Pharmacoepidemiology doi: 10.3390/pharma5010008

Authors: Elaf Abuelgasim Mark McIntyre Najla Tabbara

Background: Preterm prelabour rupture of membranes (PPROM) is the spontaneous rupture of fetal membranes prior to 37 weeks of pregnancy. Latency antibiotics, including macrolides with or without group B streptococcus (GBS)-covering antibiotics, are recommended as part of expectant management. Currently, there is no consensus on whether GBS-covering antibiotics should be prescribed. The primary objective of this retrospective cohort study was to characterize practice variation in GBS-covering antibiotic prescribing in PPROM. The secondary objective was to explore the association between maternal characteristics and GBS-covering antibiotic prescribing. Methods: Pregnant women with PPROM prescribed azithromycin (institutional standard antibiotic regimen) in 2024 and not in active labour were included. Maternal characteristics, stratified by GBS status, were compared. The association between antibiotic prescribing for GBS coverage and maternal factors was assessed using odds ratios. Two-sided p-values < 0.05 were considered statistically significant. Results: Out of the 181 admissions assessed for eligibility, 146 patients were included. Their GBS status at PPROM diagnosis was negative (19/146; 13%), positive (8/146; 5%), or unknown (119/146; 82%). The frequency of GBS-covering antibiotics prescribing was 5/8 (63%) in the positive group, 4/19 (21%) in the negative group, and 65/119 (55%) in those with an unknown GBS status. Aminopenicillin-based and penicillin regimens accounted for (69/74; 93%) of antibiotic regimens. Half (38/74; 51%) of the GBS-covering antibiotics were prescribed for 3–7 days, with a 33/74 (45%) completion rate as prescribed at PPROM diagnosis. The main reason for antibiotic discontinuation was negative GBS recto-vaginal swabs or urine cultures collected in those with an unknown GBS status at PPROM diagnosis, highlighting the role of microbiology laboratory testing in adjusting antibiotic therapy and facilitating antimicrobial stewardship. Aside from GBS status, no maternal characteristics were associated with GBS-covering antibiotic prescribing. Conclusions: At PPROM diagnosis, GBS coverage was prescribed in 21%, 63%, and 55% of patients with a negative, positive, and unknown GBS status, respectively. Only GBS status was associated with GBS-covering antibiotic prescribing. Further research is required to determine the impact of GBS coverage on perinatal outcomes.

Pharmacoepidemiology doi: 10.3390/pharma5010007

Authors: Akemi Ishikawa-Ichikawa Jorge Alberto Islas-Martínez Eduardo Rios-Garcia Luis Fernando Tejado-Gallegos Pamela Monserrat Ramírez-Marín

Background: Acalabrutinib is a selective Bruton tyrosine kinase inhibitor widely used for chronic lymphocytic leukemia and mantle cell lymphoma. Real-world safety evidence from Latin America remains limited, which restricts local benchmarking and pharmacovigilance planning. In this study we aimed to assess exposure-adjusted adverse events in routine care in Mexico. Methods: We analyzed postmarketing surveillance datasets and spontaneous reports from March 2020 to August 2024, classifying events with MedDRA and summarizing seriousness, severity, and incidence per 100 patient-years. Results: A total of 266 patients were registered; 193 had evaluable exposure and safety data, contributing 242.73 patient-years. The overall adverse event incidence was 24.71 per 100 patient-years. Twenty-eight individual case safety reports documented 60 events. Forty-four events were serious. Among 33 events with reported severity, 14 were severe, 14 moderate, and five mild. Frequently affected system organ classes were blood and lymphatic, vascular, and infections. Seven deaths were reported; most were associated with COVID-19 complications or disease progression. Conclusions: The adverse event profile observed aligns with published trial experience and supports the tolerability of acalabrutinib in Mexican practice. These country-level, exposure-adjusted estimates provide actionable context for clinicians, institutional pharmacists and pharmacovigilance teams and point to the value of strengthening report completeness to improve signal detection in routine oncology care.

Pharmacoepidemiology doi: 10.3390/pharma5010006

Authors: Fitim Alidema Arieta Hasani Alidema

Background: Pharmacovigilance is a critical component of patient safety, particularly among older adults with chronic diseases who are frequently exposed to polypharmacy. In Kosovo, adverse drug reactions (ADRs) reported by patients remain insufficiently recognized within the healthcare system. Polypharmacy, limited access to pharmaceutical counseling, and self-medication practices may contribute to increased medication-related harm. Capturing ADRs directly from patients provides valuable insight into medication safety challenges and communication gaps in clinical care. Objective: To assess the frequency, characteristics, and reporting behavior of adverse drug reactions among adults aged 60–75 years with chronic diseases in Kosovo, and to identify factors associated with awareness and reporting practices. Methods: A multicenter cross-sectional study was conducted between January and September 2025 in four major cities in Kosovo (Prishtina, Prizren, Peja, and Gjilan). A total of 1024 patients receiving continuous therapy for at least one chronic condition were surveyed using a structured questionnaire covering demographic characteristics, drug exposure, ADR experience, and reporting behavior. Statistical analyses included descriptive statistics, chi-square testing, and multivariable logistic regression to identify predictors of ADR reporting. Results: Overall, 47.3% of participants reported experiencing at least one ADR in the preceding 12 months. Among those, 39.5% reported the event to a healthcare professional, whereas 60.5% did not seek professional advice. The most frequently implicated drug classes were antihypertensives (32.8%), analgesics and non-steroidal anti-inflammatory drugs (27.4%), and antirheumatic agents (14.6%), with mainly gastrointestinal (24.1%) and cardiovascular (18.9%) manifestations. Approximately 19.8% of participants reported discontinuing medication due to adverse effects. Female patients were more likely to report ADRs compared to males (p < 0.01). Lack of prior counseling about potential side effects was independently associated with lower reporting (OR = 2.17; 95% CI: 1.41–3.33). Patients using more than six medications had a higher prevalence of ADRs (61.2%). Conclusion: Adverse drug reactions were frequently reported by older patients, while formal reporting to healthcare professionals remained limited. Strengthening patient education, improving patient–provider communication, and integrating clinical pharmacists into primary care may enhance pharmacovigilance practices and medication safety.

Pharmacoepidemiology doi: 10.3390/pharma5010005

Authors: Jumanah Qedair Asmaa A. Youssif Reham Shehada Hashem Abu Serhan

Background/Objectives: To evaluate the incidence, characteristics, and clinical outcomes of intraocular inflammation (IOI) associated with intravitreal faricimab (IVF) in patients with neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME). Methods: Following PRISMA guidelines, a comprehensive search of PubMed, Web of Science, Scopus, Embase, and CENTRAL databases was performed from their inception to February 2025. Using the random-effects model, weighted proportions, standardized mean differences, and weighted log odds ratios (OR) were pooled and calculated. A two-tailed p-value of <0.05 was considered statistically significant. The χ2 (z) test and the Higgins I2 test were used to assess studies heterogeneity. Results: We conducted a systematic review and meta-analysis of 24 studies (4761 patients; 5652 eyes). The most common diagnoses were nAMD (n = 4782, 94.6%) and DME (n = 845, 37.1%). The pooled proportion for IOI incidence in eyes receiving IVF was 3.0% (95% CI: 1.0–6.0). The odds of developing IOI did not differ significantly between the DME and nAMD groups (OR: 1.13, p = 0.78). Unspecified IOI was the most common sign (n = 210, 2.9% [95% CI: 1.2–7.3]), followed by anterior uveitis (n = 80, 1.9% [95% CI: 0.1–34.8]), vitritis (n = 63, 2.9% [95% CI: 0.2–32.1]), retinal hemorrhage (n = 27, 0.7% [95% CI: 0.0–15.3]), and endophthalmitis (n = 8, 0.5% [95% CI: 0.3–1.1]). Conclusions: While IVF demonstrates therapeutic efficacy, our findings highlight a clinically relevant risk of IOI. We, therefore, recommend vigilant clinical monitoring in patients receiving this therapy.

Pharmacoepidemiology doi: 10.3390/pharma5010004

Authors: Pierre Constant Ntoutoume Nzoghe Rim Lakhmiri Sophie Coniquet Solange Ntsame Ihsane Hmamouchi Yahia Cherrah Samira Serragui

Background: According to the literature, adverse drug reactions (ADRs) account for 5–10% of hospital admissions and affect 25–30% of hospitalized patients, but no data are available for Gabon. Objectives: To estimate the incidence of ADRs among hospitalized patients at the Libreville University Hospital Center (CHUL) and to classify them according to their frequency, severity, mechanism and preventability, while proposing appropriate risk minimization strategies. Patients and Methods: A 14-month, single-center, prospective study included all patients experiencing ADRs, excluding those without ADRs or with intentional overdoses. ADRs were analyzed using the World Health Organization (WHO) causality assessment, the ATC classification, and Rawlins and Thompson criteria. Data were actively collected from patients and hospital records. Results: Among 4999 patients, 105 experienced 177 adverse events (incidence: 3.5%, 95% CI: 1.7–2.5%). Among the identified ADRs, 42% were serious. Nausea and vomiting were the most frequent ADRs, mainly caused by analgesics (nefopam, tramadol) and antibiotics (amoxicillin–clavulanic acid). The gastrointestinal and nervous systems were the most affected. According to the Rawlins and Thompson classification, 90% of ADRs were type A, 8% type B, and 2% type E (withdrawal syndrome). Overall, 90% of ADRs were preventable. Conclusions: This study highlights the importance of pharmacovigilance at CHUL, Gabon, and emphasizes the role of healthcare professionals in ADR reporting and risk minimization.

Pharmacoepidemiology doi: 10.3390/pharma5010003

Authors: Monthon Lertcanawanichakul Phuangthip Bhoopong Husna Madoromae Tuanhawanti Sahabuddeen

Probiotics and microbiome-based therapeutics are increasingly used to prevent antibiotic-associated diarrhea (AAD) and support gut microbiota health across children, adults, and elderly populations. Evidence synthesized in this narrative review from randomized controlled trials and meta-analyses (>20,000 participants) suggests that early probiotic administration, particularly Lactobacillus rhamnosus GG, Bifidobacterium species, multistrain formulations, and Saccharomyces boulardii, is associated with a 30–40% relative reduction in AAD incidence across heterogeneous studies, with absolute risk reductions of approximately 5–12% depending on baseline risk, strain, dose, and timing. Probiotics are generally well tolerated, with mild gastrointestinal adverse effects reported in 3–5% of users and rare serious events mainly in immunocompromised individuals. However, heterogeneity in formulations, populations, and limited long-term real-world data underscores the need for further pharmacoepidemiological studies, microbiome surveillance, and evaluation of antimicrobial resistance implications.

Pharmacoepidemiology doi: 10.3390/pharma5010002

Authors: Pichitra Srimaya Tossapol Warong Sudarat Kingdang Titawadee Pradubkham Wiraphol Phimarn

Background/Objectives: Sodium-glucose cotransporter-2 (SGLT2) inhibitors are widely used in type 2 diabetes mellitus for glycemic control and cardiovascular–renal protection, but adverse effects such as acute kidney injury (AKI), urinary tract infection (UTI), euglycemic diabetic ketoacidosis (Eu-DKA), and acute pancreatitis remain concerns. We aimed to determine the prevalence of adverse drug reactions (ADRs) associated with SGLT2 inhibitor use. Methods: This retrospective study assessed the prevalence of these adverse events and identified factors associated with UTI among SGLT2 inhibitor users at Suddhavej Hospital (1 January 2019–15 August 2023). Data were extracted from the hospital electronic medical record system (BMS-HOSxP). Results: We analyzed 293 patients (59.73% male; mean age 63.08 ± 0.667 years; 62.08% aged >60). Dapagliflozin had the highest prevalence of AKI (11.42%) and UTI (13.40%). No acute pancreatitis cases were reported. Logistic regression identified female sex (odds ratios [OR] 2.31, 95% confidence intervals [CI] 1.08–4.96; p = 0.032), AKI diagnosis (OR 3.31, 95% CI 1.10–9.89; p = 0.032), age ≥ 60 years (OR 2.78, 95% CI 1.09–7.09; p = 0.033), and SGLT2 inhibitor use <6 months (OR 5.78, 95% CI 2.74–14.18; p = 0.017) as significant risk factors for UTI. Conclusions: Dapagliflozin was associated with the highest prevalence of AKI and UTIs. Female sex, AKI diagnosis, age ≥ 60 years, and SGLT2 inhibitor use <6 months were significant risk factors for UTI among SGLT2 inhibitor users.

Pharmacoepidemiology doi: 10.3390/pharma5010001

Authors: Samuel I. Nathaniel Maggie Oliver Thomas I. Nathaniel Laurie Marie Theriot Roley Richard L. Goodwin Adebobola Imeh-Nathaniel

Objective: The objective of this study was to determine whether Non-Hispanic Black (NHB) or Non-Hispanic White (NHW) Alzheimer dementia patients with neuropsychiatric symptoms (ADNPS) differ regarding treatment with second-generation antipsychotics (SGAs), central acetylcholinesterase inhibitors (CAIs), and selective serotonin reuptake inhibitors (SSRIs). Methods: Pharmacologic and demographic factors associated with male and female ADNPS were examined using retrospective data collected from a registry from 2016 and 2020 in a regional AD care center. The logistic regression model was developed to generate odds ratios (OR) to determine factors that were associated with male or female ADNPS. Results: A total of 7031 AD patients were identified. Overall, 6237 patients were NHWs, and 794 were NHBs. Among the NHW AD patients, 1909 presented with behavioral disturbances or neuropsychiatric symptoms (NPS), and 168 NHB AD patients presented with NPS. In the adjusted analysis, NHW ADNPS patients were more likely to be treated with galantamine (OR = 1.538, 95% CI, 1.001–2.364, p = 0.049), memantine (OR = 1.222, 95% CI, 1.086–1.375, p < 0.001), olanzapine (OR = 2.323, 95% CI, 1.794–3.009, p < 0.001), risperidone (OR = 4.181, 95% CI, 3.539–4.939, p < 0.001), and escitalopram (OR = 1.401, 95% CI, 1.225–1.602, p < 0.001). In contrast, NHB ADNPS patients were more likely to be treated with memantine (OR = 2.601, 95% CI, 1.746–3.875, p < 0.001) and risperidone (OR = 5.526, 95% CI, 3.411–8.951, p < 0.001). Conclusions: Our findings show the use of memantine and risperidone to treat both NHB and NHW ADNPS patients. NHW ADNPS patients were more likely to be treated with galantamine, memantine, olanzapine, risperidone, and escitalopram. In contrast, NHB patients with ADNPS were more likely to be treated with memantine and risperidone.

Pharmacoepidemiology doi: 10.3390/pharma4040028

Authors: Jiamei Liu Zizhao Zhang Yin Liu Liming Zhao Zhenna Huang Xuxiao Ye Jeff L. Lange Nafeesa Dhalwani Fan Yang Kangyin Chen Hao Zhang Jifang Zhou

Objectives: Real-world evidence that supports decision-making must meet numerous criteria, including validated identification of clinical outcomes. This study aimed to develop and validate a method for identifying new cases of myocardial infarction (MI) and ischemic stroke (IS) within real-world clinical data in China. Methods: Algorithms to identify MI and IS events were developed using ICD-10-CM codes and Chinese diagnosis keywords within the Tianjin Regional Healthcare Database. Validation followed predefined criteria: MI required cardiac troponin elevation and ischemic symptoms or cardiac troponin elevation and electrocardiogram changes; IS required clinical symptoms and neuroimaging confirmation of cerebral Magnetic Resonance Imaging (MRI) or Computerized Tomography (CT) reports. Positive predictive value (PPV) with 95% confidence intervals (CI) was calculated for each outcome. Results: Among 304 MI and 302 IS cases randomly selected, approximately half were identified using ICD-10-CM codes and half through Chinese diagnosis keywords. Overall PPV for MI was 69% (95% CI: 63–74%), with similar PPVs across identification methods. PPV increased to 88% for inpatient MI and 97% for primary inpatient MI. For IS, overall PPV was 65% (95% CI: 58–71%), with higher PPV for cases identified by ICD-10-CM codes (76%) compared to keyword-only cases (56%). PPV increased to 76% for inpatient IS and 91% for primary inpatient IS. Conclusions: The use of ICD-10-CM codes and Chinese diagnosis keywords in primary inpatient diagnoses provides a validated approach for the identification of clinical outcomes of MI and IS within real-world clinical data in China.

Pharmacoepidemiology doi: 10.3390/pharma4040027

Authors: Nisrine Haddad Abdallah Alami Christopher A. Gravel Derek Tsui Yue Chen Franco Momoli Donald Mattison Nawal Farhat Daniel Krewski

Objectives: To evaluate reports of diabetic ketoacidosis (DKA) associated with antipsychotic drug (APD) use submitted to the U.S. Food and Drug Administration’s Adverse Event Reporting System (FAERS). Methods: A retrospective pharmacovigilance analysis was conducted using FAERS data from January 2000 to December 2022. DKA cases were identified using the MedDRA preferred term “diabetic ketoacidosis” in reports listing antipsychotic drugs as suspect medications. Disproportionality analyses, including the proportional reporting ratio (PRR) and empirical Bayes geometric mean (EBGM), were used to assess reporting patterns. Multiple analyses were performed, including those restricted to primary suspect listed drugs only, expanded to incorporate secondary suspect drugs, and sensitivity analyses excluding reports submitted by legal professionals. Results: Among 19,961 DKA reports in FAERS, 2489 (12.5%) listed atypical antipsychotics as the primary suspect drug, whereas reports involving typical APDs were rare. The majority of reports were submitted by healthcare professionals (74.1%), and nearly half originated from the United States (45.4%). Hospitalization was a frequent outcome, reported in 74.3% of cases. Quetiapine and olanzapine were the most frequently reported atypical APDs, with disproportionality analyses demonstrating strong safety signals when compared to all other drugs in FAERS: olanzapine PRR 13.2 (95% CI: 12.4–14.2) and quetiapine PRR 11.8 (95% CI: 11.1–12.5). The findings remained consistent across multiple sensitivity analyses, including incorporating secondary suspect drugs, when the comparator group was restricted to only psychotropic drugs, and excluding reports submitted by lawyers. Conclusions: This pharmacovigilance analysis highlights a potential safety signal for DKA with atypical antipsychotic drugs, notably quetiapine and olanzapine. While these findings do not establish causality, they underscore the need for further investigation using clinical and epidemiological data.

Pharmacoepidemiology doi: 10.3390/pharma4040026

Authors: Patrick J. Silva Sara L. Rogers Zoya Hassan-Toufique Jian Tao Scott A. Bruce Paula K. Shireman Kenneth S. Ramos

Pharmacovigilance approaches have conventionally focused on the use of epidemiological data to detect emergent adverse drug reactions (ADRs). Recent advances in the use and availability of real-world data have expanded opportunities to detect ADR signals in medical records. We provide a limited review of pharmacovigilance practices and tools we have specifically considered implementing into our comprehensive medication management clinic and associated research programs. Use of pharmacogenomic variants has proven useful only on a limited scale as such data are reliant on low-dimensional approaches matching variants to drugs, often with small effect sizes. As such, most ADRs go unrecognized, undocumented, and unactionable. We posit that an idealized pharmacovigilance framework that relies on artificial-intelligence-assisted reporting with adjudication by pharmacovigilance experts and new models of ambulatory pharmaceutical practice would establish the following attributes: (1) all metadata relating to medication use would be available in the medical record in computable and interoperable data models, (2) digital surveillance tools would detect most ADR events with attributed pharmacological contributions, (3) all events would be characterized using standard adjudication rubrics, and (4) all events would iteratively inform an ADR knowledgebase and improve models to advance detection and prediction of ADR during the course of patient care with a focus on having the necessary tools for clinicians to prevent ADRs. This review provides a limited and focused framework for more systematic documentation of ADRs and tactics to mitigate the idiopathic nature of most ADRs.

Pharmacoepidemiology doi: 10.3390/pharma4040025

Authors: Pono Pono Vicky Cheng Victoria Skerrett Alan M. Jones

Background/Objectives: Human immunodeficiency virus (HIV) continues to be a global public health concern. Several antiretroviral drugs have been approved for the treatment, post-exposure, and pre-exposure prophylaxis of HIV. Darunavir (DRV) is a protease inhibitor (PI) approved for the management of HIV globally. This study aims to generate safety signals for DRV through data mining and analysis of adverse events (AEs) reported to the United Kingdom (UK) Medicines and Healthcare products Regulatory Agency (MHRA) Yellow Card Scheme. Methods: Disproportionality analysis was conducted using reporting odds ratio (ROR), proportional reporting ratio (PRR), and Bayesian confidence propagation neural network (BCPNN) approaches to identify potential safety signals. Results: The MHRA database contained n = 779 reports (n = 1791 AEs) attributed to DRV. The majority of AEs were reported for males. Positive safety signals were identified at both the system organ class (SOC, n = 5) and preferred term level (PT, n = 95). At SOC level, endocrine disorders emerged as a signal of interest n = 33 cases (ROR: 8.17, 95% CI: 5.78–11.56; PRR:7.96, 95% CI: 5.68–11.15; and IC: 2.85, IC025: 2.51). Among the results, 40 new potential safety signals are not listed on the product labelling in the UK. These include serious AEs such as cerebrovascular accident, brain injury, thrombosis, and pregnancy, puerperium, and perinatal AEs. Conclusions: This study provides additional real-world safety data for DRV in the UK and paves the way for future observational studies to investigate the identified safety signals.

Pharmacoepidemiology doi: 10.3390/pharma4040024

Authors: Bárbara Costa Nuno Vale

Background: Medication safety in pregnancy, puerperium, and perinatal periods is underexplored because these populations are excluded from clinical trials. EudraVigilance offers post-marketing evidence, but disproportionality analyses focus on isolated drug event pairs and may miss syndromic patterns. We applied a network- and cluster-based framework to EudraVigilance reports on antiviral use in pregnancy to improve surveillance and identify meaningful constellations. Methods: We retrieved all individual case safety reports (ICSRs) from January 2015 to June 2025, including pregnancy, puerperium, or perinatal terms, focusing on suspect antivirals. After parsing terms, disproportionality metrics were computed as a benchmark. A bipartite drug–event network was built and projected to event–event co-occurrence networks; Louvain community detection identified clusters. Clusters were characterized by size, drug mix, seriousness, overlap with disproportionality signals, and stratification across periods. Results: The dataset comprised 106,924 ICSRs and 232,067 unique pairs. Disproportionality yielded 6142 signals, mainly involving antiretrovirals (ritonavir, lamivudine, zidovudine, emtricitabine/tenofovir). Network analysis revealed clusters grouping maternal and fetal/neonatal outcomes (e.g., fetal death, low birth weight), and transplacental transfer, highlighting structures not visible in pairwise analyses. Several clusters combined high-frequency exposures with clinically relevant outcomes, suggesting early-warning potential. Conclusions: Combining disproportionality with network- and cluster-based pharmacovigilance adds value for monitoring pregnancy medication safety. Beyond individual signals, this approach reveals meaningful clusters and “bridge” reactions connecting adverse-event domains, offering a richer framework for perinatal surveillance. Despite spontaneous-reporting limits, findings generate hypotheses for mechanistic and pharmacoepidemiologic follow-up and support network methods as complements to traditional pharmacovigilance.

Pharmacoepidemiology doi: 10.3390/pharma4040023

Authors: Mary Isabel Vanegas-Rincón María A. Barón-Bolívar Javier A. Aguilar-Mejía Diana Patricia Amador-Munoz Luis Carlos Rojas-Rodríguez

Introduction: Acute iron poisoning is a potentially life-threatening condition that primarily affects the gastrointestinal, hepatic and cardiovascular systems. While it most often occurs accidentally in children, intentional overdoses in adolescents and adults remain an important clinical concern. Case description: We report the case of a 14-year-old male patient with a history of depression who intentionally ingested 100 ferrous sulfate tablets (equivalent to 118 mg/kg of elemental iron). The patient was admitted to the emergency department three hours after ingestion. He presented with vomiting tablet remnants, headache, and mild abdominal pain. Supportive measures included intestinal irrigation with polyethylene glycol (PEG), gastric protection, and N-acetylcysteine intravenous administration. The iron chelator therapy with deferoxamine was not possible because the medication was unavailable, so treatment with the oral iron chelator (deferasirox) was initiated. The iron levels gradually decreased, with no evidence of liver or cardiovascular involvement. The patient was discharged on day 20 post-ingestion with outpatient psychiatric follow-up. Discussion: This case highlights the importance of early initiation of gastrointestinal decontamination with PEG to limit systemic iron absorption. The use of deferasirox as an alternative chelating agent in the absence of deferoxamine has been associated with a favorable response. Conclusions: The rational use of oral chelators, gastrointestinal decontamination, and hepatoprotective therapies in acute iron poisoning might prevent major complications and improve prognosis. Alternative therapies can be valuable when an antidote is not immediately available; however, further clinical research is required before making a recommendation.

Pharmacoepidemiology doi: 10.3390/pharma4040022

Authors: Marios Spanakis Evangelos Bakaros Stella-Natalia Papadopoulou Agapi Fournaraki Emmanouil K. Symvoulakis

Herbal medicinal products are increasingly used alongside conventional medicines, raising the risk of potential interactions such as pharmacodynamic drug–herb interactions (PD-DHIs) that can cause serious adverse drug reactions (ADRs). This review aims to present available pharmacological, clinical and pharmacoepidemiological literature regarding potential DHIs associated with serotonin syndrome or cardiac arrhythmias. Furthermore, it assesses the current evidence using the Oxford Centre for Evidence-Based Medicine (CEBM) 2009 framework. Serotonin syndrome most often results from combining serotonergic herbs (e.g., St. John’s wort) with antidepressants like serotonin reuptake inhibitors (SSRIs), as supported by repeated case reports and mechanistic plausibility (CEBM Level 3, Grade C). Other herbs such as black cohosh, ginseng, Syrian rue, turmeric, rhodiola, ashwagandha, and L-tryptophan/5-HTP have been linked to serotonin syndrome when used with SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), or monoamine oxidase inhibitors (MAOIs), but evidence is limited (Levels 4–5, Grade D). For cardiac arrhythmias, PD-DHIs arise when herbs interact with drugs that alter cardiac electrophysiology—such as QT-prolonging agents, psychotropics, antiarrhythmics or digoxin—thereby amplifying arrhythmogenic risk. Ephedra with sympathomimetics is strongly associated with arrhythmias (Level 2–3, Grade B). Licorice may potentiate digoxin and QT-prolonging drugs via hypokalemia (Level 4, Grade C). Other related PD-DHIs include aconite with antiarrhythmics, bitter orange or caffeine with QT-prolonging psychotropics, yohimbine with cardiovascular agents, and aloe or senna with digoxin. Overall, the evidence for PD-DHIs varies from moderate to weak but large-scale pharmacoepidemiological data is scarce. Future approaches, including artificial intelligence with explainable machine learning and network pharmacology, may integrate mechanistic, clinical, and real-world data to improve early detection or prediction of PD-DHIs. However, several specific challenges must be addressed. Therefore, it is crucial for healthcare providers in both clinical and community settings to increase their awareness of these interactions and ADRs to ensure the safe use of herbal remedies alongside conventional therapies.

Pharmacoepidemiology doi: 10.3390/pharma4040021

Authors: Farhood Sadeghi Erta Rajabi Zahra Ghanbari Sajjad Fattahniya Reza Samiee Mandana Akhavan Mohammadreza Salehi Maryam Shafaati

Immunocompromised outpatients, including people living with HIV/AIDS (PLWH), diabetes, cancer, and organ transplant recipients, are at high risk of antimicrobial resistance (AMR) due to their weakened immune systems and use of immunosuppressive therapies. The high prevalence of prophylactic and therapeutic antibiotic use in this vulnerable population, coupled with frequent contact with healthcare facilities and limited outpatient antimicrobial resistance surveillance systems, contributes to the increase in antimicrobial resistance. The majority of available data pertains to inpatients, and there is a lack of comprehensive outpatient information on pathogen distribution, resistance patterns, and diagnostic challenges. Moreover, nonspecific clinical presentations, diminished inflammatory responses, and limitations of traditional diagnostic methods complicate infection diagnosis in this population. Increasing resistance surveillance, developing rapid diagnostic tools, and implementing accurate and personalized approaches are key strategies to reduce the burden of disease, mortality, and healthcare costs in the immunocompromised outpatient population. This study was designed as a narrative review based on a comprehensive search of major databases and guidelines. It aims to examine the available evidence and address the challenges associated with AMR in immunocompromised outpatients.

Pharmacoepidemiology doi: 10.3390/pharma4040020

Authors: Fiona Angus Jingkun Sun Wan-Chuen Liao Arfan Khan Li-Chia Chen

Background: Adherence to tyrosine kinase inhibitors (TKIs), the first-line treatment for renal cell carcinoma (RCC), is critical to ensure intended treatment outcomes. However, 75% of patients with RCC have persistency gaps (>7 days) within the first 90 days after initiating TKIs. This study explored factors affecting TKI adherence in RCC patients to inform future interventions. Methods: A retrospective cohort study was conducted at a specialist oncology hospital in Northwest England from October 2020 to October 2022 on patients with RCC treated with TKIs. TKI prescriptions and persistence gaps (>7 days) were identified from electronic dispensing records. Factors associated with persistence gaps were retrieved by reviewing patients’ clinical records. We used descriptive statistics to summarise the results and Kaplan–Meier analysis to assess the probability and the time to the first gap, stratified by adverse drug effect (ADE)-related and non-ADE-related gaps. Results: Among 165 included patients, 611 persistence gaps were identified. ADEs accounted for 59% (n = 464) of 787 recorded factors, with diarrhoea being the most frequent ADE (9.5%). Patients holding leftover TKIs were the primary (15.1%) non-ADE factor for persistency gaps. At least one gap was observed with 82% of patients (n = 135); 19% had ≥5 ADE-related gaps, and 25% had ≥5 non-ADE-related gaps. ADE-related gaps typically occurred within the first three months (50%), while non-ADE-related gaps were not time-dependent. Conclusions: ADEs, including diarrhoea and pain-related reactions, were the most frequently reported issues affecting TKI persistency in patients with RCC. These ADEs are likely to impact patients’ quality of life and adherence. Future qualitative research is warranted to explore patients’ care needs and additional factors such as health literacy and self-efficacy.

Pharmacoepidemiology doi: 10.3390/pharma4040019

Authors: Hiroyuki Tanaka Toshihiro Ishii

Background: While adverse drug events (ADEs) are a major public health concern, data on the occurrence of lethal or fatal ADEs in Japan are limited. Therefore, this study aimed to elucidate the characteristics and reporting trends of lethal or fatal ADEs by analyzing the Japanese Adverse Drug Event Report (JADER), a pharmacovigilance database. Methods: Of the individual ADE reports registered in the JADER database between April 2004 and March 2024 (fiscal year (FY) 2004–2023), all data involving individuals aged ≥ 20 years with complete data on sex and age were included in this analysis. Descriptive statistics were used to summarize the results. Results: The number of ADE cases registered in the JADER database increased approximately 2.3-fold from 21,824 in FY 2004 to 50,520 in FY 2023. Lethal or fatal ADE cases increased throughout the study period. In particular, the reporting rate of fatal ADEs reported in JADER appears to have increased in recent years. Lethal or fatal ADEs were reported more frequently among men and individuals aged ≥ 70 years. The recent increase in the reported rates of lethal or fatal ADEs may be largely influenced by the increased number of ADE reports associated with antineoplastic agents. The increase in the number of reports on immune checkpoint inhibitors is particularly notable. Conclusions: This study provides new insights into demographic and drug-related characteristics, as well as time trends associated with lethal or fatal ADEs in Japan. Further studies are needed to confirm these findings.

Pharmacoepidemiology doi: 10.3390/pharma4030018

Authors: Mohammed Khan Christine Hirsch Alan M. Jones

Background/Objectives: The aim of this study was to determine the suspected adverse drug reaction (ADR) profile of leukotriene receptor antagonists (LTRAs; montelukast and zafirlukast) relative to first-line asthma medications such as short-acting beta agonists (SABAs; salbutamol) and inhaled corticosteroid (ICS; beclomethasone) in the United Kingdom. to determine the chemical and pharmacological rationale for the suspected ADR signals. Methods: Properties of the asthma medications (pharmacokinetics and pharmacology) were datamined from the chemical database of bioactive molecules with drug-like properties, the European Molecular Biology Laboratory (ChEMBL). Suspected ADR profiles of the asthma medications were curated from the Medicines and Healthcare products Regulatory Authority (MHRA) Yellow Card interactive Drug Analysis Profiles (iDAP) and concatenated to the standardised prescribing levels (using Open Prescribing data) between 2018 and 2023. Results: Total ADRs per 100,000 Rx (p < 0.001) and psychiatric system organ class (SOC) ADRs (p < 0.001) reached statistical significance. Montelukast exhibited the greatest ADR rate at 15.64 per 100,000 Rx. Conclusions: Relative to the controls, montelukast displays a range of suspected system organ class level ADRs. For the credible and previously reported psychiatric ADRs, montelukast is statistically significant (p < 0.001). A mechanistic hypothesis is proposed based on polypharmacological interactions in combination with cerebrospinal fluid (CSF) levels attained. Montelukast had the highest nervous disorder ADR rate at 1.71 per 100,000 Rx, whereas beclomethasone and salbutamol had lower rates (0.43 and 0.14, respectively). These ADRs share a similar background to psychiatric ADRs with CSF penetrability involved and affecting the dopamine axis. This work further supports the monitoring of montelukast for rare but important neuropsychiatric side effects.

Pharmacoepidemiology doi: 10.3390/pharma4030017

Authors: Mayra R. C. de Souza Alciéllen M. da Silva Patrícia S. Bazoni Jéssica B. R. dos Santos Michael R. R. da Silva

Background: During the COVID-19 pandemic, analgesic use increased significantly, primarily due to self-medication for symptom relief. In Brazil, metamizole (dipyrone) is widely used despite international restrictions, highlighting the importance of evaluating its consumption patterns. Objective: To assess analgesic use during the COVID-19 pandemic. Methods: This cross-sectional study was conducted via a household survey in Alegre, Espírito Santo, Brazil. Structured questionnaires were used to collect data on sociodemographic characteristics, clinical conditions, and medication use. Descriptive statistics included frequency distributions, medians, and interquartile ranges. Factors associated with analgesic use were analyzed using Poisson regression with robust variance. Results: Among 694 participants, 31.6% reported using analgesics, with metamizole being the most frequently used (87.2%), followed by acetaminophen (paracetamol) (24.7%). Analgesic use was more common among individuals with polypharmacy, lower self-reported quality of life, better self-perceived health, and recent dental appointments. Conclusions: A high prevalence of analgesic use was identified, particularly of metamizole. Given its over-the-counter availability and growing evidence of risks such as liver injury and other adverse events, ongoing monitoring is essential. These findings underscore the need for public health strategies and pharmacist involvement to promote the rational and safe use of analgesics.

Pharmacoepidemiology doi: 10.3390/pharma4030016

Authors: Neta Shanwetter Levit Keren Filosof Jacob Glazer Daniel A. Goldstein

Background/objectives: In 9/2020, the United States Food and Drug Administration )FDA( posted a black box warning for all benzodiazepines, addressing their association with serious risks of abuse, addiction, physical dependence, and withdrawal reactions. We evaluated changes in benzodiazepine dispensing rate trends after this warning. Methods: The dataset of Clalit Health Services (Israel’s largest insurer, with 5 million members) was used to identify and collect benzodiazepine dispensing data for all patients who were dispensed these drugs at least once during the study period (1/2017–12/2021). The dispensing rate (number of patients who were dispensed benzodiazepines per month divided by the number of patients alive during that month) was calculated for each month in the study period. Linear regression and change point regression were used to review the change in trend before and after the black box warning. New users of benzodiazepines after the black box warning were analyzed by age. Results: A total of 639,515 patients using benzodiazepines were reviewed. The mean benzodiazepine dispensing rate per month was 0.21 and ranged from 0.17 (in 2/2017) to 0.24 (in 3/2020). No significant change in trend was observed before vs. after the black box warning (slopes of 0.00675 percentage points per month and 0.00001 percentage points per month, respectively; p = 0.38). The change point regression analysis identified a change point in 4/2019, which is prior to the black box warning. New users were younger after the black box warning compared to before this warning. Conclusions: The FDA black box warning did not affect the dispensing rate of benzodiazepines.

Pharmacoepidemiology doi: 10.3390/pharma4030015

Authors: Anna Peyton-Navarrete Minh Hien Chau Nguyen Alireza FakhriRavari

Proton pump inhibitors (PPIs) are widely prescribed medications primarily used to treat gastroesophageal reflux disease, peptic ulcer disease, and upper gastrointestinal bleeding. Despite clear therapeutic benefits in appropriate contexts, widespread overprescribing and extended use without clear indications have prompted significant concerns about associated risks. Accumulating evidence, predominantly from observational studies, suggests that long-term PPI use may lead to complications such as vitamin and mineral deficiencies, increased risks of infections, dysbiosis, renal dysfunction, bone fractures, cardiovascular disease, and certain malignancies. This narrative review not only synthesizes the current evidence surrounding PPI-related harms and existing deprescribing guidelines but also offers a novel perspective on how stewardship principles can be applied to promote responsible PPI prescribing. In particular, we propose a stewardship-oriented deprescribing framework rooted in implementation science, focusing on provider behavior, patient engagement, and health system-level integration. Recognizing these potential harms, evidence-based deprescribing strategies such as tapering, intermittent dosing, and transitions to alternative therapies are critical to mitigate unnecessary patient exposure. Effective implementation of deprescribing requires addressing patient, provider, and institutional barriers through educational initiatives, policy support, and structured monitoring. By promoting judicious PPI prescribing and proactive stewardship practices, clinicians can significantly reduce medication-related harm and improve patient safety.

Pharmacoepidemiology doi: 10.3390/pharma4030014

Authors: Jahnavi Udaikumar Rithish Nimmagadda Vindhya Vasini Lella Kesava Manikanta Achuta Satwik Kuppili Suraj Reddy Avula Raiya Sarwar

Introduction: Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly encompassed under nonalcoholic fatty liver disease (NAFLD), is a growing global health burden associated with progression to cirrhosis and hepatocellular carcinoma. Resmetirom, a thyroid hormone receptor-β (THR-β) agonist, and semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), have emerged as promising agents targeting distinct metabolic and inflammatory pathways. This systematic review compares the safety and efficacy of resmetirom and semaglutide in MASLD. Methods: We conducted a comprehensive search of PubMed, Embase, and Google Scholar for randomized controlled trials and clinical studies published between January 2014 and April 2025, following PRISMA guidelines. Studies assessing the efficacy and safety of resmetirom and/or semaglutide in MASLD or NASH were included. Data extraction was performed by two independent reviewers, and a narrative synthesis was undertaken due to the heterogeneity in study design and outcome measures. Results: Fourteen studies encompassing over 4500 patients were analyzed. Resmetirom demonstrated consistent reductions in hepatic fat (≥30% in >50% of patients) and improvements in fibrosis (≥1 stage in up to 26.4% of patients), as evidenced in the MAESTRO-NASH trial. Semaglutide achieved higher rates of NASH resolution (up to 62.9%) without worsening fibrosis, especially among patients with type 2 diabetes or obesity, although fibrosis improvement was less consistently observed. Resmetirom was well tolerated with low discontinuation rates, while semaglutide was associated with more frequent, yet manageable, gastrointestinal adverse events. Conclusions: Both resmetirom and semaglutide show therapeutic potential for MASLD. Resmetirom offers more consistent antifibrotic effects, while semaglutide excels in NASH resolution and metabolic improvement. The absence of direct comparative trials underscores the need for future head-to-head studies to guide tailored treatment strategies in MASLD management.

Pharmacoepidemiology doi: 10.3390/pharma4030013

Authors: Lee Nguyen

The exchange of knowledge is fundamental to the progression of health sciences [...]

Pharmacoepidemiology doi: 10.3390/pharma4020012

Authors: Giraud Ekanmian Carlotta Lunghi Helen-Maria Vasiliadis Line Guénette

Objectives: This study aimed to assess the concordance between depression and anxiety case definitions derived from algorithms based on medico-administrative data and structured interviews aligned with the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria in older adults. Methods: We analyzed data from 1405 primary care older adults (≥65 years) from the Étude sur la Santé des Aînés (ESA)-Services cohort (2011–2013) in Quebec, Canada, who had available survey and medico-administrative data. Cases of depression and anxiety were identified using algorithms incorporating combinations of hospitalization records, physician-visit claims, and medication claims for antidepressants or anxiolytics. The agreement was assessed with the kappa statistics (κ), and the algorithms’ sensitivity, specificity, and positive and negative predictive values were calculated using the case definitions derived from the DSM-IV-aligned ESA-Services interviews as the gold standard. Results: Agreements between the algorithms and the interviews were fair (κ: 0.06–0.22) for depression gooand slight (κ: 0.02–0.09) for anxiety. The algorithms had low sensitivity (2–39.7% for depression and 1.4–39.9% for anxiety) but high specificity (84.5–99.6% for depression and 73–99.2% for anxiety), depending on the algorithm. Conclusions: The agreement between algorithms based on administrative data and DSM-IV-aligned interviews for anxiety or depressive disorders was low. The two methods identified older adults with different characteristics. Despite these discrepancies, algorithms with high specificity provide valuable insights into healthcare utilization patterns associated with these disorders.

Pharmacoepidemiology doi: 10.3390/pharma4020011

Authors: Sean T. Lynch Victor Gordillo Ashley Sacks Emily Groenendaal Lidia Klepacz Eldene Towey Stephen J. Ferrando

Background: Opioid Use Disorder (OUD) has claimed the lives of many Americans, with rates of overdose steadily rising over the past decade. Despite having highly effective medications to treat this condition, many providers still hesitate to prescribe them. Psychiatric inpatient facilities have a unique opportunity to engage patients with co-occurring disorders in the treatment of OUD; however, significant barriers exist. This study describes a novel OUD–buprenorphine (BUP) consultation service that provides such care to hospitalized psychiatric patients. Methods: This IRB-approved retrospective study reviewed the medical records of 123 hospitalized psychiatric patients who received consultations from the BUP consultation service. Descriptive and comparative statistics were performed. Results: The sample was predominantly male, with significant unemployment and housing instability. Patients were hospitalized for depressive, bipolar, and schizophrenia spectrum disorders. Over 90% of patients were discharged on buprenorphine, with over 50% being connected to specialized substance use services. No increase in the length of stay was found, and no difference in outcomes was observed based on diagnosis or BUP discharge status. Discussion/Conclusions: This novel service was effective in providing OUD treatment to patients with complex co-occurring psychiatric disorders without significantly increasing their length of stay. Despite acute exacerbations in psychiatric illness, patients were able to engage in discussions regarding BUP. While the study was limited in scope, it underscores the feasibility of integrating OUD treatment in the acute psychiatric inpatient setting.

Pharmacoepidemiology doi: 10.3390/pharma4020010

Authors: Lauren F. O’Connor Jenna B. Resnik Sam Simmens Vinay Bhandaru Debra Benator La’Marcus Wingate Amanda D. Castel Anne K. Monroe

Background: The validated Screening Tool of Older People’s Prescriptions (STOPP) identifies potentially inappropriate prescribing (PIP)—treatments where potential risk outweighs potential benefit. STOPP is particularly important for people aging with HIV and comorbidities, since PIP may exacerbate symptoms and decrease adherence. Methods: We analyzed data from the DC Cohort, a longitudinal cohort of people with HIV (PWH). We applied STOPP criteria to identify PIP among DC Cohort participants aged ≥ 50 years who completed a Patient Reported Outcomes (PROs) survey. All medications prescribed in the 2 years prior to PROs survey completion were considered. Negative binomial models were used to evaluate factors associated with PIP and structural equation modeling was used to evaluate whether symptom burden mediates the relationship between PIP and quality of life. Results: Of 1048 eligible DC Cohort participants, 486 (46%) had at least one PIP. The most common systems implicated were musculoskeletal (23%), analgesic drugs (16%), and the central nervous system (13%). Age, race/ethnicity, HIV transmission factor, social determinants of health, and type of HIV care site were significantly associated with number of PIP in the crude models. In the multivariable model with just demographic variables, the association between age (aIRR: 1.03 (95% CI: 1.02, 1.04)), intravenous drug use (aIRR: 1.68 (95% CI: 1.20, 2.35)), White, non-Hispanic race (aIRR: 0.67 (95% CI: 0.50, 0.92)), site type (aIRR: 0.75 (95% CI: 0.62, 0.92)), and the expected number of PIPs remained significant. In the fully adjusted multivariable model with demographics and SDOH, the association between age, intravenous drug use, White, non-Hispanic race, and expected number of PIPs remained significant. Statistical evidence that symptom burden mediates the relationship between PIP and each of the QOL dimensions was present. Conclusions: Future interventions should work to decrease PIP among these high-risk groups, especially for PIP associated with increased symptom burden.

Pharmacoepidemiology doi: 10.3390/pharma4020009

Authors: Michael W. Strand Daniel Chow Weining Shen Jonathan H. Watanabe

Background: Incretin mimetics, including glucagon-like peptide-1 receptor agonists (GLP-1 receptor agonist) and dipeptidyl peptidase-4 (DPP-4) inhibitors, have been increasingly utilized for glycemic control in patients with type 2 diabetes (T2D). Studies have demonstrated additional improvements in weight loss, cardiovascular health, and renal outcomes. Animal studies have shown an association between GLP-1 receptor agonists and C-cell proliferation and elevated calcitonin, resulting in an FDA black box. Insulin resistance in patients with T2D, along with the use of other glucose control medications, confounds the relationship between incretin mimetics and thyroid cancers. The true effect of incretin mimetics on thyroid cancer remains uncertain and speculative due to this confounding. Methods: This retrospective cohort study compared patients with T2D, who were new users of incretin mimetics, to new users of metformin. Study patients used no other anti-diabetes medications beyond the study medications. The risks of incident thyroid cancer and subsequent thyroidectomy were quantified using Cox proportional hazards regression models fitted with adjustments for demographic and medical covariates over a three-year study period. Medullary thyroid cancer (MTC) and multiple endocrine neoplasia type II (MEN2) cases were quantified. Results: Of the 91,394 patients, 28 incretin mimetic users had a diagnosis of thyroid cancer, and nine of these patients underwent a subsequent thyroidectomy procedure. No incretin mimetic user was diagnosed with MTC or MEN2. There was no statistically significant effect on the overall incretin mimetic category (1.28 aHR, 0.83–1.96), the incretin mimetic subcategories of GLP-1 receptor agonists (1.35 aHR, 0.80–2.29), or DPP-4 inhibitor (0.62 aHR, 0.33–1.17) users in developing thyroid cancer within three years of drug initiation. Similarly, no association was found between the overall incretin mimetic category (1.02 aHR, 0.49–2.10), the subcategories of GLP-1 receptor agonists (1.26 aHR, 0.54–2.96), or DPP-4 inhibitors (0.32 aHR, 0.08–1.37) and a subsequent thyroidectomy. Conclusions: In this real-world cohort study, exposure to incretin mimetics overall or through the incretin mimetic subcategories of GLP-1 receptor agonists and DPP-4 inhibitors was not associated with risks of thyroid cancer or thyroidectomy compared to metformin users.

Pharmacoepidemiology doi: 10.3390/pharma4020008

Authors: Joep Scholl Florence van Hunsel Eugene van Puijenbroek

Objective: The aim of this study was to investigate a possible relationship between the time to onset (TTO) of adverse events following immunization (AEFIs) and recall bias and to compare it between AEFIs of COVID-19 vaccines reported though the spontaneous reporting system (SRS) and those from a cohort event monitoring (CEM) study. Methods: A retrospective study comparing TTO patterns of AEFIs of four COVID-19 vaccines from the SRS and those from a CEM study was performed. Reports concerning AEFIs related to COVID-19 vaccination were used for the study. TTO patterns were stratified for vaccination dose number, perceived burden of the AEFI, and for being pre-defined. Additionally, since menstrual disorders received much media attention, their effect on the TTO pattern was investigated for SRS reports only. Results: A total of 160,613 reports from the SRS and 19,979 from the CEM, containing 755,647 and 103,703 AEFIs, respectively, were included. For AEFIs with a short TTO, no differences in TTO patterns were observed. However, the median TTO for AEFIs from the SRS was lower with increasing TTO duration. There were differences in both median TTO and time to reporting for AEFIs reported before and during episodes of media attention, but no correlation between the two could be found. Conclusions: Based on the performed TTO analyses, recall bias does not seem to be more evident in SRS compared to CEM studies for AEFIs with a short TTO. For AEFIs with a longer TTO, this may be more pronounced.

Pharmacoepidemiology doi: 10.3390/pharma4020007

Authors: Matthew Halma Joseph Varon

Background/Objectives: Controversy exists over the use of passive reporting systems, especially the Vaccine Adverse Event Reporting System, in risk assessment. One limitation of these systems is that adverse event (AE) reporting rates cannot be calculated without knowing the number of shots administered or prescriptions in the case of pharmaceuticals. Adverse event reporting rates can be a factor in a risk assessment, though they should not be solely relied on; they can be used to compare the relative safety profiles of different vaccine products or pharmaceuticals. This study introduces the Denominator-Adjusted Rate Estimates of Substance Adverse Events Frequency Evaluation (DARE-SAFE) method to analyze pharmacovigilance reporting rates for vaccines and common pharmaceuticals. Methods: We calculated reporting rates for the top 250 most prescribed drugs in the US Food and Drug Association (FDA) Adverse Event Reporting System and common vaccines in the Vaccine Adverse Events Reporting System. For vaccines, we used USA Centers for Disease Control (CDC) dose data and OpenVAERS reports. For pharmaceuticals, we utilized prescription data from ClinCalc and FAERS reports for 2022. Results: VAERS reporting rates varied significantly across vaccine types. COVID-19 vaccines showed a 63.0 ± 0.6 times higher rate of VAERS deaths per dose and an 18.95 ± 0.02 times higher rate of total adverse event reports per dose compared to influenza vaccines. The ratio of total VAERS reports to deaths for vaccines was 73 ± 4 to 1 (R2 = 0.94). For pharmaceuticals, the ratio of total adverse event reports to deaths was 26 ± 2 (R2 = 0.46), with a strong correlation between serious adverse events and deaths (ratio 9.1 ± 0.3, R2 = 0.79). Conclusions: DARE-SAFE provides a standardized method for comparing reporting rates across different medical products. The observed differences between vaccines and pharmaceuticals, as well as among different vaccine types, warrant further investigation into reporting practices, actual safety profiles, and potential biases in surveillance systems.

Pharmacoepidemiology doi: 10.3390/pharma4010006

Authors: Shu-Yu Yao Paul T. Kocis Terrence E. Murphy Wenke Hwang

Background/Objectives: Direct oral anticoagulants (DOACs), when compared to the Vitamin K antagonist (VKA) warfarin, exhibit greater safety and effectiveness. However, DOACs may still have potential drug–drug interactions that result in major bleeding events. There is a paucity of studies on medications that have pharmacodynamic interactions with DOACs, such as selective serotonin reuptake inhibitors (SSRIs). This study evaluates the potential major bleeding risk associated with the concomitant use of SSRIs among nonvalvular atrial fibrillation (NVAF) patients who were receiving DOACs. Methods: Adult patients receiving DOACs with consecutive NVAF diagnoses were identified from the Penn State Health Electronic Health Records from 2013 to 2023. These patients were then checked for exposure (i.e., concomitant use of SSRIs). The outcome was time to the first occurrence of a major bleeding event, with a follow-up from the first DOAC prescription until a major bleeding event, death, or end of follow-up. This retrospective cohort study used a Cox cause-specific proportional hazard model to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) with inverse probability of treatment weighting to adjust for measurable confounding factors (e.g., demographics, comorbidities, comedications). Results: A total of 8657 NVAF patients who were receiving DOACs were identified. The mean age was 70.3 ± 11.95 years, and females comprised 39.8% of the study population. The baseline CHA2DS2-VASc score was 3.77 ± 1.76, and the HAS-BLED score was 2.98 ± 1.27. Among these patients, 2649 (30.6%) were co-prescribed with SSRIs. The unadjusted hazard ratio for SSRIs was 0.87 (95% CI: 0.76–0.99) and the adjusted hazard ratio was 0.68 (95% CI: 0.59–0.78). Conclusions: In patients with NVAF receiving DOACs, concomitant use of SSRIs was not associated with a higher risk of major bleeding.

Pharmacoepidemiology doi: 10.3390/pharma4010005

Authors: Nilamadhab Kar

Background/Objectives: Despite an improved knowledgebase, effective intervention, and guidelines, many patients with depression do not receive adequate treatment and treatment discontinuation and non-response are common. It was intended to explore the challenges clinicians face while managing depression in their clinical practice and their suggestions for solutions. Methods: It was an online survey of 137 psychiatrists in 18 countries including both high and low economies, using a pre-designed questionnaire; with both quantitative and qualitative measures. Results: Antidepressant prescribing appeared close to the evidence-based guidelines. There was frequent use of other medications alongside antidepressants since treatment initiation. There were many challenges in managing depression, such as treatment non-response, resistance, and discontinuation; side effects, mostly sexual problems; inadequate psychological intervention; availability and affordability of treatment modalities; comorbidities, especially substance use and personality disorders; stigma; and lack of education and training. Suggested approaches for solutions included personalized treatment, quicker follow-up, psychoeducation, blending psychological intervention into routine clinical practice, improving continuity of care, and preventing treatment discontinuation. Support from governments for improving access, making interventions affordable, and providing socio-occupational support is essential. Training and development of professionals, public education providing information, and dealing with stigma are still relevant. Conclusions: The results indicated a need for reviewing current practices in managing depression, optimizing it with available resources, and preventing treatment discontinuation, and non-response. Making treatment available and affordable, public education fighting stigma to improve treatment acceptability, and research addressing gaps in interventions, especially for treatment resistance and psychotherapy are other approaches that may improve depression management.

Pharmacoepidemiology doi: 10.3390/pharma4010004

Authors: Wael Y. Khawagi Neetu Bansal Nan Shang Li-Chia Chen

Background/Objectives: This systematic review aimed to identify a comprehensive list of potential opioid-related indicators from the published literature to assess prescribing safety in any setting. Methods: Studies that reported prescribing indicators from 1990 to 2019 were retrieved from a previously published systematic review. A subsequent search was conducted from seven electronic databases to identify additional studies from 2019 to June 2024. Potential opioid safety prescribing indicators were extracted from studies that reported prescribing indicators of non-injectable opioids prescribed to adults with concerns about the potential risk of harm. The retrieved indicators were split by each opioid, and duplicates were removed. The identified indicators were categorized by the type of problem, medication, patient condition/disease, and the risk of the indicators. Results: A total of 99 unique opioid-specific prescribing indicators were identified from 53 included articles. Overall, 42 (42%) opioid prescribing indicators focused on a specific class of opioids. Pethidine, tramadol, and fentanyl were the most frequently reported drugs (n = 22, 22%). The indicators account for six types of problems: medication inappropriate for the population (n = 20), omission (n = 8), inappropriate duration (n = 10), inadequate monitoring (n = 2), drug–disease interaction (n = 26), and drug–drug interaction (n = 33). Of all the indicators, older age (over 65) is the most common risk factor (n = 38, 39%). Central nervous system-related adverse effects are the risk of concern for the 28 (29%) indicators associated with drug–drug interactions. Furthermore, five of the six ’omission’ indicators are related to ’without using laxatives’. Conclusions: This review identified a comprehensive set of indicators for flagging patients at high risk of opioid-related harm, thereby supporting informed decision-making in optimizing opioid utilization. However, further research is essential to validate these indicators and evaluate their feasibility across diverse healthcare settings.

Pharmacoepidemiology doi: 10.3390/pharma4010003

Authors: Rodrigo Silva Marcelino Edivã Bernardo da Silva Abel Santiago Muri Gama Ananias Facundes Guimarães Silvia Regina Secoli Albert Figueras

Background/Objectivses: Antibiotic consumption patterns in remote urban areas of the Amazon region are poorly understood. This study aimed to analyze antibiotic use in the adult population of Coari, a municipality in Amazonas, Brazil. Methods: A cross-sectional study was conducted between October and November 2021 in the urban area of Coari. 394 adults were interviewed using a structured questionnaire. Data on antibiotic use, sociodemographic factors, health service access, and self-reported illnesses were collected. Poisson regression was used to estimate prevalence ratios and identify factors associated with antibiotic use. Results: The prevalence of antibiotic use was 14.7% (n = 58). The most frequently used antibiotics were azithromycin (26.9%), cefalexin (20.9%), amoxicillin (19.4%), and ciprofloxacin (13.9%). Up to 34.5% of antibiotic use was conducted without a prescription, especially among adults aged 18 to 39 (59.1%). The main health problems that led to self-medication were COVID-19 (28.6%), urinary infection (14.3%), sore throat (37.5%), and intestinal infection (60.0%). Factors associated with antibiotic use included age 18 to 39 (adjusted PR = 3.73; CI = 1.37–10.09), having a family member hospitalized (adjusted PR = 2.61; CI = 1.39–4.89), having contracted COVID-19 (adjusted PR = 2.41; CI = 1.40–4.15), and frequency of visits by the community health agent to the home (adjusted PR = 0.35 CI = 0.15–0.81). Conclusions: The high use of broad-spectrum antibiotics (Watch), particularly azithromycin, for potentially inappropriate indications highlights the need to improve the management of antibiotic use in remote regions of Brazil. Community health agents, as key professionals between health services and the community, can play a key role in promoting the rational use of antibiotics and combating antimicrobial resistance in the Brazilian Amazon context.

Pharmacoepidemiology doi: 10.3390/pharma4010002

Authors: Hansoo Kim Joshua Byrnes Kyoo Kim Duc Trong Quach Tran Thi Khanh Tuong Cuc Thi Thu Nguyen

Background/Objectives: Functional dyspepsia is associated with abdominal pain and nausea, which leads to reduced quality of life, loss of productivity, and economic loss for patients. Itopride hydrochloride (itopride) stimulates the gastrointestinal smooth muscles, thereby promoting gastric emptying. It has been shown to significantly improve symptoms in patients with functional dyspepsia without severe side effects. Itopride has been available in Vietnam for many years; however, the cost-effectiveness of the drug has not been established. The aim of this study is to estimate the cost-effectiveness of itopride for the treatment of functional dyspepsia in Vietnam. Methods: A 3-stage Markov model with the following health states—controlled functional dyspepsia, uncontrolled functional dyspepsia, and dead—was developed. Functional dyspepsia was used to assess itopride over 10 years using 8-week cycles. A broader Vietnamese societal perspective was assumed for the analysis. Input was retrieved from the literature and through local clinical input from physicians in Vietnam. Output was reported as an incremental cost-effectiveness ratio (ICER) per quality-adjusted life years (QALY). A GDP/capita threshold (very cost-effective: 1 × GDP = Vietnamese Dong (VND) 64.1 M, cost-effective: 3 × GDP = VND 192.2 M) was used as recommended by the WHO in Vietnam. One-way and probabilistic sensitivity analyses were performed. Results: Itopride use resulted in an additional 0.28 QALYs at an extra cost of VND 11.2 M. This resulted in an ICER of VND 39.7 M per QALY, which is lower than the threshold of VND 192.2 M. One-way sensitivity analyses showed that the ICER was sensitive to varying the efficacy VND 31.8 M to VND 88.3 M), cost of itopride (ICER: VND 43.1 M to VND 56.5 M), and the health utility values (ICER: VND 45.2 M to VND 55.3 M). More than 80% of the simulations in the probabilistic sensitivity analysis were cost-effective at the 1 × GDP (VND 64.1 M) threshold, and 91.3% were cost-effective at the 3 × GDP (VND 192.2 M) threshold. Conclusion: This study shows that itopride hydrochloride is a very cost-effective treatment for functional dyspepsia in Vietnam, with the ICER (VND 39.7 M/QALY) being even lower than the 1 × GDP (VND 64.1 M) threshold.

Pharmacoepidemiology doi: 10.3390/pharma4010001

Authors: Connor Frey

Background: Immuno-oncology has transformed cancer treatment, with immune checkpoint inhibitors (ICIs) like pembrolizumab playing a key role. While highly effective, these therapies can also cause immune-related adverse events. This study examines the incidence and characteristics of hepatobiliary adverse events (AEs) linked to pembrolizumab, using data from the FDA Adverse Event Reporting System (FAERS). Objective: To investigate the rates of hepatobiliary AEs linked to pembrolizumab, providing insights into the risks of liver and biliary system damage in patients prescribed pembrolizumab. Methods: This study utilized the FAERS database via OpenVigil 2.1. Adverse events (AEs) related to pembrolizumab were identified and compared to those associated with other drugs. Reporting odds ratios (RORs) were calculated to assess the likelihood of hepatobiliary AEs in pembrolizumab-treated patients. Results: In total, 594 hepatic AEs and 181 biliary AEs were identified. Significant hepatic AEs included elevated ALT (ROR 3.00, 95% CI: 2.685–3.351), hepatotoxicity (ROR 6.436, 95% CI: 5.72–7.242), and hepatic cytolysis (ROR 15.721, 95% CI: 13.854–17.84). Immune-mediated hepatitis exhibited the highest ROR of 346.716 (95% CI: 303.568–395.997). For biliary AEs, cholangitis (ROR 19.597, 95% CI: 16.852–22.791) and sclerosing cholangitis (ROR 24.735, 95% CI: 19.888–30.763) were the most prominent. Conclusions: Pembrolizumab is associated with a significant risk of hepatobiliary adverse events, particularly immune-mediated hepatitis and cholangitis. The elevated RORs for these conditions highlight the importance of close monitoring and managing liver and biliary functions in patients undergoing pembrolizumab checkpoint blockade. These findings emphasize the need for personalized treatment strategies to mitigate risks and optimize outcomes in cancer immunotherapy, especially for those with preexisting hepatobiliary conditions.

Pharmacoepidemiology doi: 10.3390/pharma3040028

Authors: Lee Nguyen Catherine Diamond

Doxycycline is a semi-synthetic antibiotic in the tetracycline family. The three common subtypes of tetracyclines include naturally occurring, semi-synthetic, and new agents. Each subtype shares specific commonalities but is substantially different in various clinical applications. The mechanism of antimicrobial activity is the same across subtypes. The structural changes to the core naphthacene ring do not alter the mechanism of action but are thought to alter the rates of adverse effects and mechanisms of resistance. Tetracyclines as a class are known to cause fixed drug eruptions, but the majority of these adverse effects were associated with naturally occurring tetracyclines. Semi-synthetic tetracyclines have limited reports of fixed drug eruptions. Here, we present a case of fixed drug eruption in a patient who previously had multiple treatment courses with doxycycline. The case involves the use of doxycycline not for the treatment of an infection but as postexposure prophylactic (PEP) antibiotic therapy to prevent the acquisition of a sexually transmitted infection. Doxycycline PEP has been shown to reduce the rate of bacterial sexually transmitted infection in men who have sex with men (MSM). Doxycycline PEP is a single dose taken orally within 24–72 h of unprotected sexual intercourse. The dosing structure allows for ease of adherence but also repeatedly exposes individuals to doxycycline, putting them at risk for adverse events such as fixed drug eruptions, as illustrated by this case report.

Pharmacoepidemiology doi: 10.3390/pharma3040027

Authors: Takuma Koinuma Manato Yoshida Manabu Akazawa

Background: Sodium–glucose cotransporter-2 inhibitors (SGLT2Is) have demonstrated effects beyond glucose-lowering, leading to their approval for treating chronic heart failure (HF) in Japan. This study examines prescription trends for SGLT2Is in patients with diabetes versus those without diabetes, focusing on their backgrounds and HF treatment status of patients without diabetes who received SGLT2I after an HF diagnosis. Methods: Using data from DeSC Healthcare Inc., we analyzed patients aged 65 and above who received their first SGLT2I prescription between October 2014 and February 2023. Patients were classified into SGLT2I-treated diabetic and non-diabetic groups. We analyzed the annual prescription trends and compared the characteristics of both groups who started SGLT2I between 2022 and 2023. Additionally, we assessed the timing of SGLT2I initiation and the use of concomitant HF treatment in patients without diabetes after HF diagnosis. Results: The proportion of patients without diabetes receiving their first SGLT2I prescription has increased since 2021. Patients without diabetes receiving SGLT2Is were older, likely owing to aging-related diseases. In patients without a confirmed diabetes diagnosis, SGLT2I was most frequently initiated at the time of HF diagnosis. Mineralocorticoid receptor antagonists (MRAs) are the most common concomitant HF medications. The increase in SGLT2I prescriptions for patients without diabetes receiving SGLT2I since 2021, particularly in older individuals, suggests that SGLT2I is being initiated either at the time of HF diagnosis or in a stepwise manner. Conclusion: In Japan, MRA is commonly used as a concomitant medication in patients without diabetes receiving SGLT2I.

Pharmacoepidemiology doi: 10.3390/pharma3040026

Authors: Connor Frey

Background/Objectives: Several drugs used to treat prostate cancer have been reported to cause cardiovascular adverse events, and this study sought to identify the real-world risk. Methods: This study utilized real-world data from the FAERS to analyze the association between prostate cancer treatment and cardiovascular adverse events. It evaluated men treated with LHRH agonists and antagonists, antiandrogens, androgen synthesis inhibitors, and PARP inhibitors from 2003 to 2023. This study included patients treated with leuprolide, goserelin, triptorelin, degarelix, relugolix, bicalutamide, flutamide, apalutamide, nilutamide, abiraterone, enzalutamide, olaparib, rucaparib, talazoparib, and niraparib. The main outcome measure was the reported odds ratio (ROR) of adverse cardiovascular event associated with these treatments. Results: Among the 4,049,329 unique adverse event reports, 4391 cardiovascular events were identified. Leuprolide (ROR 0.481, 95% CI: 0.423–0.547), triptorelin (ROR 0.527, 95% CI: 0.305–0.909), enzalutamide (ROR 0.393, 95% CI: 0.341–0.452), and olaparib (ROR 0.145, 95% CI: 0.054–0.386) reduced the risk of myocardial infarction. Goserelin increased the risk of myocardial infarction (ROR 2.235, 95% CI: 1.367–3.654). Degarelix and relugolix both increased the risk of heart failure (ROR 3.136, 95% CI: 2.186–4.497), and enzalutamide was associated with an increased risk of heart failure (ROR 1.305, 95% CI: 1.135–1.501). Bicalutamide increased the risk of unstable angina (ROR 3.019, 95% CI: 1.621–5.622) and heart failure (ROR 3.730, 95% CI: 3.085–4.510). Niraparib increased the risk of hypertension (ROR 4.154, 95% CI: 1.709–10.092). Conclusions: These findings underscore the need for clinicians to monitor cardiac complications in patients undergoing these therapies.

Pharmacoepidemiology doi: 10.3390/pharma3040025

Authors: Sofía Echeverry-Guerrero Salomé González-Vélez Ana-Sofía Arévalo-Lara Juan-Camilo Calvache-Orozco Sebastián Kurt Villarroel-Hagemann Luis Carlos Rojas-Rodríguez Andrés M. Pérez-Acosta Carlos-Alberto Calderon-Ospina

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as a potent therapeutic option for the management of obesity, demonstrating exceptional efficacy in several large-scale clinical trials. Despite their promising therapeutic outcomes, the rising popularity of these agents raises significant concerns, particularly regarding their off-label use by individuals seeking weight loss for aesthetic reasons rather than addressing underlying metabolic health conditions. This article critically evaluates the efficacy and safety of GLP-1 RAs in obesity management. Additionally, it explores the economic implications and ethical challenges associated with the increasing demand for GLP-1 RAs. By addressing these dimensions, this article aims to facilitate informed and responsible decision-making in clinical practice, highlighting the need for individualized patient assessments and careful consideration of both short- and long-term safety risks.

Pharmacoepidemiology doi: 10.3390/pharma3040024

Authors: Cecilia Cagnotta Alessia Zinzi Francesca Gargano Valerio Liguori Maria Rosaria Campitiello Alessandro Perrella Annalisa Capuano Concetta Rafaniello Ugo Trama

Background: Antibiotic resistance represents a growing concern. A new strategy developed to treat severe infections is represented by ceftazidime/avibactam (CZA/AVI). Despite the promising activities against more pathogens, continuous monitoring is required to identify potential antibiotic resistance in clinical practice settings. Therefore, real-world data from pharmacovigilance databases can help to better define the safety profile. Methods: We analyzed all Individual Case Safety Reports (ICSRs) collected in the EudraVigilance database focusing on ICSRs with at least one adverse event (AE) potentially suggestive of drug resistance (DR) and drug ineffectiveness (DI). Results: A total of 654 ICSRs related to CZA/AVI were retrieved from EudraVigilance, of which N = 378 (57.8%) were related to male and N = 230 (35.1%) to adult patients. A total of 80.2% of all AEs were serious but with a positive outcome. Overall, we found N = 129 (19.7%) cases of potential DR or DI after CZA/AVI administration. The majority of CZA/AVI-induced DR or DI occurred in adult male patients. The most frequently reported AEs were “drug ineffective” and “pathogen resistance”. Lastly, CZA/AVI was mostly used for the treatment of “Klebsiella infection” and “Pneumonia”. Conclusions: The present study showed how pharmacovigilance could play a key role in generating evidence about the safety profile of CZA/AVI. Further studies are warranted.

Pharmacoepidemiology doi: 10.3390/pharma3040023

Authors: Sura Alwan Kimberly S. Grant

The state of knowledge regarding the teratogenic effects of maternal use of medications during pregnancy is constantly evolving and is often uncertain. Timely access to high-quality information may reduce prolonged harmful exposures, decrease the number of preventable birth defects, empower patients with accurate information about the risks of exposure, and prevent unnecessary patient anxiety and pregnancy termination. In this narrative review, we describe the process by which the teratogenic risk of medications is assessed by experts in medicine, genetics, and epidemiology and how identifiable risks can be effectively communicated to patients. Risk assessment of birth defects in human pregnancy involves collecting and synthesizing available data through a proper and rule-driven evaluation of scientific literature. Expert consensus is a practical approach to determine whether a given exposure produces damage after careful consideration of gestational timing, dose and route of the exposure, maternal and fetal genetic susceptibility, as well as evidence for biological plausibility. The provision of teratogen risk counseling through appropriate interpretation of information and effective knowledge translation to the patient is critical for the prevention of birth defects and maximizing healthy pregnancies.

Pharmacoepidemiology doi: 10.3390/pharma3040022

Authors: Pramila Chandrasena Sampath Gunawardena Shanika Karunanayaka

(1) Background: Although Sri Lanka is a developing country and boasts of having a well-established healthcare system along with good healthcare indices, we are still lagging in certain aspects of healthcare. One such aspect is the deficiencies in guidelines and practices related to the handling of pharmaceutical waste. (2) Methods: This was a qualitative study performed using in-depth interviews with the help of a semi-structured questionnaire conducted among staff who are working at a ministry complex in Galle, Sri Lanka. Data analysis was performed using thematic analysis, (3) Results: There were 40 participants which included 29 (72.5%) females. Three main themes were identified, namely, (I) current knowledge, (II) perceptions, and (III) practices towards storage, disposal, and misuse of pharmaceutical waste. The death of the patient, forgetting, relieving symptoms, and adverse effects were some reasons for the accumulation of unused pharmaceuticals at home. Most of the participants did not believe that the reuse of unused medications can cause various health hazards. Moreover, all participants practiced unsafe methods such as flushing down toilets, pouring into a sink, burning, etc. (4) Conclusions: The incorrect practices and poor knowledge in the handling of pharmaceutical waste and less concern for the environment highlight the need for awareness programs to the general public and establishing proper medication waste management such drug take-back systems.

Pharmacoepidemiology doi: 10.3390/pharma3040021

Authors: Miriam Banoub Morkos Giovani Leon Mai-Chi Hong Joshua Allan Garcia Martin J. Breen Bhanu Sud Lee Nguyen

Dalbavancin, a semi-synthetic lipoglycopeptide with an extended half-life that allows for weekly dosing, is currently approved for the treatment of bacterial skin and soft tissue infections caused by susceptible gram-positive organisms. This case report discusses the successful treatment of septic arthritis with dalbavancin in a 38-year-old obese male. Septic arthritis, commonly caused by Staphylococcus aureus and Streptococcus species, was diagnosed in this patient following a mechanical fall that led to worsening shoulder pain. Given the patient’s morbid obesity and concerns about antibiotic penetration, dalbavancin 1500 mg IV biweekly was chosen for its extended half-life and ease of administration. This case underscores dalbavancin’s efficacy in managing septic arthritis in obese patients, offering a convenient alternative to traditional therapies that require a peripherally inserted central catheter (PICC line), frequent dosing, therapeutic monitoring, and prolonged hospital stays. Despite its higher cost, dalbavancin’s advantages include reduced need for PICC lines, additional staff and resources to monitor therapeutic drug levels, and fewer complications, which can offset some expenses. To our knowledge, this is the first documented case investigating the use of dalbavancin for enterococcal septic arthritis with a biweekly dosing regimen.

Pharmacoepidemiology doi: 10.3390/pharma3030020

Authors: Sarah A. Alfagih Monirah A. Albabtain Muaath Alfagih Nouf Alharbi

Background: Antibiotic resistance presents a global challenge. Community awareness of antibiotic use has not been studied extensively in Saudi Arabia. This study aimed to assess public awareness of the appropriate use and indications of antibiotics in Riyadh, Saudi Arabia. Furthermore, the responses were compared across gender and age groups. Methods: We conducted a cross-sectional study between September 2022 and October 2022, including adult participants from Riyadh. The questionnaires were distributed via electronic channels and included sections about participants’ sociodemographic data and behavior concerning antibiotic use. Results: This study included 453 respondents. There were 281 (62%) female and 172 (38%) male respondents. Most respondents were between 46 and 55 years (n = 111; 24.5%) and above 56 years (n = 134; 29.6%). Two hundred seventy-two (60%) were college/university graduates, and 113 (24.9%) were at the secondary school level. Most participants (n = 410; 90.5%) were not affiliated with or working in the health sector. One hundred thirty-nine (30.7%) participants used an antibiotic within the past six months, and 171 (37.7%) kept antibiotics at room temperature. Most participants (n = 380; 83.9%) completed the treatment plan as prescribed. Sixty-eight percent of respondents stopped taking antibiotics when they felt better, and 11.5% believed antibiotics can treat bacterial and viral infections. The responses were compared between patients of both genders and patients aged ≤55 years or older. The comparison indicated that females tended to store antibiotics as instructed by the manufacturer (p = 0.004) and disposed of the remaining antibiotics immediately after completing the treatment (p < 0.001). Furthermore, the indications for antibiotic use differed between the genders, with no difference between the age groups. Participants > 55 years tended to complete the treatment plan (p = 0.007) and continued taking antibiotics at the same time and dose as prescribed (p = 0.002). Conclusions: This study’s findings suggest that public health authorities should implement awareness intervention programs to educate the Riyadh community on the proper use of antibiotics, with target interventions for specific gender and age groups. This study’s findings should be interpreted in the context of the Riyadh community and the potential biases of cross-sectional studies.

Pharmacoepidemiology doi: 10.3390/pharma3030019

Authors: Bryan Y. Choi Namkee G. Choi C. Nathan Marti S. David Baker

Background: Despite widespread consensus on the need to reduce benzodiazepine (BZD) use in older adults, prescription rates in the U.S. have paradoxically increased over the past few decades. Objective: We examined (1) the characteristics of the BZD adverse reaction cases in patients aged 50 and older that were admitted to a healthcare facility (HCF) and experienced major effects/death, and (2) the associations between the concomitant use of opioids and/or antidepressants and HCF admission and major effects/death among BZD cases. Methods: We used the 2015–2022 National Poison Data System (NPDS), which contained data from 55 America’s Poison Centers. We fitted two multivariable logistic regression models to examine the associations between the co-use of opioids and/or antidepressants and HCF admission and major effects/death. Results: Of the BZD cases that were examined (N = 1979), 14.9% or 295 cases were admitted to healthcare facilities, and 8.5% of those who were followed up (77 out of 893 cases) experienced major effects or death. The number of co-used substances, co-use of opioids and antidepressants, atypical antipsychotics, anticonvulsants, muscle relaxants, and Gabapentin were associated with greater odds of healthcare admission. Co-use of opioids and healthcare admission were associated with greater odds of major effects/death. Conclusions: Adverse reactions and healthcare admissions are likely to be prevented when healthcare providers limit and carefully monitor BZD prescribing, especially for those who are on other medications, including prescription opioids and antidepressants.

Pharmacoepidemiology doi: 10.3390/pharma3030018

Authors: Francis Hartge Jamario Skeete Alejandro Pinedo Bethlehem Zeleke Asad Khan Raktham Mekritthikrai Cicely Anne Dye

Ventricular tachycardia poses a significant therapeutic challenge. It can manifest over a spectrum from minimal palpitation symptoms to sudden cardiac death. This makes large-scale trials on the treatment of ventricular tachycardia difficult to perform. The mechanism of ventricular tachycardia must also be understood before embarking on treatment. Patients with or without structural heart disease will have different mechanisms for the onset and propagation of these arrhythmias. Catheter ablation is an established management option for ventricular tachycardia; however, it is not always successful and anti-arrhythmic medications are often necessary to control these life-threatening arrhythmias. Although anti-arrhythmics can suppress ventricular tachycardias they also carry side effects. In certain substrates, some of these medications can exacerbate arrhythmias or heart failure. For these reasons, a multifaceted approach to treating ventricular tachycardia is necessary. This paper is a comprehensive review of the comprehensive management strategies for ventricular tachycardia. Anti-arrhythmic medications have an important role and their use in various cardiomyopathies and channelopathies is reviewed in detail. We also review the promising effects of gene therapy and artificial intelligence on different substrates for ventricular tachycardia.

Pharmacoepidemiology doi: 10.3390/pharma3030017

Authors: Dai Chihara Brian P. Hobbs Matthew J. Maurer Christopher R. Flowers

The future directions in leveraging real-world evidence (RWE) and real-world data (RWD) in the field of lymphoma, as compared to traditional experimental clinical trials, are poised to significantly impact research methodologies, treatment strategies, and patient care. Current methods of clinical trials involve a well-controlled design and patient selection bias. Integrating RWE and RWD with experimental clinical trials offers a multifaceted approach to understanding lymphoma and enhancing patient outcomes. In this review, we discuss how RWE has helped shape lymphoma clinical trials, and we compare and evaluate evidence obtained from real-world lymphoma studies/databases with that obtained from clinical trials. We also discuss methods for utilizing surrogate endpoints to facilitate clinical trials and expedite drug development. RWE can be leveraged to bridge the gap between data obtained from clinical trial populations and the broader patient population encountered in clinical practice, by highlighting differences in outcomes and the need for effective treatment strategies across diverse patient groups.

Pharmacoepidemiology doi: 10.3390/pharma3030016

Authors: Hasan Yousaf Alan M. Jones

Aims: The aim of this study was to explore the suspected adverse drug reaction (ADR) data of five licensed statins in the UK: atorvastatin, fluvastatin, pravastatin, rosuvastatin, and simvastatin. A secondary aim was to determine if there are any associations between the polypharmacological properties of the statins and their associated muscle-related side effects. Methods: The chemical database of bioactive molecules with drug-like properties, European Molecular Biology Laboratory (ChEMBL), was used to obtain data on the pharmacological interactions of statins with human proteins. The Medicines and Healthcare Products Regulatory Agency’s (MHRA) Yellow Card scheme was used to obtain reports of suspected ADRs from 2018 to 2022. The OpenPrescribing database was used to obtain the prescribing rates for statistical interpretation. Results: The study found no significant difference between the statins association with suspected ADRs across all organ classes (X2, p > 0.05). Fluvastatin was found to have a higher incidence of ADRs/100,000 Rx across multiple system organ classes. Conclusions: No significant difference was found between the suspected ADR incidence of the statins across all system organ classes.

Pharmacoepidemiology doi: 10.3390/pharma3020015

Authors: Herman Joseph Johannesmeyer Luiza Baloyan Kristica Kolyouthapong

Clostridioides difficile infection (CDI) is the leading cause of nosocomial diarrhea in the United States. Tigecycline has been proposed as a potential treatment for CDI, though limited clinical data exist to support this practice. The objective of this study was to determine if the provision of tigecycline provides a clinically meaningful benefit to inpatients with CDI. This study was a retrospective chart review enrolling inpatients receiving treatment for CDI. Patients were divided into cohorts depending on whether they received a standard antibiotic therapy regimen for CDI or an antibiotic treatment regimen that included tigecycline. The primary outcome was clinical recovery at the time of hospital discharge. A total of 39 and 22 patients were included in the standard antibiotic therapy and tigecycline groups, respectively. ATLAS (Age, Treatment, Leukocyte, Albumin, Serum creatinine) scores at the time of CDI diagnosis were similar between the two groups, though patients in the tigecycline groups were more likely to represent a recurrent episode of CDI. There was no difference in the rate of clinical recovery at the time of hospital discharge between the standard antibiotic therapy and tigecycline groups (38.5% vs. 36.4%, p = 0.8710). These data do not support the routine use of tigecycline for the treatment of CDI, though interpretation is limited due to baseline differences between groups and the retrospective, observational nature of this study.

Pharmacoepidemiology doi: 10.3390/pharma3020014

Authors: Isabella M. Y. Cheung Simon Horsburgh Ewan Smith Samantha Simkin Akilesh Gokul

Background: The paediatric use of ophthalmic chloramphenicol in New Zealand (NZ) is relatively high; however, little more is known about its utilisation, including whether this is equitable. This study aimed to describe chloramphenicol utilisation in NZ children aged five years and under, by patient ethnicity, socioeconomic deprivation, and urban/non-urban domicile. Methods: This analysis included every publicly subsidised chloramphenicol dispensing received from birth to five years of age, for every child born in NZ in 2013. Cumulative proportion of first exposure, dispensing rate per person-year, and seasonality of dispensing were quantified. These were calculated following stratification by ethnicity, socioeconomic deprivation quintile, and urban/non-urban health district. For cumulative proportion of first exposure, odds ratios (OR) were calculated and multivariate logistic regression was performed. For dispensing rate, incidence rate ratios (IRR) were calculated and zero-inflated Poisson regression was performed. Results: Almost one-quarter of NZ children received their first dispensing within the first year of life. By five years of age, 55.2% of children had received their first dispensing. By five years of age, children of Pacific ethnicity, those in the highest deprivation quintile, and in those non-urban health districts had lower odds of receiving chloramphenicol (adjusted OR 0.90, 0.79, and 0.81, respectively, all p < 0.001). In contrast, children of Māori ethnicity had higher odds (adjusted OR 1.99, p < 0.001). Māori and Pacific ethnicity, and residence in non-urban health districts, were associated with fewer dispensings (adjusted IRR 0.88, 0.75 and 0.87, all p < 0.001). In contrast, deprivation quintile was not significantly associated with dispensing rate. Conclusion: Chloramphenicol utilisation is prevalent among NZ children, and utilisation may be lower among children of Pacific ethnicity and those in non-urban areas

Pharmacoepidemiology doi: 10.3390/pharma3020013

Authors: Siobhán McGettigan Denis Curtin Denis O’Mahony

Adverse drug reactions (ADRs) are frequent and represent a significant healthcare burden. ADRs are a potentially avoidable contributor to excess unscheduled hospital admissions, higher morbidity, mortality, and healthcare costs. The objective of this review is to examine the epidemiology of ADRs in older multimorbid adults and to explore strategies for ADR prevention. ADRs in this population are often linked to commonly prescribed medications, including anticoagulants, antiplatelet agents, insulin, and non-steroidal anti-inflammatory drugs, but ADRs and adverse drug events (ADEs) in fact encompass a much broader range of culprit drugs. Age-related factors such as changes in pharmacokinetics and pharmacodynamics, multimorbidity, polypharmacy, and frailty have been associated with ADR occurrences. Various strategies have been proposed to prevent ADRs in different clinical settings, such as structured routine medication review and the use of bespoke software applications to identify potentially inappropriate prescriptions and drug interactions. Although these approaches have demonstrated some improvement in the quality of prescribing, there is still a lack of consistent evidence regarding their effectiveness in preventing ADRs. The nuanced and often intricate complexities associated with older patients’ pharmacotherapy necessitate a comprehensive approach to attenuate the impact of ADRs within this growing section of most populations globally.

Pharmacoepidemiology doi: 10.3390/pharma3020012

Authors: Taylor N. Hallet David T. Zhu Hannah Shadowen Lillia Thumma Madison M. Marcus Amy Salisbury Caitlin E. Martin

Buprenorphine is a safe and effective medication to treat opioid use disorder (OUD) in pregnant patients and is intended to be continued throughout pregnancy, delivery, and at least the one-year postpartum period. However, delivery often involves the need for acute pain management with opioid medications, such as after a cesarean section. For patients receiving buprenorphine, the provision of prescription opioids may negatively impact OUD treatment outcomes; however, not optimally managing acute pain may also impede OUD treatment benefit. Evidence is needed to disentangle the impacts of opioid prescription provision and methods of pain management in the immediate postpartum period on OUD treatment trajectories, ultimately to inform clinical guidelines tailored to the unique needs of pregnant and postpartum people receiving buprenorphine. Accordingly, this study took an initial step towards this goal to conduct a secondary analysis of a retrospective cohort of pregnant patients taking buprenorphine for OUD at the time of delivery (n = 142) to determine whether receipt of an opioid prescription at birth hospitalization discharge was associated with the time of buprenorphine discontinuation within the 12 months following delivery. Among the sample, 26% (n = 37) were prescribed an opioid at the time of birth hospitalization discharge. The number of weeks post-delivery until buprenorphine discontinuation occurred was shorter amongst patients who were prescribed an opioid (median 11 weeks) compared to patients who were not prescribed an opioid (median 39 weeks; p < 0.001 by Mann–Whitney U test). However, a Cox regression model reported that receipt of an opioid prescription following delivery did not significantly increase the hazard ratio for buprenorphine discontinuation. In other words, OUD patients not prescribed an opioid at birth hospitalization discharge continued their buprenorphine for a longer median duration after delivery compared to their counterparts who received prescription opioids; yet, this finding did not reach statistical significance when taking into account additional clinical variables. The findings indicate how further research is warranted to inform evidence-based post-delivery pain practices for postpartum OUD treatment patients.

Pharmacoepidemiology doi: 10.3390/pharma3010011

Authors: Malith Kumarasinghe Manuj C. Weerasinghe

In this cross-sectional descriptive study conducted in the Ratnapura district, Sri Lanka, we assessed the affordability of oral pediatric anti-infective medicines (OPAIMs). Using a modified WHO/HAI medicinal price methodology, we examined the availability, median price ratios (MPRs), mean percentage difference, and affordability of the standard treatment of the originator brand (OB) and lowest-priced generic (LPG) OPAIMs in 30 private and 2 state-owned pharmacies. The study revealed disparities in availability, with only 50% of private pharmacies offering all 11 medicinal drugs in their generic form. The MPRs of OPAIMs for OB and LPG varied, with three drugs exceeding the financially acceptable MPR of 2 (albendazole, amoxicillin, and erythromycin). The standard treatment with LPGs costs between 0.17 and 0.85 and between 0.06 and 0.28 days’ wages for the lowest daily salary of the private sector and unskilled public employees, respectively. We identified erythromycin and albendazole as having less than 50% availability in their generic form in private pharmacies. To address these findings, we recommend frequent pricing revisions based on exchange rates and associated costs, coupled with the establishment of a transparent scientific criterion to subsidize essential medicines deemed “unaffordable.” Failure to implement such measures amidst economic crises may adversely impact financial access to essential medications.

Pharmacoepidemiology doi: 10.3390/pharma3010010

Authors: Jing Wei Neo Qihuang Xie Pei San Ang Hui Xing Tan Belinda Foo Yen Ling Koon Amelia Ng Siew Har Tan Desmond Teo Mun Yee Tham Aaron Yap Nicholas Ng Celine Wei Ping Loke Li Fung Peck Huilin Huang Sreemanee Raaj Dorajoo

Background: Hypertension is frequently studied in epidemiological studies that have been conducted using retrospective observational data, either as an outcome or a variable. However, there are few validation studies investigating the accuracy of hypertension phenotyping algorithms in aggregated electronic health record (EHR) data. Methods: Utilizing a centralized repository of inpatient EHR data from Singapore for the period of 2019–2020, a new algorithm that incorporates both diagnostic codes and medication details (Diag+Med) was devised. This algorithm was intended to supplement and improve the diagnostic code-only model (Diag-Only) for the classification of hypertension. We computed various metrics (sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV)) to assess the algorithm’s effectiveness in identifying hypertension on 2813 chart-reviewed records. This pool was composed of two patient cohorts: a random sampling of all inpatient admissions (Random Cohort) and a targeted group with atrial fibrillation diagnoses (AF Cohort). Results: The Diag+Med algorithm was more sensitive at detecting hypertension patients in both cohorts compared to the Diag-Only algorithm (83.8 and 87.6% vs. 68.2 and 66.5% in the Random and AF Cohorts, respectively). These improvements in sensitivity came at minimal costs in terms of PPV reductions (88.2 and 90.3% vs. 91.4 and 94.2%, respectively). Conclusion: The combined use of diagnosis codes and specific antihypertension medication exposure patterns facilitates a more accurate capture of patients with hypertension in a database of aggregated EHRs from diverse healthcare institutions in Singapore. The results presented here allow for the bias correction of risk estimates derived from observational studies involving hypertension.

Pharmacoepidemiology doi: 10.3390/pharma3010009

Authors: Teimur Kayani Bachar Ahmad Rachel Chang Frank Qian Melis Sahinoz Muhammad Rehan Antonio Giaimo Erica Spatz Jiun-Ruey Hu

Although statins have served as the cornerstone for pharmacological lowering of lipid levels in atherosclerotic cardiovascular disease (ASCVD) risk reduction, many patients are unable to achieve target doses of statin medication due to side effects or target levels of cholesterol reduction on statin monotherapy. The landscape of lipid-lowering strategies has expanded in recent years, with the emergence of therapies that make use of small interfering RNA (siRNA) and antisense oligonucleotides, in addition to traditional small-molecule agents. Non-statin therapies that have shown promising results in randomized controlled trials include adenosine triphosphate-citrate lyase inhibitors, proprotein convertase subtilisin/kexin 9 (PCSK9)-inhibiting antibodies and siRNA, omega-3 polyunsaturated fatty acids, and lipoprotein(a) gene-inhibiting siRNA and ASOs, in addition to older therapies such as ezetimibe. In contrast, cholesteryl ester transfer protein (CETP) inhibitors have shown less promising results in randomized trials. The purpose of this narrative review is to summarize the evidence for these medications, with a focus on phase III randomized trials.

Pharmacoepidemiology doi: 10.3390/pharma3010008

Authors: Samantha Walczuk Francesca E. Cunningham Xinhua Zhao Diane Dong Peter A. Glassman Donald R. Miller Deborah Khachikian Anthony Au Cedric Salone Kelly Bryan Qoua Her Sherrie L. Aspinall

We described insulin glargine (originator) and insulin glargine-yfgn (biosimilar) treatment patterns, assessed effectiveness and safety outcomes, and identified reasons for switching back to the originator product from the biosimilar. This retrospective study included 328,463 Veterans 18 years of age and older who received one or more outpatient prescriptions for insulin glargine and/or insulin glargine-yfgn between 1 June 2021 and 31 December 2022. Patients were assigned to subgroups based on the initial prescription during the study period, prevalent versus incident use for originator insulin glargine, and prior versus no prior use of the originator before the biosimilar (i.e., prevalent originator non-switcher (n = 189,734), originator switch to biosimilar (n = 81,010), incident originator non-switcher (n = 49,401), and incident biosimilar (n = 8318)). There were no differences in the outcome of mean HbA1c (7.9% for all subgroups). There were also no differences in the unadjusted rates of hospitalization and/or emergency room visits for hyper- and hypoglycemia between the prevalent originator non-switcher and originator switched to biosimilar subgroups (p = 0.09 and 0.38, respectively) or the incident originator non-switcher and incident biosimilar subgroups (p = 0.054 and 0.61, respectively). Finally, none of the HbA1c or hyperglycemia outcomes adjusted for baseline characteristics were statistically different. Adjusted analyses for rates of hospitalization and/or emergency room visits for hypoglycemia could not be performed due to the low number of events. Overall, patients who received insulin glargine-yfgn had similar effectiveness and safety outcomes as patients who received the originator.

Pharmacoepidemiology doi: 10.3390/pharma3010007

Authors: Veronika Lappe Daniel Grandt Ursula Marschall Ingrid Schubert

Opioids are highly effective drugs but need close monitoring to avoid harm to patients. The aim of this study was to analyze how guideline recommendations are met for (i) the avoidance of the concomitant use of anxiolytics, hypnotics, or sedatives; (ii) the prescribing of laxatives in long-term opioid treatment; (iii) the co-prescribing of drugs to control the emetic effect of opioids; (iv) pretreatment with non-opioids; and (v) screening for depression when initiating opioids. The results are based on a routine data analysis of a large German health insurance fund. Different study populations of noncancer patients (18+ years old) treated with opioids were analyzed: 10.4% of the opioid recipients in 2021 received at least one concomitant prescription with anxiolytics, hypnotics, or sedatives; 69.3% of those with long-term opioid treatment received at least one laxative prescription. Of those with first-time opioid prescriptions, 4.8% received an antiemetic drug; 47.3% of those with a newly initiated opioid therapy received a non-opioid prescription within three months before the start of the opioid therapy; and 22.0% of patients with incident opioid prescription had at least one documentation of a depression diagnosis within three months of the first prescription. There is an urgent need to improve opioid prescribing to avoid risky combinations and adverse effects.

Pharmacoepidemiology doi: 10.3390/pharma3010006

Authors: David Y. Graham

Helicobacter pylori is a class I carcinogen that infects more than 100 million individuals in the United States. Antimicrobial therapy for H. pylori has typically been prescribed empirically rather than based on susceptibility testing. Until recently, therapeutic recommendations have generally ignored the principles of antibiotic stewardship. A combination of a proton pump inhibitor (PPI), amoxicillin, and clarithromycin (triple therapy) remains popular despite increasing clarithromycin resistance and poor cure rates. Concomitant therapy (a PPI, amoxicillin, clarithromycin, and metronidazole) is recommended and widely used despite all patients receiving at least one unneeded antibiotic. In 2020, the Food and Drug Administration approved vonoprazan, amoxicillin, and clarithromycin triple therapy, which administers unneeded clarithromycin to >90% of patients (i.e., ~6 tons of unneeded clarithromycin/million treatments). In the late 1980s, the infectious disease community functionally transferred responsibility for the management of H. pylori to gastroenterology, which has managed the infection as another common gastrointestinal disease such as constipation. In 2022, both traditional and noninvasive molecular-based susceptibility testing for H. pylori became available in the United States. In order to reduce and prevent antibiotic misuse, the infectious disease community should reclaim responsibility for the management of this important infectious disease.

Pharmacoepidemiology doi: 10.3390/pharma3010005

Authors: Alireza FakhriRavari Mazyar Malakouti

Severe acute respiratory syndrome coronavirus 2 has infected millions of people, but about 20% of infected individuals do not develop symptoms. COVID-19 is an inflammatory disease that affects a portion of individuals infected with the virus and it is associated with liver injury and other complications, leading to hospitalization, critical illness, and death. Remdesivir is an antiviral agent used for the treatment of hospitalized patients with COVID-19 to improve the time to recovery, reduce the duration of mechanical ventilation, decrease the need for supplemental oxygen, and decrease the risk of mortality. Remdesivir-associated hepatotoxicity has been observed as increased transaminases more than five times the upper limit of normal in hospitalized patients with COVID-19, but causality has not been proven. It is generally difficult to distinguish between remdesivir-associated hepatotoxicity and COVID-19-induced hepatotoxicity. The purpose of this review is to evaluate the evidence for remdesivir-associated hepatotoxicity. Current evidence suggests that elevated liver enzymes in hospitalized COVID-19 patients are more likely to be due to the infection than remdesivir, and a 5-day course of remdesivir seems to be safe in regard to hepatotoxicity.

Pharmacoepidemiology doi: 10.3390/pharma3010004

Authors: Christine Bakos-Block Andrea Yatsco A. Sarah Cohen Francine Vega Tiffany Champagne-Langabeer

Opioid use in women has increased by 300% since 1999, and opioid use disorder among pregnant women has quadrupled. The stigma of substance use disorder is a significant barrier to treatment, especially among women. The purpose of this study was to explore the experiences and perceptions of stigma among mothers and the underlying themes. (1) Background: To understand the stigmatization of women with substance use disorders, we interviewed mothers in recovery from opioid use disorder. (2) Methods: Qualitative methods and descriptive analysis was used to extrapolate themes related to the experienced stigma. (3) Results: A total of 20 mothers in recovery from opioid use disorder were interviewed and three main themes emerged from the data: internal stigma, external stigma, and healing from stigma. (4) Conclusion: The examination of stigma is important in reducing its effect on all individuals with substance use disorders, and it is important to understand gender inequities.

Pharmacoepidemiology doi: 10.3390/pharma3010003

Authors: Sarah Choe Abhinav Birda Jesse Salas Olive Anagu Natasha Mesinkovska

Tofacitinib is a Janus kinase inhibitor (JAKi) that is used off-label for the treatment of alopecia areata (AA). Its boxed warning includes an increased risk of serious adverse events (SAEs) based on the results of a safety trial in rheumatoid arthritis (RA) patients taking the medication. The purpose of this study was to investigate the differences in patients’ characteristics and SAEs profiles between RA and AA populations taking tofacitinib. The cohorts were constructed using the TrinetX database to identify the patients who were prescribed tofacitinib for RA or AA between October 2012 and October 2023. A total of 22,873 patients were included in this analysis, with 21,080 individuals in the RA cohort and 1793 individuals in the AA cohort. After matching for age, sex, and race, each cohort had a sample size of 1482. Data on the patients’ sex, age, race, comorbidities, concomitant medications, and associated SAEs were collected. The cohorts were compared by calculating the odds ratios and tested for significance associations using Fisher’s Exact Tests. Both the RA and AA cohorts were predominantly female (RA 79%, AA 70%), with mean ages of 61 ± 14 years and 38 ± 19 years (p-value < 0.0001), respectively. Both the groups showed similar racial distributions. The RA cohort had increased rates of hypertension, obesity, type 2 diabetes mellitus, and nicotine dependence compared to those of the AA cohort (p-value < 0.0001). With the exception of cyclosporine and azathioprine, the percentage of concomitant medication use was higher in all the categories in the RA cohort than those in the AA cohort (p-value < 0.0001). Higher rates of adverse events were seen in the RA cohort across all the categories, except myocardial infarction, stroke, and lymphomas/hematopoietic malignancies. Our findings show that the SAEs on the boxed warning of tofacitinib should be strongly considered when being used off-label for the treatment of AA. Clinicians must carefully assess the individual patient factors when determining the appropriateness of tofacitinib use.

Pharmacoepidemiology doi: 10.3390/pharma3010002

Authors: Seth Duwor Katharina Enthofer Christoph Ganter Prabin Poudel Anna Svarin Gerd A. Kullak-Ublick

Introduction: Calcineurin inhibitors (CNIs), ciclosporin and tacrolimus, are utilized primarily in organ transplantation and the treatment of autoimmune diseases. Since patients depend on these drugs over long periods, they face a potential risk of intoxication. This risk increases substantially when patients are overdosed or inadvertently exposed to cytochrome P450 (CYP) 3A4 inhibitors. Objectives: To analyze the utility of CYP inducers as a plausible treatment modality for acute CNI intoxication using real-world data from the WHO global pharmacovigilance database (VigiBase™) and supporting evidence from published data. Methodology: We explored all individual case safety reports (ICSRs) regarding CNI intoxications registered in VigiBase™. The queries “overdose” or “drug intoxication” were applied against the active ingredients “ciclosporin” and “tacrolimus”. Regarding the utility of CYP inducers, an extensive literature analysis was undertaken. We also report an index clinical case of a 60-year-old liver transplant patient that developed severe tacrolimus intoxication with multiple organ dysfunction at a peak concentration of 33.1 μg/L after a single dose of intravenous fluconazole. Results: Out of 143,710 documented ICSRs reported in VigiBase™ since 1992, 0.26% and 0.02% were registered as CNI overdoses and intoxications, respectively. The main etiological factor for CNI intoxication was the interaction with CYP 3A4 inhibitors (40.0% vs. case reports: 50.0%). The most commonly reported manifestation was acute kidney injury (36.7% vs. case reports: 46.3%). A total of 16.7% of intoxications led to fatal outcomes after drug withdrawal or dose reduction; however, in 43.0% of cases the exact actions undertaken were not reported. In peer-reviewed reports, 34 distinct clinical cases were treated with CYP inducers. Diverse pharmacoenhancement strategies with phenobarbital (5), phenytoin (23) and rifampicin (6) were described with a mean time of achieving the therapeutic target after 2.7 (±0.7), 3.1 (±0.5) and 4.6 (±1.0) days, respectively. In the index case, a therapeutic concentration of 4.9 [4–6 μg/L] was achieved after a 3-day regimen of rifampicin. Conclusion: In addition to general supportive treatment, the administration of phenobarbital, phenytoin, or rifampicin to reverse acute CNI intoxication is a viable treatment modality. The relatively long half-life of phenobarbital coupled with its exclusive renal elimination are potential pitfalls to reckon with. In spite of the favorable pharmacokinetic advantages of rifampicin, phenytoin offers a competitive pharmacodynamic advantage that is indisputable in patients with overt neurotoxicity.

Pharmacoepidemiology doi: 10.3390/pharma3010001

Authors: Elena A. Baybulatova Mikhail S. Chenkurov Elina A. Korovyakova Sergey K. Zyryanov Liliya Eugenevna Ziganshina

Background: The coronavirus pandemic has led to the creation of clinical guidelines by a large number of professional medical communities. However, the quality and methodology of development of Russian clinical guidelines has been little studied. The continued relevance of studying the use of DOACs (Direct oral anticoagulants) in patients with COVID-19 was the basis for conducting this study. Aim: The objective of this study was to assess DOAC consumption and expenditure in the Russian Federation during the COVID-19 pandemic and to analyze whether it was supported by the domestic evidence base for the use of DOACs in COVID-19 patients through identifying all publicly available Russian-produced CPGs (Clinical practice guidelines) for the treatment of COVID-19 and assessing their quality as the source of recommendations for the use of oral anticoagulants for the prevention of thrombotic complications in COVID-19 patients. We searched Russian databases for CPGs, published between 2020 and 2023. We identified seven relevant documents that met our inclusion criteria. Three authors analyzed Russian clinical guidelines using an AGREE II questionnaire. We calculated DOAC DDD (defined daily dose) consumption according to Russian clinical guidelines and DDD consumption in patients with COVID-19 for the period 2020–2022. Results: Seven clinical CPGs were analyzed with the AGREE II tool. It was revealed that experts gave the highest scores for the sections on scope and purpose (from 62.98% to 100%), and clarity of presentation (from 96.30% to 100%). The lowest scores were given for the sections on stakeholder involvement (33.33% to 64.81%), rigour of development (from 0% to 49.31%), applicability (from 23.61% to 50%), and editorial independence (from 0% to 50%). When comparing the total score, it was found that two clinical guidelines received the highest scores—ROPNIZ (Livzan), and ROPNIZ (Drapkina). The minimum score was registered with the NIIOZMM (Khripun) clinical guideline. No guideline received a total score of more than 70%. According to clinical recommendations, the consumption of apixaban and rivaroxaban is 15 DDD (30-day course of therapy), or 22.5 DDD (45-day course of therapy). Consumption of apixaban in the Russian Federation in 2020 and 2021 corresponds to the indicators presented in clinical recommendations (in 2020—26.59 DDD per patient with COVID-19; in 2021—15.75 DDD per patient with COVID-19), and in 2022—10.67 DDD, which is below the recommended values. In 2020, consumption of rivaroxaban in the Russian Federation was 26.59 which corresponds to data from clinical recommendations; in 2021, consumption decreased to 7.87 DDD; in 2022 it decreased to 5.48 DDD, which is 2.74 times less than recommended. Conclusions: Analysis of seven clinical recommendations revealed that such sections of clinical recommendations as scope, purpose, and clarity of presentation had the highest degree of assessment in accordance with AGREE II. The lowest scores were given for the sections on stakeholder involvement, rigour of development, applicability, and editorial independence. When comparing the total score, it was found that two clinical guidelines received the highest scores—the Russian Society for the Prevention of Non-communicable Diseases (Livzan), and the Russian Society for the Prevention of Non-communicable Diseases (Drapkina). The minimum score was registered with the Research Institute for Healthcare Organization and Medical Management of Moscow Healthcare Department clinical guideline. No guideline received a total score of more than 70%. During the pandemic, the highest DDD consumption of DOACs was in 2020, which exceeded the DOACs’ recommended DDD by Russian clinical guidelines. DOAC consumption had decreased by 2022. There was a decrease in the consumption of rivaroxaban, with an increase in apixaban’s share in the structure of DOAC consumption during the coronavirus pandemic. Obtained data indicate that in 2021 the apixaban consumption in the Russian Federation corresponded to the recommended DDD in the national guidelines, which indicates the most correct use of apixaban according to Russian GPGs.

Pharmacoepidemiology doi: 10.3390/pharma2040030

Authors: Nina Z. Y. Smith J. Douglas Thornton Susan H. Fenton Debora Simmons Tiffany Champagne-Langabeer

Prescription drug misuse is a global problem, especially in the United States (US). Clinician involvement is necessary in this crisis, and prescription drug monitoring programs (PDMPs) are a recommended tool for the prevention, recognition, and management of prescription opioid misuse. However, because of the plethora of differences between different PDMPs, research on their effects is mixed. Yet, despite varied evidence, policy on PDMP use is trending stricter and more comprehensive. We aimed to identify patterns in the research to inform clinicians and policy. Through a systematic review of four literature databases (CINAHL, Cochrane Database, Embase, and Medline/OVID), we found 56 experimental and quasi-experimental studies published between 2016 and 2023 evaluating PDMP effects on clinician behavior. To address study heterogeneity, we categorized studies by type of intervention and study outcome. The review suggests that more comprehensive PDMP legislation is associated with decreases in the number of opioid prescriptions overall and the number of risky prescriptions prescribed or dispensed. However, this review shows that much is still unknown, encourages improvements to PDMPs and policies, and suggests further research.

Pharmacoepidemiology doi: 10.3390/pharma2040029

Authors: Heather A. Ward Bao-Anh Nguyen-Khoa Robert Massouh

Nirmatrelvir/ritonavir (PAXLOVIDTM, Pfizer) is an anti-infective inhibiting CYP3A4 indicated for the treatment of COVID-19 in adults at increased risk of severe COVID-19. As a newly approved product, PAXLOVID has limited safety information regarding rare events and serious adverse events (SAEs). This review describes the characterization of the real-world safety profile of products with similar pharmacological properties to PAXLOVID and aims to understand the impact of any drug interaction on the concomitantly prescribed products. A literature search of articles in PubMed published between 2018 and 2023 was conducted to assess the real-world frequency of safety outcomes of interest, specifically those meeting the criteria of serious adverse reaction. The review was restricted to observational, noninterventional studies and included CYP3A4 inhibitors prescribed for short-term treatment of infections in the outpatient setting. Twenty-one articles were included in the review. Most focused on a small, predefined list of safety outcomes and did not provide insight into the broader range of safety outcomes that might occur for the evaluated products with similar pharmacological properties to PAXLOVID or the impact of any interaction on the concomitant product. The findings highlight the challenges in obtaining proxy safety outcomes characteristics via a review of products with comparable pharmacological properties and underscore the need to have large, rapidly accessible data sources that can contribute to the safety profile of newly authorized products in the real world.

Pharmacoepidemiology doi: 10.3390/pharma2040028

Authors: Jeanie Misko Matthew D. M. Rawlins

Background: Medicines information (MI) is a specialist area of pharmacy that provides evidence-based answers to often complex medication queries, utilising resources such as textbooks and databases. With the advent of the COVID-19 pandemic, there was a need to change the way COVID-19-related queries were answered due to the rapid evolution of information on vaccination, treatment and prevention. Methods: Medicines information queries were retrospectively reviewed utilising the centre’s medicines information database from January 2020 through December 2022 using the COVID-19 keyword to retrieve relevant queries. Information was collected on the enquirer’s role, query category, time taken to complete the query, relevant keywords and references accessed. Keywords and references were analysed further to determine the types of queries asked and which references were helpful. Results: The centre received 214 COVID-19-related queries, predominantly in 2022. Most queries were from pharmacy staff (95.8%) and related to vaccination (n = 95, 44.4%) or treatment (n = 87, 40.7%). Government and specialist organisation websites were used most commonly as reference sources (24.6% and 16.5%, respectively) for their currency with COVID-19-specific resources (such as national guidelines, COVID-19 treatment interaction checkers) and textbooks/databases used less commonly. Conclusions: MI pharmacists have demonstrated their ability to obtain reliable COVID-19-related information, utilising and interpreting information from less traditional sources.

Pharmacoepidemiology doi: 10.3390/pharma2040027

Authors: Sophie A. Roe Dayna S. DeSalve Brian J. Piper

Research Question and Objective: While the number of pharmacoepidemiological studies on stimulant-based ADHD medications has expanded rapidly in recent years, likely due to the stimulant shortage, few studies have analyzed non-stimulant ADHD medications from a pharmacoepidemiological perspective. Such research is important because a significant number of individuals with ADHD have medical or psychiatric conditions that preclude stimulant use. Furthermore, no studies, to our knowledge, have analyzed atomoxetine exchanges on the black market. In this report, we seek to fill both these gaps in the research by analyzing black market diversions of atomoxetine, a non-stimulant medication for ADHD. As ADHD medication diversion is a growing issue, we also hypothesize the pharmacoepidemiologic contributors to and implications of such diversion. Method: This study analyzed black market atomoxetine purchases entered on the web-based platform StreetRx between January 2015 and July 2019. Data included the generic drug name, dosage, purchase price, date, and location in the United States. The mean price per milligram was determined and a heatmap was generated. Results: The average price per milligram of 113 diverted atomoxetine submissions was USD 1.35 (±USD 2.76 SD) (Median = USD 0.05, Min = USD 0.01, Max = USD 20.00). The states with the most submissions included Michigan (11), Pennsylvania (9), Indiana (8), and Ohio (8). Conclusion: The cost per milligram of atomoxetine on the black market is over 50 times the cost per milligram of the generic prescribed form. Future qualitative studies should investigate reasons why individuals are motivated to purchase atomoxetine, a non-stimulant medication, on the black market (recreational vs. nootropic vs. other clinical uses).

Pharmacoepidemiology doi: 10.3390/pharma2040026

Authors: Simone L. Dam Heleen M. Masselink-Haverkate Christina M. Gant Stephan J. L. Bakker Roos M. Nijboer Willemien J. Kruik-Kollöffel Gozewijn D. Laverman

We studied the role of adherence to antihypertensive drug therapy (AHT) in blood pressure (BP) control in a type 2 diabetes (T2D) population treated in secondary care in the DIAbetes and LifEstyle Cohort Twente-1 (DIALECT-1). In addition, intensification of AHT was assessed. Adherence was determined by using the medication possession ratio (MPR), calculated with pharmacy dispensing data for a period of two years following baseline. Adherence was defined as an MPR ≥ 80%. The proportion of adherent patients was compared between patients who had BP-on target (BP-OT) and BP-not on target (BP-NOT). Of the 385 patients included, 56% achieved their BP target. The proportion of adherent patients did not differ between BP-OT and BP-NOT (96% vs. 96%; p = 0.91). Intensification of AHT, including ‘increase in dosage’ and ‘start of a new drug’, was assessed in the two years following baseline. In only 37% of patients with uncontrolled BP during follow-up was AHT intensified. To conclude, adherence to AHT was high and there does not seem to be a relationship between adherence and BP control. There is an opportunity to improve AHT in patients who do not reach their BP target.

Pharmacoepidemiology doi: 10.3390/pharma2040025

Authors: Abeer Alanazi Reem Almuhaya Mohammad Almohaimeed Nada Alahmari Noor Abdulrahim Marouj Basyouni Farah Althikrallah Jumanah Al Badwyi Abdulrahman Khallaf Khalid Albalawi Amal Almalki Khalid Alsaedi Fatima Bakarman Fatimah Alotaibi Mohammed Kanan

Overuse and misuse of antibiotics have led to the emergence of antibiotic-resistant bacteria and pose a significant threat due to adverse drug reactions, increased healthcare costs, and poor patient outcomes. Antibiotic stewardship programs, including antibiotic de-escalation, aim to optimize antibiotic use and to reduce the development of antibiotic resistance. This systematic review and meta-analysis aim to fill the gap by analyzing the current literature on the implications of antibiotic de-escalation in patients on antibiotic use, duration of hospital stay, mortality, and cost; to update clinical practice recommendations for the proper use of antibiotics; and to offer insightful information about the efficacy of antibiotic de-escalation. Based on the PRISMA 2020 recommendations, a comprehensive literature search was conducted using electronic databases and reference lists of identified studies. Eligible studies were published in English, conducted in humans, and evaluated the impact of antibiotic de-escalation on antibiotic consumption, length of hospitalization, mortality, or cost in hospitalized adult patients. Data were extracted using a standardized form, and the quality of included studies was assessed using the Newcastle–Ottawa Scale. The data from 25 studies were pooled and analyzed using the Revman-5 software, and statistical heterogeneity was evaluated using a chi-square test and I2 statistics. Among the total studies, seven studies were conducted in pediatric patients and the remaining studies were conducted in adults. The studies showed a wide range of de-escalation rates, with most studies reporting a rate above 50%. In some studies, de-escalation was associated with a decrease in antimicrobial utilization and mean length of stay, but the impact on overall cost was mixed. Our pooled analysis for mortality reported that a significant difference was observed between the de-escalation group and the non-de-escalation group in a random effect model (RR = 0.67, 95% CI 0.52–0.86, p = 0.001). The results suggest that de-escalation therapy can be applied in different healthcare settings and patient populations. However, the de-escalation rate varied depending on the study population and definition of de-escalation. Despite this variation, the results of this systematic review support the importance of de-escalation as a strategy to optimize antibiotic therapy and to reduce the development of subsequent antibiotic resistance. Further studies are needed to evaluate the impact of de-escalation on patient outcomes and to standardize the definition of de-escalation to allow for better comparison of studies.

Pharmacoepidemiology doi: 10.3390/pharma2040024

Authors: Taryn A. Eubank Chenlin Hu Anne J. Gonzales-Luna Kevin W. Garey

Vancomycin is not appreciably passaged via the colonic membrane to the gastrointestinal (GI) tract in persons with an intact gut epithelium due to its large chemical structure. However; hospitalized patients with diarrhea often have a disrupted GI tract. The aim of this study was to determine the frequency of detectable vancomycin concentrations in the stool of patients with antibiotic-associated diarrhea receiving IV vancomycin. This was a multicenter cohort study of hospitalized patients with stool samples collected for Clostridioides difficile testing. Leftover stool samples were collected from patients who had received at least 3 days of IV vancomycin. Fecal vancomycin was quantified by high-performance liquid chromatography. The study cohort included 33 unique patients, majority female (54.5%) aged 60 years (range 23–84). Eighteen of thirty-three patients (54.5%) tested positive for C. difficile toxins. The average duration of systemic vancomycin administration prior to stool collection was 3.5 (range 2–15) days. Three of 33 (9%) stool samples had a detectable vancomycin concentration (range 1.2–13.2 mcg/mL). These concentrations may promote the development of vancomycin-resistant Enterococcus or van mutations in C. difficile, leading to vancomycin resistance. Further studies on implications are warranted.

Pharmacoepidemiology doi: 10.3390/pharma2030023

Authors: Tigran Makunts Haroutyun Joulfayan Kenneth Ta Ruben Abagyan

Proton-pump inhibitors, PPIs, are widely prescribed and are available over the counter for prolonged reduction of stomach acid production and related disorders. PPIs irreversibly inhibit the hydrogen/potassium ATPase in gastric parietal cells. Recent retrospective studies have described an association between PPI use and depression. However, there is conflicting evidence that PPI therapy improves depressive symptoms. Considering the widespread use and over-the-counter availability of these drugs, further investigation into depression adverse event was warranted with a larger-scale postmarketing set of reports. Here we analyzed over 125,923 reports from the FDA Adverse Event Reporting System consisting of PPI and histamine-2 receptor antagonist monotherapy records and found a statistically significant association between use of PPIs and depression. Additionally, we analyzed each of the six currently marketed PPIs individually and observed the association with the depression adverse reaction for all of them.

Pharmacoepidemiology doi: 10.3390/pharma2030022

Authors: Suneetha Vuppu Toshika Mishra Arjun Chinamgari

The pandemic outbreak of Coronavirus disease 2019 (COVID-19) has drastically changed the picture of global healthcare. With the rapid emergence of novel variants of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that rendered the currently available therapeutic and diagnostic approaches inefficient in containing the transmission of infection, it becomes important to focus on strategies to break the transmission chain. The major approach to contain the spread of infection is the promotion of adequate hand hygiene practices in public as hands are an important source of pathogenic microbes. Hand hygiene is an important part of everyday life for maintaining a healthy and disease-free lifestyle. With the outbreak of the pandemic, people are now understanding the importance of hand hygiene practices. The global market of hand sanitizers has experienced rapid growth and high demand. This review aims to discuss the use of sanitizers during the period of COVID-19 and their role in controlling the transmission of infection. It also focuses on global market trends, the advancements in the development of sanitizer formulations, and the limitations of commercial sanitizers. Therefore, the formulation of an effective hand disinfectant is crucial for preventing future pandemic outbreaks.

Pharmacoepidemiology doi: 10.3390/pharma2030021

Authors: Giovanna Esposito Anna Cantarutti Matteo Franchi Giovanni Corrao Fabio Parazzini

This population-based study aimed at providing an overview of drug prescription patterns during pregnancy in the Italian region of Lombardy from 2010 to 2020. The cohort consisted of 780,075 deliveries identified from the regional healthcare utilization databases. The prevalence of drugs’ dispensed prescriptions was estimated as the proportion of pregnant women with at least one prescription out of the total deliveries over the entire pregnancy and by trimester. Drugs were classified according to the Anatomical Therapeutic Chemical code. In addition, interrupted time series analysis was conducted to investigate temporal trends of antibiotics’ use during the onset of the COVID-19 pandemic. A total of 497,515 women (63.8%) used at least a drug, including vitamins and minerals, at some point during pregnancy. Vitamins, minerals, and anti-anaemic preparations were prescribed in 20.8%, 13.3%, and 18.3% of deliveries over the trimesters of pregnancy. Folic acid was the most prescribed drug, with about one woman out of four, followed by iron preparations, progestogen, and antibiotics (prescription rate, respectively: 15.9%, 10.2%, and 9.8%). A decreasing trend in the dispensing of antibiotics emerged during the entire study period; however, a significant further decrease following the spread of the pandemic was observed. Further evidence is needed to monitor the use of drugs during pregnancy, determinants, and implications.

Pharmacoepidemiology doi: 10.3390/pharma2030020

Authors: Namkee G. Choi Bryan Y. Choi S. David Baker

Introduction: Given the increasing adult use of amphetamine and methylphenidate and their high misuse potential, we examined suspected suicide attempts and other intentional misuse and medical outcomes and their associations with co-used other substances among amphetamine and methylphenidate exposure cases aged 50+. Methods: Using the 2015–2021 U.S. National Poison Data System (N = 7701 amphetamine and/or methylphenidate cases), we fit two generalized linear models for a Poisson distribution with a log link function, with suspected suicide attempt versus intentional misuse and major medical effect/death versus other outcomes as the dependent variables. Results: Of all amphetamine/methylphenidate exposure cases, suspected suicide attempts and intentional misuse were 28.4% and 13.2%, respectively. Benzodiazepine use was associated with a higher likelihood, but any illicit drug use was associated with a lower likelihood of suspected suicide attempts compared to intentional misuse. The type of stimulant involved (amphetamine or methylphenidate) was not significant. The co-use of antidepressants (IRR = 1.43, 95% CI = 1.16–1.76), prescription opioids (IRR = 1.48, 95% CI = 1.21–1.81), drugs for cardiovascular disease (IRR = 1.51, 95% CI = 1.20–1.90), antipsychotics (IRR = 1.26, 95% CI = 1.02–1.55), or illicit drugs (IRR = 2.40, 95% CI = 1.82–3.15) was associated with a higher likelihood of major effect/death. Conclusions: Suspected suicide attempts or intentional misuse accounted for more than 40% of amphetamine or methylphenidate exposure cases aged 50+. The higher likelihood of major effect/death in cases involving antidepressants, antipsychotics, and cardiovascular disease drugs also suggests the confounding effects of comorbid mental and physical health problems. Careful monitoring of those who were prescribed amphetamine or methylphenidate and use other substances is needed.

Pharmacoepidemiology doi: 10.3390/pharma2030019

Authors: Hui Tan Rachel Lim Pei Ang Belinda Foo Yen Koon Jing Neo Amelia Ng Siew Tan Desmond Teo Mun Tham Aaron Yap Nicholas Ng Celine Loke Li Peck Huilin Huang Sreemanee Dorajoo

Background: Identifying patients with diabetes mellitus (DM) is often performed in epidemiological studies using electronic health records (EHR), but currently available algorithms have features that limit their generalizability. Methods: We developed a rule-based algorithm to determine DM status using the nationally aggregated EHR database. The algorithm was validated on two chart-reviewed samples (n = 2813) of (a) patients with atrial fibrillation (AF, n = 1194) and (b) randomly sampled hospitalized patients (n = 1619). Results: DM diagnosis codes alone resulted in a sensitivity of 77.0% and 83.4% in the AF and random hospitalized samples, respectively. The proposed algorithm combines blood glucose values and DM medication usage with diagnostic codes and exhibits sensitivities between 96.9% and 98.0%, while positive predictive values (PPV) ranged between 61.1% and 75.6%. Performances were comparable across sexes, but a lower specificity was observed in younger patients (below 65 versus 65 and above) in both validation samples (75.8% vs. 90.8% and 60.6% vs. 88.8%). The algorithm was robust for missing laboratory data but not for missing medication data. Conclusions: In this nationwide EHR database analysis, an algorithm for identifying patients with DM has been developed and validated. The algorithm supports quantitative bias analyses in future studies involving EHR-based DM studies.

Pharmacoepidemiology doi: 10.3390/pharma2030018

Authors: Ashley Tabah Laura S. Gold Zachary A. Marcum Ryan N. Hansen

Though it is well documented that antidepressants are associated with an increased risk of falls in older adults at the drug class level, the comparative risk between individual antidepressants for fall injury in older adults with depression is unknown. Currently, clinicians are making decisions at the drug class level without consideration of the potential that there could be safer choices within classes. We compared the risk of fall injury among initiators of bupropion, duloxetine, fluoxetine, paroxetine, and venlafaxine to those of (es)citalopram and, separately, sertraline. We performed a retrospective cohort study using the MarketScan® Medicare Supplemental claims from 2007 to 2019. Individuals had incident depression (washout in previous continually enrolled year) with a first antidepressant claim up to three months after depression diagnosis. Individuals were followed for the first three months of antidepressant use until the first occurrence of fall injury, change/discontinuation of antidepressant, discontinued insurance coverage, or end of study. Propensity score inverse probability of treatment-weighted Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals for each antidepressant comparison and fall injury. We identified 114,505 individuals (mean age 76.6 years, 68% female, 97% without prior fall). A higher risk of fall injury was associated with initiating bupropion (HR 1.20 to 1.61), duloxetine (HR 1.27 to 1.36), paroxetine (HR 1.14 to 1.22), and venlafaxine (HR 1.22 to 1.34) when compared to (es)citalopram or sertraline. New use of duloxetine, bupropion, paroxetine, and venlafaxine was associated with a higher risk of fall injury compared to (es)citalopram and sertraline.

Pharmacoepidemiology doi: 10.3390/pharma2030017

Authors: Hiroshi Kusunoki

More than 3 years have passed since the emergence of COVID-19. On 8 May 2023, COVID-19 in Japan was downgraded to Category 5 by the Infectious Disease Control Law. In Japan, at the beginning of the COVID-19 pandemic in 2020, cases of infection and deaths from severe disease were few compared with those in Western countries. However, in the medical field, screening for COVID-19 was given top priority, resulting in confusion and proving disadvantageous for many patients. The overreaction to COVID-19 as the most important issue in society can be attributed largely to statements by infectious disease experts. In addition, the mRNA vaccine emerged in 2021, and most of the population was vaccinated up to two times within a short period of less than 1 year because infectious disease experts strongly promoted vaccination. After 2022, when vaccination progressed and the Omicron strain, which is an attenuated strain, became the mainstay of SARS-CoV-2, the number of severe cases of COVID-19 decreased significantly; however, the number of infected people increased dramatically instead. A significant portion of the population is thought to have hybrid immunity due to vaccination plus natural infection and maintains high antibody titer levels. Henceforth, additional vaccination should be given preferentially to those who will benefit most from it. Conversely, measures against COVID-19 caused serious damage to the economy and society. Policies that not only address countermeasures against infection, but also those that encompass the economy and society as a whole, are necessary.

Pharmacoepidemiology doi: 10.3390/pharma2020016

Authors: Alex Orlek Eleanor Harvey Louis Fisher Amir Mehrkar Seb Bacon Ben Goldacre Brian MacKenna Diane Ashiru-Oredope

COVID-19 pandemic-related pressures on primary care may have driven the inappropriate continuation of antibiotic prescriptions. Yet, prescribing modality (repeat/non-repeat) has not previously been investigated in a pandemic context. With the approval of NHS England, we conducted a retrospective cohort study of >19 million English primary care patient records using the OpenSAFELY-TPP analytics platform. We analysed repeat/non-repeat prescribing frequency in monthly patient cohorts between January 2020 and 2022. In-depth analysis was conducted on January 2020 (“pre-pandemic”) and January 2021 (“pandemic”) cohorts (with a particular focus on repeat prescribing). Per-patient prescribing and clinical conditions were determined by searching primary care records using clinical codelists. Prescriptions in a 6-month lookback period were used to delineate repeat prescribing (≥3 prescriptions) and non-repeat prescribing (1–2 prescriptions). Associations between demographics (e.g., age, sex, ethnicity) and prescribing were explored using unadjusted risk ratios. The frequency of clinical conditions among prescribed patients was examined. Antibiotic prescribing declined from May 2020; non-repeat prescribing declined more strongly than repeat prescribing (maximum declines −26% vs. −11%, respectively). Older patients were at a higher risk of prescribing (especially repeat prescribing). Comorbidities were more common among repeat- vs. non-repeat-prescribed patients. In the pandemic cohort, the most common clinical conditions linked to repeat prescribing were COPD comorbidity and urinary tract infection. Our findings inform the ongoing development of stewardship interventions in England, targeting patient groups wherein there is a high prevalence of repeat prescribing.

Pharmacoepidemiology doi: 10.3390/pharma2020015

Authors: José Fernando Pérez-Franco Gabriela Hernández-Pliego Jocelyn Jacobo-Mendoza Vanessa Karina Martínez-Lara Luis Enrique Juárez-Villegas Patricia Clark Jessica Liliana Vargas-Neri

Late adverse events (LAEs) are an important cause of illness and disability in childhood cancer survivors (CCSs) and increase the risk of mortality. The aim of this cross-sectional study was to describe the frequency and severity of treatment-related LAEs in Mexican CCSs. The study period was between September 2018 and April 2019. We tested a sample of 82 CCSs at the Hospital Infantil de México Federico Gómez. We considered an LAE to be any medical effect related to treatment after ending cancer therapy. All LAEs were classified according to severity (using the grades of Common Terminology Criteria for Adverse Events v.5.0), diagnosis and time of occurrence after treatment. The treatment-related LAE frequency was 11.0% (95% CI; 4.2–17.8%). A total of 11 LAEs were identified in nine patients. Slightly over half of the patients were male (54.9%). The most frequent diagnosis was acute lymphoblastic leukemia (45.1%). The body systems involved in LAEs were the endocrine (55.6%), neurological (22.2%), auditory (11.1%) and renal (11.1%) systems. Obesity was the most frequent LAE (45.4%). Most LAEs were classified as grade 1 and 2 (60%). The median follow-up was 6.5 years. The odds ratio was used as a measure of association to identify characteristics associated with the LAEs. We identified that the age at diagnosis (OR = 0.71, 95% CI, 0.51–0.99; p = 0.046) and chemotherapy-only group (OR = 0.03, 95% CI, 0.00–0.86, p = 0.040) were associated with LAEs. This is the first study that describes the frequency and severity of LAEs in Mexican childhood cancer survivors.

Pharmacoepidemiology doi: 10.3390/pharma2020014

Authors: Sara Mandelli Ilaria Ardoino Alessandro Nobili Ida Fortino Carlotta Franchi

Background: The extensive use of antibiotics has contributed to the development of antibiotic resistance. Understanding the factors behind the attitude of physicians in prescribing antibiotics may be useful to address educational interventions to sensitize them to a more rational use of these drugs. This study aimed to evaluate the general practitioners’ (GPs) characteristics potentially associated with antibiotic prescription in community-dwelling adults from 2000 to 2019. Method: Multivariable linear regression models were performed to evaluate the association of GPs’ characteristics with the mean number of different antibiotics prescribed and the mean number of Defined Daily Doses (DDD) prescribed per patient. Results: We found that GPs older than 60 years prescribed a smaller number of different antibiotics per patient compared to 30–40 years old GPs (mean (standard error) 1.4 (0.5) vs. 1.8 (0.4)). In contrast older GPs prescribed more DDD compared to younger ones (28.9 (0.1) vs. 27.3 (0.3)). GPs prescribed 29 (0.1) DDD for >200 patients on polypharmacy vs. 28 (0.1) DDD for <100 patients on polypharmacy. The mean number of DDD prescribed increased by 5 units and by 16 units for each refill and switch, respectively. Conclusions: Age and number of patients in polypharmacy in charge were found to be associated with higher antibiotic prescriptions. The knowledge of the GPs-related factors could allow the stakeholders to design interventions to sensitize them to a more appropriate use of antibiotics in view of the increasing issue of antibiotic resistance.

Pharmacoepidemiology doi: 10.3390/pharma2020013

Authors: Thomas W. Wilson Joseph T. Dye Sarah Spark Nicholas J. Robert Janet L. Espirito E. Susan Amirian

We examined eligibility criteria from recent oncology clinical trials to see whether real-world data (RWD) from electronic health records (EHRs) could be used to create external control groups for clinical trials. Trials were identified from the Aggregate Analysis of ClinicalTrials.gov database; the selected trials were for oncology drugs approved by the FDA in 2020. Verbatim text from trial inclusion and exclusion criteria was qualitatively assessed by an expert panel to determine if criteria could be ascertained from structured and unstructured EHR data. Identified criteria were categorized (cancer-related, comorbidity-related, demographic, functional status, and trial operations) and subcategorized. Among 53 identified trials, 20 met the requirements for study inclusion, which included 463 eligibility criteria. Percentages of criteria by category were as follows: cancer-related factors (46%), comorbidities (20%), functional status (18%), trial operations (14%), and demographics (2%). For 18 of the 20 trials, 80% of the eligibility criteria could be ascertained with RWD; for 4 of the 20, it was 100%. When trial operation-specific criteria were excluded, all 20 met the 100% threshold. Our study indicates that both structured and unstructured data from community-based oncology-specific EHRs can be used for determining patient eligibility for external control arms for clinical trials.

Pharmacoepidemiology doi: 10.3390/pharma2020012

Authors: Siti Fauziah Abu Asrul Akmal Shafie Haarathi Chandriah

This study aimed to systematically review and explore the impact of study methods on the cost of managing adverse drug reactions (ADRs) among hospitalized patients to guide policymakers and researchers. A literature search was conducted in MEDLINE, EMBASE, CINAHL, Cochrane Library, and Google Scholar. The search was restricted to studies from 2000 to 2017. Two authors independently reviewed the studies, assessed their risk of bias, and extracted information for analysis. Data abstraction was based on the study design, ADR reporting, and costing approaches. Of 677 studies identified, 12 were included for analysis. All studies defined ADR according to WHO classifications. The percentage of admission due to ADR ranged from 0.03% to 17.11%. All studies adopted a healthcare provider perspective, using either a micro-costing (n = 7), case-mix group costing (n = 3), or average-per-diem costing (n = 2) approach. The cost per ADR widely fluctuated from USD 65.00 to USD 12,129.90 based on various factors. The micro-costing approach generally had a lower cost compared to other approaches. The cost per ADR in high-income countries was also 10 times higher than in lower- or middle-income countries. This study evidenced that the methodological heterogeneity across studies has resulted in a wide range of cost estimations for ADR management.

Pharmacoepidemiology doi: 10.3390/pharma2020011

Authors: Kannan Sridharan Muna Al Jufairi

Propylene glycol (PG) and benzyl alcohol (BA) have been shown to inhibit the metabolizing enzyme for acetaminophen in the liver. Ethanol has unpredictable effects on acetaminophen metabolism. Critically ill neonates commonly receive drug formulations containing PG, BA, and ethanol as excipients. Until now, there have been no reports on the influence of BA, PG, and ethanol as excipients in patients undergoing concomitant acetaminophen therapy. We devised the present study to evaluate whether any significant differences in plasma acetaminophen concentrations, liver function tests, and serum creatinine exist between neonates receiving excipients containing drugs compared to those without. We included neonates that were administered intravenous acetaminophen with at least one concomitant drug containing either BA, PG, or ethanol as excipients. Plasma acetaminophen concentrations and levels of liver function were evaluated using tests. The doubling of alanine aminotransferase levels was considered to be a marker of hepatotoxicity. Elevation of serum creatinine >1.5 times higher than the baseline value was considered to be indicative of an acute kidney injury. Fifty-seven neonates were recruited in the study. No significant differences in the serum acetaminophen concentrations, liver and renal function tests, and rates of successful closure of ductus arteriosus were observed between the groups. No significant changes in the serum acetaminophen levels and the clinical outcomes were observed due to the presence of BA, PG, or ethanol in concomitant drugs as excipients. Probably, drugs containing these excipients can be safely administered, and even formulations containing these excipients with acetaminophen are likely to be safe for critically ill neonates.

Pharmacoepidemiology doi: 10.3390/pharma2010010

Authors: Patricia A. Cioe William V. Lechner Jennifer W. Tidey Christopher W. Kahler

People with HIV (PWH) experience higher rates of cardiovascular events (CVEs) compared with the general population. A substantial body of evidence supports that select biomarkers of inflammation (soluble CD14 [sCD14], soluble CD163 [sCD163], highly sensitive C-reactive protein [hs-CRP], interleukin-6 [IL-6]) and coagulation (D-dimer) are elevated in PWH and related to increased rates of CVEs. Our previous work showed that smoking compared with nonsmoking was associated with significantly elevated sCD14, a biomarker of monocyte activation. We aimed to explore the effect of electronic cigarette (EC) provision on inflammatory biomarkers in PWH who smoked daily and then switched to an EC. Nineteen PWH were enrolled in a pilot study in which an EC and e-liquid were provided weekly for 8 weeks. Blood specimens for inflammatory biomarker analysis were obtained at baseline (BL) and at week 8. Biomarker levels were high at BL and did not differ significantly at week 8. There were small nonsignificant reductions in sCD163 and CRP levels. Non-significant increases in IL-6, D-dimer, and sCD14 levels were also noted. Use of ECs for 8 weeks does not appear to significantly increase or decrease inflammatory biomarker levels in SWH. Further research with larger samples and a control group is needed.

Pharmacoepidemiology doi: 10.3390/pharma2010009

Authors: Ronald Brown

COVID-19 antiviral medications approved or authorized for emergency use by the U.S. Food and Drug Administration are reported to have high efficacy in preventing severe illness, hospitalizations, and deaths. However, reports for some of these antivirals use relative risk reductions from clinical trials without absolute risk reductions. The present paper reappraises recently published clinical trial data for the COVID-19 antivirals paxlovid, remdesivir, and molnupiravir, and reports absolute risk reductions, relative risk reductions, as well as number needed to treat to reduce severe illness, hospitalizations, and deaths. Relative risk reductions are 88.88% for paxlovid (95% CI: 72.13–95.56%), 86.48% for remdesivir (95% CI: 41.41–96.88%), and 30.41% for molnupiravir (95% CI: 0.81–51.18%), while absolute risk reductions are much lower at 5.73% for paxlovid (95% CI: 3.79–7.68%), 4.58% for remdesivir (95% CI: 1.79–7.38%), and 2.96% for molnupiravir (95% CI: 0.09–5.83%). Low absolute risk reductions and the high number of patients needed to treat to reduce severe COVID-19 infections, hospitalizations, and deaths challenge the clinical efficacy of antivirals approved or authorized by the U.S Food and Drug Administration. These findings apply to other populations with similar control event rates. Accurate information should be disseminated to the public when selecting treatments for COVID-19.

Pharmacoepidemiology doi: 10.3390/pharma2010008

Authors: Cicely Anne Dye Jamario Skeete Asad Khan Michael Dunleavy Michael Dietrich Annabelle Santos Volgman Parikshit Sharma Henry Huang

Atrial fibrillation has been described as a global epidemic with a three-fold increase in prevalence in the last 50 years. As the prevalence of atrial fibrillation continues to grow, multiple landmark trials have been designed to determine the best method to treat atrial fibrillation. Initial trials have stated that rate control was not inferior to rhythm control, however, as the efficacy of rhythm control of atrial fibrillation has improved, a benefit in rhythm control has been shown. Because of this trend towards increased rhythm control, more patients have been placed on anti-arrhythmic medications. This paper will review the epidemiology and clinical impact of the utilization of anti-arrhythmic medications. As we enter the era of rhythm control, increased awareness is needed regarding the monitoring and potential adverse events that can occur with these medications. Providers must balance the increased emphasis on rhythm control with the overall clinical impact on their patients due to drug-to-drug interactions and adverse effects that can occur with different co-morbidities. If the clinical momentum towards rhythm control continues, real-world data analysis will be needed to evaluate the clinical impact of the use, risk, and benefits of anti-arrhythmic medications.

Pharmacoepidemiology doi: 10.3390/pharma2010007

Authors: Mohammed Sultan Al-Ak’hali Esam Halboub Mona Awad Kamil Wafa Hassan Alaajam Abdulaziz Mahnashi Jabbar Khubrani Abdullah Mahnashi Khalid Mahnashi Nuha Farea

This study aimed to investigate the knowledge and practices among dental practitioners in Saudi Arabia regarding the use of antimicrobials for periodontal diseases. An online questionnaire was sent to senior dental students and dental practitioners including interns, general dental practitioners (GDP), and periodontists in Saudi Arabia. Two hundred and twenty-three dental practitioners responded and participated in the study. The potential associations between the use of antimicrobials and different variables were assessed by a chi-square test. The majority of the participants (84.3%) reported prescribing systemic antimicrobials for a periodontal abscess or acute necrotizing periodontal disease. Surprisingly, 31% of participants reported prescribing systemic antimicrobials for deep localized periodontal pockets or for acute gingivitis associated with herpes simplex in children. Noteworthy is that 66% of the participants thought that mechanical periodontal treatment alone, without adjunctive antimicrobial therapy, is adequate to resolve the clinical condition in most cases of periodontal diseases. Almost half of the participants recommended the use of local antimicrobials for a periodontal pocket (45.3%), a recurrent periodontal pocket (45.4%), and refractory periodontitis (43.7%). The barriers against the use of local antimicrobials were a lack of knowledge and a lack of continuous education after graduation, as reported by 64% of the participants. In conclusion, knowledge and practices regarding antimicrobial use for periodontal diseases were inadequate, especially among practitioners other than periodontists.

Pharmacoepidemiology doi: 10.3390/pharma2010006

Authors: Robin A. Araya Fatima Tauqeer Michael Ceulemans Eva Gerbier Emeline Maisonneuve Anneke Passier Alison Oliver Alice Panchaud Angela Lupattelli Hedvig Nordeng

The objective of this study was to describe pregnancy- and birth-related experiences of postpartum women during the third wave of the COVID-19 pandemic and their association with mental health outcomes. An online questionnaire was distributed in five European countries (Belgium, The Netherlands, Norway, Switzerland, UK) between June and August 2021. Participants were recruited though social media platforms including pregnancy- and motherhood-related websites, pregnancy fora, and apps. Postpartum women were asked eleven specific questions about pregnancy- and birth-related changes and the presence of support during delivery. The Edinburgh Depression Scale was used to assess depressive and anxiety symptoms. Covariates included sociodemographics, health and reproductive characteristics, and COVID-19 status. Associations were estimated with logistic regression. The study included 1730 postpartum women. Frequent changes included the exclusion of the partner from pregnancy care appointments (83.2%), changed prenatal care settings (64.4%), and cancellation of hospital information visits (42.7%). Few women, however, were without support apart from medical staff during delivery (1.4%). The number of pregnancy- and birth-related changes was associated with each woman’s mental health status, as well as the type of change. Experiencing changes related to delivery and cancellation or reduction of prenatal examination was associated with a doubling in the odds of symptoms of major depression and anxiety postpartum. These findings highlight the importance of ensuring adequate maternity care for women’s mental health postpartum, as well as during a pandemic.

Pharmacoepidemiology doi: 10.3390/pharma2010005

Authors: Steward Mudenda Eustus Nsofu Patience Chisha Victor Daka Billy Chabalenge Webrod Mufwambi Henson Kainga Manal H.G. Kanaan Ruth L. Mfune Florence Mwaba Mildred Zulu Rabecca Tembo Wizaso Mwasinga Kennedy Chishimba Grace Mwikuma Ngula Monde Mulemba Samutela Harriet K. Chiyangi Shafiq Mohamed Scott K. Matafwali

Irrational and inappropriate prescribing of antibiotics is a major problem that can lead to the development of antimicrobial resistance (AMR). In Zambia, there is insufficient information on the prescribing patterns of antibiotics according to the World Health Organization (WHO) AWaRe classification. Therefore, this study assessed the prescribing patterns of antibiotics using the AWaRe classification during the COVID-19 pandemic at the University Teaching Hospital in Lusaka, Zambia. A cross-sectional study was conducted using 384 patient medical files at the University Teaching Hospital in Lusaka, Zambia, from August 2022 to September 2022. All antibiotics were classified according to the WHO “AWaRe” tool and assessed for appropriateness using the 2020 Zambian Standard Treatment Guidelines. Of the 384 patient medical files reviewed, antibiotics were prescribed 443 times. The most prescribed antibiotics were ceftriaxone (26.6%), metronidazole (22.6%), amoxicillin (10.4%), amoxicillin/clavulanic acid (5.6%), and azithromycin (5%). The prescribing of 42.1% of “Watch” group antibiotics was greater than the recommended threshold by the WHO. Most antibiotics were prescribed for respiratory infections (26.3%) and gastrointestinal tract infections (16.4%). The most prescribed antibiotic was ceftriaxone, a Watch antibiotic. This is a worrisome observation and calls for strengthened antimicrobial stewardship and implementation of the AWaRe framework in prescribing antibiotics.

Pharmacoepidemiology doi: 10.3390/pharma2010004

Authors: Karolini Zuqui Nunes Jonathan Grassi Andressa Bolsoni Lopes Lucas Dalvi Armond Rezende Julia Anhoque Cavalcanti Karoline Neumann Gomes Julia Antonietta Dantas da Silva Luís Carlos Lopes-Júnior

Heart disease and cancer are the main causes of morbidity and mortality worldwide. As the number of cancer survivors increases, cardiotoxicity associated with cancer treatment has become a major concern as it presents a substantial challenge in the follow-up of these patients. Here, we aimed to map the clinical indicators for cardiovascular risk in adult patients undergoing chemotherapy. A scoping review protocol adhering to the PRISMA-P statement and in accordance with the JBI guidelines will be conducted. Cochrane Library, MEDLINE/PubMed, Cochrane Library, EMBASE, Scopus, Web of Science, and PsycINFO as well as register sites such as ClinicalTrials.gov and WHO-ICTRP will be searched. Additional sources, including Google Scholar, The British Library, and medRXiv, will also be searched, with no date or idiom restrictions. A combination of subject headings, MeSH terms, Emtree terms, CINAHL Headings, and APA Thesaurus, using the Boolean terms AND/OR, will be performed. In addition, two independent researchers will conduct the overall steps of this review. The results will be presented via narrative summaries, considering the types of clinical indicators. To the best of our knowledge, this will be the first scoping review in the cardio-oncology field to map, via a rigorous review method, the clinical indicators for cardiovascular risk in adult cancer patients receiving chemotherapy.

Pharmacoepidemiology doi: 10.3390/pharma2010003

Authors: Yoshihiro Noguchi Shuji Yamashita Hirofumi Tamaki Arihiro Osanai Yoko Ino Tomoya Tachi Kazuhiro Iguchi Hitomi Teramachi

Although 5-Aminosalicylate (5-ASA) has been shown to act on the local mucosa, when 5-ASA is orally administered, most of it is absorbed in the upper gastrointestinal tract and does not reach the large intestine, where lesions are present. Therefore, different drug delivery systems have been developed for each oral 5-ASA formulation. Currently, the oral 5-ASA formulation approved in Japan is salazosulfapyridine (SALAZOPYRIN®; Pfizer Japan Inc.: Tokyo, Japan), in which 5-ASA and sulfapyridine are azo-bonded. In addition, there are several 5-ASA release formulations, including ASACOL®; ZERIA Pharmaceutical Co., Ltd.: Tokyo, Japan (delayed release formulation dependent on pH), PENTASA®; KYORIN Pharmaceutical Co., Ltd.: Tokyo, Japan (delayed release formulation dependent on time), and LIALDA®; MOCHIDA Pharmaceutical Co., Ltd.: Tokyo, Japan (delayed release formulation dependent on pH and time). Adverse events may occur because of differences in the drug delivery systems of these products. In this study, we focused on the adverse events of different 5-ASA formulations and investigated differences in the detection of safety signals for each 5-ASA formulation using disproportionality analysis. There were 15 adverse events detected only with SALAZOPYRIN®. On the other hand, ASACOL®, PENTASA®, and LIALDA® have different drug delivery systems. Although the detected signal intensities varied, the detected adverse events were not significantly different. These findings provide important insights, which should be considered by physicians during treatment selection and drug manufacturers during drug development.

Pharmacoepidemiology doi: 10.3390/pharma2010002

Authors: Kentaro Tajima Tomofumi Ishikawa Masami Tsuchiya Masafumi Kikuchi Taku Obara Nariyasu Mano

We aimed to evaluate the adverse birth outcomes of anticancer drug prescription during pregnancy using a Japanese claims database from 2005 to 2019. We applied validated claims-based algorithms to identify pregnant women with birth outcomes, and evaluated drug prescription during pregnancy. The causal relationship between anticancer drugs and adverse birth outcomes was evaluated using the Council for International Organizations of Medical Sciences Working Group VI criteria. Thirteen women with anticancer drugs prescription during pregnancy were identified (mean age: 34.6 years). Atrial/ventricular septal defect was observed in one infant after exposure to cyclophosphamide and doxorubicin for breast cancer in the second and third trimesters. One woman on several anticancer drugs (cyclophosphamide, cytarabine, daunorubicin, l-asparaginase, methotrexate, nelarabine, and vincristine) for acute lymphoblastic leukemia, one on imatinib for chronic myeloid leukemia, and one on cisplatin and fluorouracil for cervical cancer had miscarriages after exposure in the first trimester. A relationship between those anticancer drugs and miscarriage could not be ruled out, while no relationship was identified regarding the atrial/ventricular septal defect considering the period of exposure and organogenesis. Our results suggest increased risk of miscarriage with the use of several anticancer drugs such as methotrexate, imatinib, cisplatin, and fluorouracil in the first trimester.

Pharmacoepidemiology doi: 10.3390/pharma2010001

Authors: Jiayi Gong Amy Hai Yan Chan Kebede Beyene Alan Forbes Merry Andrew Tomlin Peter Jones

Unique aspects of New Zealand’s (NZ) health system allow for a novel pharmacoepidemiologic approach to conducting population-based clinical research. A defined cohort of surgical and trauma patients would facilitate future studies into opioid utilisation, outcomes, and other questions related to surgery and trauma. We aimed to describe all patients admitted to a NZ hospital with trauma or to undergo surgery between 1 January 2007 to 31 December 2019. This was a retrospective population-based study involving all hospital centres in NZ. We excluded patients with hospitalisation episodes for surgery or trauma one year before the event. We identified 1.78 million surgical only patients, 633,386 trauma only, and 250,800 trauma with surgery patients. Trauma only patients had the highest prevalence of death within one year of event (17.8%), history of opioid dispensing (18.3%), mental health disorders (17.0%) and chronic pain (2.3%). Moreover, trauma patients also had the highest prevalence of those with higher comorbidity burden. We plan to use this dataset for future research into the prevalence and outcomes of persistent opioid use, and to make our dataset available to other researchers upon request. Our findings of significant differences between cohorts suggest studies should treat surgical and trauma patients separately.

Pharmacoepidemiology doi: 10.3390/pharma1030010

Authors: Tianyu Sun Natallia Katenka Stephen Kogut Jeffrey Bratberg Josiah Rich Ashley Buchanan

Opioid use disorder (OUD) is a chronic disease requiring long-term treatment and is associated with opioid overdose and increased risk of mortality. However, existing randomized clinical trials focused on short-term treatment engagement and detoxification rather than overdose or mortality risk due to limited follow-up time and ethical considerations. We used a hypothetical trial framework to conduct a retrospective cohort study to assess the effectiveness of time-varying buprenorphine-naloxone on opioid overdose and death. We identified 58,835 insured adult patients with OUD diagnosis in the US, 2010–2017. We fit a marginal structural model using inverse probability weighting methods to account for measured baseline and time-varying confounders, as well as selection bias due to possibly differential loss-to-follow-up. We found that receipt of buprenorphine-naloxone was associated with reduced risk of opioid overdose (hazard ratio (HR) = 0.66, 95% confidence interval (CI): 0.49, 0.91), death (HR = 0.24, 95% CI: 0.08, 0.75), and overdose or death (HR = 0.58, 95% CI: 0.40, 0.84). The E-value for death was 7.8, which was larger than the upper 95% CI of the association between each measured baseline variable and all-cause death, which implies that the unmeasured confounding itself may not explain away the estimated effect of treatment on the endpoint of all-cause mortality.

Pharmacoepidemiology doi: 10.3390/pharma1030009

Authors: Efe Eworuke Austin Cosgrove Qoua Liang Her Jennifer G. Lyons Dave Martin Sruthi Adimadhyam

Background: Spironolactone is a mineralocorticoid receptor antagonist indicated for the management of heart failure with reduced ejection fraction (HFrEF). In a previous clinical trial, spironolactone significantly lowered the incidence of heart failure (HF) hospitalizations among HF patients with preserved ejection fraction (HFpEF). Real world utilization of spironolactone in HFrEF and HFpEF is unknown. Methods: We conducted a retrospective cohort study using data from FDA’s Sentinel System. We identified patients with HFrEF or HFpEF using diagnosis and procedure codes from a previously validated algorithm. We required patients to be continuously enrolled in the 183 days prior to HF diagnosis. Follow-up started on the day of HF diagnosis and ended at the earliest occurrence of a spironolactone dispensing, disenrollment, death, or end of data. We calculated the proportion of spironolactone utilization, and for those initiating treatment, we estimated the dose and duration of the first continuous treatment episode. Results: Among 2,009,529 HFrEF patients, 57.8% were male, and mean age was 73.8 ± 12.1 years. Among 9,257,514 HFpEF patients, 42.7% were male, and mean age was 73.0 ± 12.1 years. The proportion of spironolactone utilization following HFrEF diagnosis was 20.7% versus 7.6% after HFpEF. The median time (days) to initiation of spironolactone after HFrEF diagnosis was 90 (IQR: 19–385) versus 286 (IQR: 57–851) after HFpEF diagnosis. The median duration (days) of first treatment episode in HFrEF patients was 120 (IQR: 44–321) and 114 (IQR: 32–301) for HFpEF patients. The median dose was similar (25 mg/day) for both HF cohorts. Conclusion: Findings of low real-world utilization of spironolactone from our large, geographically, and demographically diverse multi-site study in the US are consistent with reports from smaller studies in the literature. Similar spironolactone dosing and duration were observed in both the HFpEF and HFrEF cohorts. Future research characterizing spironolactone treated and untreated HFpEF cohorts will be needed to identify treatment gaps.

Pharmacoepidemiology doi: 10.3390/pharma1020008

Authors: George Deeb Esperanza Diaz Svein Haavik Angela Lupattelli

This cross-sectional study sought to quantify medication use and change in use of prescription-only medications purchased in the past in Syria without medical prescription versus today in Norway in an adult population originating from Syria and living in western Norway. Data on adults born in Syria and living in Norway during December 2019–January 2020 were collected via a self-administrated questionnaire in Arabic. Participants were recruited at a community pharmacy and at a refugee center. We included 148 participants (mean age 36.4 years; 38.5% females and 60.8% males) of whom 62.6% had lived in Norway for 4–6 years. Most participants had low (45.9%) or medium (39.2%) health literacy. Painkillers and analgesics were the most widely used medications, in both Norway (69.6%) and Syria (78.4%). Use of antibiotics declined significantly in Norway (31.1%) relative to Syria (65.5%); 70.9% participants used prescription-only medications in both countries, while 6.1% and 13.5%, respectively, did so only in Norway or only in Syria. This study reports a relatively high rate of medication use, particularly painkillers and analgesics both in Syria and in Norway. Participants with low health literacy reported greater use of antibiotics than those with high level in Syria but not in Norway. Use of antibiotics decreased substantially in Norway relative to the past in Syria, reaching a comparable prevalence with that in the host community. Although uncommon, prescription-only medication use only in Norway was reported by some participants.

Pharmacoepidemiology doi: 10.3390/pharma1020007

Authors: Talip E. Eroglu Marieke T. Blom Patrick C. Souverein Anthonius de Boer Hanno L. Tan

Depolarization-blocking drugs (DB drugs) used for cardiac disease increase the risk of cardiac arrhythmia (ventricular tachycardia/ventricular fibrillation [VT/VF]) and out-of-hospital cardiac arrest (OHCA) in specific patient groups. However, it is unknown whether drugs for non-cardiac disease that block cardiac depolarization as the off-target effect increase the risk of OHCA on a population level. Therefore, we aimed to investigate OHCA risk of non-cardiac, DB drugs in the community. We conducted a population-based case-control study. We included OHCA cases from an emergency-medical-services-attended OHCA registry in the Netherlands (ARREST:2009–2018), and age/sex/OHCA-date matched non-OHCA controls. We calculated adjusted odds ratios (ORadj) of use of non-cardiac DB drugs for OHCA using conditional logistic regression. Stratified analyses were performed according to first-registered rhythm (VT/VF or non-VT/VF), sex, and age (≤50, 50–70, or ≥70 years). We included 5473 OHCA cases of whom 427 (7.8%) used non-cardiac, DB drugs and 21,866 non-OHCA controls of whom 835 (3.8%) used non-cardiac, DB drugs and found that non-cardiac, DB-drug use was associated with increased OHCA-risk when compared to no use (ORadj1.6[95%-CI:1.4–1.9]). Stratification by first-recorded rhythm revealed that this applied to OHCA with non-VT/VF (asystole) (ORadj2.5[95%-CI:2.1–3.0]) but not with VT/VF (ORadj1.0[95%-CI:0.8–1.2]; p-value interaction < 0.001). The risk was higher in women (ORadj1.8[95%-CI:1.5–2.2] than in men (ORadj1.5[95%-CI:1.2–1.8]; p-value interaction = 0.030) and at younger ages (ORadj≥70yrs1.4[95%-CI:1.2–1.7]; ORadj50–70yrs1.7[95%-CI:1.4–2.1]; ORadj≤50yrs3.2[95%-CI:2.1–5.0]; p-value interaction < 0.001). Use of non-cardiac, DB drugs is associated with increased OHCA risk. This increased risk occurred in patients in whom non-VT/VF was the first-registered rhythm, and it occurred in both sexes but more prominently among women and more strongly in younger patients (≤50 years).

Pharmacoepidemiology doi: 10.3390/pharma1020006

Authors: Ayesha Rahman Ahmed Mahiba Ahmed

The issue with the overlapping clinical symptoms from an electronic cigarette (e-cigarette) or vaping product use-associated lung injury (EVALI) and coronavirus disease 2019 (COVID-19) sometimes leads to incorrect diagnosis and, consequently, wrong treatment regimen. The purpose of this review is to study the burden of vaping-associated health consequences on the diagnosis and treatment of COVID-19 in young adults and adolescents with a misconception of e-cigarettes as a safer alternative to smoking. The online reference databases, including PubMed, Google Scholar, Web of Science, Medline, and Centers for Disease Control and Prevention (CDC), were used in the literature search, as we analyzed the complexity of timely diagnosis and treatment in the current COVID-19 era with the use of e-cigarettes. This study briefly describes the dysbiosis of the oral microbiome in e-cigarette users that could potentially aggravate the COVID-19 symptoms and lead to the complexity of timely diagnosis and treatment. Additionally, the patient case reports with a history of vaping and symptoms similar to COVID-19 disease are reviewed.

Pharmacoepidemiology doi: 10.3390/pharma1010005

Authors: Ingrid Schubert Joachim Fessler Sebastian Harder Truc Sophia Dinh Maria-Sophie Brueckle Christiane Muth on behalf of the EVITA Study Group on behalf of the EVITA Study Group

Patients with multimorbidity and multimedication require special attention from their treating physicians, as the risks of drug interactions and negative effects on adherence increase with the number of drugs. Most guidelines aim for the treatment of a single disease and do not take potential problems due to multimedication into account. In 2021, updates and evidence-based upgrades of the first version (2012) of the German Guidelines on Multimedication were issued. The aim of the article is to introduce the framework of these evidence-based guidelines, which follows the medication process in six steps: (1) inventory and medication assessment; (2) coordination with the patient; (3) prescription proposal and communication; (4) dispensing of medicines; (5) medication application and self-management; and (6) monitoring. For each step, recommendations and practice tips are presented. The central feature is a structured medication review. The target group is patients with multimorbidity and the concurrent use of five or more drugs. The Medication Appropriateness Index has been modified, and the guiding questions are recommended as guidance for the structured medication review. Overuse and undertreatment are taken into account. The guidelines were consented to in a formal process with 15 medical societies, a patient representative, and experts, as well as piloted in general practices.