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  • Fang Zhenwei, Qiu Qi, Lin Yang
    Adverse Drug Reactions Journal. 2024, 26(1): 2-5. https://doi.org/10.3760/cma.j.cn114015-20231218-00906
    Along with the reforms of the assessment and approval regime for new drugs in China in recent years, independently researched and developed innovative drugs and conditionally approved drugs in China have been more and more. The pre-market clinical trials, assessment and approval system (especially the conditional approval system), and post-market monitoring and management of new drugs in China are still in a continuous improvement stage. Thus we need to specially pay attention to the safety of innovative drugs that independently developed in China and do a good job in post-marketing safety supervision. More evidence-based information for safe use of this type of medication in patients can be provided through the following aspects: strengthening the drug safety monitoring, conducting systematic evaluation of literature data, widely collecting drug safety data through high-quality real-world research, and conducting in-depth mining of information from drug safety reports.
  • Wang Shaojun, Li Chao, Liu Caixia, Su Wuyun, Huang Congxiu
    Adverse Drug Reactions Journal. 2024, 26(1): 12-17. https://doi.org/10.3760/cma.j.cn114015-20230912-00678
    Objective To explore the occurrence of immune-related adverse events (irAEs) and the relationship to efficacy of camrelizumab in treatment for patients with non-small cell lung cancer (NSCLC). Methods Clinical data of patients with NSCLC who received camrelizumab in at the Affiliated Hospital of Inner Mongolia Medical University from December 2020 to December 2022 were collected, and the efficacy of camrelizumab and the occurrence of irAEs were retrospectively analyzed. Patients were divided into irAEs group and non-irAEs group according to whether they developed irAEs. The objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS) of the 2 groups were compared. Results A total of 48 patients were entered in the analysis, including 41 males (85.4%) and 7 females (14.6%), with an age of (65.9±7.4) years; the median treatment cycle was 9 (6, 14); the overall ORR was 52.1% (25/48), the DCR was 83.3% (40/48), and the median PFS was 11 months. Among the 48 patients, 34 patients (70.8%) had 59 times of irAEs, of which 8 patients (16.7%) had at least one irAE of grade ≥3. The median time of irAEs occurrence was 5 (3, 7) treatment cycles. The irAEs with an incidence of >10% included reactive cutaneous capillary endothelial proliferation (RCCEP), thyroid injury, skin injury, lung injury, liver injury, and blood toxicity, with the incidences of 37.5% (18/48), 18.8 (9/48), 16.7% (8/48), 12.5% (6/48), 10.4% (5/48), and 10.4% (5/48), respectively. Compared with non-irAEs group, patients in the irAEs group had higher ORR and DCR [64.7% (22/34) vs. 3/14, 91.2% (31/34) vs. 9/14] and longer median PFS (12.0 months vs. 7.0 months, hazard ratio=0.418, 95% confidence interval: 0.193-0.905), and the differences were statistically significant (all P<0.05). Conclusions The common irAEs of camrelizumab in treatment for patients with NSCLC was RCCEP, and fewer serious irAEs occurs. To a certain extent, patients who experience irAEs during camrelizumab treatment may predict a more pronounced therapeutic response.
  • Zhu Hui, Yuan Yongfang, Xu Ying
    Adverse Drug Reactions Journal. 2024, 26(1): 18-24. https://doi.org/10.3760/cma.j.cn114015-20230803-00582
    Objective To explore the occurrence, influencing factors, and predictive biomarkers of immune-related adverse events (irAEs) in malignant tumor patients treated with tislelizumab. Methods The electronic medical records of adult patients with malignant tumors, who received tislelizumab for at least one cycle from June 2020 to June 2023 at Shanghai Ninth People′s Hospital, Shanghai Jiao Tong University School of Medicine, were collected, and the occurrence and clinical characteristics of irAEs were retrospectively analyzed. Patients were divided into irAEs group and non-irAEs group according to whether they had irAEs. The clinical characteristics and detection value of biomarkers in patients of the 2 groups were compared. Multivariate logistic regression was used to analyze the risk factors of irAEs in patients. The receiver operating characteristic (ROC) curve was used to find the cutoff point of the biomarkers for predicting the irAEs. Results A total of 107 patients were entered, including 81 males (75.7%) and 26 females (24.3%), aged (61±15) years. Among them, 25 patients (23.4%) were diagnosed with tislelizumab-related irAEs, of which 6 patients (5.6%) had irAEs with a severity of grade 3 and above. A total of 28 irAEs occurred in the 25 patients, including 9 cases of thyroid dysfunction, 4 cases of immune-related enteritis, 4 cases of rashes, 3 cases of immune-related pneumonitis, 3 cases of kidney injury, 3 cases of liver injury, 1 case of immune- related myositis, and 1 case of hypertension. The median treatment cycle from the start of tislelizumab to the occurrence of irAEs was 3 (1, 5) cycles. After discontinuation of tislelizumab and/or glucocorticoids and symptomatic treatments, all 25 patients were improved. No deaths occurred due to irAEs. The results of multivariate logistic regression analysis showed that a high neutrophil-to-lymphocyte ratio (NLP) at baseline was a protective factor for irAEs [odds ratio (OR)=0.453, 95% confidence interval (CI): 0.279-0.735, P=0.001], while a high platelet-to-lymphocyte ratio (PLR) at baseline was a risk factor (OR=1.006, 95%CI: 1.002- 1.011, P=0.008). The ROC curve analysis results showed that the cutoff points of NLR and PLR at baseline for predicting the occurrence of irAEs were 1.58 (sensitivity: 0.988; specificity: 0.644) and 159.40 (sensitivity: 0.800; specificity: 0.524), respectively. Conclusions The incidence of irAEs in the tislelizumab treatment for adult malignant tumors was 23.4%. Thyroid dysfunction is most common and attentions should also be paid to immune-related enteritis, rashes, immune-related pneumonitis, kidney injury, and liver injury. Baseline levels of NLR and PLR may be biomarkers for predicting irAEs.
  • Fang Zhenwei, Zhao Yiru, Zhang Ying, Lin Yang
    Adverse Drug Reactions Journal. 2024, 26(1): 25-32. https://doi.org/10.3760/cma.j.cn114015-20230406-00252
    Objective To evaluate the efficacy and safety of hybutimibe in the treatment of hypercholesterolemia. Methods Relevant databases and clinical trial registration websites at home and abroad were searched (up to March 27, 2023), and randomized controlled trials (RCTs) of hybutimibe in the treatment of hypercholesterolemia have been collected. Patients in the trial group were given hybutimibe with or without other hypolipidemic agents, and those in the control group were given placebo or other hypolipidemic agents as same as that in the trial group. The primary outcome in effectiveness was the change rate of low-density lipoprotein cholesterol (LDL-C). The primary outcomes in safety were incidences of overall adverse events (AEs), serious AEs (SAEs), the trial termination due to AEs, and trial drug-related AEs. The secondary outcome in safety was incidence of the major AE reported in ≥ 2 trials. Meta-analysis was performed using RevMan 5.4-software. The effect sizes of counting data were expressed by the relative risk (RR) and its 95% confidence interval (CI). The effect sizes of measurement data were expressed by mean difference (MD) and its 95%CI. Results A total of 4 RCTs and 1-488 patients were entered in the analysis, including 952 patients in the trial group and 536 in the control group. The results of meta-analysis showed that at 8-12 weeks of treatment, the decrease rate of LDL-C in the trial group (hybutimibe 20 or 10-mg daily with or without atorvastatin 10-mg daily) was significantly greater than that in the control group (hybutimibe 20-mg daily: MD=-13.36%, 95%CI: -15.28% - -11.44%, P<0.001; hybutimibe 10-mg daily: MD=-10.80%, 95%CI: -14.90%- -6.71%, P<0.001); at 52 weeks of treatment, the average decrease rate (from baseline) of LDL-C in the trial group (hybutimibe 20 or 10-mg combined with atorvastatin 10-mg daily) was significantly greater than that in the control group with atorvastatin 10-mg daily monotherapy (-41.92% and -39.34% vs. -31.56%, all P<0.001); the incidences of overall AEs [47.94% (338/705) vs. 49.75% (202/406),RR=0.99, 95%CI: 0.87-1.12], SAEs[2.64% (16/606) vs. 2.79% (10/358), RR=1.19, 95%CI: 0.53-2.66], trial termination due to AEs[4.11% (29/705) vs. 4.68% (19/406), RR=0.67, 95%CI: 0.17-2.65], and trial drug-related AEs [12.38% (75/606) vs. 11.45% (41/358), RR=0.87, 95%CI: 0.37-2.06] were similar between the 2 groups at 8-12 weeks of treatment (all P>0.05). Conclusion Hybutimibe could effectively reduce LDL-C level in patients with hypercholesterolemia, with good medication safety.
  • Wang Xinyu, Zhang Yundi, Li Yue, Zong Huiying, Han Wenqian, Liu Lun, Wang Qian, Guo Lubo, Di Huifeng, Zhen Xiaohui, Sun Deqing, Su Ying, Zhang Zonglin, Peng Jing, Cao Xiaofu, Liu Ning, Liu Jian, Lu Cuicui, Wang Li, Geng Tao, Li Rongji, Sun Guodong, Zhang Fan, Zhang Lin, Ma Chuanjiang, Tan Siyuan, Qian Dongfang, Li Yan
    Adverse Drug Reactions Journal. 2023, 25(11): 649-655. https://doi.org/10.3760/cma.j.cn114015-20230706-00505
    Objective To compare the efficacy and safety of insulin degludec and insulin glargine U100 in patients with type 2 diabetes mellitus. Methods This study was a retrospective cohort study. The subjects were patients with type 2 diabetes mellitus who were hospitalized in 13-3A-level general hospitals in Shandong Province from September 2018 to December 2021. According to the type of basal insulin used, the patients were divided into insulin degludec group and insulin glargine U100 group. The basic information and laboratory test results in patients in the 2 groups were collected, the differences of fasting blood glucose level and incidence of hypoglycemia between the 2 groups were compared. The patients with complete blood glucose monitoring data in the 2 groups were selected and their blood glucose fluctuations were compared. Results A total of 1-152 patients were entered in the study, including 552 patients in the insulin degludec group and 600 patients in the insulin glargine U100 group. The difference in the basic conditions in patients in the 2 groups was not statistically significant (all P>0.05). After treatment, the fasting blood glucose levels in patients in the 2 groups were lower than those before treatment, with statistically significant differences [10.2 (8.8, 12.5) mmol/L vs. 7.5 (6.6, 8.7) mmol/L, Z=-19.443, P<0.001; 10.0 (8.6, 11.7) mmol/L vs. 7.8 (6.6, 9.0) mmol/L, Z=-15.449, P<0.001], but the difference in fasting blood glucose levels between the 2 groups after treatment was not statistically significant (Z=-1.427, P>0.05). The incidence of hypoglycemia in the insulin degludec group was lower than that in the insulin glargine U100 group [1.09% (6/552) vs. 2.83% (17/600), Z=4.481, P=0.032]. The intraday blood glucose standard deviation, maximum blood glucose fluctuation range, postprandial blood glucose fluctuation range, and average blood glucose fluctuation range in patients with complete blood glucose monitoring data in the insulin degludec group were significantly lower than those in the insulin glargine U100 group [(1.7±0.6) mmol/L vs. (2.4±1.0) mmol/L, (4.5±1.6) mmol/L vs. (6.7±2.9) mmol/L, (1.8±1.0) mmol/L vs. (3.3±1.2) mmol/L, (2.9±1.3) mmol/L vs. (4.6±2.1) mmol/L; all P<0.001]. Conclusion The efficacy of insulin degludec in the treatment of type 2 diabetes mellitus is equivalent to that of insulin glargine U100, but the risk of hypoglycemia and blood glucose fluctuation is lower.
  • Zhang Yalan, Hong Wencong, Chen Qiying
    Adverse Drug Reactions Journal. 2023, 25(11): 656-661. https://doi.org/10.3760/cma.j.cn114015-20230410-00261
    Objective To mine the risk signals of ipilimumab-related adverse events (AEs) and provide reference for the safe use in clinical practice. Methods AE reports with ipilimumab as the primary suspect drug were collected from US FDA Adverse Event Reporting System database during March 1, 2011 to September 30, 2022. AEs were standardized and classified according to the preferred term (PT) and system organ class (SOC) in Medical Dictionary for Regulatory Activites version 26.0. The AE risk signals of ipilimumab were mined using reporting odds ratio (ROR) method. An AE with reports≥3, ROR≥2, 95% confidence interval (CI) lower limit of ROR>1 was defined as a risk signal. Risk signals were analyzed using descriptive method. Results A total of 12-329 AE reports were entered in the analysis, involving 1-915 PTs. Two hundred and sixty-eight risk signals (PTs) were obtained using ROR method, involving 21 SOCs. The top 10 PTs in report number were diarrhea, colitis, rash, fever, hypophysitis, adrenal insufficiency, decreased appetite, hypothyroidism, liver disease, and dehydration, all of which were common AEs in the labels. The top 10 PTs in signal intensity were hypophysitis, lymphocytic hypophysitis, immune-mediated dermatitis, immune-mediated adrenal insufficiency, hypopituitarism, immune-mediated liver disease, adrenocorticotropic hormone deficiency, immune-mediated encephalitis, autoimmune colitis, and immune-mediated hyperthyroidism. The SOCs involved were endocrine system diseases, skin and subcutaneous tissue diseases, hepatobiliary system diseases, gastrointestinal system diseases, and nervous system diseases. A total of 36 PTs were not included in the labels, and the top 5 in signal intensity were intracranial tumor hemorrhage, radiation necrosis, malignant pleural effusion, pulmonary granuloma, and lichenoid keratosis. Conclusions The main AEs of ipilimumab are diarrhea, colitis, rash, etc. In addition, ipilimumab might cause adverse reactions such as intracranial tumor hemorrhage, radiation necrosis, and malignant pleural effusion that are not recorded in label, which should be vigilant in clinical practice.
  • Tang Yang, Ma Yanbin, Wang Shuyun, Guo Qian, Yin Donghong, Duan Jinju
    Adverse Drug Reactions Journal. 2023, 25(11): 662-668. https://doi.org/10.3760/cma.j.cn114015-20230417-00277
    Objective To understand the risk signal of ocular adverse events (AE) related to mycophenolate mofetil (MMF) and to provide reference for the safe clinical use of this drug. Methods The US FDA Adverse Event Reporting System database was searched, and the AE reports on MMF as the primary suspect drug from the 1st quarter of 2004 to the 3rd quarter of 2022 were collected. AEs were counted and classified using the preferred system organ class (SOC) and preferred term (PT) of Medical Dictionary for Regulatory Activities version 24.0, and ocular AEs were screened out. The ocular AE risk signals were explored using 3 frequency methods, including reporting odds ratio (ROR) method, proportional reporting ratio (PRR) method, and Bayesian confidence propagation neural network method, and the multi-item gamma-Possion shrinker (MGPS) method. The information of the ocular AE reports and AE risk signals of MMF were analyzed descriptively. Results A total of 402 cases of ocular AE with MMF as the primary suspect drug were collected, which involved 402 patients, 31 PTs and 5 SOCs. The 402 AE cases were reported among 33 countries, 283 of which had clinical outcome records, including death in 32 cases (11.3%), disability or blindness in 142 cases (50.2%), life-threatening in 14 cases (4.9%), and hospitalization or prolonged hospitalization in 95 cases (33.6%). Results of the frequency method showed that all 31 PTs were risk signals, while the results of the MGPS method manifested that 22 PTs were risk signals. None of the 31 PTs were recorded in the drug labels. The top 5 PTs in the number of AE reports were blindness (136 cases), cytomegalovirus chorioretinitis (37 cases), uveitis (34 cases), endophthalmitis (29 cases), and necrotising retinitis (22 cases). The ranking of signal intensity showed by the 4 methods was similar. The top 5 PTs with the high signal intensity were orbital apex syndrome [ROR=55.84, PRR=55.83, information component (IC)=5.58, empirical Bayesian geometric mean (EBGM)=47.71], quadrantanopia (ROR=43.22, PRR=43.21, IC=5.26, EBGM=38.21), retinitis viral (ROR=40.13, PRR=40.13, IC=5.16, EBGM=35.78), optic discs blurred (ROR=40.13, PRR=40.13, IC=5.16, EBGM=35.78), and serpiginous choroiditis (ROR=31.07, PRR=31.07, IC=4.83, EBGM=28.41). Conclusions The clinical manifestations of ocular AE during MMF treatment are diverse, and none of them are recorded in the drug label. The clinical outcomes are poor and can lead to blindness, which should be vigilant in clinical practice.
  • Cui Jiali, Niu Yurong, Liu Ning, Wang Huiyun, Song Shanai, Zhang Chuantao, Zhang Xiaochun, Hou Helei
    Adverse Drug Reactions Journal. 2023, 25(11): 641-648. https://doi.org/10.3760/cma.j.cn114015-20230601-00388
    Objective To explore the clinical manifestation, treatments, and outcomes of immune checkpoint inhibitor (ICI)-induced immune-mediated liver injury (IMLI). Methods The patients with ICI- related IMLI and hospitalized in the Department of Oncology, the Affiliated Hospital of Qingdao University from January 2018 to November 2022 were collected. The basic information, tumor treatments, clinical manifestation, treatments and outcomes of the patients with IMLI were retrospectively analyzed. Results A total of 29 patients were included in the study, including 17 males (58.6%) and 12 females (41.4%), with a median age of 65 years. The median treatment cycle from the use of ICI to the occurrence of liver injury was 3 cycles, and the median time was 78 days. In patients with IMLI, 48.3% (14/29) had no obvious symptoms and 51.7% (15/29) had symptoms such as decreased appetite, nausea, abdominal distension, fatigue, fever and jaundice; 44.8% (13/29) were accompanied by other immune-related adverse events. The clinical classification of IMLI was hepatocellular type in 18 patients (62.1%), cholestasis type in 4 patients (13.8%), and mixed type in 7 patients (24.1%). According to the Common Terminology Criteria for Adverse Events (CTCAE) classification, severe liver injury (≥ grade 3) accounted for 86.2% (25/29), while according to the Chinese Diagnosis and Treatment Guideline on Drug-Induced Liver Injury (DILI guidelines) classification, severe liver injury (≥ grade 2) accounted for 34.5% (10/29). All 29 patients discontinued the treatment of ICIs after occurrence of IMLI, and 28 patients were treated with glucocorticoids, 7 of which were combined with mycophenolate mofetil and/or human immunoglobulin and artificial liver; 22 patients (75.9%) were improved. In the other 7 patients that did not recover, 4 discharged automatically, 2 died, and 1 could not be judged. ICI was rechallenged in 3 patients after liver function improvement, and IMLI did not recur. Conclusions The IMLIs often occur 2 to 3 months after the start of ICI treatment, the most common clinical type is hepatocyte type, and the severity of clinical symptoms in patients vary from mild to severe. After discontinuing ICIs and receiving glucocorticoid treatments, most patients may have a good prognosis.
  • Wu Shiqi, Zhu Xuelu, Su Su, Ma Wenyao, Wang Chunguang, Yan Suying, Yue Xiaolin
    Adverse Drug Reactions Journal. 2023, 25(10): 584-591. https://doi.org/10.3760/cma.j.cn114015-20221230-01197
    Objective To investigate the current status of polypharmacy among elderly outpatients with 4 types of chronic diseases such as hypertension, diabetes mellitus, coronary atherosclerotic heart disease, and cerebrovascular disease. Methods A retrospective study was conducted on the drug use of elderly (≥65 years old) outpatients with hypertension, diabetes mellitus, coronary atherosclerotic heart disease, and cerebrovascular disease with data of Beijing Municipal Health Insurance Centre database from July 2017 to September 2017. The included patients had at least 1 of 4 types of chronic diseases. Polypharmacy was defined as ≥5 different types of medication at the first visit, and non-polypharmacy was defined as <5 types of medication. The number and severity of comorbidity were quantified using the Charlson Comorbidity Index (CCI), and the prognosis of patient was evaluated at 4 levels of 0, 1, 2, and ≥3 scores. The larger the value, the more severe the disease. Based on the Beers Criteria 2015, the potential inappropriate medication (PIM) was identified using the prescription review system of Puhua Health. Results A total of 405-608 patients were included in this study, with a median age of 74 (65-107) years , and 204-219 patients (50.35%) were female. According to the type of medication used by patients, they were divided into polypharmacy group (113-594 cases, 28.01%) and non-polypharmacy group (292-014 cases, 71.99%). The CCI of the polypharmacy group was significantly higher than that of the non-polypharmacy group (P<0.001). The proportion of patients with 0, 1, 2, and ≥3 scores in the polypharmacy group was significantly higher than that of the non-polypharmacy group, and the differences were statistically significant (all P<0.001). In terms of comorbidity, the proportions of patients among the 4 types of chronic diseases were higher in the polypharmacy group than in the non-polypharmacy group (P<0.001). In terms of concomitant diseases, the proportion of patients with hyperlipidemia, cognitive impairment, heart failure, and osteoporosis in the polypharmacy group was higher than that in the non-polypharmacy group (all P<0.001). In terms of medical treatment behaviour, the median number of medical visits was higher in the polypharmacy group than in the non-polypharmacy group [2(1,3) vs. 1(1,2), P<0.001]. In terms of evaluating the unsuitability of medication, the proportion of patients with PIM in the polypharmacy group was higher than that in the non-polypharmacy group, including repeated medication [4.60% (5-227/113 594) vs. 1.64% (4-486/292 014)], contraindications [2.97% (3-376/113 594) vs. 1.13% (3-294/292 014)], interactions [6.51% (7-399/113 594) vs. 1.94% (5-658/292 014)], and lack of indications [22.39% (25-432/113 594) vs. 13.54% (39-543/292 014)], and the differences were all significant (all P<0.001). In terms of drug use categories, the top 5 most commonly prescribed drugs in the polypharmacy group were HMG-CoA reductase inhibitors (68-318 cases, 60.14%), dihydropyridines (60-951 cases, 53.66%), angiotensin receptor antagonists(45-050 cases, 39.66%), β-receptor blockers (25-675 cases, 22.60%) and sulfonylureas (16-023 cases, 14.11%). Conclusions Polypharmacy is common in elderly patients with hypertension, diabetes mellitus, coronary artery disease, and cerebrovascular disease. The elderly patients with polypharmacy have a worse baseline status and more problems with PIM.
  • Shao Miaomiao, Sun Ximu, Zhou Han, Li Ying, Sun Yixin, Yang Changqing, Wang iaoling, Zhao Wen
    Adverse Drug Reactions Journal. 2023, 25(10): 592-600. https://doi.org/10.3760/cma.j.cn114015-20231016-00737
    Objective To understand the adverse event (AE) risk signals of 3 anti-disialoganglioside 2 (GD2) monoclonal antibodies, including dinutuximab, dinutuximab beta, and naxitamab, and to provide reference to clinical use. Methods AE reports with dinutuximab, dinutuximab beta, and naxitamab as the primary and secondary suspect drug were collected from the US FDA Adverse Event Reporting System (FAERS) database during 2015 to the 2nd quarter of 2023. AEs were standardized and classified according to the preferred term (PT) and system organ classification (SOC) in the International Medical Terminology Dictionary, Version 25.0, and AE risk signals were mined using the reporting odds ratio (ROR) method and information component (IC) method. The AE reports information and AE risk signals of 3 GD2 monoclonal antibodies were descriptively analyzed. Results A total of 630 AE reports were collected, in which the 3 GD2 monoclonal antibodies were the primary and secondary suspect drugs, including 465 reports of dinutuximab, 61 reports of dinutuximab beta, and 104 reports of naxitamab, which involved 341, 24, and 125 PTs and mapped to 19, 2, and 12 SOCs, respectively. The AEs of the 3 GD2 monoclonal antibodies were associated with the occurrence of death, life-threatening, hospitalization, or prolonged hospitali- zation adverse outcomes. Signal mining using ROR and IC methods detected a total of 142, 3, and 30 AE risk signals, of which 73, 0, and 6 were not documented in the corresponding drug instructions, respectively. The top PTs in report number were fever for both dinutuximab and dinutuximab beta, and hypotension and pain for naxitamab; the top PTs in signal intensity were puncture site abscess, device related bacteraemia, and wheezing for dinutuximab, dinutuximab beta, and naxitamab, respectively. The overlapping AE risk signals for the 3 drugs were fever and pain, with dinutuximab having the strongest signal intensity for fever and naxitamab having the strongest signal intensity for pain. Among the top 30 PTs in report number, naxitamab had significantly more AE risk signals than dinutuximab in respiratory, thoracic, and mediastinal disorders, skin and subcutaneous tissue disorders, immune system disorders, and vascular disorders. For naxitamab, the PTs that differed from dinutuximab′s AE risk signals and were not documented in the naxitamab drug instructions were respiration abnormal, cyanosis, and metabolic acidosis. Conclusions Fever, pain, and hypotension are common AEs for the 3 GD2 monoclonal antibodies. Naxitamab causes significant pain; respiration abnormal, cyanosis, and metabolic acidosis are AE risk signals specific to naxitamab and not documented in the drug instruction, which warrant clinical vigilance and prompt intervention.
  • He Yu′na, Wang Yini, Bai Hongmei, Yang Ziqi, Guo Jing, Yang Chun, Zhang Xue
    Adverse Drug Reactions Journal. 2023, 25(10): 601-606. https://doi.org/10.3760/cma.j.cn114015-20230227-20230123
    Objective To explore the occurrence and clinical characteristics of liver injury caused by immune checkpoint inhibitors (ICI) in cancer patients. Methods Medical records of cancer patients with normal liver function who used ICI during hospitalization in Beijing Friendship Hospital from January 2017 to December 2022 were collected, and those with liver injury related to ICI were screened out. The basic information of patients with ICI-related liver injury, treatment regime of ICI, concomitant medication, liver function before and after medication, intervention measures and outcomes were extracted, and the clinical characteristics of ICI-related liver injury were analyzed descriptively. Results A total of 155 patients with solid tumors were treated with ICI within the set time, of which 15 (9.7%) were diagnosed with ICI-related liver injury. Among the 15 patients, there were 6 males and 9 females, with a median age of 59 (41, 76) years. The suspected drug causing liver injury was camrelizumab in 5 patients, sugemalimab in 2 patients, serplulimab in 2 patients, toripalimab in 2 patients, sintilimab in 2 patients, penpulimab in 1 patient, and cadonilimab in 1 patient. All 15 patients received combined medication, such as traditional chemotherapy drugs, receptor tyrosine kinases inhibitors, and/or other ICIs. The median time from suspected ICI administration to liver injury in 15 patients was 22 (4-64) days, and the liver injury occurred after the first cycle of ICI treatment in 9 patients. The medians of peak value of alanine aminotransferase and aspartate aminotransferase were 157 (15-508) U/L and 131 (77-696) U/L, respectively; the total bilirubin was more than 2 times of the upper limit of normal in 3 patients. The liver injury was classified as hepatocellular type in 6 patients, cholestasis type in 5 patients, and mixed type in 3 patients; the type was unable to be determined due to lack of data in 1 patient. Among the 15 patients, 8 had liver injury of grade 2 and 7 had liver injury of grade 3; the suspected medication were discontinued after liver injury occurrence in 9 patients and did not discontinue in 6 patients. Seven and 5 patients recovered or basically had normal liver function after 1-4 months, respectively among those who stopped and did not stop ICI; the liver function did not return to normal in the other 3 patients at 2 to 9 months of follow-up. Conclusions ICI-related liver injury usually occurs after the first cycle of ICI treatment (within 1-2 months of medication), and the severity is mostly grade 2 or 3. The 3 clinical types of drug-induced liver injury (hepatocellular type, cholestatic type, and mixed type) are clinically visible. After the occurrence of liver injury, most patients have a good prognosis through timely discontinuation and/or treatments.
  • Yu Kunpeng, Xu Hongbin
    Adverse Drug Reactions Journal. 2023, 25(10): 607-613. https://doi.org/10.3760/cma.j.cn114015-20230616-00443
    Objective To explore the adherence and its influencing factors of tegafur, gimeracil and oteracil potassium (S-1) treatment in patients with tumor-node-metastasis (TNM) stage Ⅲ gastric cancer after operation. Methods Medical records of adult patients with stage Ⅲ gastric cancer after operation in the Second Affiliated Hospital of Nanjing University of Chinese Medicine from October 2018 to April 2022 and treated with oral S-1 were collected, and the S-1 adherence and its related factors in these patients were retrospectively analyzed according to their S-1 treatment information. Good adherence was defined as completing 8 cycles of S-1 treatment within 186 days (14 days of continuous medication and 7 days of discontinuation as 1 cycle). The patients were divided into good and poor S-1 adherence groups. Univariate and multivariate logistic regression analysis were performed to analyze the factors affecting S-1 adherence of patients. Results A total of 148 patients were entered in the study, including 116 males (78.4%) and 32 females (21.6%), with a median age of 67 (27-85) years. Sixty-nine patients (46.6%) completed ≥ 8 cycles of S-1 treatment within the set time and had good adherence; 79 (53.4%) patients had poor adherence. The reasons for interruption or failure to complete treatments as scheduled in the 79 patients were serious adverse reactions in 30 (38.0%) patients, refusal to treat in 27 (34.2%) patients, and poor curative effect in 22 (27.8%) patients. Univariate and multivariate logistic regression analysis showed that lack of or partial understanding of the disease [odds ratio (OR)=5.368, 95% confidence interval (CI): 1.488-19.370, P= 0.010; OR=3.393, 95%CI: 1.309-8.793, P=0.012], gastric cancer with a course of less than 1 year (OR=10.214, 95%CI: 2.400-43.472, P=0.002), and TNM stage Ⅲa (OR=3.879, 95%CI: 1.522-9.886, P=0.005) were the independent influencing factors of poor adherence to S-1 treatment in patients with gastric cancer. Conclusions Less than half of the gastric cancer patients with stage Ⅲ after operation had good adherence to S-1 treatment. Insufficient understanding of the disease, short duration of gastric cancer, and TNM stage Ⅲa were independent influencing factors for poor adherence to S-1 treatment in gastric cancer patients. Increasing patients′ understanding of the disease and strengthening patient education may be important strate- gies to improve S-1 treatment compliance.
  • Li Yun, Li Bingsheng, Yuan Zhen, Liu Bin, Li Yixiu, Ao Jian'gen
    Adverse Drug Reactions Journal. 2023, 25(10): 614-621. https://doi.org/10.3760/cma.j.cn114015-20221227-01184
    Objective To systematically evaluate the efficacy and safety of ixazomib in patients with relapsed or refractory multiple myeloma (RRMM) in the real world. Methods Relevant databases at home and abroad were searched (up to April 2022), and the literature on real-world studies of ixazomib in the treatment of RRMM was collected. The quality of the literature was evaluated with the methodological index for non-randomized studies (MINORS) scale. Data such as the effectiveness rate and incidence of adverse events in RRMM patients treated with ixazomib were extracted. The effectiveness indicators included the overall response rate (ORR), very good partial response or better (≥VGPR) rate and median progression-free survival (PFS). The safety indicators included the incidence of adverse events (AEs) and the rate of treatment termination due to AEs, etc. Stata 13.0-software was used for meta-analysis of single proportions, and the occurrence of major adverse events was analyzed by descriptive statistics. Results A total of 12-studies were entered, including 1-006 patients. The quality evaluation results showed that all of the 12-studies were with high quality. The meta-analysis of single proportions showed that ORR of ixazomib in the treatment of RRMM was 65%[95% confidence interval (CI): 58%-72%], ≥VGPR rate was 32% (95%CI: 25%-38%), the median PFS was 21.73 (95%CI: 14.37-29.08) months, the incidence of ≥ grade 3 AEs was 39% (95%CI: 24%-55%), and the incidence of treatment termination due to AEs was 6% (95%CI: 3%-10%). AEs with an incidence of ≥10% included neutropenia, thrombocytopenia, infection, anemia, diarrhea, fatigue, peripheral neuropathy, rashes, and bone pain. Conclusion In the real world, the efficacy of ixazomib in the treatment of RRMM is lower than that in clinical trials, but the safety is similar.
  • Zhang Jingyue, Yang Chong, Lan Gaoshuang, Sun Yinjuan, Zhang Linlin, Yuan Hengjie
    Adverse Drug Reactions Journal. 2023, 25(10): 577-583. https://doi.org/10.3760/cma.j.cn114015-20230420-00291
    Objective To provide a basis for the selection of antiemetic regimen by establishing an artificial intelligence model for predicting chemotherapy-induced nausea and vomiting (CINV) in cancer patients receiving platinum-based chemotherapy with high emetic risk. Methods The clinical information on cancer patients who received cisplatin or carboplatin with area under the blood concentration-time curve (AUC) ≥4 and registered in the Department of Oncology, Tianjin Medical University General Hospital from January 2018 to December 2022 was collected, including gender, age, history of alcohol consumption, history of vomiting in pregnancy, chemotherapy cycle, patient expects to have CINV, chemotherapeutic agents, antiemetic regimen, out-of-hospital antiemetic treatment, sleep of less than 7 hours on the night before chemotherapy, occurrence of CINV in the previous cycle, and creatinine clearance (Ccr). After pre-proces- sing, the data were randomly divided into the training set and the test set. The training set was used to construct the prediction model, and the test set was used to evaluate the prediction efficiency of the model. Three algorithms, gradient boosting decision tree (GBDT), random forest (RF), and logistic regression (LR), were used to build a prediction model and evaluate the model performance, respectively. The evaluation metrics included accuracy, sensitivity, recall, F1 value (the reconciled mean of sensitivity and recall), and area under the receiver operating characteristic curve (AUROC). Finally, Shapley Additive exPlanation (SHAP) was applied to analyze the interpretability of the clinical features with predictive significance. Results A total of 698 patients, 439 males (62.9%) with a median age of 64 (21, 84) years, were included in this study and received a total of 1-654 cycles of chemotherapy. The chemotherapy regimen contained cisplatin in 364 cases with 864 cycles of chemotherapy, and carboplatin with AUC ≥4 in 361 cases with 790 cycles of chemotherapy. The number of treatment cycles in which neurokinin-1 receptor antagonist (NK-1 RA), 5-hydroxytryptamine-3 receptor antagonist (5-HT3 RA), and dexamethasone were selected as the antiemetic regimen was 1 347, and in those with the selection of 5-HT3 RA and dexamethasone was 307. The Spearman′s correlation analysis showed no strong correlation between the feature variables in the patients, and all of them could be used for model building. GBDT optimal hyperparameters n_estimators=500, max_depth=9; RF optimal hyperparameters max_depth=5; LR optimal hyperparameters penalty=L2. Three prediction models, GBDT, RF and LR, were established based on the optimal hyperparameter training data, respectively. The accuracy of GBDT model was 0.903, sensitivity was 0.882, recall was 0.903, F1 value was 0.883, and AUROC was 0.778±0.036 (95%CI: 0.739-0.814); the accuracy of RF model was 0.885, sensitivity was 0.861, recall was 0.885, F1 value was 0.870, and AUROC was 0.679±0.041 (95%CI: 0.636- 0.720); the LR model had an accuracy of 0.817, a sensitivity of 0.851, a recall of 0.817, an F1 value of 0.832, and an AUROC of 0.682±0.042 (95%CI: 0.639-0.723). Ccr, age, chemotherapy cycle, history of alcohol consumption, and patient expects to have CINV were the main features predicted by the model. The risk of CINV was negatively associated with Ccr, age, and chemotherapy cycle. And the risk of CINV was lower in patients with no history of drinking alcohol and patient expects to have CINV. Conclusion The GBDT, RF, and LR models could all predict the risk of CINV in patients receiving platinum-based chemotherapy with high emetic risk, with the GBDT model having the best predictive effect.
  • Wang Dayou
    Adverse Drug Reactions Journal. 2023, 25(9): 513-516. https://doi.org/10.3760/cma.j.cn114015-20230912-00680
    The theme of World Patient Safety Day 2023 is "Engaging Patients for Patient Safety". Encouraging patients (including patients′ families, caregivers, etc.) to voice in medication safety is one of the important measures of medication safety management and pharmacovigilance, which conforms to the principles of ethics and science and is adapted to the development of society. It has been widely recognized in the world that patients participate in the safety monitoring in drug clinical trial, adverse drug reaction reporting, and information communicating and safety supervising of drug safety, and act as partners with doctors and drug regulatory agencies in drug safety. China should also attach importance to and address the obstacles in patient participation in management of medication safety, and accelerate the process of patient participation in management of medication safety.
  • Wang Jin, Zhang Lan, Hu Chaoying
    Adverse Drug Reactions Journal. 2023, 25(9): 521-526. https://doi.org/10.3760/cma.j.cn114015-20221207-01132
    Objective To explore the occurrence of rashes in healthy subjects caused by efavirenz in drug clinical trials. Methods The occurrence of rashes related to efavirenz, which was used as an enzyme inducer, in healthy subjects in 2 clinical trials conducted by the Phase I Clinical Research Center of the Department of Pharmacy, Xuanwu Hospital, Capital Medical University (our hospital) in November 2020 and October 2021 was retrospectively analyzed. The relevant databases at home and abroad (up to November 30, 2022) were searched, and the literature, in which efavirenz was applied as trial drug or enzyme inducer in healthy subjects, were collected. The cases of efavirenz-related rashes reported in the literature were reviewed. The clinical characteristics of the cases in the literature and above 2 clinical trials in our hospital were summarized and analyzed by descriptive statistics. Results A total of 40-healthy subjects were included in the 2 clinical trials, and 5 (12.5%) developed efavirenz-related rashes. The average time from taking the medicine to the appearance of rashes was 8 days. The initial symptom was skin itching. The rashes occurred mainly on the limbs and back, and mainly presented as maculopapular rashes, without other symptoms or laboratory abnormalities. Four subjects withdrew from the trial and the rashes subsided after 5-7 days of anti-allergic and symptomatic treatments; one subject was given calamine lotion for external use because of mild rashes, and continued to participate in the trial. His rashes subsided 17 days later (5 days after stopping efavirenz). Eighteen literature in which efavirenz was used as a trial drug or enzyme inducer in healthy subjects were retrieved. A total of 403-healthy subjects collected from 18 literature and our trials were included in the analysis. Of them, 19-subjects developed rashes, with a incidence of 4.7%. According to the daily dose of efavirenz, the incidence of rashes in the subjects of the 600-mg/d group was higher than that of the <600-mg/d group, but the difference was not statistically significant [5.5% (18/329) vs. 1.4% (1/74), P=0.131]. According to the course of drug, the incidence of rashes was similar in subjects between the single dose group and the continuous dose group [4.1% (4/97) vs. 4.9% (15/306), P=0.753]. Conclusion Rashes are common adverse reactions in healthy subjects after taking efavirenz, which is generally mild and can subside after timely detection and treatment.
  • Zhang Manman, Shen Wei
    Adverse Drug Reactions Journal. 2023, 25(9): 527-532. https://doi.org/10.3760/cma.j.cn114015-20230302-00139
    Objective To investigate the use of epinephrine in the treatment of anaphylaxis in the hospital. Methods The adverse drug reaction (ADR) reports of anaphylaxis in National Center for ADR Monitoring of China reported by Suqian First People Hospital from August 12, 2016 to November 30, 2022 were retrospectively analyzed. Patients with anaphylaxis were divided into shock group and non-shock group according to whether they had shock. The basic information, organs and systems involved, and severity of anaphylaxis, epinephrine use, and outcomes in patients of the 2 groups were compared. The application of epinephrine in patients with anaphylaxis of different manifestations, and the rationality of the dose and route of epinephrine were analyzed and evaluated descriptively. Results A total of 132 patients with anaphylaxis were entered in this study, including 62 males (47.0%) and 70 females (53.0%), with a median age of 53 years. There were 20 patients (15.2%) in the shock group and 112 patients in the non-shock group (84.8%). In comparison of the involving organs and systems in the anaphylaxis between the 2 groups, the cardiovascular system [100% (20/20) vs. 17.9% (20/112)], nervous system [60.0% (12/20) vs. 28.6% (32/112)], digestive system [40.0% (8/20) vs. 15.2% (17/112)], and urinary system [15.0% (3/20) vs. 1.8% (2/112)] were affected more often in patients of the shock group, while skin and mucosa were affected more often in patients of the non-shock group [88.4% (99/112) vs. 60.0% (12/20)]. The differences were all statistically significant (all P<0.05). Only 21 (15.9%) of 132 patients with anaphylaxis used epinephrine in the treatment. The proportion of patients receiving epinephrine in the shock group was significantly higher than that in the non-shock group [50.0% (10/20) vs. 9.8% (11/112), P<0.001]. Of the 21 patients who used epinephrine, 10 (47.6%) had excessive dose, and 11 (52.4%) received through subcutaneous injection, which was not recommended in the guidelines. Conclusions In the emergency treatment of anaphylaxis in patients in the Suqian First People Hospital, the proportion of epinephrine use is low, and there are also situa- tions that the dosage and administration route are unreasonable. The awareness on the importance of rational use of epinephrine should be improved in medical staffs, and relevant training should be strengthened.
  • Zhou Tiantian, Zhang Haiping
    Adverse Drug Reactions Journal. 2023, 25(9): 533-537. https://doi.org/10.3760/cma.j.cn114015-20230301-00137
    Objective To understand the current situation of skin tests before treatment with benzathine benzylpenicillin adviced by doctors of Dermatology Department on syphilis patients in China. Methods A self-designed survey questionnaire was used, which included content of 3 aspects: basic information of the respondents (question 1), the time of the skin test in syphilis patients who were schedule to receive treatment with benzathine benzylpenicillin (question 2), and the issues and suggestions regarding the current skin test method of benzathine benzylpenicillin (question 3). Based on the Collaborative Study Group on Psychodermatology of the Psychosomatic Medicine Branch of the Chinese Medical Association, the survey was conducted through online questionnaires and domestic doctors of Dermatology Department participated voluntarily. The investigation period was from July 2, 2021 to August 16, 2021. The obtained information was analyzed descriptively. Results A total of 366 electronic questionnaires were collected, of which 358 were confirmed to be valid, with a recovery rate of 97.8%. The 358 doctors of Dermatology Department were from 247 medical institutes in 20 provinces, 4 municipalities, and 4 autonomous regions across the country, including 129-3A-level first-class hospitals. The top 3 areas in number of respondents were Beijing (148 respondents, 41.3%), Yunnan province (42 respondents, 11.7%), and Henan province (25 respondents, 7%). Among the 358 doctors, 222 (62.0%) chose "conduct skin test weekly before injection of benzathine benzylpenicillin", 102 (28.5%) chose "in continuous injection, no further skin test is required for re-injection within 7 days", 33 (9.2%) chose "in continuous injection, no further skin test is required for re-injection within 72-hours", and 1 (0.3%) chose "other" and then added "further skin test is required after 48-hours of discontinuation". Compared with other medical institutions, there was a higher proportion of doctors (32.5%, 64/197) chose "in continuous injection, no further skin test is required for re-injection within 7 days" in hospitals of 3A-level first-class. Ninety one doctors (25.4%) answered question 3, all of whom believed that the current status of skin tests of benzathine benzylpenicillin had caused confusion in clinical treatment and some doctors provided suggestions such as developing standards for skin tests of benzathine benzylpenicillin and adding controlled trials. Conclusions The skin test time window and operation have not been standardized in the treatment of syphilis with benzathine benzylpenicillin in China, which hinders the standar- dized treatment of syphilis. It is urgent to develop guidance documents for the skin test of benzathine benzylpenicillin.
  • Jiang Yongxian, Ye Xi, Li Aiyan, Qin Bo, Chen Wenwen, Lang Bingchen, Li Gen
    Adverse Drug Reactions Journal. 2023, 25(9): 538-542. https://doi.org/10.3760/cma.j.cn114015-20230116-00018
    Objective To explore the clinical characteristics of anaphylaxis caused by gonado- relin in children in gonadotropin-releasing hormone (GnRH) stimulation test. Methods The research subjects were children aged ≤14 years who experienced anaphylaxis using gonadorelin in the Chengdu Adverse Reaction Center database from January 1, 2015 to December 31, 2021. The purpose of medication was GnRH stimulation test. Through the hospital information system, the children′s basic information, usage of gonadorelin, occurrence of severe allergic reactions, and treatments and outcomes of anaphylaxis were collected and retrospectively analyzed. Results A total of 14 cases of anaphylaxis in children caused by gonadorelin in the GnRH stimulation test were collected, including 3 males and 14 females, with an age of (9±2) years. All 14 cases were evaluated with a score of ≥5 using the Naranjo evaluation method. The dose of gonadorelin in the 14 children was (2.55±0.09) μg/kg and the drug was all given by intravenously injection; anaphylaxis occurred in 4 children during the first GnRH stimulation test and in 10 children during the second GnRH stimulation test. The time from medication to anaphylaxis occurence was (6.0±3.5) minutes. The symptoms of anaphylaxis in 14 children were systemic allergic reactions, involving various systems throughout the body. All children had 3 or more types of systemic damage. After anaphylaxis occurrence, gonadorelin was discontinued in all 14 patients; 5 received intramuscular injection of adrenaline, 5 received intravenous injection of adrenaline, 1 received intravenous injection of isoprenaline and intramuscular injection of adrenaline, and 3 received intravenous injection of dexamethasone only. After treatments, all children were improved. Conclusions Anaphylaxis caused by gonadorelin in children is a rare but severe adverse reaction, and the drug may have a possibility of cross allergy with GnRH analogues. Therefore, when diagnosing and treating precocious puberty in children, medication should be given under monitoring conditions.
  • Niu Ziran, Wang Zixi, Zhang Bo
    Adverse Drug Reactions Journal. 2023, 25(9): 517-520. https://doi.org/10.3760/cma.j.cn114015-20230828-00640
    Anaphylaxis is a severe, life-threatening, immediate, and systemic allergic reaction, and may lead to serious consequences due to delayed diagnose or improper treatment. Guidelines at home and abroad recommend epinephrine as a first-line treatment for anaphylaxis. But there are still some problems such as insufficient use, inappropriate administration route or dosage of epinephrine in the treatment of anaphylaxis in China. The timing (as early as possible), route (intramuscular injection is preferred), and dosage of epindphrine should strictly follow the recommendations of relevant guidlines. Epinephrine autoinjectors can win more rescue time for patients with anaphylaxis, and can be equipped and used after training by clinicians.
  • Dai Rui, Zhang Qingxia, Hu Yang, Wang Huanling, Zhao Bin, Medication Safety Panel in China Core Group of International Network for the Rational Use of Drugs
    Adverse Drug Reactions Journal. 2023, 25(8): 475-481. https://doi.org/10.3760/cma.j.cn114015-20220801-00693
    Objective To understand the current situation and problems of research design in adverse drug reaction (ADR) signal detection study in China. Methods The literature on ADR signal detection study in SinoMed, CNKI, WanFang Data and VIP databases were retrieved (up to May 30, 2022). The research purpose, research direction (target drug, target ADR), source database of signals, target drug role, reference drug, signal detection algorithm, and bias control of the literature were analyzed descriptively one by one. Results A total of 165 articles were included, of which 146 (88.5%) were published in core journals. From 2013 to 2022 (January to May, 2022), there were 4, 3, 2, 7, 8, 11, 20, 29, 55, and 26 relevant articles, respectively. Problems in these studies were as follows: research purposes were not clear in 6.7% (11/165) of the literature; target ADRs were selected as non targeted in 80.6% (133/165) of the literature; the domestic database was less utilized [only 9.7% (16/165)]; did the selection range of the target drug role were not mentioned in 33.9% (56/165) of the literature; only a single algorithm for signal detection was used in 36.4% (60/165) of the literature; bias analysis was not conducted in 85.5% (141/165) of the literature. Conclusions The domestic literature on ADR signal detection has problems of poor standardization in research design, such as unclear research purpose and direction, incomplete research items, etc. Chinese scholars should further improve the quality of research design while strengthening the research on ADR signal detection.
  • Zhao Bin
    Adverse Drug Reactions Journal. 2023, 25(8): 449-453. https://doi.org/10.3760/cma.j.cn114015-20230628-00478
    Signal detection of adverse drug reaction (ADR) is an important research method in post marketing pharmacovigilance. In recent years, the number of literature on ADR signal detection in China has increased significantly. However, there are still many problems in this kind of research, such as unclear understanding of the concept of ADR signal, unclear purpose of signal detection research, limited signal source, inadequate processing of data in detection, unduly single data mining algorithm, unduly short time period in data selection, and no processing and analysis on bias in signal detection. This paper provides some views on these common problems in order to improve the quality of ADR signal detection research in China.
  • Zhao Na, Ye Xia, Wang Zhiyan, Lu Chao, Hu Fangyuan, Yuan Lei
    Adverse Drug Reactions Journal. 2023, 25(8): 454-459. https://doi.org/10.3760/cma.j.cn114015-20221226-01168
    Objective To explore the neurological adverse events (AE) associated to brexucabtagene autoleucel (brexu-cel) and their risk of occurrence. Methods Neurological AE reports related to brexu-cel were collected through the US FDA Adverse Event Reporting System database from July 1, 2020 to September 31, 2022. The AEs were classified and counted according to the system organ class (SOC) and preferred term (PT) of Medical Dictionary for Regulatory Activities (MedDRA) 24.1. The information component (IC) method and the reporting odds ratio (ROR) method were used to perform signal mining. AEs with ≥3 reports and a lower limit of 95% confidence interval (CI) for IC>0 or that for ROR>1 were defined as positive risk signals. The proportion of patients who suffered fatal outcomes after experiencing neurological AEs related to brexu-cel was analyzed. Results A total of 1-960 neurological AE reports related to brexu-cel were collected, involving 559 patients and 22 PTs. Fifteen positive signals (PT) were detected by using the IC and ROR methods. The top 5 PTs in the number of AE reports were immune effector cell-associated neurotoxicity syndrome (153 reports), altered mental status (32 reports), encephalopathy (29 reports), tremor (27 reports), and aphasia (25 reports); the top 5 PTs with the high signal intensity were immune effector cell-associated neurotoxicity syndrome (IC=7.81, ROR=235.74), encephalopathy (IC=4.74, ROR=26.96), aphasia (IC=4.28, ROR=19.58), cerebral edema (IC=3.35, ROR=10.24), and incontinence (IC=3.04, ROR=8.22); incontinence (6 cases, IC=3.04, ROR=8.22) was not recorded in the drug instruction. Patients involved in 17 PTs, out of the 22 PTs, had fatal outcomes, and the proportion of deaths from immune effector cell-associated neurotoxi- city syndrome was 18% (28/153). The PTs with a proportion of patient deaths >50% were unresponsive to stimuli (80%, 4/5), brain oedema (75%, 6/8), cerebrovascular accident (67%, 2/3), lethargy (60%, 3/5), and seizure (57%, 4/7). Conclusions Neurological AEs related to brexu-cel are common, of which incontinence is not yet recorded in the drug instruction. The clinical outcomes of some AEs (unrespontive to stimulus, brain oedema, and lethargy) are poor and should be closely monitored.
  • Zhang Meijuan, Yin Hang, Li Jiangshuo, Hou Mengyu, Wu Jingxuan, Dong Ruihua
    Adverse Drug Reactions Journal. 2023, 25(8): 460-468. https://doi.org/10.3760/cma.j.cn114015-20221230-01194
    Objective To mine and compare the adverse event (AE) signals of allopurinol and febuxostat and provide reference for the rational and safe use of the 2 drugs in clinic. Methods The AE reports on allopurinol and febuxostat from January 1, 2009 to December 31, 2021 were collected by searching the US Food and Drug Administration Public Data Open Project (openFDA) database. AEs were classified using preferred term (PT) and systemic organ class (SOC) of the International Medical Terminology Dictionary 25.0. The AE risk signals of allopurinol and febuxostat were mined using the reporting odds ratio (ROR) method. The number of AE reports ≥3 and the lower limit of the 95% confidence interval (CI) of the ROR>1 was defined as a positive signal. The new AE risk signals of allopurinol and febuxostat were screened according to the drug labels. The radar chart was drawn according to the number of allopurinol and febuxostat risk signals. The positive PT signals were descriptively and statistically analyzed. Results The number of AE reports of allopurinol and febuxostat were 105-532 and 9-949, respectively. The analysis of the top 100 AE reports were as follows. There were 82 positive PT signals of allopurinol, involving 14 SOCs, and 61 AEs were not recorded in the drug labels; there were 86 positive PT signals of febuxostat, involving 18 SOCs, and 25 AEs were not recorded in the drug labels. The top 5 PTs in the signal strength of allopurinol were drug reaction with eosinophilia and systemic symptoms, end-stage renal disease, hypercalcemia, acute kidney injury, and chronic kidney disease; the top 5 PTs in the signal strength of febuxostat were enthesopathy, granu- loma skin, blood parathyroid hormone decreased, tenosynovitis and alanine aminotransferase abnormal. The 2 drugs had a total of 49 overlapping signals. More AE signals of allopurinol were detected in SOCs of meta- bolic and nutritional diseases, blood and lymphatic system diseases etc.; more AE signals of febuxostat were detected in SOCs of skin and subcutaneous tissue diseases, various musculoskeletal, and connective tissue diseases, etc. Conclusions Allopurinol has a higher risk of causing AEs related to kidney and urinary system, blood and lymphatic system, and metabolic system, while febuxostat has a higher risk of causing AEs related to skin and subcutaneous tissue, musculoskeletal and connective tissue, and hepatobiliary system. It is suggested that patients with gout accompanied by renal insufficiency, urinary system diseases or blood disea- ses should be careful with allopurinol, and the patients with gout accompanied by liver dysfunction should be careful with febuxostat.
  • Liu Yanhui, Ruan Wenyi, Chen Huiying, Mei Kangkang, Cai Heping
    Adverse Drug Reactions Journal. 2023, 25(8): 469-474. https://doi.org/10.3760/cma.j.cn114015-20230227-00121
    Objective To explore the risk signals of montelukast-related adverse events (AEs) in pediatric patients and provide reference for the safe use. Methods AE reports of children with montelukast as the primary suspect drug from the first quarter of 2004 to the third quarter of 2022 were collected by searching the US FDA Adverse Event Reporting System database (FAERS). AEs were standardized and classified according to the preferred terms (PT) and system organ class (SOC) of Medical Dictionary for Regulatory Activities 23.0. Proportional reporting odds ratio (PRR) method was used to mine the AE risk signals of montelukast. An AE with reports ≥3, PRR≥2, and χ2>4 was defined as a positive signal, which were analyzed using descriptive method. Results A total of 5-179 AE reports were included in the analysis, involving 1-295 PTs, and 233 positive PTs were obtained by PRR method. The top 10 PTs in AE reports were aggres- sive behavior, anxiety, suicidal ideation, abnormal behavior, depression, anger, nightmares, insomnia, crying loudly and night terrors. Except crying loudly, all of them were adverse reactions recorded in the label. The top 10 PTs in signal intensity were sensory overload, arrhythmia, separation anxiety disorder, loneliness phobia, dust allergy, Mille-Fisher syndrome, eosinophilic granuloma complicated with polyangitis, personality disorder in children, night terrors and decreased platelet adhesion. Among them, abnormal heart rate, Mille-Fisher syndrome and decreased platelet adhesion were not recorded in the label. A total of 59 of the 233 positive PTs were not recorded in the label, involving 10 SOCs. The top 5 SOCs were social environment, mental illness, injury, poisoning and surgical complications, general conditions and administration site, and respiratory, thoracic and mediastinal diseases. Conclusion The main AEs of pediatric patients receiving montelukast treatment in the US FAERS are aggressive behavior, anxiety, depression, insomnia, night terrors, etc., all of which are adverse reactions recorded in the label; adverse reactions not recorded in the drug label include abnormal heart rate, Miller-Fisher syndrome, and decreased platelet adhesion.
  • Adverse Drug Reactions Journal. 2023, 25(7): 389-397. https://doi.org/10.3760/cma.j.cn114015-20230608-00421
    In 2022, a total of 22-868 cases of medication error (ME) from 315-hospitals in 26 provincial administrative regions were collected in the National Monitoring Network for Clinical Safe Medication. The number of hospitals reporting ME increased by 14.55% compared with that in 2021 (275-hospitals), and the number of reported ME cases increased by 16.76% compared with that in 2021 (19-585 cases). In 22-868 cases of ME reports, 155 (0.68%) were classified as grade A, 18-981 (83.00%) as grade B, 3-076 (13.45%) as grade C, 422 (1.85%) as grade D, 75 (0.33%) as grade E, 156 (0.68%) as grade F, 1 (<0.01%) as grade G, and 2 (0.01%) as grade H; no MEs of grade I occurred. Among the 22-713 patients involved in MEs of grade B to I, 12-668 (55.77%) were male and 10-045 (44.23%) were female; their ages were from 1 day to 102 years; 2-453 (10.80%) were children (<18 years old), 11-374 (50.08%) were young and middle-aged adults (≥18 to <60 years old), and 8-886 (39.12%) were elderly (≥60 years old). A total of 234 patients were involved in serious MEs (grade E-I), including 134 (57.27%) males and 100 (42.73%) females, aged from 4 days to 94 years, of which 37 (15.81%) were children, 83 (35.47%) were young and middle-aged adults, 114(48.72%) were elderly. The serious MEs (grade E-I) mainly occurred in the administration link [74.36% (174/234)]. The 155 grade A MEs did not involve person who triggered the ME and place where ME occurred. Among the 22-713 grade B-I MEs, 17-102 (75.30%) were triggered by physicians, 4-072 (17.93%) by pharmacists, 764 (3.36%) by nurses, 461 (2.03%) by patients and their family members, and 314 (1.38%) by other persons; the proportion of MEs triggered by physicians increased year by year for 4 consecutive years; the triggers of serious MEs were mainly patients and their family members [61.97% (145/234)]. Among these MEs, 9-238 (40.67%) occurred in clinics, 7-183 (31.63%) in hospital wards, 4-620 (20.34%) in pharmacies, 1-063 (4.68%) in pharmacy intravenous admixture services, 213 (0.94%) in the nurse stations, 321 (1.41%) in patients′ home, 6 (0.03%) in the community health service stations, and 69 (0.30%) in other places. Among the 234-severe MEs, 129 (55.13%) occurred in the patient′s home, and the proportions of MEs and serious MEs occurred in the home increased year by year for 4 consecutive years. The top 3 contents of ME were wrong drug class (4-285, 18.40%), wrong dosage (4-115, 17.67%), and wrong administration frequency (2-808, 12.06%). The top 3 persons who discovered the ME were pharmacists (17-575, 74.74%), patients and their family members (2-654, 11.29%), and physicians (1-752, 7.45%). The top 3 factors causing ME were lack of related pharmacologic knowledge (8-665, 31.94%), tiredness (4-249, 15.66%), and insufficient training of medical workers (3-502, 12.91%).
  • Pan Shoudong, Wang Tianlong
    Adverse Drug Reactions Journal. 2023, 25(6): 321-323. https://doi.org/10.3760/cma.j.cn114015-20230420-00289
    The incidence of pediatric anesthesia emergence delirium (ED) is high, and the potential harm is significant. It can be diagnosed through the pediatric anesthesia emergence delirium scale (PAED). The risk factors of pediatric anesthesia ED include personal, surgical, and anesthetic factors. The anesthesia ED in children can be effectively prevented by relieving preoperative anxiety, optimizing anesthetic strategies, and providing effective postoperative analgesia. Alpha 2 agonists (eg. dexmedetomidine), opioids (eg. fentanyl), propofol, and ketamine have both preventive and therapeutic effects on anesthesia ED in children.
    【Key-words】 Delirium; Child; Anesthesia; Risk factors
  • Zhang Wei, Fu Jingwen, Wang Yonghui, He Tao, Lu Zhihong
    Adverse Drug Reactions Journal. 2023, 25(6): 327-331. https://doi.org/10.3760/cma.j.cn114015-20220905-00809
    Objective To explore the effect and its mechanism of nalbuphine on pruritus/paresthesia induced by fospropofol disodium under general anesthesia. Methods The study was designed as a prospective, single-center, randomized, double-blind controlled trial. Patients scheduled for surgery under general anesthesia in Xijing Hospital, Air Force Medical University from April to May 2022 were entered and randomly divided into nalbuphine group and control group using the random sequence table method. Patients of both groups were given general anesthesia with fospropofol disodium. Thirty minutes before the end of the surgery, patients in the nalbuphine group received intravenous injection of nalbuphine 0.2-mg/kg (0.1-ml/kg), while those in the control group received intravenous injection of an equal volume of 0.9% sodium chloride injection. Venous blood samples of patients in the 2 groups were collected 5-minutes before anesthesia induction and 5-minutes after awakening to detect levels of serum interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), and S-100 calcium binding protein β (S-100β). The primary indicator of the study was the incidence of pruritus/paresthesia within 30-minutes after extubation; the secondary indicators included time to eye opening upon calling, the maximum pruritus/paresthesia score within 30-minutes after extubation, nausea/ vomiting score, pain score, the incidence of pruritus/paresthesia within 24-hours after operation, the score of patient satisfaction to anesthesia, and the levels of postoperative serum inflammatory markers. Results A total of 98 patients enrolled the study, 49 in each group. There were no statistically significant differences in gender, age, body mass index, American Society of Anesthesiologists grade, operation type, operation time, or anesthesia time of patients between the 2 groups (all P>0.05). The incidence of pruritus/paresthesia and the score of pruritus/paresthesia 30-minutes after extubation were lower in the nalbuphine group than those in the control group, with statistically significant differences [24.5% (12/49) vs. 61.2% (30/49), P<0.001; 4 (2, 5) vs. 6 (5, 7), P=0.031]. At 24-hours of postoperation, the score of patient satisfaction to anesthesia in the nalbuphine group was higher than that in the control group, with a statistically significant difference [8 (7, 9) vs. 6 (3, 7), P=0.042]. Compared with the control group, the postoperative serum IL-6 in patients of the nalbuphine group was significantly lower [(329.5±105.5) ng/L vs. (398.5±102.6) ng/L, P=0.033], while differences in levels of TNF-α and S-100 β were not statistically significant (all P>0.05). Conclusion Nalbuphine can significantly reduce the incidence of pruritus/paresthesia induced by fospropofol disodium under general anesthesia and improve the patient satisfaction to anesthesia, and its mechanism may involve the inhibition of inflammatory response by nalbuphine.
  • Lin Na, Zhao Mengmeng, Wang Guyan
    Adverse Drug Reactions Journal. 2023, 25(6): 332-338. https://doi.org/10.3760/cma.j.cn114015-20230425-00308
    Objective To observe the occurrence of residual neuromuscular blockade (RNMB) in post anesthesia care unit (PACU) in patients undergoing selective laryngeal surgery under general anesthesia and provide reference for improving the safety of muscle relaxants during the perioperative period. Methods The adult patients who underwent laryngeal surgery in Beijing Tongren Hospital, Capital Medical University from July 2020 to March 2021 were collected. According to the muscle relaxants used in the surgery, the patients were divided into rocuronium bromide group, mivacurium chloride group, and cisatracurium group. The general information of patients in the different groups [age, body mass index, American Society of Anesthesiologists (ASA) classification, etc.], duration of surgery, anesthesia time, stay time in PACU, and recovery of neuromuscular function (expressed using train of four ratio, abbreviated as TOFr) were recorded and analyzed. The ability to speak and raise one′s head in PACU, as well as the occurrence of adverse events such as gastroesophageal reflux, aspiration, and dyspnea were also recorded. Results A total of 320 patients were enrolled in the study, including 188 males (58.8%) and 132 females (41.2%), with a mean age of (50±13) years. The duration of surgery was (38.6±30.1) minutes, anesthesia time was (57.2±32.8) minutes, and stay time in PACU was (34.6±11.4) minutes. There were 115, 141, and 64 patients in the rocuronium bromide, mivacurium chloride, and cisatracurium groups, respectively. The differences in age, body mass index, and ASA grade in patients among the 3 groups were not significant (all P>0.05). The anesthesia time and duration of surgery in patients of the mivacurium chloride group were shorter than those of the rocuronium bromide and cisatracurium groups [(43.53±23.90) minutes vs. (67.54±37.72) minutes and (68.84±29.34) minutes;(26.87±22.18) minutes vs. (47.16±34.83) minutes and (48.84±27.57) minutes], and the differences were statistically significant (all P<0.01). The difference in stay time in PACU among the 3 groups was not statistically significant (P>0.05). At the moment of entering PACU, 272 (88.6%) of 320 patients had TOFr<0.9, of which 105 (32.8%) had TOFr<0.7; when leaving PACU, the TOFr of all patients was>0.9. Except the time point of leaving PACU, TOFr in the rocuronium bromide group at the other time points were higher than those in the cisatracurium group (all P<0.01). Except the 2 time points of the moment of entering and leaving PACU, TOFr in the mivacurium chloride group was higher than those in the cisatracurium group (all P<0.01). At the moment of entering PACU and 5-minutes after entering PACU, TOFr in the mivacurium chloride group was lower than those in the rocuronium bromide group (all P<0.05). When entering PACU, 79 of 320 patients had saturation of pulse oximetry (SpO2)<0.95 and the difference in SpO2-among the 3 groups was statistically significant (P=0.029), of which 4 cases (6.25%) had SpO2<0.90 in the cisatracurium group, and the incidence of hypoxemia was higher than that in the other 2 groups. The differences in ability of speach and head lifting of patients among the 3 groups when entering PACU were statistically significant (P=0.036, P<0.001). No adverse events such as reflux, or aspiration, dyspnea occurred in patients in PACU. Conclusions The incidence of RNMB in patients undergoing laryngeal surgery entering PACU immediately is high and the degree of RNMB is more severe, with TOFr gradually increasing and RNMB decreasing over time. The patients who receive cisatracurium have a high incidence and severity of postoperative RNMB. Routine monitoring and neuromuscular monitoring in PACU are beneficial for patients′ perioperative safety.
  • Wang Yu, Ma Li, Luan Bo
    Adverse Drug Reactions Journal. 2023, 25(6): 339-344. https://doi.org/10.3760/cma.j.cn114015-20220726-00676
    Objective To explore the optimal dosage of dexmedetomidine for pediatric abdominal surgery under general anesthesia. Methods The study was designed as a prospective, single center, randomized controlled trial. Children who underwent abdominal surgery under general anesthesia in the First Affiliated Hospital of Air Force Military Medical University from November 2019 to December 2020 were enrolled and randomly divided into 3 groups according to dexmedetomidine dose (0.4-μg, 0.7-μg, and 1.0-μg) using the random number table method. Dexmedetomidine at corresponding dose were given by intravenous pump 15-minutes before anesthesia induction at bases of the same other anesthesia methods. The heart rate and mean blood pressure during surgery, Ramsay sedation score, sedative-agitation score (SAS), and the face-legs-activity-cry-consolability behavioral tool (FLACC) after awakening from anesthesia, and adverse reactions within 24-hours after surgery were compared in children among the 3 groups. Results A total of 150 children were entered in the study, including 77 males (51.3%) and 73 females (48.7%), aged (7±1) years with weight of (22.4±4.6) kg. The surgeries were performed for inguinal hernia, hydrocele, cryptorchidism, and appendicitis in 81 (54.0%), 36 (24.0%), 19 (12.7%), and 14 (9.3%) children, respectively. The 150 children were randomly divided into dexmedetomidine 0.4-μg group, 0.7-μg group, and 1.0-μg group, with 50 children in each group. There were no statistically significant differences in gender, age, weight, American Society of Anesthesiologists grade, or separation anxiety among children of the 3 groups (all P>0.05). The postoperative recovery time [(12±3) min vs. (9±3) min] and time to extubation [(12±3) min vs. (9±3) min] of children in the 1.0-μg group were significantly longer than those in the 0.4-μg group (both P<0.001). While the differences of the 2 indexes above in children were not significantly when compared between the 1.0 and 0.7-μg groups and the 0.7 and 0.4-μg groups (all P>0.05). During the operation, the heart rate and MBP of children in the 0.7-μg group and the 1.0-μg group were significantly lower than those in the  0.4-μg group (both P<0.001). The Ramsay sedation scores of children when awakening from anesthesia, leaving the resuscitation room, and 1 hour after operation were significantly higher in the 0.7-μg group and the 1.0-μg group than those in the 0.4-μg group, while the SAS score and FLACC score were significantly lower (all P<0.05). Compared with the 0.4-μg group, the incidence of emergence agitation [12.0% (6/50) and 8.0% (4/50) vs. 30.0% (15/50)] and the total incidence of adverse reactions [22.0% (11/50) and 16.0% (8/50) vs. 44.0% (22/50)] in children of the 0.7-μg group and the 1.0-μg group were significantly lower (all P<0.05). Conclusion Infusion of dexmedetomidine 0.7-μg/kg before anesthesia induction in pediatric abdominal surgery under general anesthesia has little effect on the awakening from anesthesia, with good sedation effect and low incidence of adverse reactions, which is the optimal dosage.
  • Li Dekun
    Adverse Drug Reactions Journal. 2023, 25(5): 257-262. https://doi.org/10.3760/cma.j.cn114015-20221031-01002
    In 2021, the National Medical Products Administration issued the“Good Pharmacovigilance Practice”(GVP), which required the marketing authorization holders to establish and continuously improve pharmacovigilance system and to carry out pharmacovigilance activities in a normalized manner. Traditional Chinese medicine was the unique variety in China. Due to its high risk in clinical application, more attention should be paid to the overall planning and coordination of various aspects in the pharmacovigi- lance, especially for the traditional Chinese medicine injections. Thus by consulting regulations and literature, the possible ideas and suggestions such as establishing organizational structure and equipping professional personnel, improving regulations and systems, streamlining information collection channels, and identifying and evaluating risk signals, etc. were proposed for traditional Chinese medicine injection enterprises in carrying out pharmacovigilance.
  • Yilimire·Abudouwaili, Zhang Haiying, Zhao shengjun
    Adverse Drug Reactions Journal. 2023, 25(5): 263-270. https://doi.org/10.3760/cma.j.cn114015-20220914-00841
    Objective To explore the toxicities and their toxic sites of 5 species of Ferula sinkiangensis K.M. Shen, including Ferula songarica (F. songarica), Ferula feruloides (F. feruloides), Ferula akitschkensis (F. akitschkensis), Ferula dissecta (F. dissecta), and Ferula syreitschikowii (F. syreitschikowii) in vitro experiments. Methods Five ethanol extracts of Ferula sinkiangensis K.M. Shen were prepared using 95% ethanol reflux method. The 5 ethanol extracts were added to human embryonic kidney epithelial cells (HKC), human normal liver cells (L02 cells), and zebrafish embryo culture medium at 5 different concentrations, respectively. The relevant blank group and normal control group were set up meanwhile. The inhibition rates of HKC and L02 proliferation at 24-hours of culture under 37.0-℃ and survival rates of zebrafish embryos at 24, 48, and 72-hours of culture under 37.0-℃ were calculated. The most toxic specie of the 5 Fragrant Ferula L. was selected and the extracts from different polar parts (petroleum ether, dichloromethane, ethyl acetate, water saturated n-butanol, and water parts) were prepared for the above mentioned cytotoxicity and zebrafish embryotoxicity tests to clarify the toxicities. Results Cytotoxicity tests showed that among 5 ethanol extracts of Fragrant Ferula L., the half inhibitory concentration (IC50) of the F. songarica (70.92-μg/ml and 42.33-μg/ml) to HKC and L02 cells were lowest, and the IC50 of F. feruloides (107.80-μg/ml and 97.92-μg/ml) were highest. The zebrafish embryotoxicity test showed that at concentration of 1.0-μg/ml, embryonic death occurred when cultured 48-hours in the F. songarica group, with a survival rate of 70% (14/20), while it had a survival rate of 100% (20/20) in the other 4 groups; at concentration of 10.0-μg/ml, the embryo survival rate in the F. feruloides group was 50% (10/20) when cultured 24-hours, while it had a survival rate of 0 (0/20) in the other 4 groups. Cytotoxicity tests were conducted using extracts from the petroleum ether, dichloromethane, ethyl acetate, water saturated n-butanol, and water parts of F. songarica, the IC50 of the petroleum ether parts (77.35-μg/ml and 67.73-μg/ml) to HKC and L02 cell proliferation were the lowest and of the water parts (731.52-μg/ml and 364.09-μg/ml) were the highest. In the zebrafish embryotoxicity test, the survival rate of zebrafish embryos in the petroleum ether group was the lowest. The survival rate was 50% at concentration of 3.0-μg/ml for 72-hours′ culture and at concentration of 10.0-μg/ml for 24-hours′ culture. The survival rate was 0 at concentration of 10.0-μg/ml for 48 and 72-hours′ culture, as well as at 30.0-μg/ml at all observation times. Conclusions Among the 5 Ferula sinkiangensis K.M. Shen, the toxicity of F. songarica is relatively high, while that of F. feruloides is relatively low. The toxic parts of F. songarica may mostly accumulate in petroleum ether parts.
  • Li Ning, Chen Huanlei, Wang Zhenhua
    Adverse Drug Reactions Journal. 2023, 25(5): 271-275. https://doi.org/10.3760/cma.j.cn114015-20221008-00896
    Objective To explore the adverse reaction risk signals of Xuesaitong injection, and provide reference for the safe and reasonable application of the drug.-Methods The risk signals of adverse reactions/events (AR/AE) associated with Xuesaitong injection were mined using 3 methods, including reporting odds ratio (ROR), proportional reporting ratio (PRR), and the Comprehensive Standard-Method of Medicines and Healthcare Products Regulatory Agency (MHRA) based on data in Shandong Province Adverse Drug Reaction Monitoring Center Database from 2018 to 2020. Results A total of 2-606 AR/AE reports with Xuesaitong injection as the primary suspect drug were collected, involving 1-209 males (46.39%) and 1-397 females (53.61%). The median age of these patients was 63 years, ranging from 10 to 100 years, and 55.72% (1-452/2-606) of them were over 60 years. Severe AR/AE accounted for 13.24% (345/2-606). AR/AE involved a total of 15 organs/systems, and relevant preferred names (PN) appeared 4-218 times. Among them, the organs/systems involved ranking top 3 in frequency were skin and accessories [37.15% (1-567/4-218)], systemic disorders [18.21% (768/4-218)], and central and peripheral nervous system [14.13% (596/4-218)]. There were a total of 19 risk signals that were positive by the ROR, PRR, and MHRA method, including sneezing, worsening palmus, discomfort in the cardiac area, dry throat, worsening headache, distention in the head, shortness of breath, convulsions, chills, high fever, chest tightness, tachycardia, worsening dizziness, papules, skin warm, palpitation, palmus, feeling cold, and erythema. The top 5 PN with severe cases were shortness of breath, high fever, convulsions, tachycardia, and chest tightness. Conclusions Xuesaitong injection can lead to severe anaphylaxis and the most common organs/systems involved are skin and accessories, systemic disorders, and central and peripheral nervous system. Severe cases often present with shortness of breath, high fever, convulsions, tachycardia, and chest tightness, which require intensive monitoring during use of the drug.
  • Quan Rui, Li Shuwen, Weng Xisheng, Li Na, Chen Weiheng
    Adverse Drug Reactions Journal. 2023, 25(5): 276-280. https://doi.org/10.3760/cma.j.cn114015-20221019-00964
    Objective To investigate the safety of Tenghuang Jiangu tablets in the treatment of knee osteoarthritis. Methods Medical records of knee arthritis patients who used Tenghuang Jiangu tablets in 43-hospitals from September 2019 to January 2021 were collected and the incidence, clinical manifestations, severity and outcome of adverse events were descriptively analyzed. Results A total of 2-505 patients were entered in the analysis, including 788 males (31.46%) and 1-717 females (68.54%), with ages of 50-76 years and a median age of 61 years. The duration of medication was (57±3) days. Among the 2-505 patients, 1-949 cases (77.80%) received the drug twice daily, 553 (22.08%) thrice daily, and 3 (0.12%) once daily; 79(3.15%) patients developed 82 adverse events during Tenghuang Jiangu tablets treatment, including 39 cases of adverse events of digestive system (42 times), 8 cases of systemic adverse events, 6 cases of infectious adverse events, 6 cases of skin and mucous membrane adverse events, 5 cases of neurological adverse events, 4 cases of respiratory system adverse events, 3 cases of eye organ adverse events, 3 cases of cardiac organoid adverse events, 3 cases of injury adverse events, and 2 cases of reproductive system and breast adverse events. A causal evaluation was conducted on the above-mentioned adverse events, with only one case evaluated as possible and the rest as suspicious. Only one patient stopped using Tenghuang Jiangu tablets after an adverse event occurred, while the other patients did not stop the medication, and all patients returned to normal after untreated or symptomatic treatments. Conclusions The incidence of adverse events in the treatment of knee osteoarthritis with Tenghuang Jiangu tablets is 3.15%. Common adverse events include digestive system adverse events, systemic adverse events, infectious adverse events, skin and mucous membrane adverse events, and neurological adverse events.
  • Tang Haochun, Meng Jun
    Adverse Drug Reactions Journal. 2023, 25(4): 193-196. https://doi.org/10.3760/cma.j.cn114015-20230323-00220
    With the widespread use of immune checkpoint inhibitors (ICIs) in cancer therapy, immune-related adverse events (irAEs) are receiving increasing attention. Among them, ICI-related pneumonitis (CIP) is more common. This article introduces the clinical features, disease classification, and treatment strategies, etc. of CIP, and suggests multidisciplinary cooperation to carried out whole-process management for patients receiving ICIs treatment, early detection, early diagnosis, and establish clear and effective prevention and early warning strategies to maximize the benefits of cancer patients.
  • Guo Nan, Gao Ping, Jin Haobin, Sheng Jia, Shi Yaru, Bi Yunyan, Lyu Zhimei, Zhang Wen
    Adverse Drug Reactions Journal. 2023, 25(4): 197-203. https://doi.org/10.3760/cma.j.cn114015-20220923-00869
    To explore the characteristics and factors affecting the occurrence of renal injury in patients with abnormal biochemical indexes of renal function after the use of immune checkpoint inhibitors (ICIs), and to provide reference for selection of clinical treatment regimen. Methods Patients who were treated with immune checkpoint inhibitors researched and developed independently in China including camrelizumab, sintilimab, tislelizumab, and toripalimab from March 1, 2021 to February 28, 2022 and showed estimated glomerular filtration rate (eGFR) <90-ml/(min·1.73 m2) and/or serum creatinine (Scr)>105-μmol/L were retrieved from the China Hospital Pharmacovigilance System. The clinical data including general information, anti-tumor treatment regimen, laboratory test results, and concomitant medications were collected. Patients were divided into kidney injury group and non-kidney injury group, and all the clinical characteristics were compared between the 2 groups, the influencing factors of kidney injury were analyzed using a binary logistic regression model, the odds ratio (OR) and its 95% confidence interval (CI) were calculated. Results A total of 222 patients were entered in the analysis, including 170 males and 52 females, with a median age of 67 (36, 85) years. Of them, 144 patients were treated with carrilizumab, 38 with sindilizumab, 31 with tirelizumab, and 9 with treprolizumab; 29 patients (13.1%) developed kidney injury, including 26 cases of grade 1 and 3 cases of grade 2 renal injuries; the time of renal injury occurrence was 19-355 days after the first application of ICIs, and the median time was 108 days. After diagnosed of kidney injury, 13 out of 29 patients stopped ICIs, of which 6 had recovered kidney function and 7 had no improvement; 16 patients continued the ICIs treatment, of which 10 patients had recovered or improved kidney function and 6 had no improvement. The clinical characteristics of patients in the 2 groups were compared, and 10 variables including age, gender, baseline renal function, previous use of carboplatin, previous radiotherapy, combined chemotherapy containing cisplatin, combined paclitaxel chemotherapy, combined tyrosine kinase inhibitor (TKI) anti-vascular therapy, combined proton pump inhibitors, and combined radiotherapy were screened for the binary logistic regression analysis. The results showed that female (OR=3.046, 95%CI: 1.149-8.077), ≤65 years (OR=3.649, 95%CI: 1.435-9.274), combined TKI anti-vascular therapy (OR=4.773, 95%CI: 1.496-15.227), and combined radiotherapy (OR=8.655, 95%CI: 1.268-59.076) were independent risk factors for the development of kidney injury. Conclusions The incidence of kidney injury in patients with eGFR <90-ml/(min·1.73 m2) and/or Scr >105-μmol/L after using ICIs is 13.1%. In these patients, female, ≤65 years, combined TKI anti-vascular therapy, and combined radiotherapy may be risk factors for the development of ICI-associated kidney injury.
  • Cai Junying, Chen Wanwen, He Yuwen
    Adverse Drug Reactions Journal. 2023, 25(4): 204-210. https://doi.org/10.3760/cma.j.cn114015-20221107-01035
    Objective To explore the influencing factors of immune checkpoint inhibitor-related pneumonitis (CIP) in lung cancer patients caused by programmed cell death 1 receptor (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors. Methods A retrospective analysis was conducted on clinical data of lung cancer patients treated with PD-1/PD-L1 inhibitors in the First Affiliated Hospital of Guangzhou Medical University from January 2018 to June 2022. Patients with CIP were included in the CIP group, and those who did not experience any immune-related adverse events during the same period were screened in a 1∶1 ratio and included in the control group. The clinical characteristics in patients of the 2 groups were compared and influencing factors of CIP were analyzed using binary logistic regression method. The effect sizes were the odds ratio (OR) and its 95% confidence interval (CI). Results A total of 246 patients (123 in the CIP group and 123 in the control group) were entered in the analysis, including 208 males and 38 females, aged (63±9) years with a range of 32 to 86 years. The diagnosis was non-small-cell lung cancer in 234 patients and small cell lung cancer in 12 patients. There were no statistically significant differences in age, gender, history of respiratory diseases, tumor histological types, TNM stages, and types of immune checkpoint inhibitors used in patients between the 2 groups (all P>0.05). Compared with the control group, patients in the CIP group had a lower body mass index [(21.5±3.2) kg/m2 vs. (22.6±3.0) kg/m2, P=0.004], higher proportion of patients with Eastern Cooperative Oncology Group Performance Scale (ECOG-PS) ≥2 points[39.0% (48/123) vs. 22.0% (27/123), P=0.004], higher proportion of patients with a history of radiation therapy [25.2% (31/123) vs. 13.8% (17/123), P=0.024], and lower proportion of patients with combination therapy with chemotherapy/targeted drugs[82.9%(102/123) vs. 97.6%(120/123), P<0.001]. Before immunotherapy, the peripheral blood interleukin-1β and interferon-α were lower [1.97 (1.04, 2.74) ng/L vs. 2.40 (1.75, 4.03) ng/L, P=0.021; 2.08 (0.89, 3.00) ng/L vs. 2.76 (1.97, 3.94) ng/L, P=0.012], lymphocyte count was lower [1.4(1.0, 1.8)×109/L vs. 1.5(1.2, 2.1)×109/L, P=0.030], and the neutrophil-to-lymphocyte ratio was higher [3.85 (2.50, 6.40) vs. 3.11 (2.25, 4.61), P=0.006] in patients of the CIP group than those in the control group. The binary logistic regression analysis showed that baseline ECOG-PS ≥2 points (OR=3.400, 95%CI: 1.180-9.798, P=0.023) and combination of PD-1/PD-L1 inhibitors and chemotherapy/targeted therapy (OR=0.047, 95%CI: 0.005-0.454, P=0.008) were independent influencing factors for the occurrence of CIP. Conclusion The ECOG-PS ≥ 2 points before immunotherapy is an influencing factor for CIP, and the combination with chemotherapy/targeted therapy may reduce the risk of developing CIP in patients treated with PD-1/PD-L1 inhibitors.
  • Chen Lu, Xu Lei
    Adverse Drug Reactions Journal. 2023, 25(4): 211-217. https://doi.org/10.3760/cma.j.cn114015-20220714-00632
    Objective To investigate the occurrence and clinical characteristics of immune-related adverse events (irAEs) caused by pembrolizumab (PEM) in elderly patients with advanced lung cancer. Methods The subjects were selected from the elderly patients with advanced lung cancer who received PEM therapy (200-mg was given by intravenous infusion once every 21 days and 21 days was a cycle) in the Affiliated Hospital of Inner Mongolia Medical University from August 2020 to July 2022. The medical records of patients meeting the inclusion criteria were collected through the Hospital Electronic Medical Record Information System, the clinical data such as patients′ basic information, pathological type of lung cancer, clinical stage, whether or not combination with chemotherapy, the occurrence time of irAEs, clinical manifestations, intervention, and prognosis were recorded and analyzed retrospectively. The irAEs were graded according to the Common Terminology Criteria for Adverse Event (CTCAE) Version 5.0 developed by the National Cancer Institute of the United States. Results A total of 100 patients were enrolled in the analysis, of which 22 (22%) patients developed irAEs. Among the 22 patients, 19 were male and 3 were female, aged from 61 to 90 years, including 15 lung squamous cell carcinomas and 7 lung adenocarcinomas. There were 4 patients with clinical stage Ⅲ and 18 patients with stage Ⅳ; one patient received PEM monotherapy and 21 patients received PEM combined with chemotherapy. A total of 28 cases of irAEs occurred in 22 patients (19 cases of 1 type of irAE, 1 case of 2, 3, and 4 types of irAE each), including 10 cases of skin irAEs (3 in grade 1, 3 in grade 2, and 4 in grade 3), 8 cases of immune-related pneumonitis (1 in grade 1, 7 in grade 2), 7 cases of irAEs involving the endocrine system (1 case of hypothyroidism in grade 1, 3 cases of hypothyroi- dism in grade 2, 1 case of adrenocortical dysfunction in grade 1, 1 case of hyperglycemia in grade 1, and 1 case of pituitary inflammation in grade 4), 2 cases of immune-associated hepatitis (1 in grade 1, 1 in grade 3), 1 case of ICI-related myocarditis in grade 3. The shortest occurrence time of the 28 cases of irAEs was on the day of initial medication, the longest was 20 days after the 17th cycle of medication, and 22 cases occurred between the 1st to 8th cycles of medication. After the occurrence of irAEs, 5 patients discontinued PEM and most received hormone and/or symptomatic treatment. Twenty patients were cured or self-healed, 1 partially recovered, and 1 was not improved. Conclusions Elderly patients with advanced lung cancer who receive PEM may experience skin, lung, endocrine system, liver, and heart irAEs, mostly occurring between the 1st to 8th cycles of medication, mostly in grades 1 and 2. Discontinuation of medication and hormone and/or symptomatic treatment can lead to a better prognosis.
  • Wang Yan, Zhao Xinyan, Jia Jidong
    Adverse Drug Reactions Journal. 2023, 25(4): 243-247. https://doi.org/10.3760/cma.j.cn114015-20220801-00695
    Immune checkpoint inhibitors (ICIs) play the role of anti-tumor by activating the immune system in human, but they can also cause immune-mediated liver injury, which is different from conventional drug-induced liver injury in the incidence, clinical manifestations, pathogenesis, and prognosis. The main pathogenesis is that ICIs block key nodes of negative regulation of the immune response, including cytotoxic T-lymphocyte-associated antigen 4 and programmed cell death 1 receptor/programmed cell death ligand 1. Liver-injury occurs when the immune system is overactivated and loses immune tolerance to the liver. Immune-mediated liver injury includes immune-mediated hepatitis and immune-mediated cholangitis. Histopathological examination of the liver shows damage in hepatocytes and bile ducts, accompanied by central venous dermatitis mostly and granulomatous lesions partially. After diagnosis of immune-mediated liver injury, treatment should be given based on the severity, and glucocorticoids or immunosuppressants are often necessary.
  • Zhang Lan, Dong Xianzhe, Wang Zhizhou
    Adverse Drug Reactions Journal. 2023, 25(3): 129-132. https://doi.org/10.3760/cma.j.cn114015-20230103-01203
    It was a very common phenomenon that an original drug was replaced by a generic drug after its patent expires. In order to further verify the efficacy and safety of domestic generic drugs selected in the national centralized volume-based procurement, the National Healthcare Security Admini stration guided a number of medical institutions to carry out large-scale real-world studies on clinical efficacy and safety of generic drugs, involving drugs for treating cardiovascular and cerebrovascular diseases, neuropsychiatric diseases, chronic hepatitis B, and tumor, and anesthetics. More than 110 thousands patients were included in the study. Evidence from real world studies and randomized controlled trials can complement each other. Because of the diversity of data, the complexity of design, the high requirements of analytical methods, and the uncertainty of the interpretation of results in the real world studies, higher requirements for the safety and efficacy evaluation and regulatory decision-making of generic drugs are put forward. Possible recommendations to constantly promote the scientificalness and standardization of the production and use of real world evidence are as follows: further strengthen the informatization construction in medical institutions and promote the standardization and convenience in real world data use, improve the scientificalness of research design and data processing, explore and improve the real world evidence quality evaluation criteria, strengthen the awareness of data security and pay attention to the participants′ privacy protection, etc.