A real-world disproportionality analysis of cyclosporine from the FDA Adverse Event Reporting System (FAERS) database.

Cyclosporine is an immunosuppressant used to prevent organ rejection in kidney, liver, and heart allogeneic transplants. This study aimed to assess the safety of cyclosporine through the analysis of adverse events (AEs) related to cyclosporine in the US Food and Drug Administration Adverse Event Reporting System (FAERS). To detect AEs associated with cyclosporine, a pharmacovigilance analysis was conducted using four algorithms on the FAERS database: reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and empirical Bayes geometric mean (EBGM). A statistical analysis was performed on data extracted from the FAERS database, covering 19,582 case reports spanning from 2013 to 2022. Among these cases, 3,911 AEs were identified, with 476 linked to cyclosporine as the primary suspected drug. Cyclosporin-induced AEs targeted 27 System Organ Classes (SOCs). Notably, the highest case at the SOC level included eye disorders, injury, poisoning, and procedural complications, as well as immune system disorders, all of which are listed on the cyclosporine label. Furthermore, we discovered novel potential AEs associated with hepatobiliary disorders, among others. Moreover, unexpected adverse drug reactions (ADRs), such as biliary anastomosis complication and spermatozoa progressive motility decrease, were identified. Importantly, these newly identified ADRs were not mentioned on the cyclosporine label, which were involved in injury, poisoning, and procedural complications, and investigations at the SOC level. The study used pharmacovigilance analysis of FAERS database to identify new and unexpected potential ADRs relating to cyclosporine, which can provide safety tips for the safe use of cyclosporine.

Consumption of antimicrobials during the period of the COVID-19 pandemic in specific macro-regions of Brazil / Consumo de antimicrobianos durante o período de pandemia de COVID-19 em macrorregiões específicas do Brasil / Consumo de antimicrobianos durante el período de la pandemia de COVID-19 en macrorregiones específicas de Brasil

Background and Objectives: The main objective was to analyze the consumption of antimicrobials (ATMs) subjected to prescription retention, and with indication for the treatment of respiratory infections in Brazil, from 2014 to 2021. Methods: This is an ecological study of mixed design. Secondary data was obtained from the National System for the Management of Controlled Products (SNGPC). Data was presented following the equation: number of total consumption of ATMs for each macro-region of Brazil by year or trimester / number of residents for each macro-region per year *1.000 inhabitants. Annual data was analyzed by Prais-Winsten, and quarterly data was analyzed by automatic forward stepwise regression. Results: The Southern region showed the highest mean rates of consumption when compared to the other macro-regions. For annual analysis, the proportion of stability, increase and decrease of consumption of ATMs was similar among macro-regions. The quarterly period registered an increase in the consumption of Amoxicillin, Amoxicillin+Clavulanate, Azithromycin and Cephalexin altogether, in the Southern, Southeastern and Northern regions. Conclusion: Our data reveals an increased consumption of some ATMs during the pandemic period in specific macro-regions of Brazil. The five macro regions have shown different patterns of ATMs consumption.(AU)

Justificativa e Objetivos: O objetivo principal foi analisar o consumo de antimicrobianos (ATMs) sujeito a retenção de receita e com indicações para tratamento de infecções respiratórias no Brasil de 2014 até 2021. Métodos: Trata-se de um estudo ecológico de desenho misto. Dados secundários foram obtidos do Sistema Nacional de Gerenciamento de Produtos Controlados (SNGPC). Dados foram apresentados conforme a seguinte equação: número total de consumo de ATMs por cada macrorregião do Brasil por ano ou trimestre/ número de residentes por cada macrorregião do Brasil por ano *1.000 habitantes. Dados anuais foram por Prais-Winsten, e dados trimestrais por regressão automática passo-a-passo. Resultados: Região Sul apresentou maiores taxas médias de consumo em comparação às demais macrorregiões. Para análise anual, a proporção de estabilidade, aumento e diminuição dos ATMs foi similar entre as macrorregiões. O trimestre registrou aumento no consumo de Amoxicilina, Amoxicilina+Clavulanato, Azitromicina e Cefalexina, juntas, nas regiões Sul, Sudeste e Norte. Conclusão: Nossos dados revelam um aumento no consumo de alguns ATMs durante o período de pandemia em macrorregiões específicas do Brasil, as cinco macrorregiões apresentaram padrões diferentes de consumo de ATMs.(AU)

Justificación y Objetivos: El objetivo principal fue analizar el consumo de antimicrobianos (ATMs) sujetos a retención de ingresos con indicaciones para el tratamiento de infecciones respiratorias en Brasil de 2014 a 2021. Métodos: Se trata de un estudio ecológico de diseño mixto. Datos secundarios obtenidos del Sistema Nacional de Gestión de Productos Controlados (SNGPC). Los datos fueron presentados siguiendo la ecuación: número de consumo total de cajeros automáticos para cada macro región de Brasil por año o trimestre / número de residentes para cada macro región por año *1.000 habitantes. Los datos anuales fueron analizados por Prais-Winsten, y trimestralmente analizados por regresión paso a paso automática hacia adelante. Resultados: La región Sur mostró las mayores tasas medias de consumo en comparación con las demás macrorregiones. Para el análisis anual, la proporción de estabilidad, aumento y disminución de ATMs fue similar entre las macrorregiones. En el trimestre se registró aumento en el consumo de Amoxicilina, Amoxicilina+Clavulanato, Azitromicina y Cefalexina, en conjunto, en las regiones Sur, Sudeste y Norte. Conclusión: Nuestros datos revelan un mayor consumo de algunos ATMs durante el período de la pandemia en macro regiones específicas de Brasil, las cinco macro regiones han mostrado diferentes patrones de consumo de ATMs.(AU)

Educational interventions in pharmacovigilance to improve the knowledge, attitude and the report of adverse drug reactions in healthcare professionals: Systematic Review and Meta-analysis.

OBJECTIVES: Underreporting of adverse drug reactions (ADRs) limits and delays the detection of signs. The aim of this systematic review with meta-analyses was to synthesize the evidence of educational interventions (EIs) efficacy in health professionals to increase ADR reporting, attitudes, and knowledge of pharmacovigilance. EVIDENCE ACQUISITION: A systematic literature review was carried out to identify randomized clinical trials evaluating the efficacy of EI in pharmacovigilance in health professionals to improve ADR reports, knowledge, and attitude toward pharmacovigilance. ADR reports were pooled by calculating Odds Ratio (OR) with a 95% confidence interval (95%CI), while pharmacovigilance knowledge and attitude were pooled by calculating a mean difference (MD) with 95%CI. In addition, the subanalysis was performed by EI type. Meta-analysis was performed with RevMan 5.4 software. PROSPERO registry CRD42021254270. RESULTS: Eight hundred seventy-five articles were identified as potentially relevant, and 11 were included in the systematic review. Metanalysis showed that EI increased ADR reporting in comparison with control group (OR = 4.74, [95%CI, 2.46 to 9.12], I2 = 93%, 5 studies). In subgroup analysis, the workshops (OR = 6.26, [95%CI, 4.03 to 9.73], I2 = 57%, 3 studies) increased ADR reporting more than telephone-based interventions (OR = 2.59, [95%CI, 0.77 to 8.73], I2 = 29%, 2 studies) or combined interventions (OR = 5.14, [95%CI, 0.97 to 27.26], I2 = 93%, 3 studies). No difference was observed in pharmacovigilance knowledge. However, the subanalysis revealed that workshops increase pharmacovigilance knowledge (SMD = 1.85 [95%CI, 1.44 to 2.27], 1 study). Only one study evaluated ADR reporting attitude among participants and showed a positive effect after the intervention. CONCLUSION: EI improves ADR reports and increases pharmacovigilance knowledge. Workshops are the most effective EI to increase ADR reporting.

Atención farmacéutica en pacientes con inmunodeficiencia adquirida y/o tuberculosis en el área ambulatoria de un hospital pediátrico / Pharmacovigilance in patients with acquired immunodeficiency and/or tuberculosis in the outpatient area of a pediatric hospital

La Atención farmacéutica (AF) ayuda a los pacientes a alcanzar objetivos terapéuticos reduciendo los problemas relacionados al medicamento (PRM). Objetivos: analizar los PRM en la práctica de la AF a pacientes con inmunodeficiencia adquirida (IDA) y/o tuberculosis (TBC) y evaluar su impacto. Método: estudio, descriptivo, observacional, en el área ambulatoria de Farmacia. Se incluyeron pacientes con IDA y/o TBC con: inicio de tratamiento, polifarmacia, reinternaciones frecuentes, regular/mala adherencia, reacciones adversas a medicamentos (RAM) previas y/o comorbilidades. Se entrevistaron pacientes o cuidadores y se registraron PRM, errores, grados de adherencia y conocimiento farmacoterapéutico, retiro oportuno de medicamentos y parámetros clínicos. Se registró la intervención farmacéutica y entregó material educativo. Se repitieron las mediciones en una segunda entrevista. Resultados: Se estudiaron 54 pacientes (28 con IDA y 26 con TBC). Se realizaron 93 intervenciones (29.9% dirigidas al prescriptor, 27.8% a otros profesionales) y se detectaron 8 RAM y 53 errores (28 IDA y 25 TBC), el principal PRM fue la mala/regular adherencia con bajo porcentaje de conocimiento farmacoterapéutico completo. Después de la AF, en IDA el grado de adherencia tuvo una mejora estadísticamente significativa (p= 0.012), también fue significativa la mejora en el retiro oportuno de la medicación (28.6% a 71.4% p=0.005 IDA). Se obtuvieron resultados favorables de carga viral (CV) en 72% pacientes con IDA y aumento de peso en 92% pacientes con TBC, aunque no fueron estadísticamente significativos. Conclusiones: mediante AF se mejoró la adherencia y la comunicación en pacientes pediátricos con IDA y/o TBC (AU)

Pharmacovigilance (PV) helps patients achieve therapeutic goals by reducing drug-related problems (DRP). Objectives: to analyze DRPs in the practice of PV in patients with acquired immunodeficiency (AIDS) and/or tuberculosis (TB) and to evaluate its impact. Methods: A descriptive, observational study was conducted in the outpatient pharmacy area. Patients with AIDS and/or TB with: treatment initiation, polypharmacy, frequent readmissions, regular/poor adherence, previous adverse drug reactions (ADR) and/or comorbidities were included. Patients or caregivers were interviewed, and DRP, errors, adherence and pharmacotherapeutic knowledge, timely drug withdrawal, and clinical parameters were recorded. The pharmaceutical intervention was recorded and educational material was delivered. Measurements were repeated in a second interview. Results: We studied 54 patients (28 with AIDS and 26 with TB). Ninety-three interventions were performed (29.9% addressed to the drug prescriber, 27.8% to other professionals) and 8 ADRs and 53 errors were detected (28 AIDS and 25 TB). The main DRP was poor/regular adherence together with a low level of complete pharmacotherapeutic knowledge. After PV, in patients with AIDS the degree of adherence statistically significantly improved (p= 0.012). The improvement in timely medication withdrawal was also significant (28.6% vs. 71.4% p=0.005 AID). Favorable viral load results were obtained in 72% of patients with AIDS and weight gain in 92% of patients with TB, although they were not statistically significant. Conclusions: PV improved adherence and communication in pediatric patients with AIDS and/or TB (AU)

Prescripción de fármacos cardiotóxicos en pacientes con enfermedades cardiovasculares / Prescription of cardiotoxic drugs in patients with cardiovascular diseases

Introducción: El uso de fármacos con potencial cardiotóxico para tratar enfermedades no cardiovasculares coexistentes resulta un agravante evitable. Objetivo: Evaluar la prescripción de 5 fármacos cardiotóxicos en pacientes con enfermedades cardiovasculares. Métodos: Se realizó un estudio descriptivo transversal (enmarcado en los estudios de utilización de medicamentos) de marzo a diciembre de 2020 en el Policlínico Santa Cruz (Artemisa, Cuba), en una población de 234 sujetos con enfermedades cardiovasculares que habían sido tratados con domperidona, azitromicina, ciprofloxacina, ibuprofeno y diclofenaco. Las variables estudiadas fueron: sexo, edad, consumo de fármacos cardiotóxicos, motivo de indicación, enfermedades cardiovasculares, forma farmacéutica, dosis diaria, intervalo de las dosis y duración del tratamiento. Se realizó un análisis estadístico descriptivo. Resultados: Los fármacos más prescritos fueron la azitromicina (n= 63), el ibuprofeno (n= 59) y la ciprofloxacina (n= 57). Sus principales motivos de indicación fueron, respectivamente, la neumonía adquirida en la comunidad (38,1 por ciento), las infecciones de piel y tejidos blandos (28,8 por ciento), y las infecciones del tracto urinario (43,8 por ciento). La principal enfermedad cardiovascular fue la hipertensión arterial. Para los 5 fármacos seleccionados se reportó su esquema terapéutico (forma farmacéutica, dosis diaria, intervalo de dosis y duración del tratamiento). Conclusiones: Aunque en todos los casos el motivo de indicación es el adecuado, los fármacos pueden sustituirse por otros de menor riesgo cardiovascular. En su mayoría, los esquemas terapéuticos son correctos, salvo en los casos de la domperidona (duración prolongada) y el diclofenaco (altas dosis)(AU)

Introduction: The use of drugs with cardiotoxic potential to treat coexisting noncardiovascular diseases results in avoidable aggravation. Objective: To assess the prescription of 5 cardiotoxic drugs in patients with cardiovascular disease. Methods: A cross-sectional descriptive study (framed in the studies of drug utilization) was carried out from March to December 2020 in the Policlínico Santa Cruz (Artemisa, Cuba), in a population of 234 subjects with cardiovascular diseases who had been treated with domperidone, azithromycin, ciprofloxacin, ibuprofen and diclofenac. The variables studied were: sex, age, consumption of cardiotoxic drugs, reason for indication, cardiovascular disease, pharmaceutical form, daily dose, dose interval, and duration of treatment. Descriptive statistical analysis was performed. Results: The most prescribed drugs were azithromycin (n= 63), ibuprofen (n= 59) and ciprofloxacin (n= 57). Their main reasons for indication were, respectively, community-acquired pneumonia (38.1 percent), skin and soft tissue infections (28.8 percent), and urinary tract infections (43.8 percent). The main cardiovascular disease was arterial hypertension. For the 5 selected drugs, their therapeutic scheme (pharmaceutical form, daily dose, dose interval and duration of treatment) was reported. Conclusions: Although in all cases the reason for indication was adequate, the drugs can be substituted by others of lower cardiovascular risk. For the most part, the therapeutic regimens are correct, except in the cases of domperidone (prolonged duration) and diclofenac (high doses)(AU)

Strengthening the Pharmacovigilance System in Mexico: Implementation of VigiFlow and VigiLyze, as ICSR and Signal Detection Management Systems.

Pharmacovigilance (PV) activities aim to identify potential risks of medicines and vaccines after they have been authorised in the market by collecting and analysing information on suspected adverse events from different stakeholders. These can be captured and transmitted electronically in the form of Individual Case Safety Reports (ICSRs). Hence, up-to-date ICSRs management systems, like VigiFlow and signal detection and management systems as VigiLyze, have an important role in the PV system of a country. In 2019, after various attempts to establish a PV database that could fulfil the needs of the country, Mexico's National Regulatory Authority, COFEPRIS (Federal Commission for the Prevention against Sanitary Risks) decided to implement these tools. This has been a successful project that is still ongoing, it has involved national and international organisations, and has required the participation and integration of different components of the national PV system. The implementation of these tools has allowed COFEPRIS to increase its reporting trends and quality of reporting, while contributing to make more efficient interactions and processes with PV stakeholders, even during the COVID-19 pandemic. It has also allowed them to strengthen their commitment to the WHO-Programme for International Drug Monitoring, while highlighting opportunities for improvement in the national PV scenario and in the PV tools themselves. The aim of this article is to describe the implementation process, give an overview of current results regarding ICSR data and processes, and highlight the achievements, challenges, and opportunities for improvement after the three years since the beginning of the project.

Temporal profile of adverse drug reactions and associated clinical factors: a prospective observational study in a neonatal intensive care unit.

OBJECTIVE: Although adverse drug reactions (ADRs) are quite common in hospitalised neonates, pharmacovigilance activities in this public are still incipient. This study aims to characterise ADRs in neonates in a neonatal intensive care unit (NICU), identifying causative drugs, temporal profile and associated factors. DESIGN: Prospective observational study. SETTING: NICU of a public maternity hospital in Natal/Brazil. PARTICIPANTS: All neonates admitted to the NICU for more than 24 hours and using at least one medication were followed up during the time of hospitalisation. PRIMARY OUTCOME MEASURES: Incidence rate and risk factors for ADRs. The ADRs were detected by an active search in electronic medical records and analysis of spontaneous reports in the hospital pharmacovigilance system. RESULTS: Six hundred neonates were included in the study, where 118 neonates had a total of 186 ADRs. The prevalence of ADRs at the NICU was 19.7% (95% CI 16.7% to 23.0%). The most common ADRs were tachycardia (30.6%), polyuria (9.1%) and hypokalaemia (8.6%). Tachycardia (peak incidence rate: 57.1 ADR/1000 neonates) and hyperthermia (19.1 ADR/1000 neonates) predominated during the first 5 days of hospitalisation. The incidence rate of polyuria and hypokalaemia increased markedly after the 20th day, with both reaching a peak of 120.0 ADR/1000 neonates. Longer hospitalisation time (OR 0.018, 95% CI 0.007 to 0.029; p<0.01) and number of prescribed drugs (OR 0.127, 95% CI 0.075 to 0.178; p<0.01) were factors associated with ADRs. CONCLUSION: ADRs are very common in NICU, with tachycardia and hyperthermia predominant in the first week of hospitalisation and polyuria and hypokalaemia from the third week onwards.

Causality assessment of adverse drug reactions in neonates: a comparative study between Naranjo's algorithm and Du's tool.

BACKGROUND: Algorithms for causality assessment of adverse drug reactions (ADRs) in a neonatal intensive care unit (NICU) are important in the management of adverse events, however, it is inconclusive which tool best suits pharmacovigilance in neonates. AIM: To compare the performance of the algorithms of Du and Naranjo in determining causality in cases of ADRs in neonates in a NICU. METHOD: This observational and prospective study was conducted in a NICU of a Brazilian maternity school between January 2019 and December 2020. Independently, three clinical pharmacists used the algorithms of Naranjo and Du in 79 cases of ADRs in 57 neonates. The algorithms were evaluated for inter-rater and inter-tool agreement using Cohen's kappa coefficient (k). RESULTS: The Du algorithm showed greater ability to identify definite ADRs (≈ 60%), but had low reproducibility (overall k = 0.108; 95% CI 0.064-0.149). In contrast, the Naranjo algorithm showed a lower proportion of definite ADRs (< 4%), but had good reproducibility (overall k = 0.402; 95% CI 0.379-0.429). The tools showed no significant correlation regarding ADR causality classification (overall k = - 0.031; 95% CI - 0.049 to 0.065). CONCLUSION: Although the Du algorithm has a lower reproducibility compared to the Naranjo, this tool showed good sensitivity for classifying ADRs as definite, proving to be a more suitable tool for neonatal clinical routine.

Identification of adverse drug reactions that may be related to pharmacogenetics in a public hospital in the South of Brazil.

BACKGROUND: Adverse drug reactions (ADRs) are of great concern in clinical practice. Pharmacogenetics can identify individuals and groups at increased risk of developing ADRs, enabling treatment adjustments to improve outcomes. The study aimed to determine the prevalence of ADRs related to drugs with pharmacogenetic evidence level 1A in a public hospital in Southern Brazil. RESEARCH DESIGN AND METHODS: ADR information was collected from the pharmaceutical registries from 2017 to 2019. Drugs that have pharmacogenetic evidence level 1A were selected. Public genomic databases were used to estimate the genotypes/phenotypes frequency. RESULTS: During the period, 585 ADRs were spontaneously notified. Most were moderate (76.3%), whereas severe reactions accounted for 33.8%. Additionally, 109 ADRs caused by 41 drugs presented pharmacogenetic evidence level 1A, representing 18.6% of all notified reactions. Depending on the drug-gene pair, up to 35% of individuals from Southern Brazil could be at risk of developing ADRs. CONCLUSIONS: Relevant amount of ADRs were related to drugs with pharmacogenetic recommendations on drug labels and/or guidelines. Genetic information could guide and improve clinical outcomes, decreasing ADR incidence and reducing treatment costs.

A Virtual Assistant in Vaccine Pharmacovigilance: Content and Usability Validation.

This article describes the process of developing and validating a virtual assistant to perform vaccine pharmacovigilance. We performed a pilot study with a panel of 22 healthcare professionals who performed content validation of the virtual assistant prototype. Usability was tested with 126 users, using the System Usability Scale. The data analysis was performed by the agreement rate and content validity index, and the κ test was used to verify the agreement between the evaluators. The content domains of the virtual assistant achieved excellent suitability, relevance, and representativeness criteria, all greater than 86%; the content validity index ranged from 0.81 to 0.98, with an average of 0.90 and an interrater reliability index of 1.00. There was excellent interrater agreement (average κ value, 0.76). The total usability score among users was 80.1, ranging from 78.2 in group 1 (users without reactions to vaccines) to 82.1 in group 2 (users with reactions) ( P = .002). The virtual assistant for vaccine pharmacovigilance obtained a satisfactory level of content validity and usability, giving greater credibility to the claim that this device provides greater surveillance and safety for patients.

Active Pharmacovigilance Project on the safety profile of Dolutegravir in Brazil.

A quantitative descriptive study based on Brazilian Active Pharmacovigilance of Dolutegravir (DTG) Project was performed to describe the adverse drug reactions (ADRs) to DTG reported and to evaluate the noncompleteness of data from DTG active pharmacovigilance in Brazil. ADRs and clinical and individual data were obtained from information from the Pharmacovigilance Questionnaire from April 2017 to August 2019. The reported ADRs were classified using the Medical Dictionary for Regulatory Activities (MedDRA). In the evaluated period, 249,066 individuals using DTG participated in the active pharmacovigilance of DTG, with 3472 (1.39%) reporting ADRs at least once. A total of 6312 ADRs were reported, of which 57.56% were persistent and 81.46% were not serious according to the individuals' reports. Most of the reported ADRs were gastrointestinal, neurological and psychiatric. ADRs related to neural tube defects and serious neuropsychiatric ADRs have been reported. Completion of more than half of the fields in the Pharmacovigilance Questionnaire was excellent. The frequency of ADR was low in relation to the number of people living with HIV (PLHIV) using DTG in Brazil, which suggests good tolerability and safety of DTG. The DTG active pharmacovigilance database in Brazil showed good data completeness.

Fatal hepatotoxicity due to sevoflurane use in a paediatric patient after aortic repair: reality or fiction? A case of pharmacovigilance.

Hepatotoxicity secondary to exposure of volatile anaesthetics is an exceptional finding, but its clinical interest depends on their frequent use, unpredictable appearance and potential severity. Halothane is the volatile anaesthetic most frequently involved in the development of liver dysfunction, especially after re-exposure. Sevoflurane has rarely been related to this life-threatening complication. We present the case of a 1-year-old girl who had undergone previous surgery for closure of a patent ductus arteriosus, and who developed severe acute hepatitis and died after undergoing surgical repair of an aortic isthmus narrowing by means of general anaesthesia with sevoflurane. Other possible causes of liver failure were excluded. This adverse event was classified as serious and was included in the national and European pharmacovigilance network, with the aim of preventing dangerous effects on patient health in clinical practice, by contributing to the enrichment of the literature.

Boletín OPS Adelante, n. 1, Sep. - Dic. 2023

Este boletín es elaborado en la Representación de la Organización Panamericana de la Salud/Organización Mundial de la Salud (OPS/OMS), México. Su objetivo principal es contribuir a la producción y difusión de información en salud pública de relevancia nacional e internacional, principalmente en áreas relacionadas con la misión esencial de la OPS, de fortalecer los sistemas de salud y mejorar la salud de los pueblos de las Américas.

Analysis of reported adverse liver reactions associated with drugs used to treat patients with coronavirus disease 2019

Abstract Hepatic injury has been documented in patients with coronavirus disease 2019 (COVID-19). However, pharmacotherapy can frequently impact liver alterations, given the known hepatotoxic potential of drugs not effective to treat COVID-19. The objective of the present study was to evaluate reports of suspected liver reactions to drugs used for treating COVID-19, compare their use for other indications among patients with COVID-19, and assess possible interactions between them. We obtained reports on drugs used to treat COVID-19 (tocilizumab, remdesivir, hydroxychloroquine, and/or lopinavir/ritonavir), registered on June 30, 2020, from the Food and Drug Administration Adverse Event Reporting System (FAERS) Public Dashboard. We then analyzed the risk of developing liver events with these drugs by calculating the reported odds ratios (ROR). We identified 662, 744, and 1381 reports related to tocilizumab, lopinavir/ ritonavir, and hydroxychloroquine use, respectively. The RORs (95% confidence intervals) were 6.32 (5.28-7.56), 6.12 (5.22-7.17), and 9.07 (8.00-10.29), respectively, demonstrating an increased risk of liver events among patients with COVID-19 when compared with uninfected patients. The elevated risk of reporting adverse liver events in patients with COVID-19 who receive these drugs, alone or in combination, highlights the need for careful drug selection and efforts to reduce drug combinations without notable benefits. Similar to any other condition, the use of drugs without established efficacy should be avoided.

Análise de eventos adversos a medicamentos provenientes do sistema on-line brasileiro e o impacto global da pandemia da COVID-19 nas notificações / Analysis of adverse drug events from the Brazilian online system and the global impact of the COVID-19 pandemic on notifications

Justificativa: Os eventos adversos a medicamentos são uma das principais causas de mortes evitáveis nos sistemas de assistência à saúde e este problema se tornou ainda mais desafiador durante a pandemia da COVID-19, devido à falta de evidências robustas acerca de medicamentos efetivos para o tratamento da doença. Ademais, uma das principais barreiras para a compreensão aprofundada deste fenômeno é a problemática da subnotificação, especialmente em países de baixa e média renda. Objetivos: Analisar o perfil e a ocorrência de eventos adversos a medicamentos notificados por profissionais da saúde, pacientes e empresas/fabricantes no sistema nacional de informação on-line (NOTIVISA) nas cinco regiões brasileiras e avaliar o impacto da pandemia de COVID-19 nas notificações de eventos adversos a medicamentos às autoridades sanitárias em âmbito global. Método: Para o alcance dos objetivos propostos, foram realizados dois estudos. O primeiro estudo consistiu em um estudo epidemiológico e foram analisadas as notificações de eventos adversos a medicamentos inseridos no banco de dados do sistema brasileiro NOTIVISA, no período de 18 março de 2014 a 04 de dezembro de 2018, por duas pesquisadoras de forma independente. Procedeu-se à análise descritiva das variáveis desfecho e preditoras de eventos adversos a medicamentos, características dos pacientes, região brasileira, grau do dano e classificação do erro de medicação. O segundo estudo envolveu revisão sistemática da literatura conduzida nas bases de dados eletrônicas: Medline, Embase, Cinahl, Scielo e literatura cinzenta, utilizando os Descritores em Ciências da Saúde (DECs) e Medical Subject Heading (MeSH). A revisão foi relatada de acordo com as diretrizes PRISMA-2020 e a seleção dos estudos, bem como a extração de dados, foram realizadas por três revisores independentes. O risco de viés foi verificado por meio da ferramenta ROBINS-I. Resultados: Um total de 6.289 notificações foram analisadas e foi verificado um crescente aumento em seu número até o ano de 2016; posteriormente, queda gradual das notificações de eventos adversos a medicamentos foi detectada no período de 2017 e 2018. Houve maior frequência de notificações na região sudeste (48%) e os casos envolveram, predominantemente, pessoas do sexo feminino (52,1%), na faixa etária dos 18 a 65 anos (56,8%) e com neoplasias (22,9%). Além disso, 96% ocorreram durante a prestação de cuidados por um profissional, mais de 78% transcorreram no período diurno e 43% resultaram em danos leves. Na revisão sistemática, foram rastreados 6.014 artigos; destes, 1.863 duplicatas foram removidas. Após triagem, 4.143 foram excluídos por não atenderem aos critérios de inclusão e oito estudos foram elegíveis para a análise qualitativa. Não foram encontradas publicações na literatura cinzenta que contemplassem os critérios de inclusão propostos para esta revisão. Os estudos contemplam notificações de eventos adversos a medicamentos oriundas de 13 países, envolveram pacientes com idade média de 55 anos e sem comorbidades. Cinco estudos evidenciam que o número de notificações aumentou durante a pandemia contraponto outras duas publicações que apontam maior número de notificações antes da pandemia. Ademais, em um estudo, o resultado foi inconclusivo. Em dois estudos, foi identificado alto risco de viés. Conclusão: Os resultados do estudo demonstram que as notificações de EAM aumentaram durante a pandemia. No período pré-pandêmico houve destaque para a região sudeste conhecida com umas mais desenvolvidas, levando a danos leves principalmente vinculados ao erro de administração do medicamento comprometendo a segurança do paciente. Se faz necessário o reforço da importância no monitoramento e da real descoberta do motivo ao qual levou ao aumento nas notificações durante o período pandêmico a fim de melhorias nos processos de saúde e capacitação profissional para obter zero danos evitáveis.

Justification: Adverse drug events are one of the leading causes of preventable deaths in health care systems and this problem has become even more challenging during the pandemic of COVID-19, due to the lack of robust evidence about effective drugs for treating the disease. Moreover, one of the main barriers to a thorough understanding of this phenomenon is the problem of underreporting, especially in low- and middle-income countries. Objectives: To analyze the profile and occurrence of adverse drug events reported by health professionals, patients, and companies/manufacturers in the national online notification system (NOTIVISA) in the five Brazilian regions and to evaluate the impact of the COVID-19 pandemic on adverse drug events notifications to health authorities globally. Method: To achieve the proposed objectives, two studies were carried out. The first study consisted of an epidemiological study and the notifications of adverse drug events entered in the database of the Brazilian NOTIVISA system from March 18, 2014, to December 04, 2018, were analyzed. Only cases involving adverse drug events were screened and this process was carried out by two researchers independently. We performed a descriptive analysis of the outcome and predictor variables of adverse drug events, patient characteristics, Brazilian region, degree of harm, and medication error classification. The second study involved a systematic literature review conducted in the electronic databases: Medline, Embase, Cinalh, Scielo and grey literature, using Health Sciences Descriptors (HSC) and Medical Subject Heading (MeSH). The review was reported according to PRISMA-2020 guidelines and the selection of studies as well as data extraction were performed by three independent reviewers. The risk of bias was checked using the ROBINS-I tool. Results: A total of 6.289 notifications were analyzed and an increasing increase in their number was verified until the year 2016, subsequently, gradual decrease in adverse drug events notifications was detected in the period of 2017 and 2018. There was a higher frequency of notifications in the southeast region (48%) and the cases predominantly involved females (52.1%), in the age group 18 to 65 years (56.8%) and with neoplasms (22.9%). In addition, 96% occurred during the provision of care by a professional, more than 78% occurred during daytime hours, and 43% resulted in minor injuries. In the systematic review, 6,014 articles were screened; of these, 1,863 duplicates were removed. After screening, 4,143 were excluded for not meeting the inclusion criteria and eight studies were eligible for qualitative analysis. No publications were found in the gray literature that met the inclusion criteria proposed for this review. The studies contemplate notifications of adverse drug events from 13 countries, involved patients with a mean age of 55 years and without comorbidities. Five studies show that the number of notifications increased during the pandemic, as opposed to two other publications that indicate a higher number of notifications before the pandemic. Moreover, in one study, the result was inconclusive. In two studies, a high risk of bias was identified. Conclusion: The results of the study show that ADE notifications increased during the pandemic. In the pre-pandemic period, there was an emphasis on the southeastern region known as the most developed, leading to mild damage mainly linked to drug administration error, compromising patient safety. It is necessary to reinforce the importance of monitoring and the real discovery of the reason that led to the increase in notifications during the pandemic period in order to improve health processes and professional training to obtain zero preventable damage.

Sistema de monitoramento de biossimilares: desenvolvimento e avaliação de protótipo / Biosimilar monitoring system: prototype development and evaluation

A evolução da biotecnologia somada à ascensão da tecnologia para recombinação do DNA impulsionou a produção de biológicos ao longo de décadas. Com o término das patentes, os biossimilares emergiram com potencial de gerar um grande impacto na acessibilidade e assim estabelecer seu lugar no mercado após comprovação da equivalência com o medicamento biológico. Entretanto, as preocupações sobre as trocas de medicamentos biológicos e biossimilares é um importante debate atual que ressalta a relevância de acompanhamento pós mercado das pessoas em uso de biofármacos. Este estudo teve como objetivo elaborar um protótipo para identificar e validar os dados necessários para a construção de um software específico para o monitoramento dos medicamentos biossimilares para doenças inflamatórias imunomediadas, tendo em vista o processo de trabalho dos profissionais de saúde e da indústria farmacêutica, considerando os aspectos legais e legislativos das agências reguladoras em benefício do doente crônico. Trata-se de uma pesquisa aplicada, com abordagem qualitativa, na modalidade pesquisa-ação. A população amostral foi constituída por profissionais de saúde, profissionais da indústria farmacêutica, agência reguladora, usuários de medicamento biológico e medicamento biossimilar e especialistas de informática que aceitaram participar da pesquisa por meio da assinatura do Termo de Consentimento Livre e Esclarecido. Abordados na primeira etapa do estudo, os apontamentos dos integrantes do Comitê de Especialistas agregaram as diretrizes estabelecidas pelas agências reguladoras e contribuíram com o levantamento de requisitos que, permeado por padrões de terminologia, direcionou o desenvolvimento dos protótipos (estático e de software). O Adobe Illustrator® foi o editor de imagens vetoriais utilizado para desenvolver o protótipo estático e contribuir para consolidar as telas, ao passo que o protótipo de software explorou as potencialidades da tecnologia Angular e favoreceu a interação do usuário com as telas desenvolvidas. Na segunda fase do estudo, os integrantes do Comitê de Avaliadores acessaram o protótipo para avaliação da tecnologia por meio da aplicação de um questionário. Os resultados evidenciam a importância de desenvolver estratégias para identificar os desvios de qualidade e dessa forma minimizar os eventuais danos das novas gerações de medicamentos. Soma-se a relevância de identificar as trocas de medicamentos biológicos e biossimilares e qualificar as informações para favorecer o acompanhamento pós mercado dos biofármacos e, assim, fortalecer a farmacovigilância e contribuir com a segurança do paciente. A aproximação entre o pesquisador e as pessoas implicadas na jornada do paciente em uso de medicamento biológico e biossimilar proporcionou a inserção de perspectivas não previstas pela literatura e, sobretudo, delineou potenciais soluções para os problemas apontados.

The evolution of biotechnology added to the rise of technology for DNA recombination boosted the production of biologicals for decades. With the end of patents, biosimilars emerged with the potential to generate a great impact on accessibility and thus establish their place in the market after proof of equivalence with biological medicine. However, concerns regarding the exchange of biological and biosimilar medicines is an important current debate that highlights the relevance of post-market monitoring of people using biopharmaceuticals. This study aimed to develop a prototype to validate the data necessary for the monitoring of biological and biosimilar medicines for immune-mediated inflammatory diseases. It is an applied research, with a qualitative approach, in the action-research modality. The sample population consisted of health professionals, professionals from the pharmaceutical industry, regulatory agency, users of biological and biosimilar products and IT specialists who agreed to participate in the research by signing the Free and Informed Consent Form. Approached in the first stage of the study, the notes of the members of the Committee of Experts added the guidelines established by the regulatory agencies and contributed to the survey of requirements that, permeated by terminology standards, guided the development of prototypes (static and software). Adobe Illustrator® was the vector image editor used to develop the static prototype and contributed to consolidate the developed screens, while the software prototype explored the potential of Angular technology and favored user interaction with the screens developed. In the second phase of the study, the members of the Committee of Evaluators accessed the prototype for evaluating the technology through the application of a questionnaire. The results show the importance of developing strategies to identify quality deviations and minimize the potential damages of new generations of medicines. biopharmaceuticals and, thus, strengthen pharmacovigilance and contribute to patient safety. The approximation between the researcher and the people involved in the journey of the patient using biological and biosimilar medicines provided the insertion of perspectives not foreseen in the literature and, above all, outlining potential solutions to the problems mentioned.

Recomendación del Comité Asesor de Vacunas y Estrategias de Inmunización (CAVEI) sobre vacunación contra viruela símica en Chile / Recommendation of the Advisory Committee on Vaccines and Immunization Strategies on monkeypox vaccination in Chile

La viruela del mono fue declarada emergencia de salud pública de importancia internacional por la Organización Mundial de la Salud el año 2022. En Chile, hasta septiembre se han confirmado sobre 450 enfermos, mayoritariamente hombres jóvenes. Este poxvirus zoonótico se transmite entre humanos por contacto estrecho; la enfermedad es autolimitada y puede ser fatal en inmunocomprometidos. La prevención mediante inmunización es importante. MVA-BN es una de las tres vacunas disponibles, de 3° generación, contiene el virus vaccinia atenuado, no replicante por lo que se puede administrar a pacientes inmunocomprometidos y mujeres embarazadas y está aprobada para viruela símica en personas > 18 años. La información disponible sobre eficacia y efectividad es limitada. El CAVEI recomienda incorporar esta vacuna para interrumpir la cadena de transmisión y reducir el riesgo de enfermedad grave, en dos dosis separadas por 28 días, por vía subcutánea, priorizando el uso post-exposición para contactos estrechos con riesgo de enfermedad grave, idealmente en los primeros 4 días y hasta 14 días post contacto de riesgo y en ausencia de síntomas. Cuando el suministro de vacunas lo permita, se recomienda prevención pre-exposición para personas con alto riesgo ocupacional o por prácticas sexuales. Esta recomendación podría modificarse según la epidemiología, el suministro de vacunas y nueva información científica.

Monkeypox was declared a public health emergency of international concern by the World Health Organization during 2022. In Chile, over 450 patients have been confirmed until September, mostly young men. This zoonotic poxvirus is transmitted from humans to humans through close contact; it is a self-limiting disease and can be fatal in people with immunodeficiency. Prevention by immunization is important. MVA-BN, one of the three vaccines available, it is a third generation vaccine, based on non-replicating modified vaccinia virus, therefore can be administered to immunocompromised patients and pregnant women and it has been approved for monkeypox in people over 18 years of age. The available information on efficacy and effectiveness is limited. The CAVEI recommends incorporating this vaccine to interrupt the chain of transmission and reduce the risk of severe disease, administered subcutaneously in two doses, 28 days apart, prioritizing post exposure use for close contacts of confirmed cases with risk of severe disease, ideally within 4 days of exposure and it can be used up to 14 days after exposure and in the absence of symptoms. When the vaccine supply allows it, its application is recommended as pre-exposure prevention for people with high-risk sexual practices or with occupational risk. This recommendation could be modified according to epidemiology, vaccines supply and new scientific information.

Perfil dos pacientes em uso de anticoagulantes orais diretos atendidos via judicial em um município de médio porte do estado de Minas Gerais / Profile of patients in the use of direct oral anticoagulants assisted judicially in a medium-sized municipality of the state of Minas Gerais

Fundamentos: O sistema de saúde brasileiro é embasado nos princípios estabelecidos na Constituição Federal, que in-cluem igualdade, universalidade, equidade e participação popular, em um modelo de saúde totalmente gratuito. O Brasil vive um grande desafio para ofertar assistência de qualidade para toda população. Muitas vezes, é necessário solicitar à justiça um suporte para conseguir acesso à saúde pública. Entre os processos judiciais envolvendo questões de saúde, a maioria são referentes ao fornecimento de medicamentos. Dentre os medicamentos solicitados, destacam-se os anticoagulantes orais diretos (DOACs), cujos estudos apontam que apresentam melhor segurança e eficácia similar em relação à varfarina, medicamento padronizado no SUS para o tratamento do tromboembolismo venoso e fibrilação atrial. Objetivo: Avaliar o perfil dos pacientes e das solicitações dos DOACs atendidos por via judicial. Métodos: Estudo documental descritivo realizado em Divinópolis/MG a partir de todos os processos julgados com parecer favorável pela justiça referentes à solicitação dos DOACs. A coleta de dados foi realizada em três fontes secundárias: os pro-cessos judiciários, prontuários dos pacientes nas unidades básicas de saúde e no Sistema de Informações em Saúde. Resultados: Foram incluídos no estudo um total de 74 processos referentes à solicitação dos DOACs no município de Divinópolis-MG. Observou-se que 74,3% dos indivíduos eram do sexo feminino, com média de idade de 70 anos. O diagnóstico mais observado foi a fibrilação atrial (36,5%). Cerca de 52,7% dos médicos registraram que houve tenta-tiva terapêutica com varfarina antes da introdução dos DOACs e a comodidade (24,3%) foi a justificativa mais utilizada por optar pelos DOACs seguida por dificuldade em controlar a RNI (20,3%). Outro dado encontrado foi que 25,7% dos pacientes nunca obtiveram na farmácia do SUS o medicamento solicitado por via judicial. Conclusão: Concluímos que a demanda judicial que afoga tanto o sistema judiciário como o sistema de saúde, poderia ser evitada se fossem seguidas as recomendações da Comissão Nacional de Incorporação de Tecnologias no Sistema Único de Saúde para estabelecer a distribuição dos insumos de saúde. Além disso, nos processos judiciais faltam informações importantes para auxiliar o juiz a emitir um parecer, sendo baseadas, na maioria das vezes, em apenas uma opinião médica. (AU)

Fundamentals: The Brazilian health system is based on the principles established in the Federal Constitution, which include equality, universality, equity, and popular participation in a completely free health model. Brazil is under great challenge to offer quality care to the entire population. It is often necessary to ask the court for support to gain access to public health.Among the court proceedings involving health issues, the majority refer to the supply of medicines. Among the drugs requested, direct oral anticoagulants (DOACs) stand out, which indicate that they have better safety and similar efficacy concerning warfarin, a standardized medication in the SUS to treat venous thromboembolism (VTE) and atrial fibrillation (AF). Objective: Assess the profile of patients and requests for direct oral anticoagulants (DOACs) served by the court. Methods: Descriptive documental study carried out in Divinópolis/MG from all cases judged with a favorable opinion by the court regarding the request of DOACs. Data collection was carried out from three secondary sources: court proceedings, medical records of patients in basic health units, and the Health Information System (SIS). Results:A total of 74 lawsuits referring to the DOACs request in the city of Divinópolis-MG were included in the study. It was observed that 74.3% of the individuals were female, with a mean age of 70 years. The most common diagnosis was atrial fibrillation (36.5%). About 52.7% of physicians reported that there was a therapeutic attempt with warfarin before the introduction of DOACs, and convenience (24.3%) was the most used justification for choosing DOACs, followed by difficulty in controlling the INR (20.3%). Another finding was that 25.7% of the patients never obtained the medication requested through the courts at the SUS pharmacy. Conclusion: We concluded that the judicial demand that drowns both the judicial system and the health system could be avoided if the recommendations of the National Commission for the Incorporation of Technologies in the Unified Health System were followed to establish the distribution of health education. In addition, in court proceedings, important information is lacking to assist the judge in issuing an opinion and is most often based on only one medical opinion. (AU)