Safety assessment of S-1: Real-world adverse event analysis from the FAERS database

Safety assessment of S-1: Real-world adverse event analysis from the FAERS database | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Safety assessment of S-1: Real-world adverse event analysis from the FAERS database Di Zhao, Jie Liu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4119504/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background The aim of this study was to gather information on adverse drug events (ADEs) associated with S1 from the US Food and Drug Administration Adverse Event Reporting System (FAERS) to evaluate its safety and provide a reference for drug use. Methods We searched the raw data of the FAERS database from its establishment to the third quarter of 2023 to screen ADE reports involving S-1. Signal detection indicators, including ROR, PRR, BCPNN, and MGPS, were used to perform statistical analysis and systematic classification of adverse drug events (ADEs) based on corresponding threshold conditions. Results A total of 186,085,022 REAC reports, and 2,011 PT signals induced by S1 as the PS were obtained. Among them, there were 856 adverse event reports of S1 as the PS. In addition, the average age of patients was 65 years and 6 months. Through screening analysis, a total of 126 PT signals involving 18 SOSCs were identified. Mainly involved in vascular disorders, general disorders, and administration site conditions such as skin and subcutaneous tissue disorders. PT with high occurrence frequency includes papules/rash/pruritus; we also found hypertension with an ROR of 95% CI 90-77121-1156 and uterine cancer with an ROR of 95% CI 90-7292-2817. Conclusions Mining and analysis of real-world adverse event data of S1 is helpful in finding potential risk signs or symptoms of adverse drug reactions, suggesting that clinical attention should be paid not only to the adverse reactions mentioned in the drug instructions but also to new suspected adverse reactions and clinical standardized medication to ensure patient medication safety. S-1 Adverse drug events Us FDA adverse Event Reporting System database Figures Figure 1 Figure 2 BACKGROUND Cancer poses a formidable challenge to global health, ranking among the principal causes of mortality and a significant barrier to enhancing life expectancy. The latest data from GLOBOCAN in 2020 reveal a staggering 19.3 million new cancer cases globally, accompanied by approximately 10 million fatalities, highlighting the immense burden of this disease[ 1 ]. Within this context, gastric cancer stands out as one of the most frequently diagnosed malignant neoplasms. In 2019, the worldwide incidence of gastric cancer, as measured by the European Organization for Research and Treatment of Cancer (EOGC), was reported at 3.7 cases per 100,000 individuals, with a 20-year cumulative decrease of 0.84 per 100,000[ 2 ]. Several key factors contribute to the development of gastric cancer, including gender[ 3 ], genetic predisposition[ 4 – 6 ], and the presence of Helicobacter pylori (Hp) infection[ 7 – 9 ]. For patients with advanced gastric cancer, chemotherapy remains a cornerstone of therapeutic intervention[ 10 ]. Surgical intervention, particularly radical total gastrectomy, has been demonstrated to significantly extend survival in patients with gastric cancer[ 11 – 13 ]. Additionally, the advent of precision medicine has led to the integration of targeted therapies and immunotherapies into the treatment paradigm for a variety of cancers[ 14 – 17 ]. These advances underscore the importance of a personalized approach to gastric cancer treatment, where clinicians must conduct a thorough assessment of both the patient's disease risk and overall health status to determine the most suitable course of treatment that aligns with the patient's tolerance and therapeutic needs. S-1 is used for unresectable locally advanced or metastatic gastric cancer[ 18 – 20 ], and can also be used for breast cancer, pancreatic cancer, cholangiocarcinoma, colorectal cancer, non-small cell lung cancer, etc. S-1 capsules consist of tegafur (FT), S-1 (CDHP), and Oxo potassium[ 21 , 22 ]. The mechanism of action is that FTS1 is gradually converted into 5-FU in vivo after oral administration. CDH preferentially selects to inhibit dihydropyrimidinedehydrogenase (DPD), a 5-FU catabolic enzyme present in the liver, thereby increasing the concentration of 5-FU from the FT[ 23 ]. With the increase of 5-FU concentration in vivo, 5 fluorocarbonucleotides, the phosphorylation product of 5-FU, can maintain a higher concentration in tumor tissue, thus enhancing the antitumor effect [ 24 ]. Oxo is distributed in the gastrointestinal tract after oral administration and can selectively and reversibly inhibit rotate phosphoribosyl transferase, thereby selectively inhibiting the conversion of 5-FU to 5 fluoronucleotides and reducing gastrointestinal toxicity without affecting the antitumor activity of 5-FU[ 25 ]. Although some studies have shown that S-1 has better efficacy, safety and economy compared with other chemotherapy drugs in the treatment of gastric cancer[ 26 , 27 ], with its wide clinical application, serious skin adverse reactions, blood and vascular system abnormalities caused by S-1 have gradually been reported and concerned[ 28 , 29 ]. Based on this, this paper mines and analyzes the adverse drug events (ADE) signals of S-1 after marketing in the US FDA adverse events reporting system (FARES) database[ 30 ]. To provide reference for the safe application of the drug in clinical practice. METHODS Data source The adverse drug event (ADE) reports for S1 from Q1 2004 to Q3 2021 encompass a total of 37 quarters over a span of 12 years. These reports were collected by searching the FDA Adverse Event Reporting System (FAERS) database, where 'S1' was used as the primary search term. By employing the generic English name 'S1', we aimed to capture all relevant adverse events associated with this drug. The terms 'PT' and 'SOC' were utilized in the Medical Dictionary for Regulatory Activities (MedDRA) version 24.0 terminology set, which is published by the Technical Coordination Council for Human Drug Registration[ 31 ]. During the data extraction process, duplicates were removed, and reports that contained product storage errors were excluded to ensure the integrity and accuracy of the data analysis. Data extraction and analysis The study collected data on the number of target adverse event AEs reported for the primary suspect drug. Potential AEs were screened using the proportion imbalance method with four grid tables referred to as Table 1 . The study utilized reporting odds ratio methods, ROR proportional reporting ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS), with X2 used to calculate ROR and PRR respectively.[ 32 – 34 ]. Among them, the effective risk signal should meet the following conditions: (1)ROR method: the number of AE reported cases should be ≥ 3,ROR > 3, and the lower limit of 95% CI of ROR should be > 1; (2)PRR method: the number of AE cases should be ≥ 3,PRR > 2, and the lower limit of 95% CI of PRR > 1; (3)BCPPN: IC025 > 0; (4)MGPS: MGPS05 > 2. A higher value indicates a stronger correlation (Table 2 ). Table 1 Four grid table. Drug-related ADEs Non-drug related ADEs Total Drug a b a + b Non-drug c d c + d Total a + c b + d N = a + b + c + d Abbreviations: ADE, adverse drug events Table 2 ROR, PRR, BCPNN, and MGPS methods, formulas, and thresholds. Method Formula Threshold ROR \(\text{R}\text{O}\text{R}=\frac{\text{a} / \text{c}}{b / d}\) a ≥ 3 ROR ≥ 3 95%CI (lower limit) > 1 \(SE\left(lnROR\right)=\sqrt{\frac{1}{\text{a}}+\frac{1}{\text{b}}+\frac{1}{\text{c}}+\frac{1}{\text{d}}}\) \(95\%CI= {\text{e}}^{\text{ln}\left(ROR\right)\pm 1.96se}\) PRR \(\text{P}\text{R}\text{R}=\frac{\text{a} / (\text{a}+\text{b})}{c / (c+d)}\) a ≥ 3 PRR ≥ 2 95%CI (lower limit) > 1 \(SE\left(lnPRR\right)=\sqrt{\frac{1}{\text{a}}-\frac{1}{\text{a}+\text{b}}+\frac{1}{\text{c}}-\frac{1}{\text{c}+\text{d}}}\) \(95\%CI= {\text{e}}^{\text{ln}\left(PRR\right)\pm 1.96se}\) BCPNN \(\text{I}\text{C}={\text{l}\text{o}\text{g}}_{2}\frac{p(x, y)}{p\left(x\right)p\left(y\right)}= {log}_{2}\frac{a(a+b+c+d)}{(a+b)(a+c)}\) IC025 > 0 \(\text{E}\left(\text{I}\text{C}\right)={\text{l}\text{o}\text{g}}_{2}\frac{(a+\gamma 11)(a+b+c+d+\alpha )(a+b+c+d+\beta )}{\left(a+b+c+d+\gamma \right)(a+b+\alpha 1)(a+c+\beta 1)}\) \(\text{V}\left(\text{I}\text{C}\right)=\frac{1}{{\left(ln2\right)}^{2}}[\frac{\left(a+b+c+d\right)-a+\gamma -\gamma 11}{\left(a+\gamma 11\right)\left(1+a+b+c+d+\gamma \right)}+\frac{\left(a+b+c+d\right)-\left(a+b\right)+a-\alpha 1}{\left(a+b+\alpha 1\right)\left(1+a+b+c+d+\alpha \right)}+\frac{\left(a+b+c+d+\alpha \right)-\left(a+c\right)+\beta -\beta 1}{\left(a+b+\beta 1\right)\left(1+a+b+c+d+\beta \right)}]\) \({\gamma }={\gamma }11\frac{(a+b+c+d+\alpha )(a+b+c+d+\beta )}{\left(a+b+\alpha 1\right)(a+c+\beta 1)}\) \(\text{I}\text{C}-2\text{S}\text{D}=\text{E}\left(\text{I}\text{C}\right)-2 \sqrt{\text{V}\left(\text{I}\text{C}\right)}\) MGPS \(\text{M}\text{G}\text{P}\text{S}=\frac{a(a+b+c+d)}{\left(a+c\right)(a+b)}\) MGPS05 > 2 \(SE\left(lnMGPS\right)=\sqrt{\frac{1}{\text{a}}+\frac{1}{\text{b}}+\frac{1}{\text{c}}+\frac{1}{\text{d}}}\) \(95\%CI= {\text{e}}^{\text{ln}\left(MGPS\right)\pm 1.96se}\) Abbreviations: ROR, reporting odds ratio; PRR, proportional reporting ratio; BCPNN, Bayesian confidence propagation neural network, and MGPS, multi-item gamma Poisson shrinker In order to prevent false positives, we set a threshold for the calculated values. A higher value indicates a stronger correlation, suggesting a higher likelihood of association between the target drug and the target adverse event. However, this does not necessarily imply a suspicious causal relationship between them. Drug names were standardized through the Medex_UIMA_1.8.3 system[ 35 ]. We conducted all statistical analyses using R 4.3.2 and Microsoft Excel software. Signal Filtering and Categorization The descriptors of adverse events (AEs) are standardized as preferred terms based on the Medical Dictionary for Regulatory Activities (MedDRa). In MedDRa, all AEs reported belong to the same parent term (PT), which are then merged and classified according to the system organ class (SOC). This approach ensures consistency and clarity in the reporting of adverse events, making it easier for regulatory authorities and healthcare professionals to interpret and analyze the data[ 31 ]. RESULTS Basic characteristics of S-1-related ADEs As of the fourth quarter of 2023, the adverse event inclusion population totaled 5,149,501 cases, and we mainly included S-1-related preferred system 2011 cases, and the specific inclusion flowchart is shown in Fig. 1 . Among them, there were 5,367 females (6,262 males) and the number of females was more than that of males. In addition, the average age of the patients was 65.00(52.00,76.00) years. The average body weight was 71.29(55.34,80.63) KG. The adverse reactions caused by topical administration were 666(77.80%). Serious adverse events accounted for 31% of the total; additional details are provided in Table 3 . Table 3 Basic information on ADEs related to S-1 from the FAERS database. Variable Total Year 2004 5(0.58) 2005 23(2.69) 2006 15(1.75) 2007 148(17.29) 2008 267(31.19) 2009 201(23.48) 2010 118(13.79) 2011 52(6.07) 2012 24(2.80) 2013 1(0.12) 2014 1(0.12) 2015 1(0.12) 2016 5(0.58) 2017 23(2.69) 2018 15(1.75) 2019 148(17.29) 2020 267(31.19) 2021 201(23.48) Sex female 536(62.62) male 288(33.64) unknow 32(3.74) Age(year) 65.00(52.00,76.00) Weight(kg) 71.29(55.34,80.63) Reporter Consumer 579(67.64) Pharmacist 200(23.36) Other health-professional 42(4.91) Physician 29(3.39) unknow 6(0.70) Reported countries other 856(100.00) Route topical 666(77.80) other 98(11.45) transdermal 92(10.75) Outcomes hospitalization 88(55.35) other serious 55(34.59) life threatening 7(4.40) disability 5(3.14) death 4(2.52) Time to onset(month) 31.00(0.00,366.00) Abbreviations: FAERS, Food and Drug Administration Adverse Event Reporting System. Continuous variables were presented as means and standard deviations and categorical variables were shown as frequencies and percentages. When we further classified the adverse events by sex, we found that the incidence of adverse events was significantly higher in women than in men. The average age of females was 69.00(56.00,79.75), which was significantly higher than that of males 61.00(15.00,73.00) (Table S1 in the appendix) S-1 signal mining Proportion of AE reports and signals corresponding to organ system classification Through the screening, a total of 126 PT signals involving 18 SOCs were obtained. According to the SOC results, the total number of vascular and lymphatic diseases was 186 cases, ROR (95%CI) was 3.78(3.25, 4.4), PRR (95%CI) was 3.51(3.06, 4.03), BCPNN(BCPNN025) was 1.81(1.59), and the total number of patients with vascular and lymphatic diseases was 186 cases. MGPS(MGPS05) was 3.51(3.09); The total number of systemic diseases and various reactions at the drug administration site was 804 cases, ROR (95%CI) was 3.55(3.24, 3.88), PRR (95%CI) was 2.48(2.34, 2.63), BCPNN(BCPNN025) was 1.31(1.19). MGPS(MGPS05) was 2.48(2.3); The total number of skin and subcutaneous tissue diseases was 164 cases, ROR (95%CI) was 1.83(1.56, 2.14), PRR (95%CI) was 1.76(1.53,2.02), BCPNN(BCPNN025) was 0.81(0.58). The median MGPS(MGPS05) was 1.76(1.54) (Table 4 ). Table 4 The signal strength of ADEs of S-1 at the SOC level in FAERS database. SOC Case Reports ROR (95% CI) PRR (95% CI) chisq BCPNN MGPS vascular disorders 186 3.78(3.25, 4.4) 3.51(3.06, 4.03) 343.04 1.81(1.59) 3.51(3.09) general disorders and administration site conditions 804 3.55(3.24, 3.88) 2.48(2.34, 2.63) 854.75 1.31(1.19) 2.48(2.3) skin and subcutaneous tissue disorders 164 1.83(1.56, 2.14) 1.76(1.53, 2.02) 56.02 0.81(0.58) 1.76(1.54) investigations 197 1.36(1.17, 1.58) 1.32(1.15, 1.51) 16.89 0.4(0.19) 1.32(1.17) nervous system disorders 182 0.9(0.78, 1.05) 0.91(0.79, 1.04) 1.71 -0.13(-0.35) 0.91(0.8) ear and labyrinth disorders 6 0.71(0.32, 1.59) 0.71(0.32, 1.59) 0.69 -0.49(-1.56) 0.71(0.37) eye disorders 29 0.7(0.48, 1) 0.7(0.49, 1) 3.78 -0.51(-1.03) 0.7(0.52) immune system disorders 9 0.51(0.26, 0.98) 0.51(0.27, 0.97) 4.27 -0.97(-1.87) 0.51(0.3) cardiac disorders 32 0.42(0.3, 0.6) 0.43(0.3, 0.61) 24.92 -1.21(-1.71) 0.43(0.32) psychiatric disorders 59 0.42(0.32, 0.54) 0.44(0.34, 0.57) 46.09 -1.19(-1.57) 0.44(0.35) gastrointestinal disorders 72 0.38(0.3, 0.47) 0.4(0.32, 0.51) 72.1 -1.33(-1.66) 0.4(0.33) injury, poisoning and procedural complications 40 0.36(0.26, 0.49) 0.37(0.27, 0.51) 45.42 -1.43(-1.88) 0.37(0.28) musculoskeletal and connective tissue disorders 38 0.35(0.25, 0.48) 0.36(0.26, 0.49) 44.75 -1.46(-1.92) 0.36(0.28) respiratory, thoracic and mediastinal disorders 34 0.33(0.23, 0.46) 0.34(0.24, 0.47) 45.82 -1.55(-2.04) 0.34(0.26) renal and urinary disorders 11 0.32(0.18, 0.58) 0.32(0.18, 0.58) 15.96 -1.63(-2.45) 0.32(0.2) infections and infestations 30 0.32(0.22, 0.45) 0.33(0.23, 0.47) 43.57 -1.61(-2.12) 0.33(0.24) metabolism and nutrition disorders 13 0.27(0.16, 0.47) 0.28(0.16, 0.48) 24.78 -1.84(-2.6) 0.28(0.18) neoplasms benign, malignant and unspecified (incl cysts and polyps) 9 0.15(0.08, 0.29) 0.15(0.08, 0.29) 43.77 -2.71(-3.61) 0.15(0.09) Abbreviations: SOC, system organ classes; ROR, reporting odds ratio; PRR, proportional reporting ratio; BCPNN, Bayesian confidence propagation neural network, and MGPS, multi-item gamma Poisson shrinker According to the number of PT reports, the top 30 adverse reactions were application site papules, application site rash and application site pruritus. ROR (95%CI) were 179.4(88.62, 363.16), 156.96(128.5, 191.72) and 148.4(124.92, 176.3), respectively. skin and subcutaneous tissue diseases mainly include skin irritation dermatitis contact, dermatitis allergic and dermatitis allergic. ROR (95%CI) were 22.96(12.68, 41.59), 14.45(6, 34.8) and 14.14(5.87, 34.04), respectively. The ROR (95%CI) of hypertension adverse reactions was 9.07(7.12, 11.56); Finally, we found that the ROR (95% CI) of incl cysts and polyps was 9.07(2.92, 28.17), as shown in Table 5 . The results were similar between male and female subjects (Table S2). For a more visual representation of all the meaningful frequencies of adverse events, we generated a frequency waterfall plot for the adverse events of S-1, as shown in Fig. 2 . Table 5 The top 30 signal strength of adverse events of S-1 ranked by MGPS at the PTs level in FAERS database. SOC PT Case Reports ROR (95% CI) PRR (95% CI) chisq BCPNN MGPS general disorders and administration site conditions application site papules 8 179.4(88.62,363.16) 178.66(88.22,361.8) 1370.18 7.44(6.48) 173.23(96.02) general disorders and administration site conditions application site rash 104 156.96(128.5,191.72) 148.52(122.09,180.68) 14855.61 7.18(6.89) 144.76(122.45) general disorders and administration site conditions application site pruritus 143 148.4(124.92, 176.3) 137.44(117.49, 160.77) 18920.7 7.07(6.82) 134.21(116.19) general disorders and administration site conditions application site discharge 6 134.94(59.98, 303.59) 134.52(60.23, 300.46) 776.78 7.04(5.95) 131.43(66.69) general disorders and administration site conditions application site erythema 141 120.82(101.63,143.65) 112.03(95.77, 131.05) 15225.54 6.78(6.53) 109.88(95.07) general disorders and administration site conditions application site scar 7 117.55(55.54, 248.8) 117.13(55.62, 246.68) 789.68 6.84(5.83) 114.78(61.29) general disorders and administration site conditions application site vesicles 34 97.13(69, 136.73) 95.43(68.39, 133.17) 3124.94 6.55(6.07) 93.87(70.51) general disorders and administration site conditions application site irritation 60 94.23(72.72, 122.09) 91.32(70.78, 117.82) 5276.64 6.49(6.12) 89.89(72.37) general disorders and administration site conditions application site burn 20 85.54(54.88, 133.33) 84.66(55.01, 130.3) 1629.36 6.38(5.76) 83.43(57.55) general disorders and administration site conditions application site dermatitis 8 83(41.24, 167.04) 82.66(40.82, 167.39) 636.12 6.35(5.4) 81.48(45.38) general disorders and administration site conditions application site discolouration 12 82.12(46.37, 145.45) 81.62(46.23, 144.1) 942.07 6.33(5.54) 80.47(49.88) general disorders and administration site conditions application site urticaria 10 81.57(43.62, 152.52) 81.15(43.34, 151.94) 780.5 6.32(5.46) 80.02(47.4) general disorders and administration site conditions application site inflammation 3 72.83(23.3, 227.67) 72.72(23.33, 226.65) 209.53 6.17(4.74) 71.81(27.67) general disorders and administration site conditions application site scab 5 60.5(25.04, 146.2) 60.34(24.98, 145.76) 288.74 5.9(4.74) 59.72(28.54) general disorders and administration site conditions application site swelling 10 41.59(22.29, 77.59) 41.37(22.1, 77.46) 391.18 5.36(4.5) 41.08(24.38) general disorders and administration site conditions application site exfoliation 6 40.59(18.16, 90.73) 40.47(18.12, 90.39) 229.34 5.33(4.25) 40.19(20.5) general disorders and administration site conditions application site reaction 14 24.53(14.48, 41.55) 24.36(14.35, 41.35) 312.36 4.6(3.87) 24.26(15.61) general disorders and administration site conditions application site pain 15 24.28(14.59, 40.4) 24.1(14.48, 40.12) 330.78 4.58(3.87) 24(15.67) skin and subcutaneous tissue disorders skin irritation 11 22.96(12.68, 41.59) 22.84(12.69, 41.12) 228.85 4.51(3.69) 22.75(13.84) skin and subcutaneous tissue disorders dermatitis contact 5 14.45(6, 34.8) 14.42(5.97, 34.83) 62.29 3.85(2.69) 14.38(6.9) skin and subcutaneous tissue disorders dermatitis allergic 5 14.14(5.87, 34.04) 14.1(5.84, 34.06) 60.73 3.81(2.66) 14.07(6.75) skin and subcutaneous tissue disorders skin reaction 4 9.02(3.38, 24.07) 9(3.38, 23.98) 28.41 3.17(1.9) 8.99(3.95) vascular disorders blood pressure inadequately controlled 66 150.46(117.35, 192.92) 145.33(114.87, 183.87) 9226.28 7.15(6.79) 141.73(115.12) vascular disorders blood pressure fluctuation 13 17.59(10.18, 30.37) 17.47(10.09, 30.24) 201.37 4.12(3.36) 17.42(11.03) vascular disorders hypertension 68 9.07(7.12, 11.56) 8.79(6.95, 11.12) 470.34 3.13(2.79) 8.77(7.16) investigations blood pressure increased 132 23.95(20.07, 28.59) 22.38(19.13, 26.18) 2693.35 4.48(4.22) 22.29(19.22) investigations blood pressure abnormal 8 17.25(8.61, 34.58) 17.18(8.65, 34.12) 121.59 4.1(3.15) 17.13(9.57) investigations blood pressure systolic increased 8 11.08(5.53, 22.2) 11.04(5.56, 21.92) 72.92 3.46(2.52) 11.02(6.16) respiratory, thoracic and mediastinal disorders nasal dryness 3 16.42(5.28, 51.04) 16.39(5.26, 51.08) 43.24 4.03(2.61) 16.35(6.33) neoplasms benign, malignant and unspecified (incl cysts and polyps) uterine cancer 3 9.07(2.92, 28.17) 9.06(2.91, 28.24) 21.47 3.18(1.76) 9.04(3.5) Abbreviations: PT, preferred term; SOC, system organ classes; ROR, reporting odds ratio; PRR, proportional reporting ratio; BCPNN, Bayesian confidence propagation neural network, and MGPS, multi-item gamma Poisson shrinker DISCUSSION Among the top 30 PT reports, general disorders and administration site conditions were the most common, such as application site papules, rash and pruritus. Secondly, skin and subcutaneous tissue disorders, such as dermatitis contact and dermatitis allergic. At the same time, we also found hypertension and the cause of uterine cancer and other adverse reactions. Recent studies have found that several clinical randomized controlled trials have shown that the most common adverse reaction of S-1 is neutropenia[ 28 , 36 , 37 ]. It also includes disorders of the skin system, and gastrointestinal systems such as nausea, vomiting, constipation, and diarrhea[ 36 ], which is consistent with the conclusions of many studies[ 38 – 40 ]. Neutropenia, a condition characterized by a decrease in the number of neutrophils, a type of white blood cell that helps fight infections, is a well-documented side effect of many chemotherapy drugs, including S-1. The primary cause of neutropenia in patients receiving S-1 is the drug's impact on the bone marrow, where blood cells are produced. S-1 can suppress the normal production of neutrophils, leading to an increased risk of infections. The gastrointestinal symptoms, such as nausea, vomiting, constipation, and diarrhea, can be attributed to the drug's effect on the gastrointestinal tract. S-1 contains tegafur, a prodrug that is converted to 5-fluorouracil (5-FU) in the body. 5-FU is known to affect the rapidly dividing cells of the gastrointestinal mucosa, which can lead to mucositis and other gastrointestinal disturbances. The dosage and schedule of S-1 administration can also influence the occurrence and severity of these symptoms. Skin reactions associated with S-1 may include rash, itching, or changes in skin color. These can be a result of the drug's impact on the DNA synthesis of rapidly dividing cells, including those of the skin, or an immune response triggered by the drug. As for the less common adverse reactions like hypertension and uterine cancer, the reasons for their occurrence can be multifactorial. Hypertension may occur because of the drug's impact on the cardiovascular system or due to the physiological stress response triggered by the cancer itself and its treatment. The association between S-1 and uterine cancer might be due to the drug's potential to affect the hormonal balance in the body, as some cancer treatments can influence the risk of developing certain types of cancer. Previously, several clinical center experiments have shown that the common adverse reactions of S-1 include rash, neutropenia, anemia, loss of appetite, diarrhea, etc.[ 41 – 43 ]. This can be explained mainly by the pharmacokinetics before and after drug use. For example, a statistically significant relationship was observed between Cmax and 5-FU concentration before and after treatment[ 44 , 45 ]. It is important to note that the development of adverse reactions can also be influenced by various patient-related factors, such as underlying health conditions, genetic predisposition, and concurrent medications. Healthcare providers should consider these factors when prescribing S-1 and closely monitor patients for the development of adverse reactions to ensure timely intervention and appropriate management. Our research has certain limitations, primarily because the FAERS database is an independent reporting system, and the reporting involves doctors, pharmacists, patients, etc., which may lead to false positives in the data mining results. Secondly, whether there is a biological correlation between the target ADE and the drug needs further evaluation by combining case analysis reference to drug instructions, literature reports, and expert opinions. These factors will inevitably result in some deviation in the study's findings, and it is necessary for future studies to conduct comprehensive evaluations based on actual clinical situations. Conclusion In this study, we used different algorithms to mine and analyze the American FAERS database and found that the main ADE signals of S-1 were reflected in skin system diseases, skin and subcutaneous tissue diseases, and various reaction diseases at the drug administration site, which was basically consistent with the instructions. However, this study also found new ADE signals such as respiratory, thoracic and mediastinal diseases. At the same time, some serious ADE signals were also observed, such as hypertension and tumor diseases. The results of this study can provide a certain guarantee for the safe clinical use of S-1. Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Availability of data and materials The US Food and Drug Administration Adverse Event Reporting System (FAERS) data are publicly available at https://open.fda.gov/data/faers/. Competing interests The authors declare that they have no competing interests. Funding None. Author contributions CRediT author statement DZ: conceptualization, methodology, formal analysis, investigation, data curation, writing - original draft, writing - review & editing, visualization. JL: conceptualization, methodology, formal analysis, investigation, data curation, writing - original draft, writing - review & editing, visualization, funding acquisition. Acknowledgements We express our gratitude to all the staff at FAERS for their valuable contribution in data acquisition. References Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F (2021) Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. 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World J Gastroenterol 20(33):11886–11893. :/10.3748/wjg.v20.i33.11886 Ter Veer E, Mohammad NH, Lodder P, Ngai LL, Samaan M, van Oijen MG, van Laarhoven HW (2016) The efficacy and safety of S-1-based regimens in the first-line treatment of advanced gastric cancer: a systematic review and meta-analysis. Gastric Cancer 19(3):696–712. :/10.1007/s10120-015-0587-8 Lordick F, Carneiro F, Cascinu S, Fleitas T, Haustermans K, Piessen G, Vogel A, Smyth EC (2022) Gastric cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol 33(10):1005–1020. :/10.1016/j.annonc.2022.07.004 Ajani JA, D'Amico TA, Bentrem DJ, Chao J, Cooke D, Corvera C, Das P, Enzinger PC, Enzler T, Fanta P et al (2022) Gastric Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 20(2):167–192. :/10.6004/jnccn.2022.0008 Zhang X, Liang H, Li Z, Xue Y, Wang Y, Zhou Z, Yu J, Bu Z, Chen L, Du Y et al (2021) Perioperative or postoperative adjuvant oxaliplatin with S-1 versus adjuvant oxaliplatin with capecitabine in patients with locally advanced gastric or gastro-oesophageal junction adenocarcinoma undergoing D2 gastrectomy (RESOLVE): an open-label, superiority and non-inferiority, phase 3 randomised controlled trial. Lancet Oncol 22(8):1081–1092. :/10.1016/s1470-2045(21)00297-7 Boku N, Ryu MH, Kato K, Chung HC, Minashi K, Lee KW, Cho H, Kang WK, Komatsu Y, Tsuda M et al (2019) Safety and efficacy of nivolumab in combination with S-1/capecitabine plus oxaliplatin in patients with previously untreated, unresectable, advanced, or recurrent gastric/gastroesophageal junction cancer: interim results of a randomized, phase II trial (ATTRACTION-4). Ann Oncol 30(2):250–258. :/10.1093/annonc/mdy540 Sarangdhar M, Tabar S, Schmidt C, Kushwaha A, Shah K, Dahlquist JE, Jegga AG, Aronow BJ (2016) Data mining differential clinical outcomes associated with drug regimens using adverse event reporting data. Nat Biotechnol 34(7):697–700. :/10.1038/nbt.3623 Brown EG, Wood L, Wood S (1999) The medical dictionary for regulatory activities (MedDRA). Drug Saf 20(2):109–117. :/10.2165/00002018-199920020-00002 Bate A, Lindquist M, Edwards IR, Olsson S, Orre R, Lansner A, De Freitas RM (1998) A Bayesian neural network method for adverse drug reaction signal generation. Eur J Clin Pharmacol 54(4):315–321. :/10.1007/s002280050466 Caster O, Aoki Y, Gattepaille LM, Grundmark B (2020) Disproportionality Analysis for Pharmacovigilance Signal Detection in Small Databases or Subsets: Recommendations for Limiting False-Positive Associations. Drug Saf 43(5):479–487. :/10.1007/s40264-020-00911-w Evans SJ, Waller PC, Davis S (2001) Use of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports. Pharmacoepidemiol Drug Saf 10(6):483–486. :/10.1002/pds.677 Brown EG (2004) Using MedDRA: implications for risk management. Drug Saf 27(8):591–602. /10.2165/00002018-200427080-00010 Park SH, Lim DH, Sohn TS, Lee J, Zang DY, Kim ST, Kang JH, Oh SY, Hwang IG, Ji JH et al (2021) A randomized phase III trial comparing adjuvant single-agent S1, S-1 with oxaliplatin, and postoperative chemoradiation with S-1 and oxaliplatin in patients with node-positive gastric cancer after D2 resection: the ARTIST 2 trial(☆). Ann Oncol 32(3):368–374. :/10.1016/j.annonc.2020.11.017 Yamada Y, Higuchi K, Nishikawa K, Gotoh M, Fuse N, Sugimoto N, Nishina T, Amagai K, Chin K, Niwa Y et al (2015) Phase III study comparing oxaliplatin plus S-1 with cisplatin plus S-1 in chemotherapy-naïve patients with advanced gastric cancer. Ann Oncol 26(1):141–148. :/10.1093/annonc/mdu472 Milano G, Etienne MC, Cassuto-Viguier E, Thyss A, Santini J, Frenay M, Renee N, Schneider M, Demard F (1992) Influence of sex and age on fluorouracil clearance. J Clin Oncol 10(7):1171–1175. /10.1200/jco.1992.10.7.1171 Pal SK, Hurria A (2010) Impact of age, sex, and comorbidity on cancer therapy and disease progression. J Clin Oncol 28(26):4086–4093. /10.1200/jco.2009.27.0579 Schwab M, Zanger UM, Marx C, Schaeffeler E, Klein K, Dippon J, Kerb R, Blievernicht J, Fischer J, Hofmann U et al (2008) Role of genetic and nongenetic factors for fluorouracil treatment-related severe toxicity: a prospective clinical trial by the German 5-FU Toxicity Study Group. J Clin Oncol 26(13):2131–2138. :/10.1200/jco.2006.10.4182 Kawazoe A, Takahari D, Keisho C, Nakamura Y, Ikeno T, Wakabayashi M, Nomura S, Tamura H, Fukutani M, Hirano N et al (2021) A multicenter phase II study of TAS-114 in combination with S-1 in patients with pretreated advanced gastric cancer (EPOC1604). Gastric Cancer 24(1):190–196. :/10.1007/s10120-020-01107-y Tabuse H, Kashiwagi H, Hamauchi S, Tsushima T, Todaka A, Yokota T, Machida N, Yamazaki K, Fukutomi A, Onozawa Y et al (2016) Excessive watering eyes in gastric cancer patients receiving S-1 chemotherapy. Gastric Cancer 19(3):894–901. :/10.1007/s10120-015-0540-x Iwasa S, Yamada Y, Fukagawa T, Eguchi Nakajima T, Kato K, Hamaguchi T, Morita S, Saka M, Katai H, Shimada Y (2011) Management of adjuvant S-1 therapy after curative resection of gastric cancer: dose reduction and treatment schedule modification. Gastric Cancer 14(1):28–34. :/10.1007/s10120-011-0003-y Cohen SJ, Leichman CG, Yeslow G, Beard M, Proefrock A, Roedig B, Damle B, Letrent SP, DeCillis AP, Meropol NJ (2002) Phase I and pharmacokinetic study of once daily oral administration of S-1 in patients with advanced cancer. Clin Cancer Res 8(7):2116–2122 van Groeningen CJ, Peters GJ, Schornagel JH, Gall H, Noordhuis P, de Vries MJ, Turner SL, Swart MS, Pinedo HM, Hanauske AR et al (2000) Phase I clinical and pharmacokinetic study of oral S-1 in patients with advanced solid tumors. J Clin Oncol 18(14):2772–2779. :/10.1200/jco.2000.18.14.2772 Additional Declarations No competing interests reported. Supplementary Files TableS12.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4119504","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":281819674,"identity":"d9f87280-22b0-44c4-abb8-8687c6ce81f0","order_by":0,"name":"Di Zhao","email":"","orcid":"","institution":"Jiangsu Provincial Hospital of Traditional Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Di","middleName":"","lastName":"Zhao","suffix":""},{"id":281819676,"identity":"65b69fd0-eaae-47c4-b147-9c8984f6139a","order_by":1,"name":"Jie Liu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4klEQVRIiWNgGAWjYBACNvnDBx98+GHDbD//YOODhIoawlr4JNiSDWf2pLEbSDAfNnhw5hhhLXISPGbSPGyH+Q0k2NIkH7YwE+Ew6QYzyRk8adLm0j1mFYkNbAz87d0J+LXIHEi2+GBhY2w554zZjcQdMgwSZ85uwK+FIeHgTaAtyQwHcoBazrAxGEjkEtKS2ADyS30DUEtBYhszEVokkplAWpgNbqSlMRCnhecYMyiQmSV7Dh+WSDhzjIegX+Tb+z+Co5KfvbHx44+KGjn+9l78WjAAD2nKR8EoGAWjYBRgBQBIc0s/dU9awgAAAABJRU5ErkJggg==","orcid":"","institution":"Jiangsu Provincial Hospital of Traditional Chinese Medicine","correspondingAuthor":true,"prefix":"","firstName":"Jie","middleName":"","lastName":"Liu","suffix":""}],"badges":[],"createdAt":"2024-03-18 02:59:21","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4119504/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4119504/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":53417029,"identity":"aa030f44-caeb-4b51-b64b-5f2717c147d6","added_by":"auto","created_at":"2024-03-25 18:02:00","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":196800,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe flow diagram of selecting S-1-related AEs from FAERS database.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAbbreviations: PT, preferred term; PS, preferred system; FAERS, Food and Drug Administration Adverse Event Reporting System\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-4119504/v1/5df1f32b3e7dc8f65da72364.png"},{"id":53417028,"identity":"c10d6669-276f-467b-849b-6a811f9e48c0","added_by":"auto","created_at":"2024-03-25 18:02:00","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":9133,"visible":true,"origin":"","legend":"\u003cp\u003eWaterfall diagram for the frequency of adverse events of S-1.\u003c/p\u003e\n\u003cp\u003eThe portion above the dashed line represents a waterfall plot of meaningful adverse events, and the portion below the dashed line represents a waterfall plot of meaningless adverse events.\u003c/p\u003e","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-4119504/v1/e56da80b130242be70400fef.png"},{"id":54090120,"identity":"c011762b-df7f-4477-9fb0-4794ea3b2f50","added_by":"auto","created_at":"2024-04-04 12:43:45","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":656039,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4119504/v1/4722a78e-f030-4e21-92e9-c91fbc00fd2e.pdf"},{"id":53417030,"identity":"99afc5de-03c4-4f78-a6d8-98fca6aa9c8d","added_by":"auto","created_at":"2024-03-25 18:02:00","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":25490,"visible":true,"origin":"","legend":"","description":"","filename":"TableS12.docx","url":"https://assets-eu.researchsquare.com/files/rs-4119504/v1/f2e4b9513a779f636542d6a0.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Safety assessment of S-1: Real-world adverse event analysis from the FAERS database","fulltext":[{"header":"BACKGROUND","content":"\u003cp\u003eCancer poses a formidable challenge to global health, ranking among the principal causes of mortality and a significant barrier to enhancing life expectancy. The latest data from GLOBOCAN in 2020 reveal a staggering 19.3\u0026nbsp;million new cancer cases globally, accompanied by approximately 10\u0026nbsp;million fatalities, highlighting the immense burden of this disease[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Within this context, gastric cancer stands out as one of the most frequently diagnosed malignant neoplasms. In 2019, the worldwide incidence of gastric cancer, as measured by the European Organization for Research and Treatment of Cancer (EOGC), was reported at 3.7 cases per 100,000 individuals, with a 20-year cumulative decrease of 0.84 per 100,000[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Several key factors contribute to the development of gastric cancer, including gender[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], genetic predisposition[\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], and the presence of Helicobacter pylori (Hp) infection[\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. For patients with advanced gastric cancer, chemotherapy remains a cornerstone of therapeutic intervention[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Surgical intervention, particularly radical total gastrectomy, has been demonstrated to significantly extend survival in patients with gastric cancer[\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Additionally, the advent of precision medicine has led to the integration of targeted therapies and immunotherapies into the treatment paradigm for a variety of cancers[\u003cspan additionalcitationids=\"CR15 CR16\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. These advances underscore the importance of a personalized approach to gastric cancer treatment, where clinicians must conduct a thorough assessment of both the patient's disease risk and overall health status to determine the most suitable course of treatment that aligns with the patient's tolerance and therapeutic needs.\u003c/p\u003e \u003cp\u003eS-1 is used for unresectable locally advanced or metastatic gastric cancer[\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], and can also be used for breast cancer, pancreatic cancer, cholangiocarcinoma, colorectal cancer, non-small cell lung cancer, etc. S-1 capsules consist of tegafur (FT), S-1 (CDHP), and Oxo potassium[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. The mechanism of action is that FTS1 is gradually converted into 5-FU in vivo after oral administration. CDH preferentially selects to inhibit dihydropyrimidinedehydrogenase (DPD), a 5-FU catabolic enzyme present in the liver, thereby increasing the concentration of 5-FU from the FT[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. With the increase of 5-FU concentration in vivo, 5 fluorocarbonucleotides, the phosphorylation product of 5-FU, can maintain a higher concentration in tumor tissue, thus enhancing the antitumor effect [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Oxo is distributed in the gastrointestinal tract after oral administration and can selectively and reversibly inhibit rotate phosphoribosyl transferase, thereby selectively inhibiting the conversion of 5-FU to 5 fluoronucleotides and reducing gastrointestinal toxicity without affecting the antitumor activity of 5-FU[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAlthough some studies have shown that S-1 has better efficacy, safety and economy compared with other chemotherapy drugs in the treatment of gastric cancer[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], with its wide clinical application, serious skin adverse reactions, blood and vascular system abnormalities caused by S-1 have gradually been reported and concerned[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Based on this, this paper mines and analyzes the adverse drug events (ADE) signals of S-1 after marketing in the US FDA adverse events reporting system (FARES) database[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. To provide reference for the safe application of the drug in clinical practice.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eData source\u003c/h2\u003e \u003cp\u003eThe adverse drug event (ADE) reports for S1 from Q1 2004 to Q3 2021 encompass a total of 37 quarters over a span of 12 years. These reports were collected by searching the FDA Adverse Event Reporting System (FAERS) database, where 'S1' was used as the primary search term. By employing the generic English name 'S1', we aimed to capture all relevant adverse events associated with this drug. The terms 'PT' and 'SOC' were utilized in the Medical Dictionary for Regulatory Activities (MedDRA) version 24.0 terminology set, which is published by the Technical Coordination Council for Human Drug Registration[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. During the data extraction process, duplicates were removed, and reports that contained product storage errors were excluded to ensure the integrity and accuracy of the data analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eData extraction and analysis\u003c/h2\u003e \u003cp\u003eThe study collected data on the number of target adverse event AEs reported for the primary suspect drug. Potential AEs were screened using the proportion imbalance method with four grid tables referred to as Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The study utilized reporting odds ratio methods, ROR proportional reporting ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS), with X2 used to calculate ROR and PRR respectively.[\u003cspan additionalcitationids=\"CR33\" citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Among them, the effective risk signal should meet the following conditions: (1)ROR method: the number of AE reported cases should be \u0026ge;\u0026thinsp;3,ROR\u0026thinsp;\u0026gt;\u0026thinsp;3, and the lower limit of 95% CI of ROR should be \u0026gt;\u0026thinsp;1; (2)PRR method: the number of AE cases should be \u0026ge;\u0026thinsp;3,PRR\u0026thinsp;\u0026gt;\u0026thinsp;2, and the lower limit of 95% CI of PRR\u0026thinsp;\u0026gt;\u0026thinsp;1; (3)BCPPN: IC025\u0026thinsp;\u0026gt;\u0026thinsp;0; (4)MGPS: MGPS05\u0026thinsp;\u0026gt;\u0026thinsp;2. A higher value indicates a stronger correlation (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eFour grid table.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDrug-related ADEs\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNon-drug related ADEs\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDrug\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eb\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ea\u0026thinsp;+\u0026thinsp;b\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-drug\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ec\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ec\u0026thinsp;+\u0026thinsp;d\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ea\u0026thinsp;+\u0026thinsp;c\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eb\u0026thinsp;+\u0026thinsp;d\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;a\u0026thinsp;+\u0026thinsp;b\u0026thinsp;+\u0026thinsp;c\u0026thinsp;+\u0026thinsp;d\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eAbbreviations: ADE, adverse drug events\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eROR, PRR, BCPNN, and MGPS methods, formulas, and thresholds.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMethod\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFormula\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eThreshold\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eROR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\text{R}\\text{O}\\text{R}=\\frac{\\text{a} / \\text{c}}{b / d}\\)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003ea\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003cp\u003eROR\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003cp\u003e95%CI (lower limit)\u0026thinsp;\u0026gt;\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(SE\\left(lnROR\\right)=\\sqrt{\\frac{1}{\\text{a}}+\\frac{1}{\\text{b}}+\\frac{1}{\\text{c}}+\\frac{1}{\\text{d}}}\\)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(95\\%CI= {\\text{e}}^{\\text{ln}\\left(ROR\\right)\\pm 1.96se}\\)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003ePRR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\text{P}\\text{R}\\text{R}=\\frac{\\text{a} / (\\text{a}+\\text{b})}{c / (c+d)}\\)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003ea\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003cp\u003ePRR\u0026thinsp;\u0026ge;\u0026thinsp;2\u003c/p\u003e \u003cp\u003e95%CI (lower limit)\u0026thinsp;\u0026gt;\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(SE\\left(lnPRR\\right)=\\sqrt{\\frac{1}{\\text{a}}-\\frac{1}{\\text{a}+\\text{b}}+\\frac{1}{\\text{c}}-\\frac{1}{\\text{c}+\\text{d}}}\\)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(95\\%CI= {\\text{e}}^{\\text{ln}\\left(PRR\\right)\\pm 1.96se}\\)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eBCPNN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\text{I}\\text{C}={\\text{l}\\text{o}\\text{g}}_{2}\\frac{p(x, y)}{p\\left(x\\right)p\\left(y\\right)}= {log}_{2}\\frac{a(a+b+c+d)}{(a+b)(a+c)}\\)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eIC025\u0026thinsp;\u0026gt;\u0026thinsp;0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\text{E}\\left(\\text{I}\\text{C}\\right)={\\text{l}\\text{o}\\text{g}}_{2}\\frac{(a+\\gamma 11)(a+b+c+d+\\alpha )(a+b+c+d+\\beta )}{\\left(a+b+c+d+\\gamma \\right)(a+b+\\alpha 1)(a+c+\\beta 1)}\\)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\text{V}\\left(\\text{I}\\text{C}\\right)=\\frac{1}{{\\left(ln2\\right)}^{2}}[\\frac{\\left(a+b+c+d\\right)-a+\\gamma -\\gamma 11}{\\left(a+\\gamma 11\\right)\\left(1+a+b+c+d+\\gamma \\right)}+\\frac{\\left(a+b+c+d\\right)-\\left(a+b\\right)+a-\\alpha 1}{\\left(a+b+\\alpha 1\\right)\\left(1+a+b+c+d+\\alpha \\right)}+\\frac{\\left(a+b+c+d+\\alpha \\right)-\\left(a+c\\right)+\\beta -\\beta 1}{\\left(a+b+\\beta 1\\right)\\left(1+a+b+c+d+\\beta \\right)}]\\)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\({\\gamma }={\\gamma }11\\frac{(a+b+c+d+\\alpha )(a+b+c+d+\\beta )}{\\left(a+b+\\alpha 1\\right)(a+c+\\beta 1)}\\)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\text{I}\\text{C}-2\\text{S}\\text{D}=\\text{E}\\left(\\text{I}\\text{C}\\right)-2 \\sqrt{\\text{V}\\left(\\text{I}\\text{C}\\right)}\\)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eMGPS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\text{M}\\text{G}\\text{P}\\text{S}=\\frac{a(a+b+c+d)}{\\left(a+c\\right)(a+b)}\\)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eMGPS05\u0026thinsp;\u0026gt;\u0026thinsp;2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(SE\\left(lnMGPS\\right)=\\sqrt{\\frac{1}{\\text{a}}+\\frac{1}{\\text{b}}+\\frac{1}{\\text{c}}+\\frac{1}{\\text{d}}}\\)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(95\\%CI= {\\text{e}}^{\\text{ln}\\left(MGPS\\right)\\pm 1.96se}\\)\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eAbbreviations: ROR, reporting odds ratio; PRR, proportional reporting ratio; BCPNN, Bayesian confidence propagation neural network, and MGPS, multi-item gamma Poisson shrinker\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIn order to prevent false positives, we set a threshold for the calculated values. A higher value indicates a stronger correlation, suggesting a higher likelihood of association between the target drug and the target adverse event. However, this does not necessarily imply a suspicious causal relationship between them. Drug names were standardized through the Medex_UIMA_1.8.3 system[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. We conducted all statistical analyses using R 4.3.2 and Microsoft Excel software.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eSignal Filtering and Categorization\u003c/h2\u003e \u003cp\u003eThe descriptors of adverse events (AEs) are standardized as preferred terms based on the Medical Dictionary for Regulatory Activities (MedDRa). In MedDRa, all AEs reported belong to the same parent term (PT), which are then merged and classified according to the system organ class (SOC). This approach ensures consistency and clarity in the reporting of adverse events, making it easier for regulatory authorities and healthcare professionals to interpret and analyze the data[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e"},{"header":"RESULTS","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n \u003ch2\u003eBasic characteristics of S-1-related ADEs\u003c/h2\u003e\n \u003cp\u003eAs of the fourth quarter of 2023, the adverse event inclusion population totaled 5,149,501 cases, and we mainly included S-1-related preferred system 2011 cases, and the specific inclusion flowchart is shown in Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. Among them, there were 5,367 females (6,262 males) and the number of females was more than that of males. In addition, the average age of the patients was 65.00(52.00,76.00) years. The average body weight was 71.29(55.34,80.63) KG. The adverse reactions caused by topical administration were 666(77.80%). Serious adverse events accounted for 31% of the total; additional details are provided in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eBasic information on ADEs related to S-1 from the FAERS database.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"2\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eYear\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2004\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5(0.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e23(2.69)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2006\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e15(1.75)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2007\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e148(17.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2008\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e267(31.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2009\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e201(23.48)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2010\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e118(13.79)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2011\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e52(6.07)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2012\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e24(2.80)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2013\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1(0.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2014\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1(0.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2015\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1(0.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2016\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5(0.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2017\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e23(2.69)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e15(1.75)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e148(17.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2020\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e267(31.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e201(23.48)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eSex\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003efemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e536(62.62)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e288(33.64)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eunknow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e32(3.74)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge(year)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e65.00(52.00,76.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eWeight(kg)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e71.29(55.34,80.63)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eReporter\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eConsumer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e579(67.64)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePharmacist\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e200(23.36)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOther health-professional\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e42(4.91)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePhysician\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e29(3.39)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eunknow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6(0.70)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eReported countries\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eother\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e856(100.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eRoute\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003etopical\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e666(77.80)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eother\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e98(11.45)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003etransdermal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e92(10.75)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eOutcomes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ehospitalization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e88(55.35)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eother serious\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e55(34.59)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003elife threatening\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7(4.40)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003edisability\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5(3.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003edeath\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4(2.52)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eTime to onset(month)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e31.00(0.00,366.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003eAbbreviations: FAERS, Food and Drug Administration Adverse Event Reporting System.\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\"\u003eContinuous variables were presented as means and standard deviations and categorical variables were shown as frequencies and percentages.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eWhen we further classified the adverse events by sex, we found that the incidence of adverse events was significantly higher in women than in men. The average age of females was 69.00(56.00,79.75), which was significantly higher than that of males 61.00(15.00,73.00) (Table \u003cspan class=\"InternalRef\"\u003eS1\u003c/span\u003e in the appendix)\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003eS-1 signal mining\u003c/h2\u003e\n \u003cdiv id=\"Sec9\" class=\"Section3\"\u003e\n \u003ch2\u003eProportion of AE reports and signals corresponding to organ system classification\u003c/h2\u003e\n \u003cp\u003eThrough the screening, a total of 126 PT signals involving 18 SOCs were obtained. According to the SOC results, the total number of vascular and lymphatic diseases was 186 cases, ROR (95%CI) was 3.78(3.25, 4.4), PRR (95%CI) was 3.51(3.06, 4.03), BCPNN(BCPNN025) was 1.81(1.59), and the total number of patients with vascular and lymphatic diseases was 186 cases. MGPS(MGPS05) was 3.51(3.09); The total number of systemic diseases and various reactions at the drug administration site was 804 cases, ROR (95%CI) was 3.55(3.24, 3.88), PRR (95%CI) was 2.48(2.34, 2.63), BCPNN(BCPNN025) was 1.31(1.19). MGPS(MGPS05) was 2.48(2.3); The total number of skin and subcutaneous tissue diseases was 164 cases, ROR (95%CI) was 1.83(1.56, 2.14), PRR (95%CI) was 1.76(1.53,2.02), BCPNN(BCPNN025) was 0.81(0.58). The median MGPS(MGPS05) was 1.76(1.54) (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab4\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eThe signal strength of ADEs of S-1 at the SOC level in FAERS database.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"7\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSOC\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCase Reports\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eROR (95% CI)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePRR (95% CI)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003echisq\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eBCPNN\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMGPS\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003evascular disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e186\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.78(3.25, 4.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.51(3.06, 4.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e343.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.81(1.59)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.51(3.09)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003egeneral disorders and administration site conditions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e804\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.55(3.24, 3.88)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.48(2.34, 2.63)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e854.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.31(1.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2.48(2.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eskin and subcutaneous tissue disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e164\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.83(1.56, 2.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.76(1.53, 2.02)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e56.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.81(0.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.76(1.54)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003einvestigations\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e197\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.36(1.17, 1.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.32(1.15, 1.51)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e16.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.4(0.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.32(1.17)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003enervous system disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e182\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.9(0.78, 1.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.91(0.79, 1.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.71\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.13(-0.35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.91(0.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eear and labyrinth disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.71(0.32, 1.59)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.71(0.32, 1.59)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.49(-1.56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.71(0.37)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eeye disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.7(0.48, 1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.7(0.49, 1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.51(-1.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.7(0.52)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eimmune system disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.51(0.26, 0.98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.51(0.27, 0.97)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.97(-1.87)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.51(0.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ecardiac disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.42(0.3, 0.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.43(0.3, 0.61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e24.92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-1.21(-1.71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.43(0.32)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epsychiatric disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.42(0.32, 0.54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.44(0.34, 0.57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e46.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-1.19(-1.57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.44(0.35)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003egastrointestinal disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.38(0.3, 0.47)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.4(0.32, 0.51)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e72.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-1.33(-1.66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.4(0.33)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003einjury, poisoning and procedural complications\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.36(0.26, 0.49)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.37(0.27, 0.51)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e45.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-1.43(-1.88)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.37(0.28)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emusculoskeletal and connective tissue disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e38\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.35(0.25, 0.48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.36(0.26, 0.49)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e44.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-1.46(-1.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.36(0.28)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003erespiratory, thoracic and mediastinal disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.33(0.23, 0.46)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.34(0.24, 0.47)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e45.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-1.55(-2.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.34(0.26)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003erenal and urinary disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.32(0.18, 0.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.32(0.18, 0.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e15.96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-1.63(-2.45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.32(0.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003einfections and infestations\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.32(0.22, 0.45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.33(0.23, 0.47)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e43.57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-1.61(-2.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.33(0.24)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emetabolism and nutrition disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.27(0.16, 0.47)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.28(0.16, 0.48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e24.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-1.84(-2.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.28(0.18)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eneoplasms benign, malignant and unspecified (incl cysts and polyps)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.15(0.08, 0.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.15(0.08, 0.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e43.77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-2.71(-3.61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.15(0.09)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\"\u003eAbbreviations: SOC, system organ classes; ROR, reporting odds ratio; PRR, proportional reporting ratio; BCPNN, Bayesian confidence propagation neural network, and MGPS, multi-item gamma Poisson shrinker\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cp\u003eAccording to the number of PT reports, the top 30 adverse reactions were application site papules, application site rash and application site pruritus. ROR (95%CI) were 179.4(88.62, 363.16), 156.96(128.5, 191.72) and 148.4(124.92, 176.3), respectively. skin and subcutaneous tissue diseases mainly include skin irritation dermatitis contact, dermatitis allergic and dermatitis allergic. ROR (95%CI) were 22.96(12.68, 41.59), 14.45(6, 34.8) and 14.14(5.87, 34.04), respectively. The ROR (95%CI) of hypertension adverse reactions was 9.07(7.12, 11.56); Finally, we found that the ROR (95% CI) of incl cysts and polyps was 9.07(2.92, 28.17), as shown in Table \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e. The results were similar between male and female subjects (Table S2). For a more visual representation of all the meaningful frequencies of adverse events, we generated a frequency waterfall plot for the adverse events of S-1, as shown in Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003ctable id=\"Tab7\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eThe top 30 signal strength of adverse events of S-1 ranked by MGPS at the PTs level in FAERS database.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003ccolgroup cols=\"8\"\u003e\u003c/colgroup\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSOC\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePT\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCase Reports\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eROR (95% CI)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePRR (95% CI)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003echisq\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eBCPNN\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMGPS\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003egeneral disorders and administration site conditions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eapplication site papules\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e179.4(88.62,363.16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e178.66(88.22,361.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1370.18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7.44(6.48)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e173.23(96.02)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003egeneral disorders and administration site conditions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eapplication site rash\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e104\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e156.96(128.5,191.72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e148.52(122.09,180.68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e14855.61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7.18(6.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e144.76(122.45)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003egeneral disorders and administration site conditions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eapplication site pruritus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e143\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e148.4(124.92, 176.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e137.44(117.49, 160.77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e18920.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7.07(6.82)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e134.21(116.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003egeneral disorders and administration site conditions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eapplication site discharge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e134.94(59.98, 303.59)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e134.52(60.23, 300.46)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e776.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7.04(5.95)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e131.43(66.69)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003egeneral disorders and administration site conditions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eapplication site erythema\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e141\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e120.82(101.63,143.65)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e112.03(95.77, 131.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e15225.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.78(6.53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e109.88(95.07)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003egeneral disorders and administration site conditions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eapplication site scar\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e117.55(55.54, 248.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e117.13(55.62, 246.68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e789.68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.84(5.83)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e114.78(61.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003egeneral disorders and administration site conditions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eapplication site vesicles\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e97.13(69, 136.73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e95.43(68.39, 133.17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3124.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.55(6.07)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e93.87(70.51)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003egeneral disorders and administration site conditions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eapplication site irritation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e94.23(72.72, 122.09)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e91.32(70.78, 117.82)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5276.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.49(6.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e89.89(72.37)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003egeneral disorders and administration site conditions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eapplication site burn\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e85.54(54.88, 133.33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e84.66(55.01, 130.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1629.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.38(5.76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e83.43(57.55)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003egeneral disorders and administration site conditions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eapplication site dermatitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e83(41.24, 167.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e82.66(40.82, 167.39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e636.12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.35(5.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e81.48(45.38)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003egeneral disorders and administration site conditions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eapplication site discolouration\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e82.12(46.37, 145.45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e81.62(46.23, 144.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e942.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.33(5.54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e80.47(49.88)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003egeneral disorders and administration site conditions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eapplication site urticaria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e81.57(43.62, 152.52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e81.15(43.34, 151.94)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e780.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.32(5.46)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e80.02(47.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003egeneral disorders and administration site conditions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eapplication site inflammation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e72.83(23.3, 227.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e72.72(23.33, 226.65)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e209.53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6.17(4.74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e71.81(27.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003egeneral disorders and administration site conditions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eapplication site scab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e60.5(25.04, 146.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e60.34(24.98, 145.76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e288.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.9(4.74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e59.72(28.54)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003egeneral disorders and administration site conditions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eapplication site swelling\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e41.59(22.29, 77.59)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e41.37(22.1, 77.46)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e391.18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.36(4.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e41.08(24.38)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003egeneral disorders and administration site conditions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eapplication site exfoliation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e40.59(18.16, 90.73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e40.47(18.12, 90.39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e229.34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5.33(4.25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e40.19(20.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003egeneral disorders and administration site conditions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eapplication site reaction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e24.53(14.48, 41.55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e24.36(14.35, 41.35)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e312.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.6(3.87)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e24.26(15.61)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003egeneral disorders and administration site conditions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eapplication site pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e24.28(14.59, 40.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e24.1(14.48, 40.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e330.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.58(3.87)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e24(15.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eskin and subcutaneous tissue disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eskin irritation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e22.96(12.68, 41.59)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e22.84(12.69, 41.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e228.85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.51(3.69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e22.75(13.84)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eskin and subcutaneous tissue disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003edermatitis contact\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e14.45(6, 34.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e14.42(5.97, 34.83)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e62.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.85(2.69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e14.38(6.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eskin and subcutaneous tissue disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003edermatitis allergic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e14.14(5.87, 34.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e14.1(5.84, 34.06)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e60.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.81(2.66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e14.07(6.75)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eskin and subcutaneous tissue disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eskin reaction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e9.02(3.38, 24.07)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e9(3.38, 23.98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e28.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.17(1.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8.99(3.95)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003evascular disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eblood pressure inadequately controlled\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e150.46(117.35, 192.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e145.33(114.87, 183.87)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e9226.28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7.15(6.79)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e141.73(115.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003evascular disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eblood pressure fluctuation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e17.59(10.18, 30.37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e17.47(10.09, 30.24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e201.37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.12(3.36)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e17.42(11.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003evascular disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ehypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e9.07(7.12, 11.56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8.79(6.95, 11.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e470.34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.13(2.79)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8.77(7.16)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003einvestigations\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eblood pressure increased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e132\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e23.95(20.07, 28.59)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e22.38(19.13, 26.18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2693.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.48(4.22)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e22.29(19.22)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003einvestigations\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eblood pressure abnormal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e17.25(8.61, 34.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e17.18(8.65, 34.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e121.59\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.1(3.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e17.13(9.57)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003einvestigations\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eblood pressure systolic increased\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e11.08(5.53, 22.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e11.04(5.56, 21.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e72.92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.46(2.52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e11.02(6.16)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003erespiratory, thoracic and mediastinal disorders\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003enasal dryness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e16.42(5.28, 51.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e16.39(5.26, 51.08)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e43.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4.03(2.61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e16.35(6.33)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eneoplasms benign, malignant and unspecified (incl cysts and polyps)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003euterine cancer\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e9.07(2.92, 28.17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e9.06(2.91, 28.24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e21.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e3.18(1.76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e9.04(3.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\"\u003eAbbreviations: PT, preferred term; SOC, system organ classes; ROR, reporting odds ratio; PRR, proportional reporting ratio; BCPNN, Bayesian confidence propagation neural network, and MGPS, multi-item gamma Poisson shrinker\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003c/div\u003e\n\u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eAmong the top 30 PT reports, general disorders and administration site conditions were the most common, such as application site papules, rash and pruritus. Secondly, skin and subcutaneous tissue disorders, such as dermatitis contact and dermatitis allergic. At the same time, we also found hypertension and the cause of uterine cancer and other adverse reactions. Recent studies have found that several clinical randomized controlled trials have shown that the most common adverse reaction of S-1 is neutropenia[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. It also includes disorders of the skin system, and gastrointestinal systems such as nausea, vomiting, constipation, and diarrhea[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e], which is consistent with the conclusions of many studies[\u003cspan additionalcitationids=\"CR39\" citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNeutropenia, a condition characterized by a decrease in the number of neutrophils, a type of white blood cell that helps fight infections, is a well-documented side effect of many chemotherapy drugs, including S-1. The primary cause of neutropenia in patients receiving S-1 is the drug's impact on the bone marrow, where blood cells are produced. S-1 can suppress the normal production of neutrophils, leading to an increased risk of infections. The gastrointestinal symptoms, such as nausea, vomiting, constipation, and diarrhea, can be attributed to the drug's effect on the gastrointestinal tract. S-1 contains tegafur, a prodrug that is converted to 5-fluorouracil (5-FU) in the body. 5-FU is known to affect the rapidly dividing cells of the gastrointestinal mucosa, which can lead to mucositis and other gastrointestinal disturbances. The dosage and schedule of S-1 administration can also influence the occurrence and severity of these symptoms. Skin reactions associated with S-1 may include rash, itching, or changes in skin color. These can be a result of the drug's impact on the DNA synthesis of rapidly dividing cells, including those of the skin, or an immune response triggered by the drug. As for the less common adverse reactions like hypertension and uterine cancer, the reasons for their occurrence can be multifactorial. Hypertension may occur because of the drug's impact on the cardiovascular system or due to the physiological stress response triggered by the cancer itself and its treatment. The association between S-1 and uterine cancer might be due to the drug's potential to affect the hormonal balance in the body, as some cancer treatments can influence the risk of developing certain types of cancer.\u003c/p\u003e \u003cp\u003ePreviously, several clinical center experiments have shown that the common adverse reactions of S-1 include rash, neutropenia, anemia, loss of appetite, diarrhea, etc.[\u003cspan additionalcitationids=\"CR42\" citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. This can be explained mainly by the pharmacokinetics before and after drug use. For example, a statistically significant relationship was observed between Cmax and 5-FU concentration before and after treatment[\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. It is important to note that the development of adverse reactions can also be influenced by various patient-related factors, such as underlying health conditions, genetic predisposition, and concurrent medications. Healthcare providers should consider these factors when prescribing S-1 and closely monitor patients for the development of adverse reactions to ensure timely intervention and appropriate management.\u003c/p\u003e \u003cp\u003eOur research has certain limitations, primarily because the FAERS database is an independent reporting system, and the reporting involves doctors, pharmacists, patients, etc., which may lead to false positives in the data mining results. Secondly, whether there is a biological correlation between the target ADE and the drug needs further evaluation by combining case analysis reference to drug instructions, literature reports, and expert opinions. These factors will inevitably result in some deviation in the study's findings, and it is necessary for future studies to conduct comprehensive evaluations based on actual clinical situations.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn this study, we used different algorithms to mine and analyze the American FAERS database and found that the main ADE signals of S-1 were reflected in skin system diseases, skin and subcutaneous tissue diseases, and various reaction diseases at the drug administration site, which was basically consistent with the instructions. However, this study also found new ADE signals such as respiratory, thoracic and mediastinal diseases. At the same time, some serious ADE signals were also observed, such as hypertension and tumor diseases. The results of this study can provide a certain guarantee for the safe clinical use of S-1.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe US Food and Drug Administration Adverse Event Reporting System (FAERS)\u0026nbsp;data are publicly available at https://open.fda.gov/data/faers/.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCRediT author statement\u003c/p\u003e\n\u003cp\u003eDZ: conceptualization, methodology, formal analysis, investigation, data curation, writing - original draft, writing - review \u0026amp; editing, visualization.\u003c/p\u003e\n\u003cp\u003eJL: conceptualization, methodology, formal analysis, investigation, data curation, writing - original draft, writing - review \u0026amp; editing, visualization, funding acquisition.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe express our gratitude to all the staff at FAERS for their valuable contribution in data acquisition.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F (2021) Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. 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J Clin Oncol 18(14):2772\u0026ndash;2779. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e:/10.1200/jco.2000.18.14.2772\u003c/span\u003e\u003cspan address=\":/10.1200/jco.2000.18.14.2772\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"S-1, Adverse drug events, Us FDA adverse Event Reporting System database","lastPublishedDoi":"10.21203/rs.3.rs-4119504/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4119504/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThe aim of this study was to gather information on adverse drug events (ADEs) associated with S1 from the US Food and Drug Administration Adverse Event Reporting System (FAERS) to evaluate its safety and provide a reference for drug use.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe searched the raw data of the FAERS database from its establishment to the third quarter of 2023 to screen ADE reports involving S-1. Signal detection indicators, including ROR, PRR, BCPNN, and MGPS, were used to perform statistical analysis and systematic classification of adverse drug events (ADEs) based on corresponding threshold conditions.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 186,085,022 REAC reports, and 2,011 PT signals induced by S1 as the PS were obtained. Among them, there were 856 adverse event reports of S1 as the PS. In addition, the average age of patients was 65 years and 6 months. Through screening analysis, a total of 126 PT signals involving 18 SOSCs were identified. Mainly involved in vascular disorders, general disorders, and administration site conditions such as skin and subcutaneous tissue disorders. PT with high occurrence frequency includes papules/rash/pruritus; we also found hypertension with an ROR of 95% CI 90-77121-1156 and uterine cancer with an ROR of 95% CI 90-7292-2817.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eMining and analysis of real-world adverse event data of S1 is helpful in finding potential risk signs or symptoms of adverse drug reactions, suggesting that clinical attention should be paid not only to the adverse reactions mentioned in the drug instructions but also to new suspected adverse reactions and clinical standardized medication to ensure patient medication safety.\u003c/p\u003e","manuscriptTitle":"Safety assessment of S-1: Real-world adverse event analysis from the FAERS database","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-25 18:01:55","doi":"10.21203/rs.3.rs-4119504/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2c748801-2a4a-47fa-9143-46be2a615c50","owner":[],"postedDate":"March 25th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-04-06T10:44:28+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-25 18:01:55","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4119504","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4119504","identity":"rs-4119504","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}