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PURPOSE: Since late 2017, the use of ulipristal acetate 5 mg (UPA; Proprietary name: Esmya) has been under review in the European Union, due to an emerging hepatic risk. In February 2018 and in July 2018, the Spanish Agency of Medicines and Medical Devices and the marketing authorization holder put two risk minimization measures (RMM) in place, in order to inform about new safety information and to mitigate this risk. This study aims to assess RMM effectiveness in Spain, by performing an interrupted time-series (ITS) analyses, between 2014 and 2019. METHOD: Two quasi-experimental ITS analyses to examine the use of UPA before and after the RMM release were performed: (a) an ecological study using aggregated data from a drug consumption database; and (b) a study using primary healthcare data gathered from electronic clinical records. RESULTS: Regulatory interventions were associated with an immediate and significant decrease level of DID (the number of DDD dispensed per 100 000 inhabitants and day) and incidence. The DID was 70% less than expected 12 months after the interventions. This value was 59% for the incidence. However, a change in the slope was not observed and the use started rising again in the last segment of the study period. CONCLUSION: Despite RMM had an immediate strong impact on UPA use, the last segment upward trend in the long-term might have been affected by the lack of comparable therapeutic alternatives. Further studies should be performed to confirm the increase trend observed and analyze subsequent measures and additional data.

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BACKGROUND: Pentobarbital is a Schedule II/III short-acting barbiturate with limited medical use in humans. Veterinary professionals use pentobarbital to euthanize dogs, cats, and other companion animals. Pentobarbital is also utilized in capital punishment and small amounts are illegally shipped or diverted to assist in suicides. However, five kilograms of pentobarbital smuggled in from Mexico was recently seized by an organized crime drug enforcement task force (along with fentanyl, heroin, and cocaine), which may suggest a shift in illicit supply. We investigated potential indicators of illicit pentobarbital use or availability in the US to help determine whether this drug is becoming an emerging public health concern. METHODS: The National Drug Early Warning System requested information on pentobarbital from its sentinel surveillance sites and collaborators and conducted a search of current literature. RESULTS: In early 2024, multiple batches of counterfeit pills (e.g., pressed as "M30s" to represent oxycodone) confiscated near the Southwest border tested positive for pentobarbital plus combinations of fentanyl, fentanyl analogs, and xylazine. Other indicators suggest pentobarbital is being smuggled in powder form and possibly sold as another drug such as heroin. One national drug analysis program detected pentobarbital in 217 drug submissions from 2020 to 2023, and there were at least 12 fatal exposures linked to use from 2020 to 2022. CONCLUSION: Continued monitoring of illicit use and availability is needed as pentobarbital may continue to appear on the illicit market. Unknown exposure can occur if the drug is mixed into counterfeit pills or sold in powder form represented to be another drug.

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Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematologic disease characterized by complement-mediated hemolysis and thrombosis. Complement component 5 (C5) inhibitors have decreased PNH-related thrombosis rates and reduced mortality compared with those of age-matched controls. A small but significantly increased risk of life-threatening Neisseria infections, especially N meningitidis, represents a long-term safety risk of complement inhibition. Objectives: To evaluate the rates of thrombosis and meningococcal infections in patients with PNH treated with the complement component 3-targeted therapy pegcetacoplan. Methods: Cumulative patient-year exposure to pegcetacoplan was calculated, and thrombotic events and meningococcal infections were reviewed in 7 clinical trials and in the postmarketing setting. The clinical trial protocols and pegcetacoplan labeling required vaccination against Streptococcus pneumoniae, N meningitidis, and Haemophilus influenzae before pegcetacoplan use; the label allowed for prophylactic antibiotic use if pegcetacoplan must be administered before vaccination. Results: As of November 13, 2022, 464 patients with PNH had 619.4 patient-years of pegcetacoplan exposure in completed/ongoing clinical trials and the postmarketing setting. Seven thrombotic events were reported: 5 in clinical trials (2 in the same patient) and 2 in the postmarketing setting. The overall thrombosis rate was 1.13 events per 100 patient-years (clinical trials: 1.22 events/100 patient-years in 409.4 years; postmarketing: 0.95 events/100 patient-years in 210.0 years). No infections with meningococcal bacteria were reported. Conclusion: Event rates for thrombosis were comparable between pegcetacoplan and previously reported rates of C5 inhibitors in patients with PNH, and no cases of meningococcal infection were reported with pegcetacoplan. Continued follow-up is required.

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BACKGROUND: Rates of synthetic opioid-related deaths over time and across regions have been compared within the US, but other indicator data could help inform prevention and harm reduction as well. We compared regional trends in fentanyl seizures to examine potential shifts in illicit fentanyl availability. METHODS: Annual trends in fentanyl seizures were examined using data from High Intensity Drug Trafficking Areas for the US overall and by region from 2017 through 2023. Multiple measures included the number of seizures, the number of powder seizures, the number of pill seizures, the total weight of seizures, the number of pills seized, and the percentage of the number of pill seizures relative to the number of total seizures. RESULTS: The percentage of seizures in pill form in the US increased from 10.3 % in 2017 to 49.0 % in 2023 (adjusted annual percentage change [AAPC]=25.2, 95 % CI: 17.6, 33.2), with 115.6 million individual pills seized in 2023. Pill weight related to total seizure weight also increased from 0.4 % to 54.5 % (AAPC=112.6, 95 % CI: 78.6, 153.2). In 2023, the plurality of seizures was in the West, in seven out of eight of our measures, with 77.8 % of seizures in the West being in pill form. Although the Midwest had lower prevalence of seizures than the West, there were notable increases in the Midwest in the number of pill seizures (AAPC=142.2, 95 % CI: 91.9, 205.8) and number of pills seized (AAPC=421.0, 95 % CI: 272.7, 628.4). Total weight of fentanyl seized increased the most in the West (AAPC=84.6, 95 % CI: 72.3, 97.8). CONCLUSIONS: The number and size of fentanyl seizures is increasing in the US, with the majority of seizures, especially in pill form, in the West. Continued monitoring of regional shifts in the fentanyl supply can help inform targeted prevention and public health response.

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Observational research utilizes patient information from many disparate databases worldwide. To be able to systematically analyze data and compare the results of such research studies, information about exposure to drugs or classes of drugs needs to be harmonized across these data. The NLM's RxNorm drug terminology and WHO's ATC classification serve these needs but are currently not satisfactorily combined into a common system. Creating such system is hampered by a number of challenges, resulting from different approaches to representing attributes of drugs and ontological rules. Here, we present a combined ATC-RxNorm drug hierarchy, allowing to use ATC classes for retrieval of drug information in large scale observational data. We present the heuristic for maintaining this resource and evaluate it in a real world database containing drug and drug classification information.

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Background: Safety issues are detected in about one third of prescription drugs in the years following regulatory agency approval. Older adults, especially those with chronic kidney disease, are at particular risk of adverse reactions to prescription drugs. This protocol describes a new approach that may identify credible drug-safety signals more efficiently using administrative health care data. Objective: To use high-throughput computing and automation to conduct 700+ drug-safety cohort studies in older adults in Ontario, Canada. Each study will compare 74 acute (30-day) outcomes in patients who start a new prescription drug (new users) to a group of nonusers with similar baseline health characteristics. Risks will be assessed within strata of baseline kidney function. Design and setting: The studies will be population-based, new-user cohort studies conducted using linked administrative health care databases in Ontario, Canada (January 1, 2008, to March 1, 2020). The source population for these studies will be residents of Ontario aged 66 years or older who filled at least one outpatient prescription through the Ontario Drug Benefit (ODB) program during the study period (all residents have universal health care, and those aged 65+ have universal prescription drug coverage through the ODB). Patients: We identified 3.2 million older adults in the source population during the study period and built 700+ initial medication cohorts, each containing mutually exclusive groups of new users and nonusers. Nonusers were randomly assigned cohort entry dates that followed the same distribution of prescription start dates as new users. Eligibility criteria included a baseline estimated glomerular filtration rate (eGFR) measurement within 12 months before the cohort entry date (median time was 71 days before cohort entry in the new user group), no prior receipt of maintenance dialysis or a kidney transplant, and no prior prescriptions for drugs in the same subclass as the study drug. New users and nonusers will be balanced on ~400 baseline health characteristics using inverse probability of treatment weighting on propensity scores within 3 strata of baseline eGFR: ≥60, 45 to <60, <45 mL/min per 1.73 m2. Outcomes: We will compare new user and nonuser groups on 74 clinically relevant outcomes (17 composites and 57 individual outcomes) in the 30 days after cohort entry. We used a prespecified approach to identify these 74 outcomes. Statistical analysis plan: In each cohort, we will obtain eGFR-stratum-specific weighted risk ratios and risk differences using modified Poisson regression and binomial regression, respectively. Additive and multiplicative interaction by eGFR category will be examined. Drug-outcome associations that meet prespecified criteria (identified signals) will be further examined in additional analyses (including survival, negative-control exposure, and E-value analyses) and visualizations. Results: The initial medication cohorts had a median of 6120 new users per cohort (interquartile range: 1469-38 839) and a median of 1 088 301 nonusers (interquartile range: 751 697-1 267 009). Medications with the largest number of new users were amoxicillin trihydrate (n = 1 000 032), cephalexin (n = 571 566), prescription acetaminophen (n = 571 563), and ciprofloxacin (n = 504,374); 19% to 29% of new users in these cohorts had an eGFR <60 mL/min per 1.73 m2. Limitations: Despite our use of robust techniques to balance baseline indicators and to control for confounding by indication, residual confounding will remain a possibility. Only acute (30-day) outcomes will be examined. Our data sources do not include nonprescription (over-the-counter) drugs or drugs prescribed in hospitals and do not include outpatient prescription drug use in children or adults <65 years. Conclusion: This accelerated approach to conducting postmarket drug-safety studies has the potential to more efficiently detect drug-safety signals in a vulnerable population. The results of this protocol may ultimately help improve medication safety.

Contexte: Des problèmes d'innocuité sont détectés dans environ un tiers des médicaments d'ordonnance au cours des années qui suivent leur approbation par l'organisme de réglementation. Les personnes âgées, en particulier celles qui sont atteintes d'insuffisance rénale chronique, sont particulièrement exposées aux effets indésirables des médicaments d'ordonnance. Ce protocole décrit une nouvelle approche qui, à partir des données administratives du système de santé, pourrait permettre d'identifier plus efficacement les signaux crédibles sur la sécurité des médicaments. Objectif: Utiliser l'informatique à haut débit et l'automatisation pour mener plus de 700 études de cohorte sur l'innocuité des médicaments chez les adultes âgés résidant en Ontario (Canada). Chaque étude comparera 74 résultats aigus (30 jours) chez des patients qui commencent un nouveau médicament sur ordonnance (nouveaux utilisateurs) à ceux d'un groupe de non-utilisateurs avec des caractéristiques de santé initiales similaires. Les risques seront évalués par strates de la fonction rénale initiale. Cadre et type d'étude: Études populationnelles de cohortes de nouveaux utilisateurs de médicaments menées à l'aide des bases de données administratives couplées du système de santé ontarien (Canada). Période étudiée: du 1er janvier 2008 au 1er mars 2020. Population source: les Ontariens de 66 ans ou plus ayant rempli au moins une ordonnance pour patient non hospitalisé par l'entremise du Program de médicaments de l'Ontario (PMO) pendant la période de l'étude (tous les résidents de la province bénéficient d'un système de soins de santé universel; les personnes âgées de 65 ans et plus bénéficient d'une couverture universelle des médicaments d'ordonnance par l'intermédiaire du PMO). Sujets: Nous avons identifié 3,2 millions d'adultes âgés dans la population source au cours de la période d'étude et constitué plus de 700 cohortes de médicaments, chacune contenant des groupes mutuellement exclusifs de nouveaux utilisateurs et de non-utilisateurs. Les non-utilisateurs se sont vu attribuer au hasard des dates d'entrée dans la cohorte qui suivaient les dates de début d'ordonnance des nouveaux utilisateurs. Les critères d'admissibilité étaient d'avoir une mesure initiale du débit de filtration glomérulaire estimé [DFGe] dans les 12 mois précédant la date d'entrée dans la cohorte (dans le groupe des nouveaux utilisateurs, le délai médian était de 71 jours avant l'entrée dans la cohorte), ne pas suivre de dialyze chronique, ne pas avoir eu de greffe rénale et n'avoir jamais eu de prescription d'un médicament de la même sous-classe que le médicament à l'étude. Les nouveaux utilisateurs et les non-utilisateurs seront jumelés selon environ 400 caractéristiques de santé initiales à l'aide de la probabilité inverse de traitement pondérée selon les scores de propension dans les trois strates de mesure du DFGe initial: ≥60 ml/min/1,73 m2; 45 à <60 ml/min/1,73 m2 et <45 ml/min/1,73 m2. Résultats: Nous comparerons les groupes de nouveaux utilisateurs et de non-utilisateurs selon 74 critères de jugement cliniquement pertinents (17 critères composites et 57 critères individuels) pendant les 30 jours suivant l'entrée dans la cohorte. Une approche prédéfinie a permis de déterminer ces 74 résultats. Plan d'analyze statistique: Dans chaque cohorte, nous calculerons les différences de risque (par régression de Poisson) et les rapports de risque (par régression binomiale) pondérés pour chaque strate de DFGe. Les interactions additives et multiplicatives par catégorie de DFGe seront examinées. Les associations médicaments-résultats répondant à des critères prédéfinis (signaux identifiés) seront examinées plus avant dans des analyses supplémentaires (survie, exposition à des témoins négatifs, analyses de la valeur E, etc.) et des visualizations. Résultats: Dans les cohortes initiales de médicaments, les médianes sont de 6 120 nouveaux utilisateurs (intervalle interquartile de 1 469 à 38 839) et de 1 088 301 non-utilisateurs (intervalle interquartile de 751 697 à 1 267 009). Les médicaments comptant le plus grand nombre de nouveaux utilisateurs sont le trihydrate d'amoxicilline (n = 1 000 032), la céfalexine (n = 571 566), l'acétaminophène sur ordonnance (n = 571 563) et la ciprofloxacine (n = 504 374). De 19 à 29 % des nouveaux utilisateurs dans ces cohortes présentaient un DFGe < 60 ml/min/1.73 m2. Limites: Malgré l'utilization de techniques robustes pour équilibrer les indicateurs de base et pour contrôler le risque de confusion par indication, il pourrait subsister des facteurs de confusion résiduels. Seuls les résultats aigus (30 jours) seront examinés. Nos sources de données ne comprennent pas les médicaments sans ordonnance (en vente libre) ni les médicaments prescrits dans les hôpitaux, et n'incluent pas l'utilization de médicaments sur ordonnance en ambulatoire chez les enfants ou les adultes de moins de 65 ans. Conclusion: Cette approche accélérée pour la réalisation d'études d'innocuité des médicaments après leur mise en marché a le potentiel de détecter efficacement les effets indésirables de ces médicaments dans une population vulnérable. Les résultats de ce protocole serviront à améliorer l'innocuité des médicaments.

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Background: Drug monitoring by drug testing of individuals under arrest provides an opportunity to detect drug use patterns within geographic areas. However, women have been omitted from large-scale monitoring efforts in criminal justice populations. The purpose of this study was to examine whether gender differences exist in drug use indicated by oral fluid collected in one U.S. jail. Methods: The study analyzed data collected in 2019-2020 from individuals under arrest (N = 191). Twenty-four percent of the sample identified as female. Oral fluid specimens were collected and then analyzed with enzyme-linked immunosorbent assay and liquid chromatography/tandem mass spectrometry. Logit regression models examined gender differences. Results: Women were more likely to test positive for methamphetamines than men (41% versus 22%, OR = 0.42, 95% CI 0.21-0.84). Significant gender differences were not found for other substances (marijuana, cocaine, and opioids), legality of drugs, or overall drug use. Conclusions: Because the National Institute on Drug Abuse aims to promote health equity, future drug monitoring in criminal justice populations should employ sampling approaches representing both women and men. This research would identify possible gender-based patterns of drug use and inform gender-based policies and clinical practices to prevent and treat drug misuse.

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Background: The overdose epidemic in the United States (US) continues to generate unprecedented levels of mortality. There is urgent need for a national data system capable of yielding high-quality, timely, and actionable information on existing and emerging drugs. Public health researchers have started using law enforcement forensic laboratory data to obtain surveillance information on illicit drugs. This study is the first to use drug reports from the entire US to examine correlations between a changing drug supply and increasing opioid-involved overdose deaths (OOD) on a national scale. Methods: This study is observational and investigates associations between law enforcement drug reports and OOD for the US from 2014 to 2019. OOD data are from the Centers for Disease Control and Prevention's National Vital Statistics System restricted-use multiple cause of death files. The US Drug Enforcement Administration's National Forensic Laboratory Information System (NFLIS) contains forensic laboratory-tested drug exhibit information for the entire US (NFLIS-Drug). Counts of forensic laboratory reports and OOD were aggregated for each state by month, quarter, and year. A difference-in-differences framework was used to estimate contemporaneous and lagged associations. Findings: Between 2014 and 2019 in the US, 249,522 OOD were reported, with the annual number nearly doubling from 28,723 to 50,179. OOD involving illicitly manufactured fentanyls (IMF) also increased substantially during this period, from 19.4% to 72.9%. In addition, 3,817,438 forensic laboratory reports in the US that were reported to NFLIS-Drug contained an opioid, stimulant, or benzodiazepine. Reports of fentanyl and fentanyl-related compounds (FFRC) had the strongest association with OOD. Each additional FFRC exhibit was associated with a 2.97% (95% CI: 1.7%, 4.1%) increase in OOD per 100,000 persons per quarter. Interpretation: Adding to the emerging consensus, protracted growth in IMF supply was more strongly associated with OOD than all other illicit drugs reported to NFLIS-Drug over the study time period. Findings demonstrate NFLIS-Drug data usefulness for research that require proxy indicators for the illicit drugs supply. A concerted effort between public health and public safety to make NFLIS-Drug more timely could strengthen its utility as a national, public health, drug surveillance system. Funding: Sangeetha Arctic Slope Mission Services, LLC, ASMS Contract No. ASM5-00017.

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Objective: Between 2012 and 2017, the U.S. Food and Drug Administration (FDA) approved 10 antidiabetic indicated therapies. Due to the limited literature on voluntarily reported safety outcomes for recently approved antidiabetic drugs, this study investigated adverse drug reactions (ADRs) reported in the FDA Adverse Event Reporting System (FAERS). Research Design and Methods: A disproportionality analysis of spontaneously reported ADRs was conducted. FAERS reports from January 1, 2012 to March 31, 2022 were compiled, allowing a 5-year buffer following drug approval in 2017. Reporting odds ratios were calculated for the top 10 ADRs, comparing new diabetic agents to the other approved drugs in their therapeutic class. Results: 127,525 reports were identified for newly approved antidiabetic medications listed as the primary suspect (PS). For sodium-glucose co-transporter-2 (SGLT-2) inhibitors, the odds of blood glucose increased, nausea, and dizziness being reported was greater for empagliflozin. Dapagliflozin was associated with greater reports of weight decreased. Canagliflozin was found to have a disproportionally higher number of reports for diabetic ketoacidosis, toe amputation, acute kidney injury, fungal infections, and osteomyelitis. Assessing glucagon-like peptide-1 (GLP-1) receptor agonists, dulaglutide and semaglutide were associated with greater reports of gastrointestinal adverse drug reactions. Exenatide was disproportionally associated with injection site reactions and pancreatic carcinoma reports. Conclusion: Pharmacovigilance studies utilizing a large publicly available dataset allow an essential opportunity to evaluate the safety profile of antidiabetic drugs utilized in clinical practice. Additional research is needed to evaluate these reported safety concerns for recently approved antidiabetic medications to determine causality.

Adverse drug reactions reported for antidiabetic medications Introduction: This study investigated the trends in voluntary reporting of adverse drug reactions for recently approved antidiabetic medications. Methods: Data from the FDA Adverse Events Reporting System were evaluated. The top 10 adverse drug reactions were compared between antidiabetic medications in the same therapeutic class. Results: We identified 127,525 adverse drug reaction reports for the newer approved antidiabetic medications. For SGLT-2 inhibitors, empagliflozin was associated with greater reports of blood glucose increase, nausea, and dizziness; weight decreased was reported more often for dapagliflozin; and diabetic ketoacidosis, toe amputation, acute kidney injury, fungal infections, and osteomyelitis were reported more commonly for canagliflozin. Assessing GLP-1 receptor agonists, the odds of gastrointestinal adverse drug reactions being reported was greater for dulaglutide and semaglutide. Exenatide was disproportionally associated with injection site reactions and pancreatic carcinoma reports. Conclusion: Medication safety studies using a large publicly available dataset allows an essential opportunity to evaluate the safety profile of antidiabetic drugs in the real-world setting. Additional research is needed to determine if the reported safety concerns for recently approved antidiabetic medications to determine causality.

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BACKGROUND: Abacavir/dolutegravir/lamivudine has been indicated in Korea since 2015 for treatment of human immunodeficiency virus type 1 (HIV-1) infection in combination. This regulatory post-marketing surveillance (PMS) study evaluated the real-life safety and effectiveness of abacavir/dolutegravir/lamivudine in patients with HIV-1 in clinical practice in Korea. MATERIALS AND METHODS: This open-label post-marketing surveillance examined data from consecutive patients (aged ≥12 years) with HIV-1 infection receiving abacavir/dolutegravir/lamivudine according to locally approved prescribing information; treatment-naïve and treatment-experienced patients were permitted. Data regarding patient demographics, medical history, clinical characteristics, medications (HIV-1 related and concomitant), resource utilization and comorbidities were extracted from patient records over a 1-year treatment period. Outcomes included safety of abacavir/dolutegravir/lamivudine (primary endpoint) and real-life effectiveness according to physician's global assessment and the proportion of patients with plasma HIV-1 RNA count <50 copies/mL at 48 weeks. RESULTS: Of 663 patients treated with abacavir/dolutegravir/lamivudine at 27 centers in Korea (June 2015 - June 2021), 656 were eligible for the safety analyses and 484 for effectiveness analyses. Patients were mostly male (94.8%) mean age was 42.2 ± 14.0 years and mean weight was 68.1 ± 11.0 kg. Adverse events (AEs, n = 656 in total) were mostly mild in severity, with the most common being nasopharyngitis (7.9%), retching (7.5%), headache (4.9%). Of 121 adverse drug reactions (ADRs), the most frequent were retching (4.4%), headache (1.8%) and dizziness (1.7%). Of 55 serious AEs, the most frequent were anogenital warts (1.1%). Of 2 serious ADRs, nothing was unexpected, and both resolved. The risk of experiencing an AE while receiving abacavir/dolutegravir/lamivudine appeared to be especially increased in patients receiving concomitant medications for other conditions. Abacavir/dolutegravir/lamivudine effectively suppressed HIV-1 (96.1% of patients had plasma HIV-1 RNA <50 copies/mL), and 99.0% of patients showed symptom improvement based on physician assessment. CONCLUSION: Results of this PMS study showed that abacavir/dolutegravir/lamivudine administered as highly active antiretroviral therapy was well tolerated and effective in patients with HIV-1 infection.

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The National Forensic Laboratory Information System (NFLIS) is a drug surveillance program of the US Drug Enforcement Administration that systematically collects data on drugs that are seized by law enforcement and submitted to and analyzed by the Nation's forensic laboratories (NFLIS-Drug). NFLIS-Drug data are increasingly used in predictive modeling and drug surveillance to examine drug availability patterns. Given the complexity of the data and data collection, there are some common methodological pitfalls that we highlight with the aim of helping researchers avoid these concerns. The analysis done for this Technical Note is based on a review of the scientific literature that includes 428 unique, refereed article citations in 182 distinct journals published between January 1, 2005, and April 30, 2021. Each article was analyzed according to how NFLIS-Drug data were mentioned and whether NFLIS-Drug data were included. A sample of 37 articles was studied in-depth, and data issues were summarized. Using examples from the literature, this Technical Note highlights eight broad concerns that have important implications for the proper applications, interpretations, and limitations of NFLIS-Drug data with suggestions for improving research methods and accurate reporting of forensic drug data. NFLIS-Drug data are timely and provide key information to inform drug use trends across the United States; however, our present analysis shows that NFLIS-Drug data are misunderstood and represented in the literature. In addition to highlighting these issues, DEA has created several resources to assist NFLIS data users and researchers, which are summarized in the discussion.

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Introducción: las reacciones adversas a los medicamentos se relacionan con la seguridad de los productos farmacéuticos. En Cuba, en el año 2018 se realizó la reformulación de heparina, como parte de la mejora continua de calidad, es objetivo realizar la vigilancia de este medicamento en la práctica clínica habitual para evaluar su perfil de seguridad, a partir de notificaciones espontaneas desde junio, 2018 hasta diciembre 2021. Método: se realizó un estudio observacional, descriptivo y transversal de serie de casos. El universo, estuvo compuesto por notificaciones del producto que aparecen en la base de datos nacional. Se agruparon y analizaron en variables como: tipo de reacción, sistemas de órganos afectados, antecedentes patológicos, grupo etario, y sexo del paciente. Se clasificaron en severidad, causalidad y frecuencia. Se realizó un análisis estadístico descriptivo de las variables recogidas. Resultados: se notificaron 31 reacciones adversas, entre las que sobresalieron: sangramiento, hematomas, eritema, habones, rash, rubefacción, temblor, urticaria, e irritación en la zona de inyección. El sistema de órganos más afectado fue la piel (51,61%). Los antecedentes patológicos, el grupo geriátrico (60-86 años) y el sexo femenino condicionaron la aparición de dichas reacciones. Los mayores porcientos respondieron a las reacciones clasificadas como moderadas, probables y frecuentes. La estadística descriptiva permitió la organización en tablas y gráficos. Conclusiones: el estudio permitió conocer el perfil de seguridad de este producto de recién incorporación al mercado nacional. (AU)

Introduction: adverse drug reactions relate to the safety of pharmaceuticals. In Cuba, in 2018 the reformulation of heparin was carried out, as part of the continuous improvement of quality, it is objective to carry out the surveillance of this drug in the usual clinical practice to evaluate its safety profile, from spontaneous notifications from June, 2018 to December 2021. Method: an observational, descriptive and cross-sectional case series study was conducted. The universe was composed of product notifications that appear in the national database. They were grouped and analyzed in variables such as: type of reaction, affected organ systems, pathological history, group, age and sex of the patient. They were classified into severity, causality and frequency. A descriptive statistical analysis of the collected variables was performed. Results: 31 adverse reactions were reported, among which stood out: bleeding, bruising, erythema, hives, rash, flushing, tremor, urticaria, and irritation at the injection site. The most affected organ system was the skin (51.61%). The pathological history, the geriatric group (60-86 years) and the female sex conditioned the appearance of these reactions. The largest percentages responded to reactions classified as moderate, probable, and frequent. Descriptive statistics allowed the organization into tables and graphs. Conclusions: the study allowed to know the safety profile of this product of recent incorporation to the national market. (AU)

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BACKGRUOUND: The efficacy and safety of denosumab have been established in a phase 3, randomized, placebo-controlled trial in Korean postmenopausal women with osteoporosis. This postmarketing surveillance study was aimed to investigate the safety and effectiveness of denosumab in Korean real-world clinical practice. METHODS: Patients with osteoporosis who had received denosumab per the Korean approved indications in the postmarketing setting between September 2014 and September 2019 were enrolled. The primary endpoint was the incidence of adverse events (AEs) and adverse drug reactions (ADRs). The secondary endpoint was the percent change from baseline in bone mineral density (BMD) of the lumbar spine, total hip, and femoral neck. RESULTS: Of the 3,221 patients enrolled, 3,185 were included in the safety analysis set; 2,973 (93.3%) were female, and the mean± standard deviation (SD) age was 68.9±9.9 years. The mean±SD study period was 350.0±71.4 days. AEs, fatal AEs, and ADRs occurred in 19.3%, 0.8%, and 1.6%, respectively. The most frequent AEs, occurring in >0.5% of patients, were dizziness (0.7%), arthralgia (0.7%), back pain (0.6%), and myalgia (0.6%). Hypocalcemia occurred in 0.3% of patients. There were no cases of osteonecrosis of the jaw and atypical femoral fracture. Mean±SD percent change from baseline in BMD of the lumbar spine, total hip, and femoral neck was 7.3%±23.6%, 3.6%±31.4%, and 3.2%±10.7%, respectively. CONCLUSION: The safety and effectiveness of denosumab in Korean patients with osteoporosis in this study were comparable with those in the Korean randomized controlled trial, with no new safety findings.

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BACKGROUND: Sharp exacerbations of the US overdose crisis are linked to polysubstance use of synthetic compounds. Xylazine is a veterinary tranquilizer, long noted in the street opioid supply of Puerto Rico, and more recently Philadelphia. Yet its national trends, geographic distribution, and health risks are poorly characterized. METHODS: In this sequential mixed-methods study, xylazine was increasingly observed by ethnographers in Philadelphia among drug-sellers and people who inject drugs (PWID). Subsequently, we systematically searched for records describing xylazine-present overdose mortality across the US and assessed time trends and overlap with other drugs. RESULTS: In 10 jurisdictions - representing all four US Census Regions - xylazine was increasingly present in overdose deaths, rising from 0.36% of deaths in 015m 6.7% in 2020. The highest xylazine prevalence data was observed in Philadelphia, (25.8% of deaths), followed by Maryland (19.3%) and Connecticut (10.2%). Illicitly-manufactured-fentanyls were present in 98.4% of xylazine-present-overdose-deaths - suggesting a strong ecological link - as well as cocaine (45.4%), benzodiazepines (28.4%), heroin (23.3%), and alcohol (19.7%). PWID in Philadelphia described xylazine as a sought-after adulterant that lengthens the short duration of fentanyl injections. They also linked it to increased risk of soft tissue infection and naloxone-resistant overdose. CONCLUSIONS: Xylazine is increasingly present in overdose deaths, linked to the proliferation of illicitly-manufactured-fentanyls. Ethnographic accounts associate it with profound risks for PWID. Nevertheless, many jurisdictions do not routinely test for xylazine, and it is not comprehensively tracked nationally. Further efforts are needed to provide PWID with services that can help minimize additional risks associated with a shifting drug supply.

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INTRODUCTION: The use of new psychoactive substances (NPSs) has markedly increased worldwide; thus, it is important to monitor NPS-related effects. The Taiwan Emergency Department Drug Abuse Surveillance (TEDAS) project aims to assess the patterns of recreational drug use in patients presenting to emergency departments (EDs) across the country. Here, we report the preliminary results of this project. METHODS: This observational study included the collection and analysis of urine samples and assessment of the clinical presentation of patients from 79 EDs across Taiwan. Clinical features were recorded through a questionnaire filled by attending doctors or nurses who collected urine samples for clinical diagnosis. Urine samples were analyzed for 110 drugs and metabolites using electrospray ionization liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: Between February and November 2019, a total of 2649 patients were enrolled for urine drug analysis. A total of 675 cases older than 12 years (males, n = 480) had NPS or other illicit drugs detected in their urine samples. Overall, 1271 counts of drugs, among which 717 (56.4%) were NPS. At least one NPS was detected in 340 patients (50.4%), and 292 cases were positive for multiple drugs. The most frequently detected drug was methamphetamine/amphetamine, followed by synthetic cathinones, ketamine and its two analogs, and opioids. The most common drug combination was cathinones plus ketamine and/or its analogs (n = 56). Younger patients (OR = 3.3, p≤.0001) and women (OR = 1.5, p = .01) were more likely to have NPS detected in their urine samples. NPS-positive cases frequently experienced chest pain (OR = 2.6, p = .03), tachycardia (OR = 2.6, p = .0002), and suicide attempt/non-suicidal self-harm (OR = 1.8, p = .004), whereas depressed consciousness (OR = 0.5, p = .001) was less frequent among NPS-positive cases than among other illicit drug-positive cases. CONCLUSIONS: The TEDAS project provides a nationwide epidemiological profile of recreational drug use in Taiwan. More than half of the recreational drugs were NPSs, which were comprehensively detected using LC-MS/MS.

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OBJECTIVES: Successful treatment of delirium depends on the detection of the reversible contributors. Drugs with delirogenic properties are the most prevalent reversible cause of delirium. METHODS: This observational study is based on data from Arzneimittelsicherheit in der Psychiatrie, a multicenter drug surveillance program in German-speaking countries recording severe adverse drug reactions (ADRs) in psychiatric inpatients. The present study analyzes drug-induced delirium (DID) during treatment with antidepressants and antipsychotics. RESULTS: A total of 436 565 psychiatric inpatients were treated with antidepressants and/or antipsychotics during the observation period from 1993 to 2016 in the participating 110 hospitals. Overall, 254 cases (0.06% of all patients treated with antidepressants and/or antipsychotics) of DID were detected. Implicated either in combination or alone (multiple drugs were implicated in 70.1% of DID), clomipramine (0.24%), amitriptyline (0.21%), and clozapine (0.18%) showed the highest incidence rates of DID. When implicated alone (98 cases overall), clozapine (0.11%) followed by amitriptyline (0.05%) were most likely causally associated with the occurrence of DID. Drugs with strong antimuscarinic properties generally exhibited higher risk of DID. CONCLUSIONS: With an incidence rate of <0.1%, the use of antidepressants and antipsychotics was rarely associated with DID within the Arzneimittelsicherheit in der Psychiatrie program. Tricyclic antidepressants and clozapine were the most commonly implicated psychotropic drugs. These data support the specific role of antimuscarinic properties in DID.

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BACKGROUND: The integrase strand transfer inhibitor dolutegravir has been indicated in Korea since 2014 for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in combination with other antiretroviral agents. This regulatory post-marketing surveillance (PMS) study evaluated the real-life safety and effectiveness of dolutegravir in patients with HIV-1 in clinical practice in Korea. MATERIALS AND METHODS: This open-label PMS study examined data from consecutive patients (aged ≥12 years) with HIV-1 infection receiving dolutegravir according to locally approved prescribing information; treatment-naïve and treatment-experienced patients were permitted. Data regarding patient demographics, medical history, clinical characteristics, medications (HIV-related and concomitant), and comorbidities were extracted from patient records over a 1-year treatment period. Outcomes included the safety of dolutegravir (primary endpoint) and real-life effectiveness according to the Physician Global Assessment (PGA) and the proportion of patients with plasma HIV-1 RNA count <50 copies/mL at 48 weeks. RESULTS: Of 147 patients treated with dolutegravir at 18 centers in Korea (August 2014 - August 2020), 139 were eligible for the safety analyses and 75 for effectiveness analyses. Patients (mean age 47 years) were mostly male (92.8%) and received dolutegravir in combination with nucleoside reverse transcriptase inhibitor (70.5%) or protease inhibitors (21.6%). Adverse events (AEs) (n = 179 in total) were mostly mild in severity, with the most common being nasopharyngitis (5.0%), dyspepsia (5.0%), pruritus (4.3%), and rash (4.3%). Of 16 adverse drug reactions (ADRs), the most frequent were rash, diarrhea, headache, insomnia, and somnolence (1.4% each). Of 2 serious ADRs, only 1 (gastroenteritis) was unexpected, and both resolved. The risk of experiencing an AE while receiving dolutegravir appeared to be especially increased in patients receiving concomitant medications for other conditions. Dolutegravir effectively suppressed HIV-1 (93.3% of patients had plasma HIV-1 RNA <50 copies/mL), and 100% of patients showed symptom improvement based on physician global assessment. CONCLUSION: Results of this PMS study showed that dolutegravir administered as highly active antiretroviral therapy was well tolerated and effective in patients with HIV-1 infection.

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INTRODUCTION: Most hospital urine toxicology screens detect a fixed, limited set of common substances. These tests are fast and accurate but may miss emerging trends in substance use in the community and clinical acumen alone is insufficient for identifying new substances. METHODS: This prospective cohort study examined de-identified urine specimens obtained from patients visiting the Emergency Department (ED) at Prince George's Hospital Center (PGHC), between October 15, 2019 to November 6, 2019 and tested positive for one or more substances. The Emergency Department Drug Surveillance System (EDDS) collects quarterly exports from de-identified electronic health records (EHRs) containing urinalysis results for drug related ED visits. We performed a feasibility study of a new urine specimen submission by collecting a stratified sample of 151 urine specimens from PGHC ED patients. The specimens were tested for 240 drugs using liquid chromatography-tandem mass spectrometry (LC-MS/MS). This paper presents a comparison between the PGHC and expanded testing results. RESULTS: The expanded urinalysis panel found more cocaine (37% vs. 20%; p < 0.01) and benzodiazepine positives (21% vs. 11%; p < 0.05) than would have been detected by the hospital screen. Additionally, the expanded toxicology panel identified fentanyl in 4-14% of the samples. CONCLUSION: The EHR data submitted to EDDS from the hospital urine toxicology screen correctly identified hospital substance use patterns over the approximate 1 month study period. The expanded testing also uncovered drugs that the hospital might consider adding to their routine screen. EDDS is a feasible system for monitoring and confirming recent substance use trends among ED patients.

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Resumo A fiscalização sanitária busca proteger a saúde da população impedindo que medicamentos fora do padrão, falsificados ou não registrados sejam consumidos e causem danos à saúde. Este ensaio objetiva contribuir para o debate acerca da fiscalização sanitária de medicamentos, num contexto de exposição contínua dos indivíduos a riscos que interferem no processo saúde-doença. Baseado nas reflexões sobre o risco sanitário e a sociedade de risco, associado à filosofia da vida de Canguilhem e à ergologia de Schwartz, discorre sobre a necessidade de se compreender a atividade humana e o trabalho para agir sobre o risco. Foram identificados possíveis desafios para a ação da fiscalização sanitária: (1) revisão conceitual; (2) atualização normativa; (3) desenvolvimento de mecanismos e ferramentas regulatórias; e (4) ampliação da capacidade técnica - formativa. Para enfrentá-los, considera-se um caminho promissor o envolvimento e a participação dos diversos atores nos espaços de cooperação e colaboração, bem como a construção de fórum permanente de debates ou de câmeras técnicas/setoriais. Estudos que dão visibilidade ao trabalho concreto das equipes de fiscalização sanitária e que analisam a atividade humana na relação entre o prescrito e o real podem ajudar a compreender a experiência de lidar com o risco, a adequação das normas, as necessidades de formação, entre outros.

Abstract Drug health surveillance protects the health of the population by preventing substandard, falsified, or unregistered drugs from being consumed and causing harm. This essay discusses drug health surveillance in a context of continuous exposure of individuals to risks that directly interfere with the health-disease process. Based on reflections about health risk and risk society, associated with Canguilhem's philosophy of life and Schwartz's ergology, it argues for the need to understand human activity and work to act on risk. Possible challenges for health inspection action include: (1) conceptual review; (2) regulatory updating; (3) development of regulatory mechanisms and tools; and (4) expansion of technical and training capacity. To face them, the involvement and participation of the various actors in cooperation and collaboration spaces, as well as the construction of a permanent forum of discussion or technical/sectorial meetings, is considered promising. Studies that highlight the concrete work of supervision teams and that analyze human activity in the relationship between the prescribed and the real can help to understand the experience of dealing with risk, the adequacy of standards, training needs, among others.

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BACKGROUND: NIDA's National Drug Early Warning System (NDEWS) was established in 2014 with the mission of identifying and monitoring emerging drugs in the United States. Identification of emerging drugs has been complicated, however, by the rapid development of novel psychoactive substances such that users often cannot identify and report the drugs they have ingested. Biologic testing of urine, hair or blood is the only way to reliably identify the substances recently used. Unfortunately, the large number of up-to-date tests required is beyond the resources available to most organizations. METHODS: The DOTS study tested the feasibility of recruiting organizations to submit up to 25 de-identified urine specimens for testing for approximately 240 drugs, at no cost to them. The results were for epidemiologic purposes only and not for clinical use. Eleven sites who had questions about their patients or the results of their organization's more limited urinalysis screens participated. These sites included drug treatment programs, medical examiners, hospitals and a criminal justice testing program. RESULTS: Extensive polydrug use and geographic differences in the drugs detected were found. All sites found the DOTS collaborating laboratory's test results to be very useful for understanding the types of drugs being used recently and to assess the adequacy of their testing protocols. CONCLUSIONS: The U.S. should consider establishing a program of expanded testing of already collected de-identified urine specimens in order to identify emerging drugs and track local patterns of use and availability.

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