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.

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.

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.

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.

Tocilizumab related adverse events: A cross-section analysis of FDA Adverse Event Reporting System / 中国临床药理学与治疗学

AIM: To analyze the adverse events (AE) of tocilizumab by using the FDA Adverse Event Reporting System (FAERS) database. METHODS: AE reports related to tocilizumab were extracted from the FAERS database. Disproportionality analysis of reporting odds ratio (ROR) and Medicines and Healthcare Products Regulatory Agency (MHRA) methods were performed for safety signal detection. RESULTS: A total of 19 773 reports associated with tocilizumab as the primary or secondary suspected drugs were extracted from the FAERS database between July 2014 to March 2019. AEs of drug ineffective, pain, drug intolerance, fatigue and rash were commonly reported. There were 13 642 serious AE reports, and 602 reports of death outcome. The proportion of serious and death outcome AEs of male patients was significantly higher than female, and these proportions were significantly higher in children and elderly compared with others. Respectively 602 and 490 of tocilizumab signals were detected by ROR method and MHRA method, including common AEs such as infection, drug hypersensitivity, leukopenia, and hepatic enzyme increased, and signals not indicated in label, for instance, pulmonary fibrosis, interstitial lung disease, pancreatic toxicity and demyelination, were also detected. CONCLUSION: The commonly reported AEs of tocilizumab include drug inefficiency, pain, drug intolerance, fatigue and rash. Pulmonary fibrosis, interstitial lung disease, pancreatic toxicity and demyelination, which not indicated in label, should be further assessed and be cautious in COVID-19 treatment.