Disproportionality analysis and “perpetrator” or “accomplice” review of Baloxavir Marboxil in public FAERS database

Disproportionality analysis and “perpetrator” or “accomplice” review of Baloxavir Marboxil in public 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 Disproportionality analysis and “perpetrator” or “accomplice” review of Baloxavir Marboxil in public FAERS database Fang Sun, Hong-Li Guo, Ya-Hui Hu, Yang Zhang, Feng Chen, Jin Xu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6884001/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 04 Feb, 2026 Read the published version in BMC Infectious Diseases → Version 1 posted 10 You are reading this latest preprint version Abstract Background Baloxavir marboxil (Xofluza™) was approved global in 2018, which is a first-in-class cap-dependent endonuclease inhibitor of the influenza virus polymerase PA subunit. Despite indicating that Baloxavir marboxil is effective and well-tolerated through a series of clinical trials, studies on its safety in real-world settings are scarce. Methods We conducted an evaluation of adverse events associated with Baloxavir marboxil by means of data mining within the FDA Adverse Event Reporting System (FAERS) database spanning from the fourth quarter of 2018 to the second quarter of 2024. Initially, we used four algorithms designed for disproportionality analysis (ROR, PRR, BCPNN, and MGPS) to identify signals of disproportionate reporting. Subsequently, we conducted a detailed differential analysis on the identified signals, examining variables such as sex, age, and concomitant medication usage. Furthermore, we undertook a case-by-case review of indications and co-administered drugs to elucidate the clinical contexts of the affected patient populations. Results 1765 reports and 3624 adverse events with Baloxavir marboxil as the primary suspected drug were filtered out. 35 signals of disproportionate reporting involving 15 system organ class were identified, including two unexpected adverse reaction signals: rhabdomyolysis and international normalised ratio increased. Males, especially those over 65 years old, contributed most to the reports of rhabdomyolysis. In a case-by-case analysis of the DRUG dataset regarding co-administered medications, (i) all patients taking warfarin concomitantly, with a median age of 68, experienced elevated INR levels or other severe hemorrhagic events, and the Ω shrinkage measure for the Baloxavir marboxil - warfarin interaction yielded a result of Ω 025 = 1.42; (ii) the usage frequency of hypotensive agents across the study population was considerable, ranking just below that of influenza-related pharmaceuticals, specifically NSAIDs and antibiotics; (iii) among the deceased patients, whose median age was 73, their medication profile indicated a high utilization of hypotensive agents, in addition to NSAIDs and antitussive & expectorant & antiasthmatic agents. Conclusion This research has enhanced the comprehension of the safety spectrum of Baloxavir marboxil, offering novel insights for its clinical application. Definitive risk management strategies still require large-scale clinical and experimental research. baloxavir acid influenza disproportionality analysis pharmacovigilance adverse events Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 1 Introduction Influenza viruses often threaten public health on a seasonal epidemic basis, and occasional global pandemic. Although symptoms are typically mild, there remains a substantial risk of morbidity and mortality among vulnerable populations, including the elderly, neonates, pregnant individuals, and those with compromised immune systems or pre-existing medical conditions ( 1 ). It has been estimated that globally, up to approximately 650,000 respiratory-related fatalities each year can be attributed to influenza infections ( 2 , 3 ). Even today, we must never forget that the influenza epidemic during the First World War was supposed to have killed more soldiers than the war itself ( 4 ). The development of anti-influenza virus drugs is extremely important. In February 2018, Baloxavir marboxil (Xofluza™; baloxavir acid) was approved in Japan and in October of the same year it was approved in the United States. Baloxavir marboxil (BXM, formerly S-033188) is a prodrug which can be metabolized to active form baloxavir acid (BXA, formerly S-033447) in vivo, and the latter is a first-in-class cap-dependent endonuclease inhibitor of the influenza virus polymerase PA subunit ( 5 , 6 ). This makes it the first new drug approved global for the treatment of recently circulating influenza viruses since the marketing of the neuraminidase inhibitors (NAIs) oseltamivir and zanamivir in 1999 (USA), laninamivir in 2010 (Japan), and peramivir in 2014 (USA) ( 4 ). This novel mechanism partially alleviates the current issue of influenza viruses developing resistance to neuraminidase inhibitors. A series of previous clinical trials and several years of post-marketing use have confirmed generally its efficacy and good tolerability ( 7 – 9 ). And BXM is now in post-marketing pharmacovigilance phase ( 4 , 10 ), to address safety issues that remained undetected in clinical trials because of the rigorous exclusion criteria employed and limited clinical practice. The FDA Adverse Event Reporting System (FAERS) is currently one of the world’s largest public pharmacovigilance databases, contains tens of millions of adverse drug event and medication errors reported by physicians, pharmacists, manufacturers, and others ( 11 , 12 ). Increasing evidence indicates that FAERS plays a significant role in detecting rare adverse drug reactions and in early identification of drug-related safety signals from a large population in real world ( 13 – 18 ). The aim of this study is to delineate the safety signal profile of BXM and thoroughly investigate the underlying information of the detected signals through FAERS data mining, which can provide some reference for its clinical surveillance and risk identification. 2 Materials and methods 2.1 Data sources The study is designed as an observational, retrospective vigilance analysis, involving data from the fourth quarter (Q4) of 2018 (FDA marketing approval of BXM) to the second quarter (Q2) of 2024 (the most recent update of the FAERS database at the time this study was performed) were downloaded from the FAERS database, that is free and publicly accessible ( https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html ). Each quarterly document of the FAERS database consists of seven orthogonal datasets and an additional deleted file. Five types of datasets were used, including patient demographic and administrative information (DEMO), drug/biologic information (DRUG), adverse event encodings (REAC), patient outcomes (OUTC), and indication/diagnosis for use (INDI). All documents were downloaded from the FAERS database in ASCII format. 2.2 Data cleaning As FAERS is a spontaneous reporting system, duplicate records are inevitable and need to be deleted. To ensure the uniqueness of the reports, firstly, we deleted seriatim the cases based on the caseid provided in the additional deleted file for each quarterly document. Then, we performed the deduplication process according to the FDA recommendations by selecting the higher primaryid when the caseid are the same and selecting the most recent FDA_DT when the primaryid are the same ( 19 ). Finally, by checking whether the number of dataset entries matches the count of unique primaryid values, we can verify that all duplicate entries have been completely excluded. Cases of BXM as the primary suspected (PS) drug were identified using the generic name (prod_ai column as Baloxavir Marboxil). In the same report, if BXM was identified as the PS drug, other drugs in the role_cod field as “secondary suspect”, “concomitant”, or “interacting” were considered concomitant drugs. The adverse events were coded using the preferred terms (PTs), which were mapped to the corresponding primary system organ class (SOC) level based on the standardized Medical Dictionary for Regulatory Activities (MedDRA) version 27.0. 2.3 Pharmacovigilance signal detection Disproportionality analysis is widely utilized in pharmacovigilance studies to identify safety signals and explore potential causal relationships between drugs and adverse events ( 20 , 21 ). Four disproportionality analysis methods were applied in this study, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS). The first two are the most commonly used frequency counting methods, and the latter two are the most representative Bayesian methods to explore potential adverse event signals ( 19 , 22 , 23 ). The fourfold table for disproportionality analysis, formula and criteria of the four algorithms for BXM signal detection are shown in Supplementary Table 1–2. In this work, to minimize the bias caused by the deficiencies of a certain algorithm as much as possible, a PT was further considered to be an effective signal of disproportionate reporting (SDR) only when it met the criteria of all four algorithms simultaneously. 2.4 Statistical analysis Descriptive analysis was employed to summarize the clinical features of cases occurred BXM-related adverse events, including sex, age, weight, occurred country, reporters, reporting year and quarter. The sunburst plot is used to analyze the distribution of different PTs detected and their hierarchical relationship with SOCs. Fishers exact test was used for hypothesis testing of categorical variables, while t-test is for the continuous variables. The contingency table employed for the volcano plot, along with the criteria for ROR and Fishers exact test, are presented in Supplementary Table 3. A p value less than 0.05 was considered statistically significant. All data processing and statistical analyses were performed using Jupyter Notebook 6.5.4, providing a Python 3 (ipykernel) computational environment. 3 Results 3.1 Descriptive analysis The comprehensive data collection and processing workflow of this study was illustrated in Fig. 1 . A total of 11,334,240 cases were obtained from the DEMO datasets initially. After data cleaning, 1,753,072 records were removed, comprising 71,614 cases in the deleted file for each quarterly document and 1,681,458 duplicate records. Then, we matched the DRUG datasets with the DEMO and REAC datasets, 1765 reports and 3624 adverse events with BXM as the PS drug were filtered out. The clinical characteristics of the 1765 BXM-associated adverse event reports are shown in Table 1 . Sex data were available for 1388 cases. Among these, females accounted for 53.24% (n = 739) and males accounted for 46.76% (n = 649). Age data was available for 1149 cases, with the median age of 32 years (IQR: 11–60). Dividing the patients into six different age groups using 5, 12, 18, 65 and 80 years as cutoffs, we observed that the cases aged 18–65 years accounted for a higher proportion compared with other age groups (n = 451, 39.25%), the second is the group aged 5–12 years (n = 329, 28.63%), next is the 65 to 80 years (n = 142, 12.36%), the group aged 12 to 18 and the group beyond 80 years only accounted for 9.23% (n = 106) and 8.62% (n = 99), respectively. It is a remarkable fact that 23 cases under 5 years old contributed 2%, but FDA has not yet approved BXM used for these children. Weight data was available for only 14.33% of cases, with a median weight of 65.83 kg (IQR: 53–81). Most patients weighed 20–80 kg (70.36%, n = 178). Regarding the reporting countries, the highest number of cases (n = 1021, 57.98%) was reported from the USA, followed by Japan (n = 697, 39.58%) and China (n = 32, 1.82%). Excluding 4 reports with unknown reporters, physicians (MD) reported the most adverse event reports at 38.05% (n = 670), consumers and pharmacists reported the adverse events at 33.90% (n = 597) and 13.17% (n = 232), respectively. Interestingly, about 80% of adverse event reports associated with BXM were concentrated in the years 2019 and 2020, the number of adverse event reports rapidly plummeted thereafter. Table 1 Characteristics BXM-associated AE reports (n = 1,765) Number of events Available number, n Case number, n Case proportion, % Sex 1388 78.64 Female 739 53.24 Male 649 46.76 NA 377 21.36 Age (years) 1149 65.10 < 5 23 2.00 ≥ 5 329 28.63 ≥ 12 106 9.23 ≥ 18 451 39.25 ≥ 65 142 12.36 ≥ 80 99 8.62 NA 616 34.90 Median (IQR) 32 (11, 60) Weight (kg) 253 14.33 80 68 26.88 NA 1512 85.67 Median (IQR) 65.83(53, 81) Reported countries 1761 99.77 US 1021 57.98 JP 697 39.58 CN 32 1.82 Others 11 0.62 NA 4 Reporters 1761 99.77 MD 670 38.05 PH 232 13.17 HP 176 9.99 CN 597 33.90 OT 86 4.88 NA 4 0.23 Reporting year 1765 100.00 2024Q1 & Q2 83 4.70 2023 132 7.48 2022 77 4.36 2021 39 2.21 2020 647 36.66 2019 777 44.02 2018Q4 10 0.57 MD: physician, PH: pharmacist, HP: health-professional, CN: Consumer, OT: Others. 3.2 Signal detection and distribution at the SOC level and the PT level Among all of 3624 BXM-associated adverse events involving 562 kinds of PTs, 35 kinds of signaling PTs involved 15 SOCs met the criteria of four algorithms used for disproportionality analysis in this study simultaneously, excluding those signaling PTs involving influenza-related complications, as well as PTs covering medication administration and pharmaceutical quality issues, specifically “influenza”, “pneumonia influenzal”, “pneumonia bacterial”, “pneumonia”, “bronchitis”, “intentional product use issue”, “medication error”, “no adverse event”, “off label use”, “prescribed underdose”, “product administered to patient of inappropriate age, and “product packaging quantity issue”. Then, the most frequently occurring PTs were categorized under “gastrointestinal disorders” (primary SOC), with “diarrhoea” and “vomiting” each including 106 and 88 cases, respectively. However, the PTs with the strongest signal strength is “delirium febrile” (ROR = 1589.22) and “febrile convulsion” (ROR = 105.92), which are categorized under “psychiatric disorders” and “nervous system disorders”, respectively. Notably, two signals not mentioned in the BXM label were discovered: specifically, “rhabdomyolysis” and “international normalised ratio (INR) increased”. The case number and signal strength of dissociated adverse events at the SOC level and the PT level are described in Tables 2 and 3 . The signal strength, proportion, and hierarchical relationships of all signaling PTs are displayed in Fig. 2 A. Owing to the limitation in displaying interactive graphics within the text, we have specifically included sunburst charts for “gastrointestinal disorders” (with the highest frequency) and “psychiatric disorders” (as the highest intensity), see Fig. 2 B and C. Table 2 The case number and signal strength of BXM-associated adverse events at the SOC level ROR PRR BCPNN MGPS SOC a b c d ROR 95%CI-L PRR X 2 IC IC025 EBGM EBGM05 Blood and lymphatic system disorders 22 3602 611184 36341641 0.36 0.24 0.37 24.42 -1.45 -2.08 0.37 0.24 Cardiac disorders 43 3581 710049 36242776 0.61 0.45 0.62 10.39 -0.70 -1.16 0.62 0.46 Congenital, familial and genetic disorders 1 3623 104150 36848675 0.10 0.01 0.10 8.34 -3.35 -5.53 0.10 0.01 Ear and labyrinth disorders 16 3608 159022 36793803 1.03 0.63 1.03 0.01 0.04 -0.76 1.03 0.63 Eye disorders 36 3588 694200 36258625 0.52 0.38 0.53 15.41 -0.92 -1.42 0.53 0.38 Gastrointestinal disorders 446 3178 3040990 33911835 1.57 1.42 1.50 79.77 0.58 0.42 1.50 1.35 General disorders and administration site conditions 758 2866 6330835 30621990 1.28 1.18 1.22 36.54 0.29 0.16 1.22 1.13 Hepatobiliary disorders 41 3583 302417 36650408 1.39 1.02 1.38 4.37 0.47 -0.03 1.38 1.02 Immune system disorders 76 3548 443155 36509670 1.76 1.41 1.75 24.65 0.81 0.44 1.75 1.39 Infections and infestations 256 3368 2169372 34783453 1.22 1.07 1.20 9.34 0.27 0.07 1.20 1.06 Injury, poisoning and procedural complications 865 2759 4356283 32596542 2.35 2.17 2.02 508.44 1.02 0.90 2.02 1.88 Investigations 89 3535 2326753 34626072 0.37 0.30 0.39 90.60 -1.36 -1.68 0.39 0.32 Metabolism and nutrition disorders 14 3610 725132 36227693 0.19 0.11 0.20 46.79 -2.34 -3.11 0.20 0.12 Musculoskeletal and connective tissue disorders 57 3567 2023873 34928952 0.28 0.21 0.29 106.69 -1.80 -2.19 0.29 0.22 Neoplasms benign, malignant and unspecified (incl cysts and polyps) 8 3616 1149645 35803180 0.07 0.03 0.07 100.44 -3.82 -4.79 0.07 0.04 Nervous system disorders 270 3354 2744705 34208120 1.00 0.89 1.00 0.00 0.00 -0.19 1.00 0.89 Pregnancy, puerperium and perinatal conditions 7 3617 128043 36824782 0.56 0.27 0.56 2.47 -0.84 -1.98 0.56 0.27 Product issues 26 3598 622172 36330653 0.42 0.29 0.43 20.44 -1.23 -1.81 0.43 0.29 Psychiatric disorders 120 3504 1918916 35033909 0.63 0.52 0.64 26.06 -0.65 -0.93 0.64 0.53 Renal and urinary disorders 57 3567 835127 36117698 0.69 0.53 0.70 7.75 -0.52 -0.93 0.70 0.54 Reproductive system and breast disorders 12 3612 232265 36720560 0.53 0.30 0.53 5.13 -0.92 -1.79 0.53 0.30 Respiratory, thoracic and mediastinal disorders 147 3477 1742406 35210419 0.85 0.72 0.86 3.50 -0.22 -0.47 0.86 0.73 Skin and subcutaneous tissue disorders 176 3448 2093076 34859749 0.85 0.73 0.86 4.42 -0.22 -0.46 0.86 0.74 Social circumstances 3 3621 183895 36768930 0.17 0.05 0.17 12.60 -2.59 -4.11 0.17 0.05 Surgical and medical procedures 1 3623 494798 36458027 0.02 0.00 0.02 47.18 -5.60 -7.67 0.02 0.00 Vascular disorders 31 3593 707912 36244913 0.44 0.31 0.45 21.68 -1.16 -1.70 0.45 0.31 Table 3 The case number and signal strength of BXM-associated adverse events at the PT level ROR PRR BCPNN MGPS PT a b c d ROR 95%CI-L PRR X 2 IC IC025 EBGM EBGM05 SOC Abnormal behaviour 26 3598 14199 36938626 18.80 12.78 18.67 434.22 4.22 2.88 18.64 12.67 Psychiatric disorders Altered state of consciousness 18 3606 11487 36941338 16.05 10.10 15.98 252.42 4.00 2.42 15.95 10.04 Nervous system disorders Anaphylactic reaction 35 3589 28974 36923851 12.43 8.91 12.32 363.8 3.62 2.70 12.30 8.82 Immune system disorders Anaphylactic shock 19 3605 12623 36940202 15.42 9.82 15.35 254.55 3.94 2.44 15.33 9.76 Immune system disorders Cardio-respiratory arrest 7 3617 15540 36937285 4.60 2.19 4.59 19.68 2.20 0.45 4.59 2.19 Cardiac disorders Colitis ischaemic 29 3595 3054 36949771 97.60 67.61 96.83 2724.59 6.58 3.95 95.92 66.45 Gastrointestinal disorders Cyanosis 5 3619 6611 36946214 7.72 3.21 7.71 29.19 2.95 0.42 7.71 3.20 Vascular disorders Cystitis haemorrhagic 4 3620 2097 36950728 19.47 7.30 19.45 69.88 4.28 0.44 19.41 7.28 renal and urinary disorders Delirium 16 3608 17899 36934926 9.15 5.60 9.11 115.55 3.19 1.84 9.11 5.57 Psychiatric disorders Delirium febrile 7 3617 45 36952780 1589.22 716.22 1586.15 9596.33 10.42 1.81 1372.77 618.67 Psychiatric disorders Depressed level of consciousness 11 3613 19446 36933379 5.78 3.20 5.77 43.35 2.53 1.08 5.77 3.19 Nervous system disorders Diarrhoea 106 3518 400547 36552278 2.75 2.27 2.70 114.53 1.43 1.11 2.70 2.22 Gastrointestinal disorders Disseminated intravascular coagulation 7 3617 5856 36946969 12.21 5.81 12.19 71.82 3.61 1.13 12.18 5.80 Blood and lymphatic system disorders Drug eruption 12 3612 9332 36943493 13.15 7.46 13.11 134.12 3.71 1.85 13.1 7.43 Skin and subcutaneous tissue disorders Encephalopathy 8 3616 12347 36940478 6.62 3.31 6.61 38.05 2.72 0.89 6.60 3.30 Nervous system disorders Enterocolitis 6 3618 3846 36948979 15.93 7.15 15.91 83.70 3.99 1.03 15.88 7.13 Gastrointestinal disorders Enterocolitis haemorrhagic 4 3620 654 36952171 62.43 23.35 62.37 240.06 5.95 0.62 61.99 23.18 Gastrointestinal disorders Erythema multiforme 14 3610 4258 36948567 33.65 19.89 33.53 440.38 5.06 2.56 33.42 19.76 Skin and subcutaneous tissue disorders Face oedema 9 3615 7555 36945270 12.17 6.33 12.15 91.97 3.60 1.46 12.13 6.31 General disorders and administration site conditions Febrile convulsion 5 3619 482 36952343 105.92 43.86 105.77 513.6 6.71 1.08 104.7 43.35 Nervous system disorders Haematochezia 15 3609 40435 36912390 3.79 2.28 3.78 30.73 1.92 0.87 3.78 2.28 Gastrointestinal disorders Hallucination 16 3608 43427 36909398 3.77 2.31 3.76 32.39 1.91 0.90 3.76 2.30 Psychiatric disorders Hepatic function abnormal 16 3608 21205 36931620 7.72 4.73 7.69 93.16 2.94 1.67 7.69 4.70 hepatobilliary disorders Hyperpyrexia 4 3620 2101 36950724 19.43 7.28 19.41 69.73 4.28 0.44 19.38 7.26 General disorders and administration site conditions International normalised ratio increased * 7 3617 7479 36945346 9.56 4.55 9.54 53.5 3.25 0.99 9.54 4.54 Investigations Lip swelling 8 3616 15605 36937220 5.24 2.62 5.23 27.35 2.39 0.70 5.23 2.61 Gastrointestinal disorders Loss of consciousness 36 3588 61523 36891302 6.02 4.33 5.97 148.99 2.58 1.88 5.96 4.29 Nervous system disorders Lower respiratory tract congestion 4 3620 1950 36950875 20.94 7.85 20.92 75.71 4.38 0.46 20.88 7.82 Respiratory, thoracic and mediastinal disorders Melaena 23 3601 11054 36941771 21.35 14.16 21.22 442.27 4.40 2.87 21.17 14.05 Gastrointestinal disorders Rhabdomyolysis * 25 3599 17774 36935051 14.43 9.74 14.34 310.01 3.84 2.62 14.32 9.66 musculoskeletal and connective tissue disorders Seizure 25 3599 81142 36871683 3.16 2.13 3.14 36.57 1.65 0.91 3.14 2.12 Nervous system disorders Shock 6 3618 10526 36942299 5.82 2.61 5.81 23.90 2.54 0.47 5.81 2.61 Vascular disorders Swelling of eyelid 4 3620 5132 36947693 7.96 2.98 7.95 24.28 2.99 0.12 7.94 2.98 Eye disorders Urticaria 37 3587 87965 36864860 4.32 3.13 4.29 93.50 2.10 1.47 4.29 3.10 Skin and subcutaneous tissue disorders Vomiting 88 3536 243663 36709162 3.75 3.03 3.68 173.04 1.88 1.51 3.68 2.98 Gastrointestinal disorders * Unexpected adverse reaction signals. 3.3 Concomitant drugs In this study, if BXM was identified as the PS drug, other drugs in the role_cod field as “secondary suspect”, “concomitant”, or “interacting” were considered concomitant drugs. Excepting for duplicate entries and 36 entries with BXM as secondary suspect, 1698 rows involving 470 cases remained. Due to the presence of multi-component medications, we processed the data on concomitant medications. In simple terms, we split most of the multi-component medications, for example, “amlodipine besylate\azilsartan” and “amlodipine besylate\telmisartan”, each with one record, would be split into “amlodipine besylate” with 2 records, “azilsartan” with one record, and “telmisartan” with one record. However, there are some fixed multi-component medications that we did not split, such as “carbidopa\levodopa”, “sulfamethoxazole\trimethoprim”, “piperacillin sodium\tazobactam sodium”, etc. It is worth noting that all multi-component medications containing “acetaminophen” were split. Finally, we gathered 418 types of concomitant medications through case-by-case examination, disregarding the distinction between specific salts of the same drug. As these drugs exhibited significant overlap in their therapeutic categories, we proceed to classify them into 66 therapeutic categories with reference to the ATC codes ( https://atcddd.fhi.no/atc_ddd_index/ ) and the MCDEX Clinical Drug Reference (MCDEX, version 2008), as well as their indications in INDI, proprietary drug names, dose, and route in DRUG (where available on a case-by-case basis). Thus, we can conduct a more precise analysis. Figure 3 A presents the top 20 concomitant drugs, along with the case counts and their respective percentages within the complete set of cases. Similarly, Fig. 3 B illustrates the top 20 therapeutic categories, detailing the case counts and their proportion within the complete set of cases. Acetaminophen, carbocysteine, oseltamivir, dextromethorphan, amlodipine, were the most frequently concomitant drugs, accounting for 11.73% (n = 207), 3.80% (n = 67), 3.0% (n = 53), 2.15% (n = 38) and 1.98% (n = 35), respectively. However, the top five categories are indeed Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), antitussives & expectorants & antiasthmatics (ATEA), hypotensives, antiallergics, as well as antibiotics, accounting for 15.35% (n = 271), 15.01% (n = 265), 7.99% (n = 141), 6.35% (n = 112) and 4.65% (n = 82), respectively. 3.4 Outcomes of cases We evaluated the potential harm of BXM-associated adverse events by investigating the reporting rate of severe outcomes, including death (DE), disabilities (DS), hospitalization-initial or prolonged (HO), life-threatening (LT), and other serious outcomes (OT). The number and percentage of serious outcomes were shown in Fig. 3 C. Removing two cases of congenital anomaly, in 907 cases with reported outcomes, the death, disabilities, hospitalization and life-threatening rates were 10.89%, 1.32%, 34.21% and 6.93%, respectively. Because of the gravity of mortality, we conducted a distinct analysis on the demographic traits and clinical medications for fatal cases. In the 80 cases of death outcomes that mentioned sex, the proportion of death outcomes in males was significantly higher than that in females (male, n = 48/649; female, n = 32/739; p = 0.0154). The age distribution of these cases exhibited a severe skewness. Among the 79 cases that reported age, the median age was 73 years (IQR: 55.5–86.5). Furthermore, there was no significant statistical difference in the age distribution between males and females. Figure 3 D effectively illustrates these details. We further analyzed the concomitant medications and their corresponding indications in the cases with a fatal outcome, aiming to investigate the patterns of polypharmacy and comorbidity in these cases. For the DRUG file and the INDI file, the entries can be linked using the “prod_ai” and “drug_seq” fields. Ultimately, among the 99 cases with a fatal outcome, 40 individuals reported concomitant medications, ranging from one to dozens of different medications, totaling 195 records of concomitant medication involving 119 types. However, only 108 records (33 types) of indications were found, and the remaining entries without indications were filled with “unknown”. As mentioned in our Concomitant drugs analysis , we manually classified each concomitant medication case-by-case into a therapeutic category by referencing the ATC codes ( https://atcddd.fhi.no/atc_ddd_index/ ) and the MCDEX Clinical Drug Reference (MCDEX, version 2008), as well as their indications in INDI, proprietary drug names, dose, and route in DRUG (where available on a case-by-case basis). Finally, these 119 medications (multi-component medications were not split because their proportion is small) fell into 40 therapeutic categories. Therefore, we used a Sankey diagram to display the data flow from these concomitant medications to their indications and therapeutic categories (Fig. 4 ). The diagram clearly shows the comorbidity of the patients, such as the top three indications being influenza, hypertension and fever, and the top five categories are indeed NSAIDs, antitussives & expectorants & antiasthmatics (ATEA), antibiotics, gastric antisecretory drugs, as well as hypotensives. In the right pink bar of this plot, we have specifically highlighted therapeutic categories with high flow in other colors, such as hypotensives and diuretic & hypotensives, which are shown in red. 3.5 Signal differentiation analysis We used a volcano plot to explore the differential characteristics of the signals detected in this study, with factors examined including sex, age, weight, dosage, and whether hypotensive medications were used concomitantly. The results are shown in Fig. 5 . The left side of Fig. 5 displays the differential signals at the PT level, while the right side shows the differentiation at the corresponding SOC level. In the graph, the y-axis represents the strength of the significance of the difference. The higher the y-value, the smaller the p-value of the statistical test, and the horizontal dashed line indicates the position of p = 0.05. We only display signals with p < 0.05 differences in the graph. The larger the dot in the graph, the higher the frequency of the signal, with different colors representing different PTs. Different SOCs are further distinguished by a gray edge line on the outer circle. The x-axis represents the fold change in signal intensity differentiation between the two samples. From the graph, we can observe that sex and age are significant factors affecting the differentiation of adverse reaction signals. Males, especially those over 65 years old, contribute the most to rhabdomyolysis reported, whereas females contribute more to the reporting of gastrointestinal disorders (see Figs. 5 A, C, E, G). Individuals under the age of 18 were more likely to report psychiatric disorders such as abnormal behavior, while the 18 to 65 age group is more inclined to report gastrointestinal disorders such as diarrhoea and colitis ischaemic, as well as anaphylactic reaction (Figs. 5 B and F). Besides rhabdomyolysis, the over-65 age group also reported adverse reaction of nervous and psychiatric system disorders (Figs. 5 C and G). Patients concurrently taking hypotensive medication have shown higher reported rate for international normalised ratio increased, loss of consciousness, disseminated intravascular coagulation and shock (Figs. 5 D and H). We also examined the impact of weight and dosage on signal differentiation, but unfortunately, due to extensive missing data on weight and dosage in the original dataset, no significant differences were found between signals. The influence of these two factors may need to be explored in subsequent analyses. 4 Discussion Baloxavir Marboxil was first approved by the FDA in October 2018. In the data segment extracted for this study, adverse reaction reports from 2018 to 2020 accounted for 80% of the total data. Nevertheless, we detected two signals of disproportionate reporting not mentioned in the product labeling, specifically “rhabdomyolysis” and “international normalised ratio (INR) increased”. Yunsong Li and colleagues, in their post-marketing safety comparison analysis of oseltamivir and baloxavir marboxil, also mentioned the occurrence of rhabdomyolysis, which is consistent with our findings ( 24 ). Furthermore, we analyzed the differential factors associated with the occurrence of rhabdomyolysis, and the results indicate that elderly males, especially those over the age of 65, are more prone to this adverse reaction. What is the underlying mechanism behind BXM-induced rhabdomyolysis? Is it a result of the drug’s inherent pharmacological properties, or does it stem from interactions with other substances that are known to trigger rhabdomyolysis? Out of 25 recorded cases of rhabdomyolysis, 15 individuals reported taking concomitant medications. Among them, nine cases combined the use of several categories of drugs could lead to rhabdomyolysis adverse reactions ( 25 ), including: antilipemic agents: rosuvastatin (n = 1), atorvastatin calcium (n = 1), ezetimibe (n = 2); psycho-therapeutic agents: haloperidol (n = 2), risperidone (n = 2), olanzapine (n = 1), sertraline hydrochloride (n = 1); antigout agents: allopurinol (n = 1), febuxostat (n = 1); sedatives and hypnotics: flunitrazepam (n = 3), diazepam (n = 1), nitrazepam (n = 1), lorazepam (n = 1), zolpidem tartrate (n = 2). Additionally, there have been reports that several antiviral drugs such as telbivudine ( 26 ), lamivudine ( 27 ), entecavir ( 28 ), adefovir dipivoxil ( 29 ), and oseltamivir ( 30 ) also carry a risk of inducing rhabdomyolysis ( 28 , 30 ). Nevertheless, it cannot be confirmed that BXM elevates the risk of rhabdomyolysis when taken alongside these medications because of influenza virus infection itself is also a risk factor for inducing rhabdomyolysis ( 25 , 31 , 32 ). The exact mechanism requires more experimental research for elucidation, and a greater number of adverse reaction reports involving BXM should be gathered for in-depth analysis. Nonetheless, there is a clear consensus: if individuals on BXM therapy present with symptoms like muscle pain and weakness, regardless of whether they are also taking other drugs prone to causing rhabdomyolysis, they should be vigilant for the occurrence of rhabdomyolysis. It is recommended to monitor serum creatine kinase and electrolyte levels and to intervene promptly to prevent life-threatening complications stemming from severe damage to skeletal and cardiac muscles. Considering that alcohol is also a factor that can cause rhabdomyolysis, patients should be advised to refrain from alcohol intake while taking BXM, particularly the male who have a tendency towards heavy alcohol consumption. We first reported the SDR of an increased normalised ratio (INR). Among the data included in this study, 7 patients were involved. Since the normalised ratio is typically only monitored regularly in patients taking anticoagulants such as warfarin, we investigated the concomitant medications of these 7 cases. As expected, 6 of them reported concurrent use of warfarin. Given that anticoagulants also accounted for a significant proportion and the warfarin followed closely behind the 20th place in the Concomitant drug section, we then matched the DEMO and REAC data for all patients using warfarin. After comprehensively case-by-case examination, the results revealed that a total of 12 patients reported the use of warfarin (excluding the patient who reported an increased normalised ratio (INR) without reporting the use of warfarin), with 6 experiencing an increased normalised ratio (INR), and the remaining 6 reporting different bleeding events, including: internal haemorrhage, small intestinal haemorrhage, cystitis haemorrhagic, renal haemorrhage, acute kidney injury, and pulmonary alveolar haemorrhage. Meanwhile, among the latter, 4 patients required hospitalization (HO), and 2 reported life-threatening outcomes (LT). Is there any basis to believe that the primary suspected drugs (PS) might have been misidentified, and might these occurrences be particularly susceptible to adverse effects resulting from warfarin? However, the reporters of these 12 cases were all physicians (n = 6) or pharmacists (n = 6), not non-professionals such as consumers. In fact, as early as March 2019, Japan Ministry of Health, Labour and Welfare added bleeding symptoms to adverse reaction package inserts as a possible adverse event for BXM, because 13 patients with bleeding symptoms were identified among influenza patients taking the drug ( 33 ). Even though serval later studies assert that the incidence of bleeding events with BXM was not higher than that for patients who received neuraminidase inhibitors and influenza patients who did not receive any anti-influenza drugs. The above includes a large-scale retrospective cohort study ( 34 ) and a retrospective survey research based on a questionnaire for physicians ( 33 ), however they were both unable to fully account for associated underlying diseases and other concomitant drugs owing to the lack of data. The latest pharmacovigilance study on the correlation between antiviral influenza treatments and hemorrhage-related adverse events indicates that some signals for gastrointestinal hemorrhage were observed (ROR = 2.53 for BXM, ROR = 1.17 for oseltamivir) ( 35 ). Meanwhile, Tohoku University Hospital reported a case of a patient with implantable ventricular assist device whose INR was significantly increased from the target range after BXM administration, and before this, he had been frequently self-measured INR and precisely controlled the warfarin dose ( 36 ). The author suggests in the text that the interaction between warfarin and BXM might be responsible. From the analysis of the data in this study, we align with his conjecture. Warfarin is widely recognized for its substantial interpatient variability and having a tight therapeutic index primarily due to the high protein binding rate and extensive hepatic metabolism, and it has many significant drug-drug interactions, mainly occurring with medications that induce or inhibit the cytochrome P450 (CYP450) pathway ( 37 ). It has been reported that several antiviral drugs can potentiate the activity of warfarin or increase the INR, such as oseltamivir ( 38 ), darunavir/ritonavir ( 39 ), tipranavir ( 40 ), nelfinavir, and saquinavir ( 41 ). Although the product insert for BXM indicates that, according to prior in vitro experimental research ( 4 , 42 ), BXM is not expected to result in clinically meaningful drug-drug interactions with substrates, inhibitors, and inducers of P450 enzymes, and at therapeutic doses, it does not impact the pharmacokinetics of other medications by competing P-gp. Nonetheless, considering it is a medication metabolized through uridine monophosphate glu-curonosyl transferase 1A3 (UGT1A3) and cytochrome 3A4 (CYP3A4) and has been demonstrated to exert a mild inhibitory effect on CYP2B6, CYP2C8, CYP3A4, and P-gp in vitro ( 43 ), the true nature of its drug-drug interactions may yet be determined by the collection of clinical usage data, particularly with those medications that are highly influenced by factors such as protein binding rates, drug-metabolizing enzymes, and drug transporters. The Ω shrinkage measure is utilized by the World Health Organization Uppsala Monitoring Center (WHO-UMC) to identify signals of drug-drug interactions ( 44 ). Previous studies have indicated that it exhibits the most conservative trend in signal detection among algorithm based on frequentist statistics ( 45 , 46 ). The detection positive criterion is that the lower limit of the 95% confidence interval of the Ω (Ω 025 ) should be greater than 0. Consequently, after processing the REAC data pertaining to BXM and warfarin from the database and utilizing the algorithm, the calculated Ω (Ω 025 ) value for BXM-warfarin interactions was 3.48 (1.42). Therefore, while further clinical and experimental evidence is required for validation, we have offered a reference for medical practitioners. When issuing BXM to patients on warfarin therapy, it might be advisable to advise them to more frequently monitor their INR to prevent severe hemorrhagic incidents. Considering the maximum signal intensity observed for BXM-related adverse events pertaining to psychiatric disorders, an in-depth analysis was performed on instances exhibiting psychiatric adverse responses. This scrutiny disclosed that within the cohort of 59 psychiatric system adverse reaction cases, the distribution included 30 male subjects, 17 female subjects, and 12 cases where sex was unspecified. Among these, 30 individuals were younger than 18 years of age, while 15 were aged 18 years or above; the remaining 14 cases did not provide information regarding age. Geographically, Japan documented 46 occurrences, the United States recorded 11 incidents, and China reported 2 cases. The adverse reactions encompassed only four distinct preferred terms (PT), with “abnormal behavior” impacting 26 individuals, “delirium” affecting 16 individuals, “hallucination” occurring in 16 individuals, and “febrile delirium” in seven individuals. Outcome data were available for 44 patients, revealing hospitalization outcomes (HO) for 17 individuals, life-threatening outcomes (LT) for 5 individuals, and other treatment outcomes (OT) for 31 individuals. Notably, six out of the seven cases involving “febrile delirium” occurred in subjects who were less than 12 years old. In signal differentiation analysis, it has also been indicated that there is a significant difference in the strength of psychiatric system disorder signals between individuals under 18 years of age and others. Therefore, BXM, like other neuraminidase inhibitor antiviral drugs for influenza, may feature psychiatric system disorders as a notable safety concern, necessitating special attention towards younger patients during its application ( 24 , 47 , 48 ). In the analysis of concomitant medications in all cases, hypotensive agents hold a 3rd position, even outperformed both antiallergics and antibiotics against flu symptoms. It is important to emphasize that the hypotensive agents referred to in this study include alfa or beta blocking agents, agents acting on the renin-angiotensin system, calcium channel blockers, vasodilators and agents acting principally on the central nervous system. Therefore, the hypotensives mentioned here are not only for hypertension but also for all cardiovascular diseases that require these treatments. Volcano plot analysis shows that patients concurrently taking hypotensive medication contributed more reports of international normalized ratio increased, loss of consciousness, disseminated intravascular coagulation, and shock. In the Sankey diagram analysis of deceased patients, hypotensive drugs ranked fifth among concomitant medications, and the indications connected to the “diuretic & hypertensives” (such as hydrochlorothiazide), excluding that were not mentioned, were all hypertensions. This means that if the “diuretics & hypotensives” drugs were combined with the “hypotensives” drugs, the hypotensives agents would be the third most common concomitant medication in terms of flow, even surpassing the antibiotics and following only ATEA related to influenza (see Fig. 4 , red color). These analyses appear to indicate that these signals act more as proxies for pre-existing cardiovascular conditions, which make individuals susceptible to severe influenza complications. Therefore, similarly to research based on vaccines ( 49 – 51 ), annual timely vaccination and other preventive measures, are the best choice for these individuals, even if the first-in-class anti-influenza drugs have been launched. In this study, during the signal detection process, we intentionally excluded those detected PTs involving influenza-related complications, as well as PTs covering medication administration and pharmaceutical quality issues (as detailed in the previous text), in reference to other drug safety vigilance research ( 52 – 54 ). However, it should be noted that among the 3624 BXM-related adverse reaction entries screened, the top three most frequent PTs were “no adverse event” (n = 473, ROR = 57.03), “off label use” (n = 380, ROR = 6.5), and “intentional product use issue” (n = 278, ROR = 31.67). The number of occurrences for these was much higher than the highest frequency signal detected in the preceding text, “diarrhoea” (n = 106, ROR = 2.75), and much higher than the highest influenza-related complication signal “pneumonia” (n = 92, ROR = 4.91). This phenomenon is rare in other drugs. It may suggest that for BXM, a single-dose, newly approved medication, patient education on drug use is particularly important. As this is not the purpose of the current study, we will not elaborate in detail. In this manuscript, we have compiled and analyzed all available data pertaining to BXM from the FDA Adverse Event Reporting System (FAERS) spanning from the fourth quarter of 2018 to the second quarter of 2024. Utilizing four algorithms designed for disproportionality analysis, we identified 35 adverse event signals (PTs) associated with 15 distinct System Organ Classes (SOCs), encompassing the highest frequency signaling gastrointestinal disorders and the highest intensity signaling psychiatric disorders. Notably, rhabdomyolysis and increased international normalized ratio (INR) were also identified as SDRs, despite their absence in the product labeling. Our comprehensive analysis revealed several key observations: The reporting rate of psychiatric disorders is higher in pediatric patients, while gastrointestinal disorders and anaphylactic reactions reported significantly increase in adults. Females contribute more to the reporting of gastrointestinal disorders, whereas males, especially those over 65 years old, contribute most to the emergence of rhabdomyolysis. In terms of co-administered medications, all patients taking warfarin concomitantly, with a median age of 68, experienced elevated INR levels or other severe hemorrhagic events, and the Ω shrinkage measure for the BXM-warfarin interaction yielded a result of Ω 025 = 1.42; the usage frequency of hypotensive agents across the study population is considerable, ranking just below that of influenza-related pharmaceuticals, specifically NSAIDs and antibiotics; among the deceased patients, theose median age was 73, and their medication profile indicated a high utilization of hypotensive agents, in addition to NSAIDs and antitussive & expectorant & antiasthmatic (ATEA) agents. This study has several potential limitations. Firstly, since the FAERS database is a spontaneous reporting system and permits submissions from diverse contributors, the analyses based on this data do not represent the incidence rates and exact causality ( 20 , 21 ). Secondly, this spontaneous reporting system cannot require users to provide all necessary information, resulting in different levels of missing data for various variables across the datasets, which may bias the detection of signals and the results of statistical analyses. Thirdly, since BXM have a singular dosing regimen and the dosage for patients with different body weights is relatively uniform (e.g., 20–80 kg: 40 mg; >80 kg: 80 mg), this results in a significant lack of data on dosage, body weight, and frequency of administration compared to other medications, and THER datasets are mostly meaningless. This also preclude examining the impact of these factors on the analysis. Fourthly, the scope of this study is limited, leaving certain aspects unexplored, such as the relationship between the use of antacids and outcomes, and the population characteristics of patients with outcomes other than death. In summary, the disproportionality analysis and the data mining on public database utilized in this paper cannot overcome the inherent limitations of the spontaneous reporting system and the drug characteristics, and it cannot establish exact causal relationships. However, it does play an important role. Its results can offer references for pharmaceutical managers, physicians, and patients, and provide insights for subsequent clinical use and research endeavors. 5 Conclusion This study identified two unexpected adverse reaction signals. More importantly, a distinctive analysis was conducted, including age, sex, body weight, dosage, and concomitant medications. Through the analysis of concomitant medications in patients with elevated INR, a hypothesis of drug-drug interactions was proposed. It was anticipated that the analysis combining concomitant medications with indications would reveal the clinical conditions of the target population. This exploration was successful in the analysis of deceased patients, appearing to indicate that their outcomes act more as proxies for pre-existing cardiovascular conditions, which make individuals susceptible to severe influenza complications. The findings of this paper can provide references for clinical use and risk management for relevant stakeholders. Definitive risk management strategies still require large-scale clinical and experimental research. Abbreviations BXM Baloxavir marboxil FAERS FDA Adverse Event Reporting System DEMO Demographic and administrative information DRUG Drug/biologic information REAC Adverse event encodings OUTC Patient outcomes INDI Indication/diagnosis for use PS Primary suspected drug PTs Preferred terms SOC System organ class ROR Reporting odds ratio PRR Proportional reporting ratio BCPNN Bayesian confidence propagation neural network MGPS Multi-item gamma Poisson shrinker SDR Signal of disproportionate reporting INR International normalised ratio NSAIDs Nonsteroidal Anti-Inflammatory Drugs ATEA Antitussives & expectorants & antiasthmatics DE Death DS Disabilities HO Hospitalization-initial or prolonged LT Life-threatening OT Other serious outcomes ISDN Isosorbide dinitrate AMC\CLVP Amoxicillin\clavulanate potassium CHLPM\CDN\MEPH Chlorpheniramine maleate\dihydrocodeine phosphate\methylephedrine hydrochloride APAP Acetaminophen APAP\CAF\PMZ\SALAMIDE Acetaminophen\caffeine\promethazine\salicylamide Declarations Acknowledgements Thanks to the US FDA for providing a free source of data for the study. Data availability statement The datasets analyzed during the current study are available in the US FAERS database (https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html). All data generated by the present study are available from the corresponding author on reasonable request. Author contributions FS, JX: Conceptualization. FS, H-LG, Y-HH: Data collection, collation, and analysis. FS: Writing the manuscript. YZ: Reviewing the data and methods. FC, H-LG: Revised the manuscript. FC: Project administration, Funding acquisition. All authors contributed to the article and approved the final submitted manuscript. Funding This study was supported by the Specially Appointed Medical Expert Project of the Jiangsu Commission of Health (2019). Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. 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Supplementary Files Attachment.docx Cite Share Download PDF Status: Published Journal Publication published 04 Feb, 2026 Read the published version in BMC Infectious Diseases → Version 1 posted Editorial decision: Revision requested 11 Sep, 2025 Reviews received at journal 22 Jul, 2025 Reviews received at journal 20 Jul, 2025 Reviewers agreed at journal 16 Jul, 2025 Reviewers agreed at journal 15 Jul, 2025 Reviewers invited by journal 14 Jul, 2025 Editor invited by journal 18 Jun, 2025 Editor assigned by journal 16 Jun, 2025 Submission checks completed at journal 16 Jun, 2025 First submitted to journal 12 Jun, 2025 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. 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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-6884001","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":486330264,"identity":"c21902eb-cb47-41cb-b1d7-1e6759099396","order_by":0,"name":"Fang Sun","email":"","orcid":"","institution":"Children’s Hospital of Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Fang","middleName":"","lastName":"Sun","suffix":""},{"id":486330265,"identity":"d907ff9a-3d00-4c00-861e-a832995a1f2a","order_by":1,"name":"Hong-Li Guo","email":"","orcid":"","institution":"Children’s Hospital of Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Hong-Li","middleName":"","lastName":"Guo","suffix":""},{"id":486330266,"identity":"9751b77c-f2ed-402d-8059-cb673edf7753","order_by":2,"name":"Ya-Hui Hu","email":"","orcid":"","institution":"Children’s Hospital of Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Ya-Hui","middleName":"","lastName":"Hu","suffix":""},{"id":486330267,"identity":"61e8be51-e447-4aa8-9c08-c8e08e564121","order_by":3,"name":"Yang Zhang","email":"","orcid":"","institution":"Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yang","middleName":"","lastName":"Zhang","suffix":""},{"id":486330268,"identity":"1f611b76-355c-4fe5-8a59-b7f7e8eb5719","order_by":4,"name":"Feng Chen","email":"","orcid":"","institution":"Children’s Hospital of Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Feng","middleName":"","lastName":"Chen","suffix":""},{"id":486330270,"identity":"da67a47a-4f22-4b41-bb22-9cfd9a686b6d","order_by":5,"name":"Jin Xu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAtklEQVRIiWNgGAWjYHCChAMgkp+Z+fAD0rRItrOlGZBml8F5HgUJ4lTeSHh4uIDBLs/4MA+DAUONTTRBLZIzEhIOz2BILjY7zHvgAcOxtNwGQlr4JYBaeBgOJG47zJdgwNhwmLAWNpiWzc08BhJEaYHbsoGZWC2SPQ9AWpITZxwGBnICMX4xOJ6T/JmHwS6xv//w4QcfamwIa2Fg4ElgYPwHZScQVg4C7AeIUzcKRsEoGAUjFwAABAA89MG9XEIAAAAASUVORK5CYII=","orcid":"","institution":"Children’s Hospital of Nanjing Medical University","correspondingAuthor":true,"prefix":"","firstName":"Jin","middleName":"","lastName":"Xu","suffix":""}],"badges":[],"createdAt":"2025-06-13 02:38:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6884001/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6884001/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12879-026-12724-w","type":"published","date":"2026-02-04T15:58:50+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":87038334,"identity":"2ea27d87-921d-45f6-aa78-a55151224a11","added_by":"auto","created_at":"2025-07-18 13:27:13","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":436438,"visible":true,"origin":"","legend":"\u003cp\u003eFlow diagram of data collection and processing of BXM-associated adverse events. AEs: adverse events; ROR: reporting odds ratio; PRR: proportional reporting ratio; BCPNN: Bayesian confidence propagation neural network; MGPS: multi-item gamma Poisson shrinker; PTs: preferred terms; SOC: system organ class.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6884001/v1/b1fb15584f87e56aa47ec88c.jpeg"},{"id":87038330,"identity":"52461168-c0b4-409a-87a6-e69b32094093","added_by":"auto","created_at":"2025-07-18 13:27:13","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":408197,"visible":true,"origin":"","legend":"\u003cp\u003eThe sunburst plot of all signaling PTs. \u003cstrong\u003eA\u003c/strong\u003e: the outer ring represents individual PTs, middle ring represents the SOC of PTs, and the inner ring are their root which represents all the detected signals from BXM-associated adverse events. The size of each sector area indicates the proportion of cases for the corresponding PT signal or their SOC. The color gradient of each sector in the outer ring represents the ROR values for individual PTs. Owing to the limitation in displaying interactive graphics within the text, we have specifically included sunburst charts for gastrointestinal disorders (with the highest frequency, \u003cstrong\u003eB\u003c/strong\u003e) and psychiatric disorders (as the highest intensity, \u003cstrong\u003eC\u003c/strong\u003e).\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6884001/v1/248e9ea5ece64f38367b8f06.jpeg"},{"id":87036055,"identity":"1a90acd3-4a64-4014-847d-804f01e75812","added_by":"auto","created_at":"2025-07-18 13:19:13","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":381997,"visible":true,"origin":"","legend":"\u003cp\u003eConcomitant drugs and Outcomes analysis. \u003cstrong\u003eA\u003c/strong\u003e presents the top 20 concomitant drugs. \u003cstrong\u003eB\u003c/strong\u003eillustrates the top 20 categories of concomitant drugs. For \u003cstrong\u003eA\u003c/strong\u003e and \u003cstrong\u003eB\u003c/strong\u003e, color green represents case counts, and color pink represents corresponding proportions within the complete set of cases. \u003cstrong\u003eC\u003c/strong\u003e displays the incidence of various severe outcomes, including death (DE), disabilities (DS), Hospitalization-initial or prolonged (HO), life-threatening (LT), and other serious outcomes (OT). The number of cases and the percentage of various serious outcomes are shown on the right side and in the middle of the bars, respectively. \u003cstrong\u003eD\u003c/strong\u003e illustrates the age distribution and gender differences among 80 cases of death outcomes. ATEA: Antitussives \u0026amp; expectorants \u0026amp; antiasthmatics; NSAIDs: Nonsteroidal anti-inflammatory drugs.\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6884001/v1/ce1392b9458e2091607c0378.jpeg"},{"id":87036059,"identity":"cfa71092-2c78-484b-b569-f9b54685bc49","added_by":"auto","created_at":"2025-07-18 13:19:13","extension":"jpeg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1624806,"visible":true,"origin":"","legend":"\u003cp\u003eSankey plot illustrating the concomitant medications and their corresponding indications in the cases with a fatal outcome. The green bar in the middle represents 119 kinds of concomitant medications (multi-component medications not separated), the sky-blue bar on the left represents 33 indications, and the pink bar on the right represents 40 therapeutic categories. The size of the bars represents the number of reports they have, and the gray arcs illustrate the flow of the drug between indications and therapeutic categories. The total flow size is 195 entries involving combination medications. In the right pink bar, we have specifically highlighted therapeutic categories with high flow in other colors, such as hypotensives and diuretic \u0026amp; hypotensives, which are shown in red. ISDN: Isosorbide dinitrate, AMC\\CLVP: Amoxicillin\\clavulanate potassium, CHLPM\\CDN\\MEPH: Chlorpheniramine maleate\\dihydrocodeine phosphate\\methylephedrine hydrochloride, APAP: acetaminophen, APAP\\CAF\\PMZ\\SALAMIDE: Acetaminophen\\caffeine\\promethazine\\salicylamide, ATEA: Antitussives \u0026amp; expectorants \u0026amp; antiasthmatics.\u003c/p\u003e","description":"","filename":"floatimage5.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6884001/v1/b9b7792770763aea84249eef.jpeg"},{"id":87036060,"identity":"5c50baf4-edd5-408b-8211-280409407ab3","added_by":"auto","created_at":"2025-07-18 13:19:13","extension":"jpeg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":534667,"visible":true,"origin":"","legend":"\u003cp\u003eVolcano plots for signal differentiation analysis. The left side (\u003cstrong\u003eA\u003c/strong\u003e-\u003cstrong\u003eD\u003c/strong\u003e) displays the differential signals at the PT level, while the right side (\u003cstrong\u003eE\u003c/strong\u003e-\u003cstrong\u003eH\u003c/strong\u003e) shows the differentiation at the corresponding SOC level. A horizontal dashed line indicating the position of \u003cem\u003ep \u003c/em\u003e= 0.05. We only display signals with \u003cem\u003ep \u003c/em\u003e\u0026lt; 0.05 differences in the graph. The larger the dot in the graph, the stronger the frequency of the signal, with different colors representing different PTs. Different SOCs are further distinguished by a gray edge line on the outer circle.\u003c/p\u003e","description":"","filename":"floatimage7.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-6884001/v1/488d082a898945978c4c753e.jpeg"},{"id":102235521,"identity":"94047041-6877-4460-a9c8-0d5a60f90e8f","added_by":"auto","created_at":"2026-02-09 16:16:44","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4755918,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6884001/v1/19f06254-fbb1-4782-a5ad-398cc1f2b045.pdf"},{"id":87036050,"identity":"d11d3e1c-d6ac-43e7-823b-d0b194ba049d","added_by":"auto","created_at":"2025-07-18 13:19:12","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":18690,"visible":true,"origin":"","legend":"","description":"","filename":"Attachment.docx","url":"https://assets-eu.researchsquare.com/files/rs-6884001/v1/7e076645e9411b7c9448c7a0.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Disproportionality analysis and “perpetrator” or “accomplice” review of Baloxavir Marboxil in public FAERS database","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003eInfluenza viruses often threaten public health on a seasonal epidemic basis, and occasional global pandemic. Although symptoms are typically mild, there remains a substantial risk of morbidity and mortality among vulnerable populations, including the elderly, neonates, pregnant individuals, and those with compromised immune systems or pre-existing medical conditions (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). It has been estimated that globally, up to approximately 650,000 respiratory-related fatalities each year can be attributed to influenza infections (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Even today, we must never forget that the influenza epidemic during the First World War was supposed to have killed more soldiers than the war itself (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). The development of anti-influenza virus drugs is extremely important.\u003c/p\u003e\u003cp\u003e In February 2018, Baloxavir marboxil (Xofluza\u0026trade;; baloxavir acid) was approved in Japan and in October of the same year it was approved in the United States. Baloxavir marboxil (BXM, formerly S-033188) is a prodrug which can be metabolized to active form baloxavir acid (BXA, formerly S-033447) in vivo, and the latter is a first-in-class cap-dependent endonuclease inhibitor of the influenza virus polymerase PA subunit (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). This makes it the first new drug approved global for the treatment of recently circulating influenza viruses since the marketing of the neuraminidase inhibitors (NAIs) oseltamivir and zanamivir in 1999 (USA), laninamivir in 2010 (Japan), and peramivir in 2014 (USA) (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). This novel mechanism partially alleviates the current issue of influenza viruses developing resistance to neuraminidase inhibitors. A series of previous clinical trials and several years of post-marketing use have confirmed generally its efficacy and good tolerability (\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). And BXM is now in post-marketing pharmacovigilance phase (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e), to address safety issues that remained undetected in clinical trials because of the rigorous exclusion criteria employed and limited clinical practice.\u003c/p\u003e\u003cp\u003eThe FDA Adverse Event Reporting System (FAERS) is currently one of the world\u0026rsquo;s largest public pharmacovigilance databases, contains tens of millions of adverse drug event and medication errors reported by physicians, pharmacists, manufacturers, and others (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Increasing evidence indicates that FAERS plays a significant role in detecting rare adverse drug reactions and in early identification of drug-related safety signals from a large population in real world (\u003cspan additionalcitationids=\"CR14 CR15 CR16 CR17\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe aim of this study is to delineate the safety signal profile of BXM and thoroughly investigate the underlying information of the detected signals through FAERS data mining, which can provide some reference for its clinical surveillance and risk identification.\u003c/p\u003e"},{"header":"2 Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1 Data sources\u003c/h2\u003e\u003cp\u003eThe study is designed as an observational, retrospective vigilance analysis, involving data from the fourth quarter (Q4) of 2018 (FDA marketing approval of BXM) to the second quarter (Q2) of 2024 (the most recent update of the FAERS database at the time this study was performed) were downloaded from the FAERS database, that is free and publicly accessible (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html\u003c/span\u003e\u003cspan address=\"https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). Each quarterly document of the FAERS database consists of seven orthogonal datasets and an additional deleted file. Five types of datasets were used, including patient demographic and administrative information (DEMO), drug/biologic information (DRUG), adverse event encodings (REAC), patient outcomes (OUTC), and indication/diagnosis for use (INDI). All documents were downloaded from the FAERS database in ASCII format.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Data cleaning\u003c/h2\u003e\u003cp\u003eAs FAERS is a spontaneous reporting system, duplicate records are inevitable and need to be deleted. To ensure the uniqueness of the reports, firstly, we deleted seriatim the cases based on the caseid provided in the additional deleted file for each quarterly document. Then, we performed the deduplication process according to the FDA recommendations by selecting the higher primaryid when the caseid are the same and selecting the most recent FDA_DT when the primaryid are the same (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Finally, by checking whether the number of dataset entries matches the count of unique primaryid values, we can verify that all duplicate entries have been completely excluded. Cases of BXM as the primary suspected (PS) drug were identified using the generic name (prod_ai column as Baloxavir Marboxil). In the same report, if BXM was identified as the PS drug, other drugs in the role_cod field as \u0026ldquo;secondary suspect\u0026rdquo;, \u0026ldquo;concomitant\u0026rdquo;, or \u0026ldquo;interacting\u0026rdquo; were considered concomitant drugs. The adverse events were coded using the preferred terms (PTs), which were mapped to the corresponding primary system organ class (SOC) level based on the standardized Medical Dictionary for Regulatory Activities (MedDRA) version 27.0.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3 Pharmacovigilance signal detection\u003c/h2\u003e\u003cp\u003eDisproportionality analysis is widely utilized in pharmacovigilance studies to identify safety signals and explore potential causal relationships between drugs and adverse events (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). Four disproportionality analysis methods were applied in this study, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS). The first two are the most commonly used frequency counting methods, and the latter two are the most representative Bayesian methods to explore potential adverse event signals (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). The fourfold table for disproportionality analysis, formula and criteria of the four algorithms for BXM signal detection are shown in Supplementary Table\u0026nbsp;1\u0026ndash;2. In this work, to minimize the bias caused by the deficiencies of a certain algorithm as much as possible, a PT was further considered to be an effective signal of disproportionate reporting (SDR) only when it met the criteria of all four algorithms simultaneously.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e2.4 Statistical analysis\u003c/h2\u003e\u003cp\u003eDescriptive analysis was employed to summarize the clinical features of cases occurred BXM-related adverse events, including sex, age, weight, occurred country, reporters, reporting year and quarter. The sunburst plot is used to analyze the distribution of different PTs detected and their hierarchical relationship with SOCs. Fishers exact test was used for hypothesis testing of categorical variables, while t-test is for the continuous variables. The contingency table employed for the volcano plot, along with the criteria for ROR and Fishers exact test, are presented in Supplementary Table\u0026nbsp;3. A \u003cem\u003ep\u003c/em\u003e value less than 0.05 was considered statistically significant. All data processing and statistical analyses were performed using Jupyter Notebook 6.5.4, providing a Python 3 (ipykernel) computational environment.\u003c/p\u003e\u003c/div\u003e"},{"header":"3 Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003e3.1 Descriptive analysis\u003c/h2\u003e\u003cp\u003eThe comprehensive data collection and processing workflow of this study was illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. A total of 11,334,240 cases were obtained from the DEMO datasets initially. After data cleaning, 1,753,072 records were removed, comprising 71,614 cases in the deleted file for each quarterly document and 1,681,458 duplicate records. Then, we matched the DRUG datasets with the DEMO and REAC datasets, 1765 reports and 3624 adverse events with BXM as the PS drug were filtered out.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe clinical characteristics of the 1765 BXM-associated adverse event reports are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Sex data were available for 1388 cases. Among these, females accounted for 53.24% (n\u0026thinsp;=\u0026thinsp;739) and males accounted for 46.76% (n\u0026thinsp;=\u0026thinsp;649). Age data was available for 1149 cases, with the median age of 32 years (IQR: 11\u0026ndash;60). Dividing the patients into six different age groups using 5, 12, 18, 65 and 80 years as cutoffs, we observed that the cases aged 18\u0026ndash;65 years accounted for a higher proportion compared with other age groups (n\u0026thinsp;=\u0026thinsp;451, 39.25%), the second is the group aged 5\u0026ndash;12 years (n\u0026thinsp;=\u0026thinsp;329, 28.63%), next is the 65 to 80 years (n\u0026thinsp;=\u0026thinsp;142, 12.36%), the group aged 12 to 18 and the group beyond 80 years only accounted for 9.23% (n\u0026thinsp;=\u0026thinsp;106) and 8.62% (n\u0026thinsp;=\u0026thinsp;99), respectively. It is a remarkable fact that 23 cases under 5 years old contributed 2%, but FDA has not yet approved BXM used for these children. Weight data was available for only 14.33% of cases, with a median weight of 65.83 kg (IQR: 53\u0026ndash;81). Most patients weighed 20\u0026ndash;80 kg (70.36%, n\u0026thinsp;=\u0026thinsp;178). Regarding the reporting countries, the highest number of cases (n\u0026thinsp;=\u0026thinsp;1021, 57.98%) was reported from the USA, followed by Japan (n\u0026thinsp;=\u0026thinsp;697, 39.58%) and China (n\u0026thinsp;=\u0026thinsp;32, 1.82%). Excluding 4 reports with unknown reporters, physicians (MD) reported the most adverse event reports at 38.05% (n\u0026thinsp;=\u0026thinsp;670), consumers and pharmacists reported the adverse events at 33.90% (n\u0026thinsp;=\u0026thinsp;597) and 13.17% (n\u0026thinsp;=\u0026thinsp;232), respectively. Interestingly, about 80% of adverse event reports associated with BXM were concentrated in the years 2019 and 2020, the number of adverse event reports rapidly plummeted thereafter.\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\u003eCharacteristics BXM-associated AE reports (n\u0026thinsp;=\u0026thinsp;1,765)\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\u003cp\u003eNumber of events\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAvailable number, n\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCase number, n\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCase proportion, %\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSex\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1388\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e78.64\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e739\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e53.24\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e649\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e46.76\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e377\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e21.36\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge (years)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1149\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e65.10\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.00\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e329\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e28.63\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e106\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9.23\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e451\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e39.25\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;65\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e142\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e12.36\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;80\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e99\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e8.62\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e616\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e34.90\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian (IQR)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u003cp\u003e32 (11, 60)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWeight (kg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e253\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e14.33\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.77\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e20\u0026thinsp;~\u0026thinsp;80\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e178\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e70.36\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026gt;\u0026thinsp;80\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e68\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e26.88\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1512\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e85.67\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedian (IQR)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e\u003cp\u003e65.83(53, 81)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReported countries\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1761\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e99.77\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1021\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e57.98\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eJP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e697\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e39.58\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCN\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.82\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOthers\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.62\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReporters\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1761\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e99.77\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e670\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e38.05\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePH\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e232\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e13.17\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e176\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9.99\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCN\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e597\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e33.90\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e86\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4.88\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.23\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReporting year\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1765\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e100.00\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2024Q1 \u0026amp; Q2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e83\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4.70\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2023\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e132\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7.48\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2022\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4.36\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2021\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e39\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.21\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2020\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e647\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e36.66\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2019\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e777\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e44.02\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2018Q4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.57\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003eMD: physician, PH: pharmacist, HP: health-professional, CN: Consumer, OT: Others.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003e3.2 Signal detection and distribution at the SOC level and the PT level\u003c/h2\u003e\u003cp\u003eAmong all of 3624 BXM-associated adverse events involving 562 kinds of PTs, 35 kinds of signaling PTs involved 15 SOCs met the criteria of four algorithms used for disproportionality analysis in this study simultaneously, excluding those signaling PTs involving influenza-related complications, as well as PTs covering medication administration and pharmaceutical quality issues, specifically \u0026ldquo;influenza\u0026rdquo;, \u0026ldquo;pneumonia influenzal\u0026rdquo;, \u0026ldquo;pneumonia bacterial\u0026rdquo;, \u0026ldquo;pneumonia\u0026rdquo;, \u0026ldquo;bronchitis\u0026rdquo;, \u0026ldquo;intentional product use issue\u0026rdquo;, \u0026ldquo;medication error\u0026rdquo;, \u0026ldquo;no adverse event\u0026rdquo;, \u0026ldquo;off label use\u0026rdquo;, \u0026ldquo;prescribed underdose\u0026rdquo;, \u0026ldquo;product administered to patient of inappropriate age, and \u0026ldquo;product packaging quantity issue\u0026rdquo;. Then, the most frequently occurring PTs were categorized under \u0026ldquo;gastrointestinal disorders\u0026rdquo; (primary SOC), with \u0026ldquo;diarrhoea\u0026rdquo; and \u0026ldquo;vomiting\u0026rdquo; each including 106 and 88 cases, respectively. However, the PTs with the strongest signal strength is \u0026ldquo;delirium febrile\u0026rdquo; (ROR\u0026thinsp;=\u0026thinsp;1589.22) and \u0026ldquo;febrile convulsion\u0026rdquo; (ROR\u0026thinsp;=\u0026thinsp;105.92), which are categorized under \u0026ldquo;psychiatric disorders\u0026rdquo; and \u0026ldquo;nervous system disorders\u0026rdquo;, respectively. Notably, two signals not mentioned in the BXM label were discovered: specifically, \u0026ldquo;rhabdomyolysis\u0026rdquo; and \u0026ldquo;international normalised ratio (INR) increased\u0026rdquo;. The case number and signal strength of dissociated adverse events at the SOC level and the PT level are described in Tables\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. The signal strength, proportion, and hierarchical relationships of all signaling PTs are displayed in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA. Owing to the limitation in displaying interactive graphics within the text, we have specifically included sunburst charts for \u0026ldquo;gastrointestinal disorders\u0026rdquo; (with the highest frequency) and \u0026ldquo;psychiatric disorders\u0026rdquo; (as the highest intensity), see Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB and C.\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\u003eThe case number and signal strength of BXM-associated adverse events at the SOC level\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"17\"\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\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c14\" colnum=\"14\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c15\" colnum=\"15\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c16\" colnum=\"16\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c17\" colnum=\"17\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e\u003cp\u003eROR\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c13\" namest=\"c12\"\u003e\u003cp\u003ePRR\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c15\" namest=\"c14\"\u003e\u003cp\u003eBCPNN\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c17\" namest=\"c16\"\u003e\u003cp\u003eMGPS\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSOC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ea\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003eb\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003ec\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003ed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u003cp\u003eROR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e95%CI-L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003ePRR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e\u003cp\u003eX\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003eIC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eIC025\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c16\" namest=\"c15\"\u003e\u003cp\u003eEBGM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003eEBGM05\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBlood and lymphatic system disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e3602\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e611184\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e36341641\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u003cp\u003e0.36\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e0.37\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e\u003cp\u003e24.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e-1.45\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003e-2.08\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c16\" namest=\"c15\"\u003e\u003cp\u003e0.37\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e0.24\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCardiac disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e43\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e3581\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e710049\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e36242776\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u003cp\u003e0.61\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e0.62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e\u003cp\u003e10.39\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e-0.70\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003e-1.16\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c16\" namest=\"c15\"\u003e\u003cp\u003e0.62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e0.46\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCongenital, familial and genetic disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e3623\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e104150\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e36848675\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u003cp\u003e0.10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e0.10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e\u003cp\u003e8.34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e-3.35\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003e-5.53\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c16\" namest=\"c15\"\u003e\u003cp\u003e0.10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e0.01\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEar and labyrinth disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e3608\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e159022\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e36793803\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u003cp\u003e1.03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e1.03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e\u003cp\u003e0.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e0.04\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003e-0.76\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c16\" namest=\"c15\"\u003e\u003cp\u003e1.03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e0.63\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEye disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e36\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e3588\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e694200\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e36258625\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u003cp\u003e0.52\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.38\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e0.53\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e\u003cp\u003e15.41\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e-0.92\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003e-1.42\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c16\" namest=\"c15\"\u003e\u003cp\u003e0.53\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e0.38\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGastrointestinal disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e446\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e3178\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3040990\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e33911835\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u003cp\u003e1.57\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e1.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e1.50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e\u003cp\u003e79.77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e0.58\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003e0.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c16\" namest=\"c15\"\u003e\u003cp\u003e1.50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e1.35\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGeneral disorders and administration site conditions\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e758\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e2866\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e6330835\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e30621990\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u003cp\u003e1.28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e1.18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e1.22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e\u003cp\u003e36.54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e0.29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003e0.16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c16\" namest=\"c15\"\u003e\u003cp\u003e1.22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e1.13\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHepatobiliary disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e41\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e3583\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e302417\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e36650408\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u003cp\u003e1.39\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e1.02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e1.38\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e\u003cp\u003e4.37\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e0.47\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003e-0.03\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c16\" namest=\"c15\"\u003e\u003cp\u003e1.38\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e1.02\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eImmune system disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e76\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e3548\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e443155\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e36509670\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u003cp\u003e1.76\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e1.41\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e1.75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e\u003cp\u003e24.65\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e0.81\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003e0.44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c16\" namest=\"c15\"\u003e\u003cp\u003e1.75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e1.39\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eInfections and infestations\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e256\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e3368\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2169372\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e34783453\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u003cp\u003e1.22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e1.07\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e1.20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e\u003cp\u003e9.34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e0.27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003e0.07\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c16\" namest=\"c15\"\u003e\u003cp\u003e1.20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e1.06\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eInjury, poisoning and procedural complications\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e865\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e2759\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4356283\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e32596542\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u003cp\u003e2.35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e2.17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e2.02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e\u003cp\u003e508.44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e1.02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003e0.90\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c16\" namest=\"c15\"\u003e\u003cp\u003e2.02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e1.88\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eInvestigations\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e89\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e3535\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2326753\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e34626072\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u003cp\u003e0.37\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e0.39\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e\u003cp\u003e90.60\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e-1.36\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003e-1.68\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c16\" namest=\"c15\"\u003e\u003cp\u003e0.39\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e0.32\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMetabolism and nutrition disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e3610\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e725132\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e36227693\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u003cp\u003e0.19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e0.20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e\u003cp\u003e46.79\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e-2.34\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003e-3.11\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c16\" namest=\"c15\"\u003e\u003cp\u003e0.20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e0.12\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMusculoskeletal and connective tissue disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e57\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e3567\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2023873\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e34928952\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u003cp\u003e0.28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e0.29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e\u003cp\u003e106.69\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e-1.80\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003e-2.19\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c16\" namest=\"c15\"\u003e\u003cp\u003e0.29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e0.22\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNeoplasms benign, malignant and unspecified (incl cysts and polyps)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e3616\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1149645\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e35803180\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u003cp\u003e0.07\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e0.07\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e\u003cp\u003e100.44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e-3.82\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003e-4.79\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c16\" namest=\"c15\"\u003e\u003cp\u003e0.07\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e0.04\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNervous system disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e270\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e3354\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2744705\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e34208120\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.89\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e\u003cp\u003e0.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e0.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003e-0.19\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c16\" namest=\"c15\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e0.89\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePregnancy, puerperium and perinatal conditions\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e3617\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e128043\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e36824782\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u003cp\u003e0.56\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e0.56\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e\u003cp\u003e2.47\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e-0.84\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003e-1.98\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c16\" namest=\"c15\"\u003e\u003cp\u003e0.56\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e0.27\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eProduct issues\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e3598\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e622172\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e36330653\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u003cp\u003e0.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e0.43\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e\u003cp\u003e20.44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e-1.23\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003e-1.81\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c16\" namest=\"c15\"\u003e\u003cp\u003e0.43\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e0.29\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePsychiatric disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e120\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e3504\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1918916\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e35033909\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u003cp\u003e0.63\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.52\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e0.64\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e\u003cp\u003e26.06\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e-0.65\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003e-0.93\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c16\" namest=\"c15\"\u003e\u003cp\u003e0.64\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e0.53\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRenal and urinary disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e57\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e3567\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e835127\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e36117698\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u003cp\u003e0.69\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.53\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e0.70\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e\u003cp\u003e7.75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e-0.52\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003e-0.93\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c16\" namest=\"c15\"\u003e\u003cp\u003e0.70\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e0.54\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReproductive system and breast disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e3612\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e232265\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e36720560\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u003cp\u003e0.53\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e0.53\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e\u003cp\u003e5.13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e-0.92\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003e-1.79\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c16\" namest=\"c15\"\u003e\u003cp\u003e0.53\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e0.30\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRespiratory, thoracic and mediastinal disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e147\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e3477\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1742406\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e35210419\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u003cp\u003e0.85\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.72\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e0.86\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e\u003cp\u003e3.50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e-0.22\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003e-0.47\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c16\" namest=\"c15\"\u003e\u003cp\u003e0.86\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e0.73\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSkin and subcutaneous tissue disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e176\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e3448\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2093076\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e34859749\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u003cp\u003e0.85\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.73\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e0.86\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e\u003cp\u003e4.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e-0.22\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003e-0.46\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c16\" namest=\"c15\"\u003e\u003cp\u003e0.86\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e0.74\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSocial circumstances\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e3621\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e183895\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e36768930\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u003cp\u003e0.17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e0.17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e\u003cp\u003e12.60\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e-2.59\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003e-4.11\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c16\" namest=\"c15\"\u003e\u003cp\u003e0.17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e0.05\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSurgical and medical procedures\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e3623\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e494798\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e36458027\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u003cp\u003e0.02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e0.02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e\u003cp\u003e47.18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e-5.60\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003e-7.67\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c16\" namest=\"c15\"\u003e\u003cp\u003e0.02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e0.00\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVascular disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e31\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e\u003cp\u003e3593\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e707912\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e36244913\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c8\" namest=\"c7\"\u003e\u003cp\u003e0.44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.31\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e0.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e\u003cp\u003e21.68\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e-1.16\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003e-1.70\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c16\" namest=\"c15\"\u003e\u003cp\u003e0.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c17\"\u003e\u003cp\u003e0.31\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eThe case number and signal strength of BXM-associated adverse events at the PT level\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"14\"\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\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c14\" colnum=\"14\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003eROR\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e\u003cp\u003ePRR\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e\u003cp\u003eBCPNN\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c13\" namest=\"c12\"\u003e\u003cp\u003eMGPS\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePT\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\u003ec\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003ed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eROR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e95%CI-L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003ePRR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eX\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eIC\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eIC025\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eEBGM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003eEBGM05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eSOC\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAbnormal behaviour\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3598\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e14199\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e36938626\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e18.80\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e12.78\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e18.67\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e434.22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e4.22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e2.88\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e18.64\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e12.67\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003ePsychiatric disorders\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAltered state of consciousness\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3606\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e11487\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e36941338\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e16.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e10.10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e15.98\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e252.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e4.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e2.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e15.95\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e10.04\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eNervous system disorders\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAnaphylactic reaction\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3589\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e28974\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e36923851\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e12.43\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e8.91\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e12.32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e363.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e3.62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e2.70\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e12.30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e8.82\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eImmune system disorders\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAnaphylactic shock\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3605\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e12623\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e36940202\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e15.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e9.82\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e15.35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e254.55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e3.94\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e2.44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e15.33\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e9.76\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eImmune system disorders\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCardio-respiratory arrest\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3617\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e15540\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e36937285\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e4.60\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e2.19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e4.59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e19.68\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e2.20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e0.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e4.59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e2.19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eCardiac disorders\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eColitis ischaemic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3595\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3054\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e36949771\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e97.60\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e67.61\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e96.83\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e2724.59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e6.58\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e3.95\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e95.92\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e66.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eGastrointestinal disorders\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCyanosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3619\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6611\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e36946214\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e7.72\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e3.21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e7.71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e29.19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e2.95\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e0.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e7.71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e3.20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eVascular disorders\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCystitis haemorrhagic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3620\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2097\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e36950728\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e19.47\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e7.30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e19.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e69.88\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e4.28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e0.44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e19.41\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e7.28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003erenal and urinary disorders\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDelirium\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3608\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e17899\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e36934926\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e9.15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e5.60\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e9.11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e115.55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e3.19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e1.84\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e9.11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e5.57\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003ePsychiatric disorders\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDelirium febrile\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3617\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e36952780\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1589.22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e716.22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1586.15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e9596.33\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e10.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e1.81\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e1372.77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e618.67\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003ePsychiatric disorders\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDepressed level of consciousness\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3613\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e19446\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e36933379\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e5.78\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e3.20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e5.77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e43.35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e2.53\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e1.08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e5.77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e3.19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eNervous system disorders\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiarrhoea\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e106\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3518\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e400547\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e36552278\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2.75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e2.27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e2.70\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e114.53\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e1.43\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e1.11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e2.70\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e2.22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eGastrointestinal disorders\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDisseminated intravascular coagulation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3617\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5856\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e36946969\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e12.21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e5.81\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e12.19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e71.82\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e3.61\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e1.13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e12.18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e5.80\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eBlood and lymphatic system disorders\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDrug eruption\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3612\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9332\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e36943493\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e13.15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e7.46\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e13.11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e134.12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e3.71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e1.85\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e13.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e7.43\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eSkin and subcutaneous tissue disorders\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEncephalopathy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3616\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e12347\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e36940478\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e6.62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e3.31\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e6.61\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e38.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e2.72\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e0.89\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e6.60\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e3.30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eNervous system disorders\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEnterocolitis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3618\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3846\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e36948979\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e15.93\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e7.15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e15.91\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e83.70\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e3.99\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e1.03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e15.88\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e7.13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eGastrointestinal disorders\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEnterocolitis haemorrhagic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3620\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e654\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e36952171\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e62.43\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e23.35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e62.37\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e240.06\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e5.95\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e0.62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e61.99\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e23.18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eGastrointestinal disorders\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eErythema multiforme\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3610\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4258\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e36948567\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e33.65\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e19.89\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e33.53\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e440.38\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e5.06\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e2.56\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e33.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e19.76\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eSkin and subcutaneous tissue disorders\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFace oedema\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3615\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7555\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e36945270\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e12.17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e6.33\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e12.15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e91.97\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e3.60\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e1.46\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e12.13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e6.31\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eGeneral disorders and administration site conditions\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFebrile convulsion\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3619\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e482\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e36952343\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e105.92\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e43.86\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e105.77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e513.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e6.71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e1.08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e104.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e43.35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eNervous system disorders\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHaematochezia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3609\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e40435\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e36912390\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3.79\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e2.28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e3.78\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e30.73\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e1.92\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e0.87\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e3.78\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e2.28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eGastrointestinal disorders\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHallucination\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3608\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e43427\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e36909398\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3.77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e2.31\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e3.76\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e32.39\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e1.91\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e0.90\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e3.76\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e2.30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003ePsychiatric disorders\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHepatic function abnormal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3608\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e21205\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e36931620\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e7.72\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e4.73\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e7.69\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e93.16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e2.94\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e1.67\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e7.69\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e4.70\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003ehepatobilliary disorders\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHyperpyrexia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3620\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2101\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e36950724\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e19.43\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e7.28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e19.41\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e69.73\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e4.28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e0.44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e19.38\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e7.26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eGeneral disorders and administration site conditions\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eInternational normalised ratio increased\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3617\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7479\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e36945346\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e9.56\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e4.55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e9.54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e53.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e3.25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e0.99\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e9.54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e4.54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eInvestigations\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLip swelling\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3616\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e15605\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e36937220\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e5.24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e2.62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e5.23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e27.35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e2.39\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e0.70\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e5.23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e2.61\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eGastrointestinal disorders\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLoss of consciousness\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e36\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3588\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e61523\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e36891302\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e6.02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e4.33\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e5.97\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e148.99\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e2.58\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e1.88\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e5.96\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e4.29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eNervous system disorders\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLower respiratory tract congestion\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3620\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1950\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e36950875\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e20.94\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e7.85\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e20.92\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e75.71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e4.38\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e0.46\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e20.88\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e7.82\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eRespiratory, thoracic and mediastinal disorders\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMelaena\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3601\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e11054\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e36941771\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e21.35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e14.16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e21.22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e442.27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e4.40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e2.87\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e21.17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e14.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eGastrointestinal disorders\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRhabdomyolysis\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3599\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e17774\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e36935051\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e14.43\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e9.74\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e14.34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e310.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e3.84\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e2.62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e14.32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e9.66\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003emusculoskeletal and connective tissue disorders\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSeizure\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3599\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e81142\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e36871683\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3.16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e2.13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e3.14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e36.57\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e1.65\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e0.91\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e3.14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e2.12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eNervous system disorders\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eShock\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3618\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e10526\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e36942299\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e5.82\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e2.61\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e5.81\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e23.90\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e2.54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e0.47\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e5.81\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e2.61\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eVascular disorders\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSwelling of eyelid\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3620\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5132\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e36947693\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e7.96\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e2.98\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e7.95\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e24.28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e2.99\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e0.12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e7.94\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e2.98\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eEye disorders\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUrticaria\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e37\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3587\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e87965\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e36864860\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e4.32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e3.13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e4.29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e93.50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e2.10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e1.47\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e4.29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e3.10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eSkin and subcutaneous tissue disorders\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVomiting\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e88\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3536\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e243663\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e36709162\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3.75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e3.03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e3.68\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e173.04\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e1.88\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e1.51\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e3.68\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u003cp\u003e2.98\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eGastrointestinal disorders\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"14\"\u003e\u003csup\u003e*\u003c/sup\u003e Unexpected adverse reaction signals.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003e3.3 Concomitant drugs\u003c/h2\u003e\u003cp\u003eIn this study, if BXM was identified as the PS drug, other drugs in the role_cod field as \u0026ldquo;secondary suspect\u0026rdquo;, \u0026ldquo;concomitant\u0026rdquo;, or \u0026ldquo;interacting\u0026rdquo; were considered concomitant drugs. Excepting for duplicate entries and 36 entries with BXM as secondary suspect, 1698 rows involving 470 cases remained. Due to the presence of multi-component medications, we processed the data on concomitant medications. In simple terms, we split most of the multi-component medications, for example, \u0026ldquo;amlodipine besylate\\azilsartan\u0026rdquo; and \u0026ldquo;amlodipine besylate\\telmisartan\u0026rdquo;, each with one record, would be split into \u0026ldquo;amlodipine besylate\u0026rdquo; with 2 records, \u0026ldquo;azilsartan\u0026rdquo; with one record, and \u0026ldquo;telmisartan\u0026rdquo; with one record. However, there are some fixed multi-component medications that we did not split, such as \u0026ldquo;carbidopa\\levodopa\u0026rdquo;, \u0026ldquo;sulfamethoxazole\\trimethoprim\u0026rdquo;, \u0026ldquo;piperacillin sodium\\tazobactam sodium\u0026rdquo;, etc. It is worth noting that all multi-component medications containing \u0026ldquo;acetaminophen\u0026rdquo; were split. Finally, we gathered 418 types of concomitant medications through case-by-case examination, disregarding the distinction between specific salts of the same drug. As these drugs exhibited significant overlap in their therapeutic categories, we proceed to classify them into 66 therapeutic categories with reference to the ATC codes (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://atcddd.fhi.no/atc_ddd_index/\u003c/span\u003e\u003cspan address=\"https://atcddd.fhi.no/atc_ddd_index/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) and the MCDEX Clinical Drug Reference (MCDEX, version 2008), as well as their indications in INDI, proprietary drug names, dose, and route in DRUG (where available on a case-by-case basis). Thus, we can conduct a more precise analysis. Figure\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA presents the top 20 concomitant drugs, along with the case counts and their respective percentages within the complete set of cases. Similarly, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB illustrates the top 20 therapeutic categories, detailing the case counts and their proportion within the complete set of cases. Acetaminophen, carbocysteine, oseltamivir, dextromethorphan, amlodipine, were the most frequently concomitant drugs, accounting for 11.73% (n\u0026thinsp;=\u0026thinsp;207), 3.80% (n\u0026thinsp;=\u0026thinsp;67), 3.0% (n\u0026thinsp;=\u0026thinsp;53), 2.15% (n\u0026thinsp;=\u0026thinsp;38) and 1.98% (n\u0026thinsp;=\u0026thinsp;35), respectively. However, the top five categories are indeed Nonsteroidal Anti-Inflammatory Drugs (NSAIDs), antitussives \u0026amp; expectorants \u0026amp; antiasthmatics (ATEA), hypotensives, antiallergics, as well as antibiotics, accounting for 15.35% (n\u0026thinsp;=\u0026thinsp;271), 15.01% (n\u0026thinsp;=\u0026thinsp;265), 7.99% (n\u0026thinsp;=\u0026thinsp;141), 6.35% (n\u0026thinsp;=\u0026thinsp;112) and 4.65% (n\u0026thinsp;=\u0026thinsp;82), respectively.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003e3.4 Outcomes of cases\u003c/h2\u003e\u003cp\u003eWe evaluated the potential harm of BXM-associated adverse events by investigating the reporting rate of severe outcomes, including death (DE), disabilities (DS), hospitalization-initial or prolonged (HO), life-threatening (LT), and other serious outcomes (OT). The number and percentage of serious outcomes were shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC. Removing two cases of congenital anomaly, in 907 cases with reported outcomes, the death, disabilities, hospitalization and life-threatening rates were 10.89%, 1.32%, 34.21% and 6.93%, respectively.\u003c/p\u003e\u003cp\u003eBecause of the gravity of mortality, we conducted a distinct analysis on the demographic traits and clinical medications for fatal cases. In the 80 cases of death outcomes that mentioned sex, the proportion of death outcomes in males was significantly higher than that in females (male, n\u0026thinsp;=\u0026thinsp;48/649; female, n\u0026thinsp;=\u0026thinsp;32/739; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.0154). The age distribution of these cases exhibited a severe skewness. Among the 79 cases that reported age, the median age was 73 years (IQR: 55.5\u0026ndash;86.5). Furthermore, there was no significant statistical difference in the age distribution between males and females. Figure\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eD effectively illustrates these details.\u003c/p\u003e\u003cp\u003eWe further analyzed the concomitant medications and their corresponding indications in the cases with a fatal outcome, aiming to investigate the patterns of polypharmacy and comorbidity in these cases. For the DRUG file and the INDI file, the entries can be linked using the \u0026ldquo;prod_ai\u0026rdquo; and \u0026ldquo;drug_seq\u0026rdquo; fields. Ultimately, among the 99 cases with a fatal outcome, 40 individuals reported concomitant medications, ranging from one to dozens of different medications, totaling 195 records of concomitant medication involving 119 types. However, only 108 records (33 types) of indications were found, and the remaining entries without indications were filled with \u0026ldquo;unknown\u0026rdquo;. As mentioned in our \u003cb\u003eConcomitant drugs analysis\u003c/b\u003e, we manually classified each concomitant medication case-by-case into a therapeutic category by referencing the ATC codes (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://atcddd.fhi.no/atc_ddd_index/\u003c/span\u003e\u003cspan address=\"https://atcddd.fhi.no/atc_ddd_index/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) and the MCDEX Clinical Drug Reference (MCDEX, version 2008), as well as their indications in INDI, proprietary drug names, dose, and route in DRUG (where available on a case-by-case basis). Finally, these 119 medications (multi-component medications were not split because their proportion is small) fell into 40 therapeutic categories. Therefore, we used a Sankey diagram to display the data flow from these concomitant medications to their indications and therapeutic categories (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). The diagram clearly shows the comorbidity of the patients, such as the top three indications being influenza, hypertension and fever, and the top five categories are indeed NSAIDs, antitussives \u0026amp; expectorants \u0026amp; antiasthmatics (ATEA), antibiotics, gastric antisecretory drugs, as well as hypotensives. In the right pink bar of this plot, we have specifically highlighted therapeutic categories with high flow in other colors, such as hypotensives and diuretic \u0026amp; hypotensives, which are shown in red.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003e3.5 Signal differentiation analysis\u003c/h2\u003e\u003cp\u003eWe used a volcano plot to explore the differential characteristics of the signals detected in this study, with factors examined including sex, age, weight, dosage, and whether hypotensive medications were used concomitantly. The results are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e. The left side of Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e displays the differential signals at the PT level, while the right side shows the differentiation at the corresponding SOC level. In the graph, the y-axis represents the strength of the significance of the difference. The higher the y-value, the smaller the p-value of the statistical test, and the horizontal dashed line indicates the position of \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.05. We only display signals with \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 differences in the graph. The larger the dot in the graph, the higher the frequency of the signal, with different colors representing different PTs. Different SOCs are further distinguished by a gray edge line on the outer circle. The x-axis represents the fold change in signal intensity differentiation between the two samples.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eFrom the graph, we can observe that sex and age are significant factors affecting the differentiation of adverse reaction signals. Males, especially those over 65 years old, contribute the most to rhabdomyolysis reported, whereas females contribute more to the reporting of gastrointestinal disorders (see Figs.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eA, C, E, G). Individuals under the age of 18 were more likely to report psychiatric disorders such as abnormal behavior, while the 18 to 65 age group is more inclined to report gastrointestinal disorders such as diarrhoea and colitis ischaemic, as well as anaphylactic reaction (Figs.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eB and F). Besides rhabdomyolysis, the over-65 age group also reported adverse reaction of nervous and psychiatric system disorders (Figs.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eC and G). Patients concurrently taking hypotensive medication have shown higher reported rate for international normalised ratio increased, loss of consciousness, disseminated intravascular coagulation and shock (Figs.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eD and H). We also examined the impact of weight and dosage on signal differentiation, but unfortunately, due to extensive missing data on weight and dosage in the original dataset, no significant differences were found between signals. The influence of these two factors may need to be explored in subsequent analyses.\u003c/p\u003e\u003c/div\u003e"},{"header":"4 Discussion","content":"\u003cp\u003e Baloxavir Marboxil was first approved by the FDA in October 2018. In the data segment extracted for this study, adverse reaction reports from 2018 to 2020 accounted for 80% of the total data. Nevertheless, we detected two signals of disproportionate reporting not mentioned in the product labeling, specifically \u0026ldquo;rhabdomyolysis\u0026rdquo; and \u0026ldquo;international normalised ratio (INR) increased\u0026rdquo;. Yunsong Li and colleagues, in their post-marketing safety comparison analysis of oseltamivir and baloxavir marboxil, also mentioned the occurrence of rhabdomyolysis, which is consistent with our findings (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). Furthermore, we analyzed the differential factors associated with the occurrence of rhabdomyolysis, and the results indicate that elderly males, especially those over the age of 65, are more prone to this adverse reaction. What is the underlying mechanism behind BXM-induced rhabdomyolysis? Is it a result of the drug\u0026rsquo;s inherent pharmacological properties, or does it stem from interactions with other substances that are known to trigger rhabdomyolysis? Out of 25 recorded cases of rhabdomyolysis, 15 individuals reported taking concomitant medications. Among them, nine cases combined the use of several categories of drugs could lead to rhabdomyolysis adverse reactions (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e), including: antilipemic agents: rosuvastatin (n\u0026thinsp;=\u0026thinsp;1), atorvastatin calcium (n\u0026thinsp;=\u0026thinsp;1), ezetimibe (n\u0026thinsp;=\u0026thinsp;2); psycho-therapeutic agents: haloperidol (n\u0026thinsp;=\u0026thinsp;2), risperidone (n\u0026thinsp;=\u0026thinsp;2), olanzapine (n\u0026thinsp;=\u0026thinsp;1), sertraline hydrochloride (n\u0026thinsp;=\u0026thinsp;1); antigout agents: allopurinol (n\u0026thinsp;=\u0026thinsp;1), febuxostat (n\u0026thinsp;=\u0026thinsp;1); sedatives and hypnotics: flunitrazepam (n\u0026thinsp;=\u0026thinsp;3), diazepam (n\u0026thinsp;=\u0026thinsp;1), nitrazepam (n\u0026thinsp;=\u0026thinsp;1), lorazepam (n\u0026thinsp;=\u0026thinsp;1), zolpidem tartrate (n\u0026thinsp;=\u0026thinsp;2). Additionally, there have been reports that several antiviral drugs such as telbivudine (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e), lamivudine (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e), entecavir (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e), adefovir dipivoxil (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e), and oseltamivir (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e) also carry a risk of inducing rhabdomyolysis (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). Nevertheless, it cannot be confirmed that BXM elevates the risk of rhabdomyolysis when taken alongside these medications because of influenza virus infection itself is also a risk factor for inducing rhabdomyolysis (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). The exact mechanism requires more experimental research for elucidation, and a greater number of adverse reaction reports involving BXM should be gathered for in-depth analysis. Nonetheless, there is a clear consensus: if individuals on BXM therapy present with symptoms like muscle pain and weakness, regardless of whether they are also taking other drugs prone to causing rhabdomyolysis, they should be vigilant for the occurrence of rhabdomyolysis. It is recommended to monitor serum creatine kinase and electrolyte levels and to intervene promptly to prevent life-threatening complications stemming from severe damage to skeletal and cardiac muscles. Considering that alcohol is also a factor that can cause rhabdomyolysis, patients should be advised to refrain from alcohol intake while taking BXM, particularly the male who have a tendency towards heavy alcohol consumption.\u003c/p\u003e\u003cp\u003eWe first reported the SDR of an increased normalised ratio (INR). Among the data included in this study, 7 patients were involved. Since the normalised ratio is typically only monitored regularly in patients taking anticoagulants such as warfarin, we investigated the concomitant medications of these 7 cases. As expected, 6 of them reported concurrent use of warfarin. Given that anticoagulants also accounted for a significant proportion and the warfarin followed closely behind the 20th place in the \u003cb\u003eConcomitant drug\u003c/b\u003e section, we then matched the DEMO and REAC data for all patients using warfarin. After comprehensively case-by-case examination, the results revealed that a total of 12 patients reported the use of warfarin (excluding the patient who reported an increased normalised ratio (INR) without reporting the use of warfarin), with 6 experiencing an increased normalised ratio (INR), and the remaining 6 reporting different bleeding events, including: internal haemorrhage, small intestinal haemorrhage, cystitis haemorrhagic, renal haemorrhage, acute kidney injury, and pulmonary alveolar haemorrhage. Meanwhile, among the latter, 4 patients required hospitalization (HO), and 2 reported life-threatening outcomes (LT). Is there any basis to believe that the primary suspected drugs (PS) might have been misidentified, and might these occurrences be particularly susceptible to adverse effects resulting from warfarin? However, the reporters of these 12 cases were all physicians (n\u0026thinsp;=\u0026thinsp;6) or pharmacists (n\u0026thinsp;=\u0026thinsp;6), not non-professionals such as consumers.\u003c/p\u003e\u003cp\u003eIn fact, as early as March 2019, Japan Ministry of Health, Labour and Welfare added bleeding symptoms to adverse reaction package inserts as a possible adverse event for BXM, because 13 patients with bleeding symptoms were identified among influenza patients taking the drug (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). Even though serval later studies assert that the incidence of bleeding events with BXM was not higher than that for patients who received neuraminidase inhibitors and influenza patients who did not receive any anti-influenza drugs. The above includes a large-scale retrospective cohort study (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e) and a retrospective survey research based on a questionnaire for physicians (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e), however they were both unable to fully account for associated underlying diseases and other concomitant drugs owing to the lack of data. The latest pharmacovigilance study on the correlation between antiviral influenza treatments and hemorrhage-related adverse events indicates that some signals for gastrointestinal hemorrhage were observed (ROR\u0026thinsp;=\u0026thinsp;2.53 for BXM, ROR\u0026thinsp;=\u0026thinsp;1.17 for oseltamivir) (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e). Meanwhile, Tohoku University Hospital reported a case of a patient with implantable ventricular assist device whose INR was significantly increased from the target range after BXM administration, and before this, he had been frequently self-measured INR and precisely controlled the warfarin dose (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e). The author suggests in the text that the interaction between warfarin and BXM might be responsible. From the analysis of the data in this study, we align with his conjecture. Warfarin is widely recognized for its substantial interpatient variability and having a tight therapeutic index primarily due to the high protein binding rate and extensive hepatic metabolism, and it has many significant drug-drug interactions, mainly occurring with medications that induce or inhibit the cytochrome P450 (CYP450) pathway (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e). It has been reported that several antiviral drugs can potentiate the activity of warfarin or increase the INR, such as oseltamivir (\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e), darunavir/ritonavir (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e), tipranavir (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e), nelfinavir, and saquinavir (\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e). Although the product insert for BXM indicates that, according to prior in vitro experimental research (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e), BXM is not expected to result in clinically meaningful drug-drug interactions with substrates, inhibitors, and inducers of P450 enzymes, and at therapeutic doses, it does not impact the pharmacokinetics of other medications by competing P-gp. Nonetheless, considering it is a medication metabolized through uridine monophosphate glu-curonosyl transferase 1A3 (UGT1A3) and cytochrome 3A4 (CYP3A4) and has been demonstrated to exert a mild inhibitory effect on CYP2B6, CYP2C8, CYP3A4, and P-gp in vitro (\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e), the true nature of its drug-drug interactions may yet be determined by the collection of clinical usage data, particularly with those medications that are highly influenced by factors such as protein binding rates, drug-metabolizing enzymes, and drug transporters. The Ω shrinkage measure is utilized by the World Health Organization Uppsala Monitoring Center (WHO-UMC) to identify signals of drug-drug interactions (\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e). Previous studies have indicated that it exhibits the most conservative trend in signal detection among algorithm based on frequentist statistics (\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e). The detection positive criterion is that the lower limit of the 95% confidence interval of the Ω (Ω\u003csub\u003e025\u003c/sub\u003e) should be greater than 0. Consequently, after processing the REAC data pertaining to BXM and warfarin from the database and utilizing the algorithm, the calculated Ω (Ω\u003csub\u003e025\u003c/sub\u003e) value for BXM-warfarin interactions was 3.48 (1.42). Therefore, while further clinical and experimental evidence is required for validation, we have offered a reference for medical practitioners. When issuing BXM to patients on warfarin therapy, it might be advisable to advise them to more frequently monitor their INR to prevent severe hemorrhagic incidents.\u003c/p\u003e\u003cp\u003eConsidering the maximum signal intensity observed for BXM-related adverse events pertaining to psychiatric disorders, an in-depth analysis was performed on instances exhibiting psychiatric adverse responses. This scrutiny disclosed that within the cohort of 59 psychiatric system adverse reaction cases, the distribution included 30 male subjects, 17 female subjects, and 12 cases where sex was unspecified. Among these, 30 individuals were younger than 18 years of age, while 15 were aged 18 years or above; the remaining 14 cases did not provide information regarding age. Geographically, Japan documented 46 occurrences, the United States recorded 11 incidents, and China reported 2 cases. The adverse reactions encompassed only four distinct preferred terms (PT), with \u0026ldquo;abnormal behavior\u0026rdquo; impacting 26 individuals, \u0026ldquo;delirium\u0026rdquo; affecting 16 individuals, \u0026ldquo;hallucination\u0026rdquo; occurring in 16 individuals, and \u0026ldquo;febrile delirium\u0026rdquo; in seven individuals. Outcome data were available for 44 patients, revealing hospitalization outcomes (HO) for 17 individuals, life-threatening outcomes (LT) for 5 individuals, and other treatment outcomes (OT) for 31 individuals. Notably, six out of the seven cases involving \u0026ldquo;febrile delirium\u0026rdquo; occurred in subjects who were less than 12 years old. In signal differentiation analysis, it has also been indicated that there is a significant difference in the strength of psychiatric system disorder signals between individuals under 18 years of age and others. Therefore, BXM, like other neuraminidase inhibitor antiviral drugs for influenza, may feature psychiatric system disorders as a notable safety concern, necessitating special attention towards younger patients during its application (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eIn the analysis of concomitant medications in all cases, hypotensive agents hold a 3rd position, even outperformed both antiallergics and antibiotics against flu symptoms. It is important to emphasize that the hypotensive agents referred to in this study include alfa or beta blocking agents, agents acting on the renin-angiotensin system, calcium channel blockers, vasodilators and agents acting principally on the central nervous system. Therefore, the hypotensives mentioned here are not only for hypertension but also for all cardiovascular diseases that require these treatments. Volcano plot analysis shows that patients concurrently taking hypotensive medication contributed more reports of international normalized ratio increased, loss of consciousness, disseminated intravascular coagulation, and shock. In the Sankey diagram analysis of deceased patients, hypotensive drugs ranked fifth among concomitant medications, and the indications connected to the \u0026ldquo;diuretic \u0026amp; hypertensives\u0026rdquo; (such as hydrochlorothiazide), excluding that were not mentioned, were all hypertensions. This means that if the \u0026ldquo;diuretics \u0026amp; hypotensives\u0026rdquo; drugs were combined with the \u0026ldquo;hypotensives\u0026rdquo; drugs, the hypotensives agents would be the third most common concomitant medication in terms of flow, even surpassing the antibiotics and following only ATEA related to influenza (see Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, red color). These analyses appear to indicate that these signals act more as proxies for pre-existing cardiovascular conditions, which make individuals susceptible to severe influenza complications. Therefore, similarly to research based on vaccines (\u003cspan additionalcitationids=\"CR50\" citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e), annual timely vaccination and other preventive measures, are the best choice for these individuals, even if the first-in-class anti-influenza drugs have been launched.\u003c/p\u003e\u003cp\u003eIn this study, during the signal detection process, we intentionally excluded those detected PTs involving influenza-related complications, as well as PTs covering medication administration and pharmaceutical quality issues (as detailed in the previous text), in reference to other drug safety vigilance research (\u003cspan additionalcitationids=\"CR53\" citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e). However, it should be noted that among the 3624 BXM-related adverse reaction entries screened, the top three most frequent PTs were \u0026ldquo;no adverse event\u0026rdquo; (n\u0026thinsp;=\u0026thinsp;473, ROR\u0026thinsp;=\u0026thinsp;57.03), \u0026ldquo;off label use\u0026rdquo; (n\u0026thinsp;=\u0026thinsp;380, ROR\u0026thinsp;=\u0026thinsp;6.5), and \u0026ldquo;intentional product use issue\u0026rdquo; (n\u0026thinsp;=\u0026thinsp;278, ROR\u0026thinsp;=\u0026thinsp;31.67). The number of occurrences for these was much higher than the highest frequency signal detected in the preceding text, \u0026ldquo;diarrhoea\u0026rdquo; (n\u0026thinsp;=\u0026thinsp;106, ROR\u0026thinsp;=\u0026thinsp;2.75), and much higher than the highest influenza-related complication signal \u0026ldquo;pneumonia\u0026rdquo; (n\u0026thinsp;=\u0026thinsp;92, ROR\u0026thinsp;=\u0026thinsp;4.91). This phenomenon is rare in other drugs. It may suggest that for BXM, a single-dose, newly approved medication, patient education on drug use is particularly important. As this is not the purpose of the current study, we will not elaborate in detail.\u003c/p\u003e\u003cp\u003eIn this manuscript, we have compiled and analyzed all available data pertaining to BXM from the FDA Adverse Event Reporting System (FAERS) spanning from the fourth quarter of 2018 to the second quarter of 2024. Utilizing four algorithms designed for disproportionality analysis, we identified 35 adverse event signals (PTs) associated with 15 distinct System Organ Classes (SOCs), encompassing the highest frequency signaling gastrointestinal disorders and the highest intensity signaling psychiatric disorders. Notably, rhabdomyolysis and increased international normalized ratio (INR) were also identified as SDRs, despite their absence in the product labeling.\u003c/p\u003e\u003cp\u003eOur comprehensive analysis revealed several key observations: The reporting rate of psychiatric disorders is higher in pediatric patients, while gastrointestinal disorders and anaphylactic reactions reported significantly increase in adults. Females contribute more to the reporting of gastrointestinal disorders, whereas males, especially those over 65 years old, contribute most to the emergence of rhabdomyolysis. In terms of co-administered medications, all patients taking warfarin concomitantly, with a median age of 68, experienced elevated INR levels or other severe hemorrhagic events, and the Ω shrinkage measure for the BXM-warfarin interaction yielded a result of Ω\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;1.42; the usage frequency of hypotensive agents across the study population is considerable, ranking just below that of influenza-related pharmaceuticals, specifically NSAIDs and antibiotics; among the deceased patients, theose median age was 73, and their medication profile indicated a high utilization of hypotensive agents, in addition to NSAIDs and antitussive \u0026amp; expectorant \u0026amp; antiasthmatic (ATEA) agents.\u003c/p\u003e\u003cp\u003eThis study has several potential limitations. Firstly, since the FAERS database is a spontaneous reporting system and permits submissions from diverse contributors, the analyses based on this data do not represent the incidence rates and exact causality (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). Secondly, this spontaneous reporting system cannot require users to provide all necessary information, resulting in different levels of missing data for various variables across the datasets, which may bias the detection of signals and the results of statistical analyses. Thirdly, since BXM have a singular dosing regimen and the dosage for patients with different body weights is relatively uniform (e.g., 20\u0026ndash;80 kg: 40 mg; \u0026gt;80 kg: 80 mg), this results in a significant lack of data on dosage, body weight, and frequency of administration compared to other medications, and THER datasets are mostly meaningless. This also preclude examining the impact of these factors on the analysis. Fourthly, the scope of this study is limited, leaving certain aspects unexplored, such as the relationship between the use of antacids and outcomes, and the population characteristics of patients with outcomes other than death. In summary, the disproportionality analysis and the data mining on public database utilized in this paper cannot overcome the inherent limitations of the spontaneous reporting system and the drug characteristics, and it cannot establish exact causal relationships. However, it does play an important role. Its results can offer references for pharmaceutical managers, physicians, and patients, and provide insights for subsequent clinical use and research endeavors.\u003c/p\u003e"},{"header":"5 Conclusion","content":"\u003cp\u003eThis study identified two unexpected adverse reaction signals. More importantly, a distinctive analysis was conducted, including age, sex, body weight, dosage, and concomitant medications. Through the analysis of concomitant medications in patients with elevated INR, a hypothesis of drug-drug interactions was proposed. It was anticipated that the analysis combining concomitant medications with indications would reveal the clinical conditions of the target population. This exploration was successful in the analysis of deceased patients, appearing to indicate that their outcomes act more as proxies for pre-existing cardiovascular conditions, which make individuals susceptible to severe influenza complications. The findings of this paper can provide references for clinical use and risk management for relevant stakeholders. Definitive risk management strategies still require large-scale clinical and experimental research.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eBXM\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eBaloxavir marboxil\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eFAERS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eFDA Adverse Event Reporting System\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eDEMO\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eDemographic and administrative information\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eDRUG\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eDrug/biologic information\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eREAC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAdverse event encodings\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eOUTC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ePatient outcomes\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eINDI\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eIndication/diagnosis for use\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ePrimary suspected drug\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePTs\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003ePreferred terms\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSOC\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eSystem organ class\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eROR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eReporting odds ratio\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003ePRR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eProportional reporting ratio\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eBCPNN\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eBayesian confidence propagation neural network\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eMGPS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eMulti-item gamma Poisson shrinker\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eSDR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eSignal of disproportionate reporting\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eINR\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eInternational normalised ratio\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eNSAIDs\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eNonsteroidal Anti-Inflammatory Drugs\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eATEA\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAntitussives \u0026amp; expectorants \u0026amp; antiasthmatics\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eDE\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eDeath\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eDS\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eDisabilities\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eHO\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eHospitalization-initial or prolonged\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eLT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eLife-threatening\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eOT\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eOther serious outcomes\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eISDN\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eIsosorbide dinitrate\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eAMC\\CLVP\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAmoxicillin\\clavulanate potassium\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eCHLPM\\CDN\\MEPH\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eChlorpheniramine maleate\\dihydrocodeine phosphate\\methylephedrine hydrochloride\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eAPAP\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAcetaminophen\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv class=\"DefinitionListEntry\"\u003e\u003cdiv class=\"Term\"\u003eAPAP\\CAF\\PMZ\\SALAMIDE\u003c/div\u003e\u003cdiv class=\"Description\"\u003e\u003cp\u003eAcetaminophen\\caffeine\\promethazine\\salicylamide\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThanks to the US FDA for providing a free source of data for the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets analyzed during the current study are available in the US FAERS database (https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html). All data generated by the present study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFS, JX: Conceptualization. FS, H-LG, Y-HH: Data collection, collation, and analysis. FS: Writing the manuscript. YZ: Reviewing the data and methods. FC, H-LG: Revised the manuscript. FC: Project administration, Funding acquisition. All authors contributed to the article and approved the final submitted manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by the Specially Appointed Medical Expert Project of the Jiangsu Commission of Health (2019).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study utilized publicly available and anonymized datasets, which do not require ethical approval under the Declaration of Helsinki guidelines. All data were accessed and analyzed in compliance with the original data providers \u0026lsquo;terms of use\u0026rsquo;.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003ePaules C, Subbarao K, Influenza. Lancet. 2017;390(10095):697\u0026ndash;708.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eIuliano AD, Roguski KM, Chang HH, Muscatello DJ, Palekar R, Tempia S, et al. Estimates of global seasonal influenza-associated respiratory mortality: a modelling study. 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Front Pharmacol. 2024;15:1420478.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"baloxavir acid, influenza, disproportionality analysis, pharmacovigilance, adverse events","lastPublishedDoi":"10.21203/rs.3.rs-6884001/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6884001/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003e Baloxavir marboxil (Xofluza\u0026trade;) was approved global in 2018, which is a first-in-class cap-dependent endonuclease inhibitor of the influenza virus polymerase PA subunit. Despite indicating that Baloxavir marboxil is effective and well-tolerated through a series of clinical trials, studies on its safety in real-world settings are scarce.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe conducted an evaluation of adverse events associated with Baloxavir marboxil by means of data mining within the FDA Adverse Event Reporting System (FAERS) database spanning from the fourth quarter of 2018 to the second quarter of 2024. Initially, we used four algorithms designed for disproportionality analysis (ROR, PRR, BCPNN, and MGPS) to identify signals of disproportionate reporting. Subsequently, we conducted a detailed differential analysis on the identified signals, examining variables such as sex, age, and concomitant medication usage. Furthermore, we undertook a case-by-case review of indications and co-administered drugs to elucidate the clinical contexts of the affected patient populations.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003e1765 reports and 3624 adverse events with Baloxavir marboxil as the primary suspected drug were filtered out. 35 signals of disproportionate reporting involving 15 system organ class were identified, including two unexpected adverse reaction signals: rhabdomyolysis and international normalised ratio increased. Males, especially those over 65 years old, contributed most to the reports of rhabdomyolysis. In a case-by-case analysis of the DRUG dataset regarding co-administered medications, (i) all patients taking warfarin concomitantly, with a median age of 68, experienced elevated INR levels or other severe hemorrhagic events, and the Ω shrinkage measure for the Baloxavir marboxil - warfarin interaction yielded a result of Ω\u003csub\u003e025\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;1.42; (ii) the usage frequency of hypotensive agents across the study population was considerable, ranking just below that of influenza-related pharmaceuticals, specifically NSAIDs and antibiotics; (iii) among the deceased patients, whose median age was 73, their medication profile indicated a high utilization of hypotensive agents, in addition to NSAIDs and antitussive \u0026amp; expectorant \u0026amp; antiasthmatic agents.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eThis research has enhanced the comprehension of the safety spectrum of Baloxavir marboxil, offering novel insights for its clinical application. Definitive risk management strategies still require large-scale clinical and experimental research.\u003c/p\u003e","manuscriptTitle":"Disproportionality analysis and “perpetrator” or “accomplice” review of Baloxavir Marboxil in public FAERS database","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-18 13:19:08","doi":"10.21203/rs.3.rs-6884001/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-09-11T11:50:59+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-22T23:58:08+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-20T06:55:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"222437664497987585307288638948694614308","date":"2025-07-16T12:21:49+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"197802864346336829740147691430450529331","date":"2025-07-15T14:50:24+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-07-14T10:25:44+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-06-18T11:27:22+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-06-16T23:17:02+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-06-16T23:16:16+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Infectious Diseases","date":"2025-06-13T02:23:45+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f0fa5b1b-ef4f-4912-b31b-73c18da1ec73","owner":[],"postedDate":"July 18th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-02-09T16:14:48+00:00","versionOfRecord":{"articleIdentity":"rs-6884001","link":"https://doi.org/10.1186/s12879-026-12724-w","journal":{"identity":"bmc-infectious-diseases","isVorOnly":false,"title":"BMC Infectious Diseases"},"publishedOn":"2026-02-04 15:58:50","publishedOnDateReadable":"February 4th, 2026"},"versionCreatedAt":"2025-07-18 13:19:08","video":"","vorDoi":"10.1186/s12879-026-12724-w","vorDoiUrl":"https://doi.org/10.1186/s12879-026-12724-w","workflowStages":[]},"version":"v1","identity":"rs-6884001","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6884001","identity":"rs-6884001","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}