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

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

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

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

Rational drug repurposing for alzheimer's treatment using in-silico ligand and structure-based approaches

Abstract Alzheimer's disease is a devastating neurodegenerative disorder characterized by memory loss and cognitive decline. New AD treatments are essential, and drug repositioning is a promising approach. In this study, we combined ligand-based and structure-based approaches to identify potential candidates among FDA-approved drugs for AD treatment. We used the human acetylcholinesterase receptor structure (PDB ID: 4EY7) and applied Rapid Overlay of Chemical Structures and Swiss Similarity for ligand-based screening.Computational shape-based screening revealed 20 out of 760 FDA approved drugs with promising structural similarity to Donepezil, an AD treatment AChE inhibitor and query molecule. The screened hits were further analyzed using docking analysis with Autodock Vina and Schrodinger glide. Predicted binding affinities of hits to AChE receptor guided prioritization of potential drug candidates. Doxazosin, Oxypertine, Cyclopenthiazide, Mestranol, and Terazosin exhibited favorable properties in shape similarity, docking energy, and molecular dynamics stability.Molecular dynamics simulations confirmed the stability of the complexes over 100 ns. Binding free energy analysis using MM-GBSA indicated favourable binding energies for the selected drugs. ADME, formulation studies offered insights into therapeutic applications and predicted toxicity.This comprehensive computational approach identified potential FDA-approved drugs (especially Doxazosin) as candidates for repurposing in AD treatment, warranting further investigation and clinical assessment.

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

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

General considerations for clinical pharmacology of antitumor antibody-conjugated drugs: Implications from FDA review cases / 中国临床药理学与治疗学

Antibody-drug conjugates (ADCs) are conjugated by a linker between an antibody drug targeting a specific antigen and a payload, such as a small cytotoxic drug. ADCs combine the potent killing effect of traditional small cytotoxic drugs with the tumor targeting property of antibody drugs. As of February 2022, the U.S. Food and Drug Administration (FDA) had approved 12 ADC antitumor agents. Based on the analysis of clinical pharmacology review reports of approved ADC drugs combined with relevant guidelines, it is found that in the development of ADC, in addition to the general research in clinical pharmacology, there are special considerations in dose selection and dose modification for special population due to the special anti-tumor mechanism of ADC. It is hoped that this paper will be enlightening to domestic researchers when developing ADC.

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

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

ADE signal mining and analysis of axitinib based on FAERS database / 中国药房

OBJECTIVE To provide references for the clinical safe use of axitinib. METHODS Adverse drug event （ADE） data for axitinib were collected from the US FDA Adverse Event Reporting System （FAERS） database from the first quarter of 2012 to the fourth quarter of 2022. The data were mined and analyzed by utilizing the ratio-of-reporting-ratio （ROR） method and comprehensive standard method of the United Kingdom’s Medicines and Healthcare Products Regulatory Agency （MHRA） of proportional imbalance measurement. RESULTS A total of 13 962 reports of axitinib-related ADEs were obtained， with patients’ age concentrated in 65-85 years （43.25%）， gender predominantly male （65.23%）， country of reporting predominantly US （60.01%）， and serious ADE outcomes mostly hospitalization or prolonged hospitalization （31.51%）. A total of 172 ADE risk signals were detected， involving 18 system and organ classifications （SOC）， mainly systemic diseases and various reactions at the site of administration （3 749 cases， 30.84%） and gastrointestinal system diseases （2 067 cases， 17.00%）. ADE risk signals that occurred more frequently were generally consistent with the drug instruction， such as diarrhea， fatigue， and hypertension； new ADE risk signals requiring clinical attention were death， immune-mediated nephritis， and PT signals contained in the SOC of various benign， malignant， and tumors of undetermined nature （including cysts and polyps）. CONCLUSIONS For ADEs that occur frequently with axitinib and are already contained in the drug instruction （e.g. hypertension， diarrhea）， they should be adequately evaluated before administration， especially for patients with combined use of immune checkpoint inhibitors and patients with underlying hypertension； for ADEs with stronger signals and newer ADEs （e. g. death， disease progression， tumor progression）， the patient’s disease progression should be closely monitored during the treatment period for potentially fatal ADEs； for its rare ADEs （e. g.immune-mediated nephritis， scrotal ulcer， non-infectious encephalitis）， clinical validation should be further strengthened.

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

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

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

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

A study of prescribing patterns in high-risk pregnancy at a tertiary care hospital

Background: High-risk pregnancy is defined as pregnancy complicated by factors that can adversely affect maternal and perinatal outcome. About 10–30% of pregnancies are high risk which accounts for 70–80% perinatal mortality and morbidity. Drug utilization data help to monitor the drugs prescribed and to assess the outcome by evaluating appropriateness and rationality of prescription. Aims and Objectives: This study aims to evaluate the pattern of drug use in high-risk pregnancy and to assess the WHO core prescribing indicator and US FDA category. Materials and Methods: A total of 250 case record forms of pregnant women admitted to high-risk ward were analyzed. Patient’s demographic data and detailed information about prescription were recorded and analyzed as per the WHO core drug prescribing indicators and US-FDA category. Descriptive statistics were used. Results: A total of 1121 drugs were prescribed among which antimicrobials (33.7%) were used more frequently followed by antihypertensive (13.9%), intravenous (609, 54.2%) route was the major route of drug administration, followed by oral (527, 47%), intramuscular (33, 2.9%), and subcutaneous (16, 1.4%). Average number of drugs per encounter was 4.48, percentage of encounters with an antimicrobials prescribed is around 70.4%, percentage of drugs prescribed by generic name was 93.5%, percentage of drugs prescribed from essential drugs list was 73.3%, and percentage of encounters with an injection prescribed was 50.4%. Majority of drugs belong to the US-FDA pregnancy Category B (45.04%), followed by Category C (39.4%), A (10.8%), and D (4.6%). Conclusion: Majority of drugs were prescribed by generic name and belonged to Category B drugs which are considered safe. Standards of prescription were in accordance with the WHO prescribing indicators. Overall prescribing behavior is rational and encouraging.

Common Approaches of Cytochrome P450 (CYP) Induction Assays

The induction of enzymes is a defensive mechanism for some xenobiotics, but it may alter the drug's safety and efficacy by altering the activity of metabolic enzymes. One of the major families of enzymes involved in phase I metabolism is Cytochrome P450 (CYP) enzymes which may get induced by certain drugs. Concomitant administration of drugs due to chronic disease or polypharmacy, inducers among them may cause toxicity or reduce the plasma concentration at a sub-therapeutic level. This is one of the dangerous types of drug-drug interactions, but predictable & preventable. The CYPs get induced by three nuclear receptors, including the aryl hydrocarbon receptor (AhR); constitutive androstane receptor (CAR); the pregnane X receptor (PXR). Without identification during drug development, enzyme induction phenomenon of a new drug molecule may get noticed only during pharmacovigilance. Though, this CYP induction may not be a barrier for drug development, it may cause possible DDI and treatment failure. According to FDA guidelines, pharmaceutical industries adopted In-vitro, Ex-vivoand In-vivotechniques based on different developmental stages. The results are also interpreted based on regulatory bodies guidelines. For In-vitroassay best accepted method is using primary hepatocytes either fresh or cryopreserved, for Ex-vivoliver slices of different species and in-vivo, clinical investigations are the extreme option. This paper reviews current industry approaches of CYP induction assays to evaluate potentiality for a new drug molecule as an inducer

FDA Premarket Pathways for Combination Products / 中国医疗器械杂志

Combination products face unique R&D, manufacturing, clinical, and regulatory challenges compared to individual devices, drugs, or biological products. Based on the interpretation of the relevant policies and the latest principles of combination products, this paper expounds the FDA's guidance, application trends, and application strategies for the pre-market pathways of combination products, with a view to providing relevant information for Chinese researchers and manufacturers when they start to entry the United States market.

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

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

Data mining of adverse drug reaction signals for ado-trastuzumab emtansine and brentuximab vedotin based on FAERS database / 中国药房

OBJECTIVE To analyze the adverse drug reaction （ADR）signals of ado-trastuzumab emtansine and brentuximab vedotin，so as to provide reference for clinical medication safety. METHODS Using the FDA adverse drug event reporting system （FAERS）database and OpenVigil 2.1 data platform ，the ADR of the two drugs were collected from being approved by FDA to the Sep. 30th，2021. The ADR signals were detected by frequency method and sorted according to the occurrence frequency and signal strength respectively. RESULTS & CONCLUSIONS A total of 2 319 and 3 178 ADR reports related to ado-trastuzumab emtansine and brentuximab vedotin were collected ，215 and 329 ADR signals were detected respectively. According to the occurrence frequency，the most frequent ADR s of the two drugs were thrombocytopenia （109 cases）and febrile neutropenia （198 cases）， separately，which were consistent with the drug instructions. According to the signal strength ，the spider nevus of ado-trastuzumab emtansine（report odds ratio of 451.46）and the noninfectious endocarditis of brentuximab vedotin （report odds ratio of 304.35） ranked first ，both of which were not reported in the drug instructions. It is suggested that attention should be paid not only to the most common ADR s of blood and lymphatic system caused by both drugs ，but also to the ADRs not reported in the drug instructions such as spider nevus of ado-trastuzumab emtansine and noninfective endocarditis of brentuximab vedotin.

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

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

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

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

Data-mining of Adverse Drug Events Signals for Tocilizumab Based on US FAERS Database / 中国药房

OBJECTIVE：To provide reference for clinical safe and rational drug use by mining adverse drug events （ADE） signals for tocilizumab. METHODS ：Data of ADE reports related to tocilizumab in the first quarter of 2015 to second quarter of 2020 were collected from US FDA adverse event reporting system. After data standardization ，the proportional imbalance method was used for ADE signal mining. RESULTS ：A total of 163 718 ADE reports were extracted ，in which tocilizumab was primary suspected drug ，involving 26 674 patients. In 26 674 patients，the proportion of female （73.69％）was higher than that of male （19.04％），and the age was mainly 60-74 years old （21.19％）. Among the 163 718 ADE reports ，the main reporting countries were the United States （70.15％），Canada（15.95％），Japan（3.33％），Australia（3.05％）and Brazil （1.43％）；consumers （31.35％）and doctors （24.94％）were the main reporting staff. A total of 747 ADE signals for tocilizumab were obtained ， commonly rheumatoid arthritis ，joint pain and pain ；and the signals as the increase of disability assessment scale score ，the decrease of disability assessment scale score ，abnormal diastolic blood pressure and abnormal systolic blood pressure were strong. A total of 33 kinds of ADE signals were found ，which were not recorded in the instructions of tocilizumab ，and mainly abnormal laboratory indicators such as decreased oxygen saturation ，decreased blood pressure and abnormal heart rate. ADE mainly involved 27 system organs ，including musculoskeletal and connective tissue ，various reactions of systemic diseases and drug delivery site ， various examinations. CONCLUSIONS ：In addition to the ADE mentioned in the drug instructions ，when using tocilizumab in clinic，attention should also be paid close to blood oxygen saturation ，blood pressure ，blood routine indexes and other laboratory indicators，and intervention measures should be taken early when ADE occurs ，so as to ensure the safety and effectiveness of drug use.

ADR Signal Mining of Rivaroxaban Based on FDA Adverse Event Reporting Database / 中国药房

OBJECTIVE：To excavate the ADR signals of rivaroxaban and provide reference for its safe and rational use in clinic. METHODS ：Based on FDA adverse event reporting system （FAERS），the ADRs of rivaroxaban reported from September 2008 to December 2020 in FDA ’s Open Data Program were mined using ratio of reports to odds （ROR）and proportional report ratio （PRR）. The related ADRs were analyzed ，and the corresponding system organ classification （SOC）was mapped. At the same time，the basic information such as gender ，age and indications of the patients were statistically reported. RESULTS & CONCLUSIONS：Among 9 373 236 ADR reports extracted ，102 027 ADR reports with rivaroxaban as concomitant and suspected drug were obtained ；883 ADR signals were mined ，involving 27 systems. Among 102 027 reports，the proportion of female patients （41 294 cases，40.47％）was similar to that of male patients （41 071 cases，40.26％）. The patients were mainly ＞50 to 75 years old（29 261 cases，28.68％）and ＞75 years old （21 470 cases，21.04％）. The reporting year was mainly in 2018（18 446 cases， 18.08％）；main reporting country was the United States （75 390 cases，73.89％）；there were 35 046 cases（34.35％）of severe ADR reports ，mainly involving hospital or prolonged hospital stay. The SOC of rivaroxaban ADR singal mainly focused on diseases of the blood and lymphatic system ，vascular diseases ，various types of examination and nervous system diseases. Among top 20 preferred terms of ADRs with the highest frequency ，except for pulmonary embolism ，acute kidney injury and atrial fibrillation ，the rest were mainly bleeding related ADRs ，of which intracranial hemorrhage was the more seriou s ADR. Intracranial hemorrhage may occur when rivaroxaban is used for the prevention of atrial fibrillation and cerebrovascular accidents ， and pulmonary embolism may occur when rivaroxaban is used for the prevention of pulmonary embolism ，（deep）venous thrombosis and thrombosis. Great importance should be paid on it.

Safety Signal Mining for 7 Kinds of Fluid Therapy Drug Based on FAERS Database / 中国药房

OBJECTIVE：To mine t he data of adverse even ts of 7 kinds of commonly used fluid therapy drugs （normal Ringer ’ s solution ，Ringer’s lactate solution ，Ringer’s acetate solution ，hydroxyethyl starch ，succinylated gelatin ，dextran and human albumin） based on FAERS database of FDA ，in order to provide reference for carrying out fluid therapy in clinic safely. METHODS：Data from the first quarter of 2004 to the fourth quarter of 2019（64 quarters）in FAERS database were downloaded. After data cleaning ，adverse drug event report cases related to 7 kinds of fluid therapy drug as the primary and secondary suspected drugs were extracted ，and ADR signal was mined by using the reporting odds ratio method （ROR）and the proportional reporting ratio method （PRR）. RESULTS ：A total of 2 383 adverse event reports were extracted ，including 26 reports（1.09％）of normal Ringer’s solution ，479 reports（20.10％）of Ringer ’s lactate solution ，65 reports（2.73％）of Ringer ’s acetate solution ，256 reports （10.74％）of hydroxyethyl starch ，79 reports（3.32％）of succinylated gelatin ，154 reports（6.46％）of dextran ，1 324 reports （55.56％）of human albumin. Totally 879 cases（36.89％）were male and 985 cases（41.33％）were female ，the rest were unknown. The main age was 18-64 years old （950 cases，39.87％）；most of the reporters were doctors （634 cases，26.60％）. Totally 382 cases（16.03％）died. Among the adverse event reports of fluid therapy drugs ，70 cases（14.61％）administered Ringer ’s lactated solution and 259 cases（19.56％）administered human albumin died. Among them ，the top three adverse events in the number of reports were immune system diseases ，heart organ diseases ，vascular and lymphatic diseases. CONCLUSIONS ：ADRs of fluid therapy drugs are mainly related to immune system and heart organ. In the process of them ，especially for patients with allergic history and heart disease ，patients’volume indicators should be closely monitored ；during fluid therapy ，especially during the use of colloids ， great importance should be attached to renal and urinary system related adverse events ， and renal function should be closely monitored .

Analysis of innovative drug category 1.2 in traditional Chinese medicine and considerations on quality control of extracts / 中国中药杂志

In this article, the essence of innovative drug category 1.2 extracts and preparations in the new version of the New Drug Registration Category of traditional Chinese medicines(TCM) was analyzed by combing through the history of provisions on drug registration and comparing with other categories of drugs. After analyzing the characteristics of this type of preparations, the author concluded that the quality control objectives of category 1.2 extract should focus on ensuring the quality consistency of the active ingredients/components in batches, so as to guarantee the consistency of drug quality and efficacy. With reference to the relevant technical requirements for herbal medicinal products in European Medicines Agency(EMA) and botanicals in Food and Drug Administration(FDA),the key points in quality control of the extract should include the content and composition of the therapeutic constituents, the type and content of the concomitants, and the influence of exogenous contaminants on drug safety.