatory requirements for the NHPs industry vary between and within countries/regions, primarily focusing on reporting serious ADRs. To support effective benefit-risk assessment of NHPs and safeguard public health, future policy-oriented research should assess the impact of these regulatory differences on industry practice and for pharmacovigilance for NHPs, examine requirements in countries not included here, and explore pathways towards international regulatory harmonisation.
Correction: Liver Safety of the Dual Neurokinin‑1/‑3 Receptor Antagonist Elinzanetant.
Lewis JH, Andrade RJ, Larrey D … +5 more , Horsmans Y, Anderson RA, Trajanovic M, Groettrup-Wolfers E, Zuurman L
Drug Saf · 2026 Apr · PMID 41995785 · Publisher ↗
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Risk of Fetal Exposure to Teratogenic Medications: Development of Evidence for the Teratogenic Risk Impact and Mitigation (TRIM) Tool.
Wang Y, Ewig CLY, Smolinski NE … +8 more , Toyserkani GA, LaCivita C, Zhou EH, Dal Pan GJ, Thai TN, Maro JC, Rasmussen SA, Winterstein AG
Drug Saf · 2026 Jul · PMID 41995784 · Full text
INTRODUCTION: Preventing fetal exposure to teratogenic medications is a public health priority. The Teratogenic Risk Impact Mitigation (TRIM) tool has been developed to support regulatory decisions regarding risk mitigat...
INTRODUCTION: Preventing fetal exposure to teratogenic medications is a public health priority. The Teratogenic Risk Impact Mitigation (TRIM) tool has been developed to support regulatory decisions regarding risk mitigation programs. One of the explicit TRIM criteria requires medication-specific quantification of fetal exposure risk. OBJECTIVE: To develop and compare population-based estimates of fetal exposure risk for medications with known teratogenicity. METHODS: This retrospective US population-based cohort study used claims data from Medicaid and MarketScan databases from 01/2014 to 12/2018. Data were analyzed from 12/2023 to 12/2024. We included female patients aged 12-55 years with ≥ 1 teratogenic medication prescription. A validated algorithm identified pregnancies that ended with a live or non-live outcome among medication users. We estimated the fetal exposure rate as the number of pregnancies per at-risk medication exposure time, accounting for teratogenic risk profiles (e.g., ACE inhibitors exert risk in 2nd/3rd trimesters). Rates were averaged across databases to generate tertiles of high/medium/low fetal exposure risk. RESULTS: Among 59,815,213 female enrollees (31,905,714 Medicaid; 27,909,499 MarketScan), 12,819,073 used ≥ 1 teratogenic medication. Fetal exposure rates ranged from 0-1512 per 1000 user-years (tertiles: 2.9 and 11.5), with higher rates observed in Medicaid. Medications that exhibited high rates included fluconazole (1512/1000 user-years, 95% CI 1504.5-1518.6) and sulfamethoxazole/trimethoprim (295, 95% CI 233.6-492.2), vedolizumab (53, 95% CI 46.7-60.2) and several anticonvulsants. Two medications, phentermine-topiramate, with a current risk mitigation program, and fingolimod, with a released risk management program, were also ranked in the highest tertile. Fetal exposures to medications prescribed for acute conditions occurred more frequently through initiation during pregnancy, while those for chronic medications occurred mostly because of conception during treatment. CONCLUSIONS: Fetal exposure risks differed across medications and populations, influenced by treatment chronicity, relevant teratogenic risk periods, and patient demographics, which can inform the development of risk mitigation programs. Data gleaned from this analysis will be used as an ordinal "fetal exposure risk" criterion score in our development of the TRIM decision tool.
Sexual Dysfunction with Antipsychotics: Emerging Clues from a Disproportionality Analysis of the World Health Organization VigiBase.
Pavlidis E, Siafis S, Arzenton E … +10 more , Crisafulli S, Raschi E, Moretti U, Isidori AM, Jannini EA, Trifirò G, Seifritz E, Barbui C, Gastaldon C, Schoretsanitis G
Drug Saf · 2026 Apr · PMID 41979819 · Publisher ↗
INTRODUCTION: Antipsychotic-associated sexual adverse drug reactions (ADRs) are well known in clinical practice, although efforts to understand differences between antipsychotics and distinct types of sexual ADRs are lim...
INTRODUCTION: Antipsychotic-associated sexual adverse drug reactions (ADRs) are well known in clinical practice, although efforts to understand differences between antipsychotics and distinct types of sexual ADRs are limited. OBJECTIVE: The aim of this study was to assess and prioritize the profile of each antipsychotic regarding sexual ADRs reporting, and to account for potential confounders. METHODS: We used VigiBase to conduct a case/non-case study using a customized clinically guided search strategy of antipsychotic-related sexual ADRs. The reporting odds ratio (ROR) and Bayesian information component (IC) with relevant 95% confidence intervals (95% CIs) were used as disproportionality measures to identify signals of disproportionate reporting (SDRs). Antipsychotics were compared with all other drugs and with thiazides (positive control). Sensitivity analyses included non-serious reports, excluding patients with potentially confounding co-medication(s), excluding adolescent and elderly patients, and including cases with co-reported hyperprolactinemia. Analyses were stratified by sex. Antipsychotics were ranked in terms of clinical priority using qualitative and quantitative criteria. RESULTS: We included 5195 cases of antipsychotic-related sexual ADRs (43.1% serious, median time to onset of 61 days, 36.1% physician-reported). Several SDRs emerged in males (erectile dysfunction [3487 reports; ROR 2.49, 95% CI 2.40-2.57]; priapism [2372 reports; ROR 15.55, 95% CI 14.82-16.32]) and females (decreased libido [373 reports; ROR 1.61, 95% CI 1.46-1.79]) for all antipsychotic classes, except for muscarinic antagonists in females (ROR 0.64, 95% CI 0.55-0.73; IC - 0.65, 95% CI - 0.86 to - 0.45). In both sexes, the highest number of reports were for risperidone, aripiprazole and olanzapine. The SDRs disappeared in the sensitivity analysis including only non-serious cases and cases with co-reported hyperprolactinemia. Sexual ADRs for all antipsychotics were classified as of moderate priority, with the exception of fluspirilene (low priority). CONCLUSIONS: Notwithstanding limitations, including inability to infer causality, these findings raise the hypothesis that sexual ADRs could be a class effect of antipsychotics, yet possibly reversible, in both women and men. REGISTRATION: The protocol is registered to the Open Science Framework: https://osf.io/96eq7 .
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