Signal mining and analysis of adverse drug event signals of darolutamide / 中国药房

OBJECTIVE To explore and analyze the adverse drug event （ADE） signals of darolutamide and provide a reference for its clinical safe use. METHODS ADEs related to darotamide were collected based on the US FDA adverse event reporting system （FAERS） database from the third quarter of 2019 to the third quarter of 2022. Data mining and analysis were conducted by the report odds ratio （ROR） and proportional reporting ratio （PRR） methods. RESULTS A total of 565 ADE reports related to darolutamide were extracted， 356 ADE reports about darolutamide as the primary suspected drug were included， 38 ADE signals with darolutamide as the primary suspected drug were excavated， involving 15 system organ class （SOC）， mainly concentrated in patients over 65 years old. The SOC of darotamide ADE signal mainly focused on various examinations， systemic diseases and various reactions at the administration site， benign/malignant tumors or those with unknown nature （including cystic and polypoid）， kidney and urinary system diseases. A total of 13 ADE signals not mentioned in the instructions included increased prostate-specific antigen， dysphagia， cognitive impairment， erectile dysfunction， rhabdomyolysis， gynecomastia and decreased platelet count， etc. CONCLUSIONS When using darolutamide， in addition to ADE in the drug instruction， we should pay close attention to potential ADE， such as increased prostate-specific antigen， rhabdomyolysis， gynecomastia and decreased platelet count， so as to avoid drug withdrawal or organ damage caused by ADE.

Mining and analysis of acalabrutinib-induced ADE risk signals based on FDA adverse event reporting system / 中国药房

OBJECTIVE To provide reference for the clinically safe application of acalabrutinib by mining and analyzing the risk signals of adverse drug events （ADE）. METHODS The acalabrutinib-induced ADE reports were extracted from the U.S. FDA adverse event reporting system using the OpenVigil 2.1 platform from November 1， 2017 to March 31， 2023. The reporting odds ratio （ROR） method and composite criteria method from the Medicines and Healthcare Products Regulatory Agency （MHRA） were used for detection of ADE signals. RESULTS There were 7 869 ADE reports of acalabrutinib as the primary suspect drug and 142 ADE positive signals were detected from them， involving 20 system organ classes， which was generally consistent with the ADE recorded in the drug instruction of acalabrutinib， mainly involving general disorders and administration site conditions， various inspection， blood and lymphatic system disorders， various neurological disorders and cardiac disorders. In addition， this study identified several new potential ADE signals that were not mentioned in the drug instruction， including sudden cardiac death， pulmonary toxicity， tumor lysis syndrome， pleural effusion， dyspepsia， gastroesophageal reflux disease， bone pain， decreased blood pressure， and abnormal blood sodium， etc. CONCLUSIONS When using acalabrutinib， in addition to paying attention to the ADE recorded in its instructions， the risk of serious ADE that may lead to death， such as sudden cardiac death and pulmonary toxicity， should also be evaluated to avoid or reduce the occurrence of ADE as much as possible.

Mining and analysis for adverse drug event signals of liver failure in underage population based on the FAERS database / 中国药房

OBJECTIVE To conduct data mining on drugs causing liver failure in underage populations based on the FDA Adverse Event Reporting System （FAERS） database， so as to provide reference for clinical use of related drugs. METHODS The data on reported adverse drug event （ADE） of liver failure in this population （under 18 years old） from the first quarter of 2013 to the third quarter of 2022 were retrieved from the FAERS database for mining and analysis； they were divided into infants（≤1 year old）， young children（＞1-＜6 years old）， children（6-＜12 years old） and adolescents（12-＜18 years old） according to the age. The reporting odds ratio （ROR）， proportional reporting ratio and Bayesian confidence propagation neural network of the proportional imbalance method were used to screen ADE signals. RESULTS A total of 1 051 ADE reports of liver failure were collected from the underage population involving 60 drugs. The highest incidence was found in adolescents （410 cases， 39.01%）， followed by young children （297 cases， 28.26%）. The instructions of 14 drugs did not mention hepatobiliary system injury and liver failure risk， including 31 cases of levetiracetam （2.95%），18 cases of metronidazole （1.71%）， 16 cases of each of topiramate and methylprednisolone （1.52% each）， 12 cases of dexamethasone （1.14%）， 11 cases of tisagenlecleucel （1.05%）， 10 cases of each of ferrous sulfate， metformin and busulfan （0.95% each）， 9 cases of propofol （0.86%）， 8 cases of onasemnogene abeparvovec （0.76%）， 5 cases of each of diphenhydramine and omeprazole （0.48% each）， 4 cases of sebeliesterase α （0.38%）， totaling 165 cases， accounting for 15.70% of the total reported cases. Metformin was contrary to the known liver safety， and E-mail：libingchemical@163.com metronidazole and levetiracetam were new risk signals， which caused more serious clinical outcomes. CONCLUSIONS Fourteen new pharmacovigilance signals which cause liver failure in the underage population are found in this study； the liver function of patients should be closely monitored when using these drugs. Among those drugs， metformin neither undergoes liver metabolism nor has been reported in the relevant literature， and the liver-related ADE caused by metformin deserves further attention. The clinical outcomes caused by metronidazole and levetiracetam are relatively serious and need to be given sufficient attention.

Signal mining of valproic acid-induced adverse drug events based on FAERS / 中国药房

OBJECTIVE To provide reference for clinically safe and rational drug use through mining and analyzing adverse drug event （AE） signals induced by valproic acid （VPA）. METHODS Reporting Odds Ratio （ROR） and Bayesian Confidence Propagation Neural Network （BCPNN） methods of Measures of Disproportionality were performed to mine and analyze the data of VPA-related AE reports in the US FDA Adverse Event Reporting System （FAERS） database from the first quarter of 2013 to the fourth quarter of 2022. RESULTS A total of 1 253 （ROR） and 1 109 （BCPNN） valid signals of preferred terms （PT） were obtained after data processing by the two analysis methods， involving 27 system organs （SOC）， mainly focusing on nervous system disorders， psychiatric disorders， general disorders and administration site conditions. Signals that did not appear in the instruction were associated with 2 SOCs： ear and labyrinth disorders， infections and infestations. CONCLUSIONS As a first-line broad-spectrum anti-epileptic drug， attention should also be paid to eye toxicity and infection risk in the clinical application in addition to paying attention to common adverse events in the instruction.

Risk signal mining of ixazomib based on the database of FAERS / 中国药房

OBJECTIVE To explore the risk signal of ixazomib and provide a reference for clinically rational drug use. METHODS The Open Vigil 2.1 online tool was used to extract the data of adverse drug events （ADE） reported by the database of FDA adverse event reporting system （FAERS） from the launch of ixazomib in America （November 20th， 2015） to the latest update of the Open Vigil website （March 31st， 2023）. The data were mined by using the proportional reporting ratio （PRR） and Bayesian confidence propagation neural network （BCPNN） of the proportional imbalance method. The signals were coded by system organ class （SOC） and preferred term （PT） according to MedDRA v25.1. RESULTS A total of 13 841 ADE reports with ixazomib as the “primary subject” were extracted， involving slightly more male patients （49.53%）， and most of them were 65 years old and above （72.48%）； the reports came from 57 countries/regions， mainly America （52.90%）. A total of 186 positive signals were excavated， with 51 high-intensity， 99 medium-intensity， and 36 low-intensity signals， involving 19 SOCs. The top 50 PT in frequency and signal intensity of PRR included neuropathy peripheral （414 cases， high-intensity signal）， platelet count decreased （379 cases， high-intensity signal）， thrombocytopenia （360 cases， high-intensity signal）， cytopenia （75 cases， high-intensity signal） and neurological symptoms （41 cases， high-intensity signal）. SOC involved included nervous system disorders， investigations， and blood and lymphatic system disorders. ADE occurred most frequently in gastrointestinal diseases （2 588 cases）， including diarrhea （1 077 cases， high-intensity signal）， nausea （737 cases， medium-intensity signal）， vomiting （459 cases， medium-intensity signal）， constipation （275 cases， medium-intensity signal）， and so on. The positive signals of infections and infestations contained the largest number of PTs， and most of them were not recorded in the drug instruction， including 12 high-intensity signals （1 030 cases） and 30 medium-intensity signals （627 cases）， which were mainly distributed in lung infection， upper respiratory infection， gastrointestinal infection， sepsis， herpes zoster and so on. The signals of cardiac amyloidosis （7 cases， high-intensity signal） and acute coronary syndrome （14 cases， high-intensity signal） of cardiac disorders and renal dysfunction （91 cases， medium-intensity signal） of renal and urinary disorders were all strong and had not been recorded in the drug instruction. CONCLUSIONS In addition to routine attention to the common ADE of ixazomib in gastrointestinal diseases，nervous system disorders and blood and lymphatic system disorders， clinical attention should also be paid to various infections that may occur during the treatment of patients， and the occurrence of cardiovascular toxicity and renal dysfunction should be monitored.

Mining and analysis of adverse drug events signals of nilotinib based on FDA adverse event database / 中国药房

OBJECTIVE To provide a reference for safe drug use in clinic. METHODS ADE reports related to nilotinib from the first quarter of 2007 to the fourth quarter of 2022 were collected from the US FDA adverse event reporting system database. The reporting odds ratio （ROR） and proportional reporting ratio （PRR） of disproportionality measures were used to mine potential ADE signals，which were compared with drug instruction and related case report， and were screened and analyzed according to the designated medical events （DME） list formulated by the European Medicines Agency. RESULTS Totally 23 332 cases of ADE with nilotinib as the primary suspected drug were reported. A total of 359 positive signals were obtained，involving 24 system organ classes （SOC），mainly concentrated in various examinations，heart organ diseases，vascular and lymphatic diseases，all kinds of nervous system diseases，etc. Among them，ADEs such as vertebral artery stenosis，coronary artery stenosis，arterial disease，liver infection and the second primary malignant tumor were not mentioned in the instructions. Seven DMEs were detected，of which bone marrow failure，pulmonary hypertension and deafness were not mentioned in the drug instruction. CONCLUSIONS The common ADE signals of nilotinib excavated in this study are consistent with the instructions. In clinical use，special attention should be paid to DME not mentioned in the instructions such as bone marrow failure，pulmonary hypertension and deafness； cardiac function， blood glucose and blood lipid indexes should be monitored closely.

Safety of human papilloma virus vaccine based on Vaccine Adverse Event Reporting System from 2006 to 2021 / 中国生物制品学杂志

@#Objective To investigate the characteristics of distribution of adverse event(AE)associated with human papillomavirus(HPV)vaccine by analysis of data on AE collected from the Vaccine Adverse Event Reporting System(VAERS).Methods The data on AE reported in VAERS from January 1st,2006 to December 31st,2021 were analyzed and compared by using Pearson Chi-square test and Mann-Whitney U test.Results A total of 53 571 cases of AE were included in the study,in which the ratio of male to female was 0. 25∶1,and the median age of vaccinees was 15 years. A portion of 36. 1%of AE occurred after the first dose,while 90. 7% occurred within 3 d after vaccination. Both the gender ratios(χ~2=72. 570,P < 0. 001) and the median ages(Z = 4. 255,P < 0. 001)of vaccinees in non-serious and serious adverse event(SAE)showed significant difference. In terms of classification of SAE,hospitalization,prolonged hospitalization and disability were more common in females than in males,of which the percentages decreased with the increasing age. Among the AE,syncope was the most common clinical symptom. In the SAE,the highest proportion of deaths was caused by HPV2 vaccine,which was 19. 0%. The proportion of prolonged hospitalization caused by HPV4 vaccine was higher than that by HPV9vaccine. In general,HPV4 vaccine was more prone to cause SAE than HPV9 vaccine(χ~2=183. 267,P < 0. 001).Conclusion In all the AE,the largest proportion occurred in the age group of 9 ～ 17 years,followed by those in the groups of 18 ～ 26 and 27 ～ 45 years. Most of the AE occurred after the first dose. The clinical symptoms of AE caused by three vaccines were different. The analysis of distribution characteristics of AE may provide a reference for the study on clinical safety of HPV vaccine and optimization of vaccination.

CHINA PH ARMACY Volume 33，Number 4，February 28，2022 Semimonthly Table of Contents Empirical study on the influential factors of the drug complaint and reportin g system in China / 中国药房

OBJECTIVE To improve the drug complaint and reporting system in China ，and to provide reference for improving the social multi-component governance level of the drug safety. METHODS Taking Guangdong province as an example ， literature review ，questionnaire survey ，structural equation model and other methods were used to analyze influential factors of the drug complaint and reporting system ，such as “Internet+”approach，drug quality ，specialized drug knowledge ，complaint and reporting procedures ，complaint and reporting methods ，complaint and reporting motivation ，governmental reward ，administrative review or litigation. RESULTS & CONCLUSIONS A total of 3 375 questionnaires were received ，all of which were valid ；the vast majority of respondents lived in Guangdong province. The results of the empirical analysis of the influential factors of drug complaint and reporting system showed that the path coefficients of “Internet + ”approach and specialized drug knowledge ， complaint and reporting procedures ，complaint and reporting methods were all greater than 0.9，indicating“Internet+”promoted the transformation of the way and behavior of complaint and reporting. It is suggested that the design of the drug complaint and reporting system should not only attract the public to participate in drug complaint and reporting ，but also cultivate the public ’s management capacity through the approach of internet ， standardize professional anti-counterfeiting behavior ， promote the institutional reform of “digital government ”，and appropriately adjust the work responsibilities of drug regulatory department ，so as to reduce the number of drug complaint and reporting in China ，and optimize the drug safety governance system.

Data mining of adverse drug reaction of iodine contrast media based on spontaneous reporting system / 中国药房

OBJECTIVE To mine the risk sig nals o f iodine contrast media from spontaneous reporting system. METHODS Reporting odds ratio ，proportional reporting ratio ，Medicines and Healthcare Products Regulatory Agency and Bayesian confidence propagation neural network were used to mine risk signals of 5 iodine contrast media （iopamidol，iohexol，iopromide，ioversol， iodixanol）. RESULTS 1 164（2 446 case times ）adverse drug reaction of iodine contrast media were included ，a total of 14 risk signals involving systems/organs such as respiratory system （3，2，4，3，2 for the above 5 iodine contrast media ）and immune system and 32 specific adverse drug reaction signals including anaphylactic shock ，rash and flushing （11，7，7，3，4 for the above 5 iodine contrast media ）were found in 5 iodine contrast media. CONCLUSIONS The risk signals of 5 iodine contrast media verify that there is a certain correlation between these drugs and above adverse drug reactions. It is suggested that before using iodine contrast media in clinic ，it is necessary to pay attention to whether the patient has a history of tumor and combined medication ，evaluate the patient’s renal function ，and give preventive measures such as hydration in advance. When using iodine contrast media ，it is necessary to pay attention to the temperature ，dose and injection rate. And medical staff need to follow up the patient ’s situation in time after using iodine contrast media to avoiding the impact of delayed adverse reactions.

Adverse drug event signal mining of semaglutide based on FDA Adverse Event Reporting System database / 中国药房

OBJECTIVE To exc avate the adverse drug event （ADE）signals of semaglutide and provide reference for its clinical rational use. METHODS The proportional unbalance method was used to mine the signals of all semaglutide ADE reports from FDA Adverse Event Reporting System （FAERS）up to September 2021. The basic situations of the reported cases were analyzed. The corresponding system organ classification （SOC）was mapped and compared with the adverse drug reactions recorded in the drug instructions. Preferred terms （PT）of patients with different indications were analyzed. RESULTS A total of 6 661 semaglutide ADE reports were extracted and 194 valid signals were mined. Among 6 661 cases of ADE ，the proportion of men （43.40％）was lower than women （52.65％）；the age was mainly distributed in ＞40-65 years old （29.00％）and ＞65 years old （22.61％）；the reporting country was mainly the United States （83.88％）；the report year was mainly concentrated in 2021 （40.88％），with an increasing trend year by year ；the main outcome was hospitalization or prolonged hospitalization in serious ADE reports （17.78％）. Semaglutide ADE signal was mapped to the main SOC ，mainly including gastrointestinal diseases ，various injuries，poisoning and operation complications ，metabolic and nutritional diseases ，various examinations. The screening criteria were based on the report odds ratio ＞10 or ADE reported cases ＞50，and 48 new potential adverse drug reactions were added to the drug description. Among the indications with the top two reported cases （type 2 diabetes and obesity ，overweight，weight control），the frequency of gastrointestinal system related ADE reports represented by nausea ，vomiting and diarrhea was higher ， which was similar to the drug instructions. CONCLUSIONS This study supplemented 48 new potential adverse drug reactions based on the drug instructions of semaglutide. At present ，it can be considered that semaglutide is safe.

Descripción de las características de los incidentes clínicos reportados en el año 2020 al sistema de reporte voluntario de un hospital pediátrico de Costa Rica / Description of the characteristics of the clinical incidents reported in 2020 to the voluntary reporting system of a pediatric hospital in Costa Rica

El objetivo del presente manuscrito fue describir los incidentes clínicos que fueron enviados al sistema de reporte voluntario durante el año 2020, que funciona en el Hospital Nacional de Niños de Costa Rica, perteneciente a la Caja Costarricense de Seguro Social. Se realizó un estudio observacional descriptivo de los datos consolidados que se enviaron durante los meses de enero a diciembre del año 2020. Durante el año 2020 el 1,6% de los pacientes atendidos en el hospital experimentó algún tipo de incidente clínico. El total de egresos disminuyó un 38,4% en comparación con los egresos del año 2019, sin embargo, los incidentes clínicos reportados aumentaron en el año 2020 un 37,6%, especialmente a partir del mes de agosto. No se reportaron eventos centinela en este año. Los servicios que realizaron mayor cantidad de reportes fueron Cuidados Intensivos (14,3%), Cirugía General (12%), Neonatología (9,8%) e Infectología (9%). El día en el cual se reportaron más incidentes fue el miércoles (27,8%), en el primer turno hospitalario se reportaron la mayoría de los casos (48,1%) y estos incidentes ocurrieron predominantemente a individuos masculinos (66%). Respecto de la edad de los pacientes, la mayoría estuvo en el rango de edad de 1 año a menos de 5 años (36,1%), seguido por el rango de edad de mayores de 29 días a menores de 1 año (24,1%). La mayor parte de los casos estuvieron relacionados con el cuidado que se brindaba al paciente (63,9%). El 41,4% de los incidentes requirieron medidas clínicas pero las secuelas fueron transitorias. El 51,1% de los casos ameritó algún tipo de cuidado médico adicional a su esquema terapéutico al ingreso. El 96% de los incidentes clínicos fueron reportados por personal de enfermería. La mayoría de los incidentes clínicos (35,3 %) en este período fueron errores relacionados con notas en el expediente digital.

The objective of this manuscript was to describe the clinical incidents that were sent to the voluntary reporting system during 2020 at the National Children's Hospital of Costa Rica, belonging to the Costa Rican Social Security Fund.A descriptive observational study of the consolidated data that was sent during the months of January to December of the year 2020 was carried out.During 2020, 1.6% of the patients treated in the hospital experienced some type of clinical incident. The total discharges decreased by 38.4% compared to the discharges of the year 2019, however, the reported clinical incidents increased in the year 2020 by 37.6%, especially from the month of August. Sentinel events were not reported this year. The services that made the highest number of reports were Intensive Care (14.3%), General Surgery (12%), Neonatology (9.8%) and Infectiology (9%). The day on which the most incidents were reported was Wednesday (27.8%), in the first hospital shift most of the cases were reported (48.1%) and these incidents occurred predominantly to male individuals (66%). Regarding the age of the patients, the majority were in the age range from 1 year to less than 5 years (36.1%), followed by the age range from over 29 days to under 1 year (24, 1%). Most of the cases were related to the care provided to the patient (63.9%). 41.4% of the incidents required clinical measures but the sequelae were transitory. 51.1% of the cases merited some type of additional medical care to their therapeutic scheme upon admission. 96% of clinical incidents were reported by nursing staff. Most of the clinical incidents (35.3%) in this period were errors related to notes in the digital file.

Retrospectiva de 20 anos de atividade da Unidade de Farmacovigilância do Porto, Portugal / Looking back on 20 years of work at the Porto Pharmacovigilance Centre, Portugal / Retrospectiva de 20 años de actividad de la Unidad de Farmacovigilancia de Oporto, Portugal

Resumo: Desde 1963 que a farmacovigilância foi reconhecida como uma área prioritária na saúde pública a nível global pela Organização Mundial da Saúde, garantindo a monitorização permanente da segurança dos medicamentos. O objetivo deste trabalho foi caracterizar as reações adversas a medicamentos recebidas pela Unidade de Farmacovigilância do Porto (UFPorto), Portugal, ao longo de duas décadas de atividade. Foram consideradas todas as notificações de suspeitas de reações adversas a medicamentos recebidas entre janeiro de 2001 e dezembro de 2019. Foram calculadas as taxas de notificação anuais, assim como a sua distribuição por origem, tipo de notificador e local de exercício da atividade, gravidade, conhecimento prévio e causalidade das reações adversas a medicamentos notificadas. No período em estudo, a UFPorto recebeu 9.711 notificações de suspeitas de reações adversas a medicamentos. As instituições hospitalares são aquelas que mais notificam (n = 6.003; 64%), assim como o médico entre os profissionais de saúde (n = 5.284; 54,4%). Os eventos adversos mais frequentemente reportados são graves (n = 6.275; 72%) e encontram-se descritos no respectivo Resumo das Características do Medicamento (n = 6.978; 72%). À maioria das notificações avaliadas pela UFPorto foi atribuído o grau de causalidade "provável" (n = 7.473; 77%), independentemente do tipo de notificador. Os resultados obtidos são concordantes com outros dados previamente reportados na literatura médica internacional e em relatórios oficiais nacionais. Contudo, continua-se a verificar taxas de subnotificação acentuadas, face ao esperado. Ao longo de aproximadamente 20 anos de atividade da UFPorto, tem-se verificado um aumento da sua atividade nas diversas vertentes da segurança do medicamento.

Abstract: Since 1963, the World Health Organization has acknowledged pharmacovigilance as a priority area in global public health, guaranteeing permanent monitoring of drug safety. This study aimed to characterize the reports of adverse drug reactions received by the Porto Pharmacovigilance Centre (UFPorto), Portugal, in the unit's two decades of work. The analysis included all reports of suspected adverse drug reactions received from January 2001 to December 2019. We calculated the annual reporting rates and distribution by origin, type of notifier and place of work, severity, prior knowledge, and causality of the reported adverse drug reactions. During the study period, UFPorto received 9,711 notifications of suspected adverse drug reactions. Hospital institutions reported the most suspected adverse drug reactions (n = 6,003; 64%), as did physicians among healthcare workers (n = 5,284; 54.4%). The most frequently reported adverse events were severe (n = 6,275; 72%) and are described in the respective Summary of Product Characteristics (n = 6,978; 72%). Most of the reports received by UFPorto were evaluated as having "probable" causality (n = 7,473; 77%), independently of the type of notifier. The results are consistent with other data previously reported in the international medical literature and official national reports. However, the underreporting rates are still higher than expected. In approximately 20 years, UFPorto has experienced an increase in its activity in various areas of drug safety.

Resumen: Desde 1963 la farmacovigilancia fue reconocida por la Organización Mundial de la Salud, como un área prioritaria en la salud pública a nivel global, garantizando la monitorización permanente de la seguridad de los medicamentos. El objetivo de este trabajo fue caracterizar las reacciones adversas a medicamentos recibidas por la Unidad de Farmacovigilancia de Oporto (UFPorto), Portugal, a lo largo de dos décadas de actividad. Se consideraron todas las notificaciones de sospechas de reacciones adversas a medicamentos, recibidas entre enero de 2001 y diciembre de 2019. Se calcularon las tasas de notificación anuales, así como su distribución por origen, tipo de notificador y lugar de ejercicio de la actividad, gravedad, conocimiento previo y causalidad de las reacciones adversas a medicamentos notificadas. En el período de estudio, la UFPorto recibió 9.711 notificaciones de sospechas reacciones adversas a medicamentos. Las instituciones hospitalarias son quienes más notifican (n = 6.003; 64%), así como el médico entre los profesionales de salud (n = 5.284; 54,4%). Los eventos adversos más frecuentemente reportados son graves (n = 6.275; 72%) y se encuentran descritos en lo respectivo Resumen de las Características del Medicamento (n = 6 978; 72%). A la mayoría de las notificaciones evaluadas por la UFPorto se le atribuyó el grado de causalidad "probable" (n = 7.473; 77%), independientemente del tipo de notificador. Los resultados obtenidos son concordantes con otros datos previamente reportados en la literatura médica internacional y en informes oficiales nacionales. No obstante, se continúa verificando tasas de subregistro acentuadas, frente a lo esperado. A lo largo de aproximadamente 20 años de actividad de la UFPorto, se ha verificado un aumento de su actividad en las diversas vertientes de la seguridad del medicamento.

ADE Risk Signal Mining Related to Belimumab Based on the FARES Database / 中国药房

OBJECTIVE：To prov ide referen ce for clinical safe and rational use of belimumab by mining the risk signals of adverse drug event （ADE）. METHODS ：ADE reports related to belimumab were collected from FDA adverse event reporting system（FAERS）from the first quarter of 2015 to the first quarter of 2021. The reporting odds ratio （ROR）method and the Medicines and Healthcare Products Regulatory Agency （MHRA）method were adopted to mine the ADE risk signals related to belimumab，setting the threshold as the number of reports ＞3 and the lower limit of 95％ CI ＞1（ROR method ）and the proportional reporting ratio （PRR）＞2，and χ2 ＞4（MHRA method ）. ADEs were counted and classified by using the preferred system organ class （SOC）and preferred term （PT）of Medical Dictionary for Regulatory Activities （MedDRA）. RESULTS & CONCLUSIONS：A total of 3 529 ADE reports with belimumab as the primary suspicious drug were screened ，in which female patients（90.31％）were much more than male patients （6.15％）；age distribution was concentrated in 18-59 years old （41.80％）. There were 1 234 cases（34.97％）of severe ADE reports ，mainly involving hospital or prolonged hospital stay. Most of the reporters were consumers or other non-medical professionals （81.84％）. North America reported the most （70.39％）and the main reporting country was the United States （2 029 reports）. A total of 180 PTs were mined from 3 529 reports，in addition to PTs associated with primary disease （systemic lupus erythematosus ，pain，arthralgia，pyrexia，weight decreased ，swelling，oropharyngeal pain ， etc.），PTs related to medication error （product dose omission ，inappropriate schedule of product administration ，underdose， product availability issue ，etc.）and PTs related to infection （influenza，urinary tract infection ，infection，sinusitis，etc.）were reported in a large number of cases. Twenty-six SOCs were involved ，the top 10 SOC in ADE reports were all kinds of injuries ， poisoning and surgical complications （2 225 reports），infections and infectious diseases （1 247 reports），general disorders and administration site conditions （1 196 reports），musculoskeletal and connective tissue disorders （1 195 reports），surgical and medical procedures（515 reports），etc. PTs in SOC in the first place （all kinds of injuries ，poisoning and surgical complications ）of ADE reports were all related to medication error ；herpes zoster ，kidney infection and cellulitis in SOC in the second place （infections and infectious diseases ）of ADE reports were not included in the drug instruction of belimumab ；most PTs in SOCs such as various nervous system diseases ，immune system diseases ，mental diseases ，benign，malignant and unknown tumors （including cystic and polypoid）which were taken attention in clinic were not included in the drug instruction of belimumab. It is suggested to avoid medication errors as far as possible in clinical use of belimumab ，and to guard against adverse reactions such as herpes zoster ， kidney infection ，cellulitis and various nervous system diseases ，immune system diseases and mental diseases. In addition ，the patients with malignant tumor or related history should use belizumab carefully.

Medication evaluation and adverse reaction monitoring in patient on peritoneal dialysis with pancytopenia induced by vancomycin / 药学实践杂志

Objective To provide reference for anti-infection treatment and individual pharmaceutical care in patient on peritoneal dialysis. Methods The plasma concentration of vancomycin in patient on peritoneal dialysis was monitored by clinical pharmacists. The anti-infection treatment plan was evaluated and adjusted according to the bacterial culture and drug sensitivity results of the abdominal dialysis fluid. The adverse reactions of pancytopenia induced by vancomycin were documented. Results Infection in the patient on peritoneal dialysis was effectively controlled. The related indicators of pancytopenia were improved. Conclusion A case of pancytopenia induced by vancomycin in the patient on peritoneal dialysis was analyzed to get clinical staff's attention to this adverse reaction and improve the safety of vancomycin administration.

Mining and Evaluation of Post-marketing Safe Alert Signals of Pegaspargase and L-asparaginase Based on BCPNN Method / 中国药房

OBJECTIVE： To mine and evaluate the post-marketing safety alert signals of pegaspargase （PEG-ASP） and L-asparaginase （L-ASP），and compare the safety differences between them ，so as to provide reference for clinical safe and rational drug use. METHODS ： The adverse drug event （ADE） reports of PEG-ASP and L-ASP issued by FDA adverse event reporting system from Jan. 1st，2004-Jun. 30th，2020 were retrieved. BCPNN method was used to mine the safety signals of these two drugs under the condition that the lower limit of information component （IC－2SD）＞0 and the number of events ≥3. The medium and strong signals of two drugs with IC －2SD≥1.5 were evaluated and compared in 8 system organ class，such as gastrointestinal system ，hepatobiliary system ，blood and lymphatic system ，blood vessels and lymphatic vessels ， nervous system ，immune system ，metabolism and nutrition ，various examinations. IC value of specific ADE signal and its 95％ confidence interval were analyzed by time scanning spectrum. RESULTS & CONCLUSIONS ：The reports of PEG-ASP and L-ASP as suspected drugs were 2 324 and 3 824；67 and 68 medium and strong signals were included ，respectively. In gastrointestinal system，the common strong signal of PEG-ASP and L-ASP was necrotic pancreatitis. In hepatobiliary system ，both of them showed strong signal in venoocclusive liver disease ，and this ADE was not included in the drug instruction. In blood and lymphatic system ， common strong signals of the two drugs were febrile neutropenia ，coagulation disorder ，neutropenia and febrile bone marrow regeneration disorder ；in blood vessels and lymphatic vessels ，in addition to haemodynamic instability ，IC values of other signals of L-ASP were higher than those of PEG-ASP. In nervous system ，IC values of other signals of L-ASP were higher than those of PEG-ASP except for intracranial haemorrhage. In immune system ，anaphylactic reaction was a medium signal for L-ASP but was a strong signal for PEG-ASP. In metabolism and nutritional diseases ，except for tumor lysis syndrome ，IC values of other signals of L-ASP were higher than those of PEG-ASP. The results of time scanning spectrum showed that the signals of necrotic pancreatitis and coagulation disorder of PEG-ASP were stable ，while the signals of veno occlusive liver disease and hypersensitivity were unstable and needed to be observed ；above four signals of L-ASP were stable signals. When using PEG-ASP or L-ASP clinically ， close attention should be paid to the safety problems such as hypersensitivity ，coagulation disorder ，thrombosis，necrotic pancreatitis，venoocclusive liver disease and hypoproteinemia.

Analysis of adverse reactions risk signal of Xinyuan Capsules based on national ADR monitoring spontaneous reporting system / 中国中药杂志

In recent years, the safety problems and events of traditional Chinese medicine represented by liver injury have occurred frequently. In particular, Polygonum multiflorum has been widely used and considered as a "non-toxic" tonic traditional Chinese medicine for thousands of years. However, in recent years, frequent reports of liver injury events have attracted widespread attention at home and abroad, which has made unfavorable impacts on traditional Chinese medicine and its international development. Some scho-lars have found that susceptible genes of P. multiflorum on liver injury lay a scientific foundation for formulating rational comprehensive prevention and control measures for liver injury risk of P. multiflorum and its relevant preparations. But what are the risk signals of adverse reactions of P. multiflorum in clinical application? Spontaneous reporting system is an important way to monitor and find adverse drug reaction(ADR) signals after the drug is launched in the market. It can find the ADR signals in time and effectively, and then effectively prevent and avoid the occurrence of adverse drug events. At present, the data mining technique has gradually become the main method of ADR/adverse event(AE) report analysis and evaluation at home and abroad. Specifically, Bayesian confidence propagation neural network in Bayesian method is a commonly used risk signal early warning analysis method. In this paper, BCPNN method was used to excavate the risk signals of adverse reactions of Xinyuan Capsules, a traditional Chinese medicine preparation containing P. multiflorum, such as nausea, diarrhea, rash, dizziness, vomiting, abdominal pain, headache, liver cell damage, so as to provide evidence-based evidence for clinical safe and rational use of drugs.

Analysis of adverse reactions of Xianling Gubao preparation based on real world SRS data / 中国中药杂志

From January 1, 2004 to July 21, 2016 a total of 2 796 cases of adverse drug reaction/adverse event(ADR/AE) after the use of Xianling Gubao Capsules/Tablets were reported by National Adverse Drug Reaction Monitoring Center. The following results were obtained by analyzing the reports of 2 796 cases of adverse drug reactions/adverse drug events after the use of Xianling Gubao Capsules/Tablets. A total of 75 patients, accounting for 2.68% of the total ADR/AE time, had severe ADR/AE events. Among them, 30 patients were aged 65 and above, accounting for 40.00% of the total number of severe ADR/AE patients. All the patients with ADR/AE were aged 45-64 years, which totaled 1 346 cases and took up 48.14% of the total patients with ADR/AE. All of ADR/AE cases and severe ADR/AE cases were orally given Xianling Gubao Capsules/Tablets. Females accounted for 52.50% and 76.00%, respectively, and the proportion of females was significantly higher than that of males. Among patients with a medical history of ADR/AE, severe ADR/AE was higher than the average, accounting for about 1.33%. The proportion of cases orally given 1-3 tablets of Xianling Gubao Capsules/Tablets in all ADR/AE cases and severe ADR/AE cases was 95.32% and 96.00%, which conformed to the usage in the package insert. All ADR/AE cases and severe ADR/AE cases orally given Xianling Gubao Capsules/Tablets twice daily occupied the highest proportions, or 77.00% and 61.00%, respectively. The proportion of severe ADR/AE cases orally given Xianling Gubao Capsules/Tablets was slightly higher than that of all ADR/AE cases in the medication frequency, which didn't conform to the usage in the package insert. All the symptoms of ADR/AE orally given Xianling Gubao Capsules showed many manifestations, and the top 10 symptoms were nausea, rash, itching, stomach dysfunction, vomiting, abdominal pain, dizziness, diarrhea, anaphylaxis, and reflux heartburn. The symptoms of severe ADR/AE after oral administration of Xianling Gubao Capsules were varied, and the top 10 symptoms were abnormal liver function, rash, suffocation, itching, dizziness, vomiting, anaphylaxis, abdominal pain, weakness, and convulsions. Abnormal liver function accounted for 44.12%. All of ADR/AE cases occurred within 2 days after oral administration of Xianling Gubao Capsules/Tablets, accounting for 54.26%. Severe ADR/AE occurred within 2 days after the use of Xianling Gubao Capsules/Tablets, accounting for 25.34%. The proportion of ADR/AE cases occurring within 15 days after oral administration of Xianling Gubao Capsules/Tablets increased again(57.33%). The overall trend contained two peaks.

Analysis of adverse drug reaction/adverse event and early warning signal mining of Ginkgo biloba Dropping Pills based on SRS data / 中国中药杂志

In order to understand the characteristics of adverse drug reaction/adverse event(ADR/AE) of Ginkgo biloba Dropping Pills and evaluate the safety of clinical use after marketing, 407 ADR/AE case report data of Ginkgo biloba Dropping Pills collected by National Center for ADR Monitoring System during 2009-2018 was systematically analyzed, and its general characteristics were analyzed using descriptive statistical methods. The results showed that among the 407 cases of spontaneous reporting system(SRS) data, 401 cases were general ADR/AE, accounting for 98.5%, and 6 cases were severe ADR/AE, accounting for 1.5%; there were more females than males(171/150) in ADR/AE, and they were mainly middle-aged and elderly people aged 45-64 years(152 cases, accounting for 37.35%); gastrointestinal system(23.89%) was mostly involved in ADR/AE. The top ten clinical symptoms were nausea(15.49%), dizziness(9.88%), vomiting(8.11%), rash(5.60%), chest tightness(5.46%), palpitations(5.31%), pruritus(4.72%), headache(4.57%), abdominal distension(3.83%), gastric dysfunction(3.54%); proportional reporting ratio(PRR) and Bayesian confidence progressive neural network method(BCPNN) were adopted to mine ADR/AE warning signals. Due to the small sample size, there were only 0-2 ADR/AE cases with various symptoms in many quarters, with no warning signal by PRR and BCPNN methods. The findings suggest that ADR/AE of Ginkgo biloba Dropping Pills based on SRS system was not recorded in the package insert, and further active monitoring studies shall be conducted to improve relevant ADR/AE information and pay attention to its clinical drug safety issues.

Creating a Checklist and a Survey on Research That Used the Japanese Adverse Drug Event Report Database / 医薬品情報学

Objective: The purpose of this study was to create a checklist that summarizes checkpoints that should be noted when using the Japanese Adverse Drug Event Report database (JADER). After we created the checklist, we then used it to survey published academic papers that used JADER.Method: First, we created a draft checklist for research that uses JADER by citing the report of CIOMS working group VIII “Practical Aspects of Signal Detection in Pharmacovigilance”. Then, we conducted a pilot test and revised the draft checklist. Finally, the checklist was completed after the review by a pharmacoepidemiology expert. The checklist was applied to published academic papers that used JADER, and the fulfill rate of each checkpoints was calculated.Results: A “checklist of important points to be noted during research that uses the data mining method in JADER (mainly signal detection by disproportionality analysis)” was created. We also revealed problems with published academic papers that used JADER. For example, some researchers were thought to be inappropriately using JADER as a source of their research while others used an inappropriate version of MedDRA.Conclusion: The checklist created in this study summarizes key points that could be noted in research that uses JADER and is thought to contribute to an improvement in quality of research that uses JADER. Additionally, in our investigation of published academic papers that used JADER, we found the possibility that both the role of signal detection and the impact on analysis of JADER using the updated MedDRA version are not well understood.

Detection and Analysis of Safety Signals of Chloroquine Based Upon FDA Adverse Event Database / 中国药学杂志

OBJECTIVE: To analyze and evaluate the safety signals of chloroquine in the patients, and to provide a valuable reference for rational use in clinic. METHODS: Both the reporting odds ratio (ROR) method and Bayesian confidence propagation neural network (BCPNN) were applied to analyze safety signals of chloroquine based upon the adverse drug events (ADEs) data ranging from 2004 to 2020 as reported in the Adverse Event Reporting System (FAERS) database of the Food and Drug Administration (FDA), and to systematically assesse the safety signals of chloroquine phosphate on various organs systems. RESULTS: Among the 2 063 reports of ADEs studied, 557 reports were considered to be mainly caused by chloroquine. The results demonstrated that the high-risk ADEs signals of chloroquine involved various systems, such as atrioventricular block complete (ROR=2.90, IC-2SD=1.64), ventricular fibrillation (ROR=3.40, IC-2SD=1.27), blindness (ROR=27.51, IC-2SD=0.55), cardiogenic shock (ROR=6.86, IC-2SD=0.54), vomiting (ROR=1.70, IC-2SD=1.83). Moreover, some rare ADEs with high-risk signals showed a correlation with chloroquine, including hypokalaemia (ROR=4.18,IC-2SD=1.51), renal failure acute (ROR=3.08, IC-2SD=0.30), methaemoglobinaemia (ROR=4.37, IC-2SD=0.03), and pyrexia (ROR=1.80, IC-2SD=1.84), which were consistent with literature reports. However, these ADEs were not listed in instruction and worth much attention in clinic. Moreover, basic diseases of patients and drug incompatibility need much attention to prevent the occurrence and exacerbation of chloroquine-related adverse reactions. CONCLUSION: A comprehensive analysis of the ADEs signals of chloroquine could shed some light on understanding of its safety characteristics and would provide valuable information for rational use of chloroquine in clinic, especially in treatment of COVID-19.