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.

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.

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.

Research on FDA Data Standards Program in the United States and Its Enlightenment to China / 中国药房

OBJECTIVE：To study FDA data standards program in the United States ，and to provide reference for constructing medicine data standards in China. METHODS ：By analyzing the governance organization and policy system of FDA data standards program in the United States ，the experience were summarized for data standards development mode and development procedure ， and relevant suggestions were put forward for medicine data standards construction in China. RESULTS & CONCLUSIONS ：The organization of FDA data standards program is led by the Chief Scientist Office of FDA ，coordinated by the Data Standards Advisory Board ，specifically responsible by the Data Standards Program Board under the center for Drug Evaluation and Research ， and participated by other regulatory centers and offices under FDA. FDA data standards program is composed of 4 subsystems as data standards strategy ，data standards program action plan ，data standards catalog and data standard communication plan. According to the federal laws and regulations of the United States ，the demand of FDA and pharmaceutical industry for data standards and the importance of data standards ，the strategic objectives of data standards development are proposed ，and the strategic objectives are refined into specific projects through the data standards program action plan. These programs strictly follow the“data standards development process ”and gradually advance quarterly ，and new data standards will be included in the Data Standards Catalog . At the same time ，FDA strengthen the cooperation and communication with internal and external stakeholders through the data standards program communication plan. It is suggested that China should learn from the experience of FDA data standards program construction ，establish a medical and health data standards program management mode ，strengthen the participation of internal and external stakeholders ，establish data standards committee ，formulate data standards catalog ，and provide clear and unified data standards for the pharmaceutical industry ，so as to promote the construction of medicine data standards in China.

Botanical Drug Development-Guidance for Industry and Expert Views on Botanical Drug Development in the US / 世界科学技术-中医药现代化

The definition of new drugs in China and the US has no major differences on chemical drugs and biologics.However,Chinese medicines,which are regulated as over-the-counter (OTC) or prescription drugs in China,are mostly regulated as food and/or dietary supplements without FDA approved medicinal use for marketing.The FDA Guidance for Industry-Botanical Drug Products (2004) and the recently revised Guidance for Botanical Drug Development (2016) paved the way for Chinese herbal medicine and other botanical mixtures to be further developed as new drugs through clinical trials and other nonclinical studies.FDA recognizes the value of traditional medicines as part of the previous human experiences to support the safety and speed up early phase clinical trials of botanical products under investigational new drug (INDs) applications.The revised Guidance included addition recommendations for late phase development,like phase 2 trials and new drug applications (NDA),to resolve some of the unique challenges on batch-tobatch consistency (e.g.,a totality of evidence approach,including raw material control,bioassays,multiple-batch and multiple-dose clinical trials,and etc.).The approval of Veregen and Fulyzaq (now Mytesi) are new molecular entity / new chemical entity type of new drugs,treasured fruits from several hundred INDs studying botanicals.With those NDA examples,it is expected that further study of Chinese herbal medicines as new botanical drugs through further clinical and nonclinical development will be fruitful.On the other hand,long-term commitments are universal for new drug development.And it will also be true for bringing Chinese herbal medicines as botanical new drugs to international markets.It still takes time to see whether artesunate tablets can be verified through further clinical trials and achieve the same level of Coartem.

A New Bioanalytical Method Development & Validation for Simultaneous Estimation of Esomeprazole and Naproxen in Human Plasma by Using RP-HPLC.

Aim: A new reverse phase high performance liquid chromatography (RP-HPLC) method for the quantitative determination of Esomeprazole and Naproxen in human plasma was developed and validated as per US-FDA guidelines. Methodology: The drug was spiked in the plasma and extracted with mobile phase by precipitation method. The extracted analyte was injected into Symmetry C18 (4.6 x 150mm, 5μm, Make: XTerra) or equivalent, maintained at ambient temperature and effluent was monitored at 285nm. The mobile phase was composed of potassium dihydrogen phosphate and acetonitrile [HPLC Grade] in the ratio of 60:40. The pH of the potassium buffer was adjusted to 3.0 by using Ortho Phosphoric Acid. The flow rate was maintained at 1.0 mL/min. Results: The developed method shows high specificity for Esomeprazole and Naproxen. The calibration curve for Esomeprazole and Naproxen was linear from 1.0 to 6.0 ppm (r2= 0.999) and 25.0 to 150.0 ppm (r2= 0.999) respectively. The inter-day and intra-day precision was found to be within limits. The proposed method was adequate sensitivity, reproducibility, and specificity for the determination of esomeprazole and naproxen in plasma. The Lower limit of quantification (LLOQ) for the drug Esomeprazole and Naproxen were found to be 0.04μg/ml and 0.4μg/ml respectively. The average percent recovery for the drugs Esomeprazole and Naproxen were found to be 98.97-99.84 & 99.80-100.95 respectively and reproducibility was found to be satisfactory. Conclusion: The proposed method was accurate, and precise for the quantification of Esomeprazole and Naproxen in the plasma. The proposed can also be used for routine analysis in quality control. The method was validated for parameters like selectivity, sensitivity, precision, intermediate precision, accuracy, linearity, recovery & stability. This RP -HPLC method is suitable for determining the concentration of Esomeprazole and Naproxen in plasma and it can applied for routine analysis for determination of the Esomeprazole and Naproxen from dosage form during pharmacokinetic study.