Pancreatitis induced by Pegaspargase in children: a real-world pharmacovigilance analysis based on Food and Drug Administration Adverse Event Reporting System

Pancreatitis induced by Pegaspargase in children: a real-world pharmacovigilance analysis based on Food and Drug Administration Adverse Event Reporting System | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 20 January 2025 V1 Latest version Share on Pancreatitis induced by Pegaspargase in children: a real-world pharmacovigilance analysis based on Food and Drug Administration Adverse Event Reporting System Authors : Wenwen Zhang 0000-0002-0511-4651 , Bin Luo , Zhuo Liu , Jie Mi , Yanping Yang , and Yuan Li 0009-0009-8488-7553 [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.173738716.63422238/v1 231 views 119 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Pegaspargase, a pegylated form of native Escherichia coli- derived L-asparaginase, is indicated for treating acute lymphoblastic leukemia (ALL) as a component of multi-agent chemotherapy. Although it has been approved for marketing, real-world, long-term safety information in children is still lacking. We aimed to investigate the adverse events (AEs) caused by Pegaspargase through data mining of the Food and Drug Administration Adverse Event Reporting System (FAERS) database, thereby providing a reference for clinical safety in pediatric populations. A disproportionality analysis was conducted to quantify the correlation between Pegaspargase and AEs, using four algorithms. Subgroup analyses were performed to identify differences between AEs in different clinical characteristics, aiming to assess the risk factors in Pegaspargase-associated pancreatitis. Among 21,161,817 reports, 847 implicated Pegasparagase as the primary suspected drug, uncovering AEs across 26 organ systems. Notably, we identified four previously unlisted AEs. Furthermore, the occurrence of pancreatitis-related is closely related to the age (χ 2 = 8.219, p < 0.05). This research offers a new viewpoint on clinical safety evaluations related to Pegasparagase and provides some references for improving the safety of clinical medication in pediatric populations. Introduction Acute lymphoblastic leukemia (ALL) is the most common form of cancer in children. The global incidence of ALL was 1.04 cases per 100,000 persons, and the mortality was 0.7 per 100,000 persons [1, 2]. The treatment of ALL includes long-term use of multi-agent chemotherapy, of which asparaginase (killing leukemic cells by depleting asparagine levels) is a cornerstone component [3]. Pegaspargase, a pegylated form of native Escherichia coli- derived L-asparaginase, is indicated for treating lymphoblastic (ALL) as a component of multi-agent chemotherapy in pediatric and adult patients [4]. Compared with L-asparaginase, Pegaspargase helps reduce the occurrence of hypersensitivity reactions and the administration frequency [5, 6]. According to clinical trial results, Pegaspargase is notable for significant toxicity in up to 20-25% of ALL patients, including hypersensitivity reactions, thrombosis, pancreatitis, glucose intolerance, hemorrhage, veno-occlusive disease, and hepatotoxicity [7, 8]. Pancreatitis is the most common (>5%) grade≥ 3 AEs associated with Pegaspargase, and previous studies have demonstrated that failure to complete the full Pegaspargase treatment cycle due to pancreatitis is closely correlated with an increased risk of ALL recurrence [9, 10]. Due to the limitations of clinical trials, such as small sample sizes and short observation periods [11], which can’t reflect the safety information of Pegaspargase in real-world. Therefore, data from the real world are crucial for understanding the safety profile of Pegaspargase across the pediatric population. FDA Adverse Event Reporting System (FAERS) is a public database that is designed to facilitate post-marketing safety monitoring of drug and therapeutic products [12]. Data mining techniques were increasingly used to explore and analyze data from the FAERS database to identify potential associations between drugs and AEs [13]. In this study, we retrospectively excavated and analyzed the Adverse Events (AEs) of Pegaspargase by data mining in FAERS from January 2004 to March 2024, and aimed to comprehensively evaluate and characterize Pegaspargase-associated AEs by FAERS databases, serving as a reference for further prevention and use. Data sources and Study design This study is a retrospective data analysis from January 2004 to March 2024, utilizing the FAERS database. As a spontaneous report system, the FAERS database is based on the International Safety Reporting Guidelines (ICH E2B) issued by ICH. AEs in the FAERS reports are coded using the Medical Dictionary for Regulatory Activities 26.0 (MedDRA 26.0) of Preferred Terms (PTs). Moreover, the generic name (Pegaspargase) and trade name (ONCASPAR) were defined as target drugs in the drug information of the FAERS database. Clinical characteristics including gender, age, reporting area, and reporting time were collected with Pegaspargase-related AEs. The flow chart of this study is shown in Figure 1 . Subgroup analyses were performed to determine the distinctions of pancreatitis AE reports in comparison to non-pancreatitis AE reports of Pegaspargase and evaluate the risk of occurring pancreatitis AEs. Adverse event reports related to pancreatitis were assessed through a systematic categorization based on sex, age, weight, and outcomes. The study was conducted in accordance with the Basic & Clinical Pharmacology & Toxicology policy for experimental and clinical studies [14]. Data mining algorithms Data mining algorithms have been developed to identify adverse drug signals that are reported more frequently than anticipated. Disproportionality analysis is a statistical signal detection technique in pharmacovigilance studies, playing a vital role in identifying potential signals indicating AEs associated with a drug [15]. According to the standardized categorization of MedDRA 26.0, when the reported preferred term (PT) of an AE report belonged to the system organ class (SOC) of Gastrointestinal disorders (SOC: 10017947), the report was considered a Pancreatitis case. The association between Pegaspargase and AEs was determined by the reporting odds ratio (ROR), the proportional ratio (PRR), the information component (IC) given by the Bayesian confidence propagation neural network (BCPNN), and the empirical Bayes geometric mean (EBGM) [16]. The data chosen for analysis of this study were AE signals that met four algorithm standards. For a comprehensive understanding of the mathematical equations and criteria that govern each of these algorithms, we refer readers to Supplementary Table S1 . We removed the reports with input errors (EVENT-DT earlier than START-DT) and inaccurate data entries. All data processing and statistical analyses were performed using MYSQL 8.0, Microsoft 2022, and GraphPad Prism 9. Results 1 General characteristics From January 2004 to March 2024, 21,161,817 AE reports were submitted to the FAERS database, among which 847 reports on Pegasparagase injection were reported. The characteristics of AE reports submitted for Pegasparagase are described in Table 1 . Among all the reports, males (n=445, 52.54%) accounted for a larger proportion than females (n=363, 42.86%). In pancreatitis-related reports, females (n=40, 51.2%) accounted for a larger proportion than males (n=35, 44.8%). Patients aged 6-12 years accounted for the largest percentages of reports (33.29%) in all AE reports, and patients aged 12-18 accounted for the largest percentages of reports (39.7%) in pancreatitis-related reports. Serious outcomes of pancreatitis-related reports were 97.5%, and the serious reports were 94.33% in all AE reports. Hospitalization-initial or prolonged was the most frequently reported serious outcome in pancreatitis-related reports (62.82%) and all AE reports (63.16%). 2 Time to onset of Pegasparagase-associated adverse events. The onset time of Pegasparagase-associated AEs was extracted from the database. As Figure 2 illustrates, results indicated that most AE cases occurred 30 days (44.98%) after the initiation of Pegasparagase. The AEs reported onset time, and the median onset time was 10 days (interquartile range [IOR]0.00- 27.00). 3 Signal of system organ class There were 3602 adverse events detected by the reporting odds ratio (ROR), the proportional ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS). The detail is shown in Figure 3 . The signal strength of AEs of Pegasparagase at the System Organ Class (SOC) level is described in Table 2 . The AEs of Pegasparagase occurred in targeting 26 SOCs. The significant SOCs were “Gastrointestinal disorders” (SOC: 10017947), “Nervous system disorders” (SOC: 10029205), and “Respiratory, thoracic and mediastinal disorders” (SOC: 10038738). The 10 pts in Gastrointestinal disorders were Pancreatitis (PT: 10033645), Lip swelling (PT: 10024570), Ascites (PT: 10003445), Pancreatitis acute (PT: 10033647), Colitis (PT: 10009887), Pancreatitis necrotizing (PT: 10033654), Pancreatic pseudocyst (PT: 10033635), Enteritis (PT: 10014866), Pancreatitis hemorrhagic (PT: 10033650), and Gastrointestinal necrosis (PT: 10017982). 4 Top 30 PTs for the positive signal strength of Pegasparagase We further examined PT signals the top 30 PTs for the positive signal strength of Pegasparagase conforming to the four algorithms simultaneously are shown in Table 3 . In this study, Anaphylactic reaction (PT:10002198), Pancreatitis (PT:10033645), Febrile bone marrow aplasia (PT:10053213), Superior sagittal sinus thrombosis (PT:10042567), Pancreatitis necrotizing (PT:10033654), Blood culture positive (PT:10005488), Cerebral infarction (PT:10008118), Hypofibrinogenaemia (PT:10051125), Venous thrombosis (PT:10047249), Cerebral mass effect (PT:10067086) and Jugular vein thrombosis (PT:10023237) have been reported in patients treated with Pegasparagase, which are indicated in the label of Pegasparagase. Pancreatitis-related PTs in this study were pancreatitis-related reports (PT: 10033645), pancreatitis-related reports (PT: 10033647), pancreatitis-related reports (PT: 10033654), and pancreatitis-related reports (PT: 10033650). 5 Top 30 PTs for the frequency of the positive signal of Pegasparagase We also explored the top 30 PTs for the frequency of positive signals of Pegaspargase, conforming to all four algorithms simultaneously, as shown in Table 4 . The top five PTs are divided into Anaphylactic reaction (n = 96, PT: 10002198), Vomiting (n = 88, PT: 10047700), Urticaria (n = 66, PT: 10046735), Hypersensitivity (n = 59, PT: 10020751), Hypotension (n = 57, PT: 10021097). There are four PTs: Febrile bone marrow aplasia (n = 24, PT: 10053213), Pleural effusion (n = 19, PT: 10035598), Ascites (n = 16, PT: 10003445), and Mental status changes (n = 16, PT: 10048294) that are not included in Pegaspargase labels. Discussion This study utilized the FAERS database and pharmacovigilance methodology to explore the complex association between Pegaspargase and AEs in the pediatric population. It also provided an in-depth examination of Pegaspargase’s safety profile in real-world settings. While safety studies for Pegaspargase have been conducted, most are based on adult clinical trial data. The conditions in clinical trials are typically more stringent than in real-world settings. Therefore, research based on real-world data in children is essential to complement clinical trial findings. Our results revealed various AEs caused by Pegaspargase, identifying 812 primary AE terms (Preferred Term, PT) across 26 organ systems. Comparing these with the listed adverse drug reactions (ADRs) in the drug’s label, we identified some valuable new ADR signals, such as Febrile bone marrow aplasia, Pleural effusion, Ascites, and Mental status changes. A clinical study retrospectively indicated that Pegaspargase led to Hepatic sinusoidal obstruction syndrome, which caused Ascites [17], and Pegaspargase has the potential to induce cerebral venous sinus thrombosis, which may manifest clinically as alterations in mental status [18]. These AEs merit further validation to enhance the clinical medication safety of Pegaspargase, and the mechanism studies associated with these unexpected AEs also need further exploration. Hypersensitivity reaction is the most common adverse reaction of Pegasparagase [19], including anaphylaxis, bronchospasm, hypotension, local erythema or swelling, rash, and urticaria. Our results ( Table 4 ) show that Anaphylactic reaction (n = 96), Urticaria (n = 66), Hypersensitivity (n = 59), Hypotension (n = 57), Dyspnoea (n = 56) are the five PTs with the highest frequency. It was reported that antigen-specific IgG and/or IgE through the immunoglobulin receptors FcγRIII and FcεRI may mediate Pegasparagase hypersensitivity [20]. Premedicate patients with acetaminophen, diphenhydramine, or famotidine 30-60 minutes before administration of Pegasparagase to decrease the risk and severity of hypersensitivity reactions. Previous reports indicated that the occurrence of ADRs is significantly influenced by gender, age, and concomitant drugs [21, 22]. We found that the risk of Pegaspargase-related pancreatitis increased with patient age ( p < 0.05), and the Patient sex didn’t impact the occurrence of pancreatitis, which is consistent with the findings of the previous report [23]. Pegaspargase-related pancreatitis (PAP) is a severe and potentially fatal type of drug-induced pancreatic toxicity during combination chemotherapy for ALL in children and adolescents [24]. Our results show that pancreatitis is the most strongly associated serious ADR among the various AEs treated with Pegasparagase, which contains Pancreatitis (n=49, ROR = 16.96, PRR = 16.74, IC = 4.02, EBGM = 16.26), Pancreatitis necrotizing (n=10, ROR = 47.17, PRR = 47.04, IC = 5.44, EBGM = 43.33), and Pancreatitis hemorrhagic (n=4, ROR = 42.11, PRR = 42.06, IC = 5.29, EBGM = 39.08). In all AEs, the incidence of pancreatitis is 9.21%, which is lower than the findings reported in the phase III clinical trials [25]. The precise pathophysiology of Pegasparagase-associated pancreatitis remains unclear. It is hypothesized that systemic reduction in asparagine levels leads to diminished protein synthesis. Organs with increased protein turnover, such as the pancreas and liver, are most at risk [26, 27]. Insufficient secretion of pancreatic FGF21 may be the toxicological mechanism and therapeutic target of Pegasparagase-associated pancreatitis [28]. A retrospective review conducted at a single center indicated that the mechanism underlying Pegasparagase-associated pancreatitis is linked to elevated triglyceride levels [29, 30]. PRSS1 and PRSS2 encode for the proteases cationic and anionic trypsinogen, respectively, previous reports found and validated variants in the PRSS1-PRSS2 locus associated with the risk of PAP in children with ALL [31]. Although there are many studies on the mechanism of PAP, the exact mechanism is still elusive. Consequently, further exploration into this mechanism is needed in future studies. Clinical physicians should assess serum amylase and lipase levels to confirm early signs of pancreatic inflammation in those who were treated with Pegasparagase. Discontinue Pegasparagase in patients where pancreatitis is suspected, or pancreatitis has been confirmed [32]. It was reported that Octreotide was used successfully as a Chemoprotectant to prevent Pegasparagase-induced pancreatitis [33]. Conclusions Through a comprehensive and systematic analysis of the FAERS database, we assess the post-marketing safety profile of Pegasparagase in children. The AE signals we have identified are strongly concordant with the information presented in the drug label issued by the FDA. Notably, our research revealed four unexpected and significant AEs, thereby expanding the current information on ADRs as outlined in the drug label. To establish a definitive connection between Pegasparagase and these newly identified AEs, further prospective clinical trials are imperative. Our research offers a new viewpoint on clinical safety evaluations related to Pegasparagase and provides some references for improving the safety of the clinical medication. Author contributions Yuan Li and Yanping Yang supervised the team activity. All authors contributed to the study’s conception and design. Material preparation, data collection, and analysis were performed by Bin Luo, Wenwen Zhang, and Jie Mi. The first draft of the manuscript was written by Wenwen Zhang and Bin Luo. Yanping Yang and Zhuo Liu commented on previous versions of the manuscript. All authors read and approved the final manuscript. Data Availability N/A - All supporting data are included within the main article. Conflict of Interest Statement The authors declare no competing interests. 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Figure 1 Flowchart of identifying adverse event cases of Pegaspargase from the FAERS database Figure 2 Time to onset of Pegaspargase-related AEs Figure 3 The Venn diagram of the four methods combined. (AE signals meet the criteria specified by all four algorithms simultaneously. ROR, reporting odds ratio; PRR, proportional reporting ratio; BCPNN, bayesian confidence propagation neural networks of information component; EBGM, empirical Bayes geometric mean) Table 1 Clinical characteristics of reports with Pegaspargase from the FAERS database. All of AEs Gastrointestinal disorders Pancreatitis Statistics a p value b Gender Female (%) 363 (42.86) 116 (41.28) 40 (51.2) 1.955 0.162 Male (%) 445 (52.54) 155 (55.16) 35 (44.8) Not Specified (%) 39 ( 4.60) 10 (3.56) 3 (3.8) Age (years) ＜3(%) 113 (13.34) 25 (8.90) 4 (5.1) 8.219 0.042 ≥3，＜6(%) 213 (25.15) 65 (23.13) 15 (19.2) ≥6，＜12(%) 282 (33.29) 109 (38.79) 28 (35.8) ≥12，＜18(%) 239 (28.22) 82 (29.18) 31 (39.7) Serious outcome Serious 799 (94.33) 272 (96.80) 76 (97.50) 1.345 0.246 Non-Serious 48 (5.67) 9 (3.20) 2 (2.50) Outcome Hospitalization- Initial or Prolonged 535 (63.16) 198 (70.46) 49 (62.82) 2.476 0.290 Life-Threatening 150 (17.71) 50 (17.79) 8 (10.25) Death 61 (7.20) 24 (8.54) 7 (8.97) Other 325 (38.37) 79 (28.12) 14 (17.94) Note: Data in bold indicates statistical significance. Abbreviations: AE, adverse event. a The Pearson chi-square test, chi-squared value (χ 2 ). Pancreatitis group compared with All of AEs. b P value, two-tailed threshold of p < 0.05. Table 2 The adverse events distribution of blinatumomab at the SOC level in FAERS database. ROR PRR BCPNN MGPS Four methods Case Percentage (%) Gastrointestinal disorders 17 16 14 18 10 420 11.66 Nervous system disorders 26 24 24 36 19 412 11.44 Investigations 30 31 28 58 22 376 10.44 Respiratory, thoracic and mediastinal disorders 11 11 11 17 10 308 8.55 General disorders and administration site conditions 8 8 7 8 5 280 7.77 Infections and infestations 22 22 13 31 11 238 6.61 Skin and subcutaneous tissue disorders 5 4 3 3 2 228 6.33 Vascular disorders 15 14 14 13 10 198 5.50 Blood and lymphatic system disorders 9 8 9 6 5 197 5.47 Immune system disorders 6 6 6 6 6 192 5.33 Metabolism and nutrition disorders 13 14 11 10 8 177 4.91 Hepatobiliary disorders 8 8 7 9 7 116 3.22 Injury, poisoning and procedural complications 5 5 4 7 3 108 3.00 Cardiac disorders 5 4 5 6 3 105 2.92 Psychiatric disorders 1 1 1 1 1 54 1.50 Eye disorders 3 3 3 3 2 51 1.42 Renal and urinary disorders 2 1 1 3 1 51 1.42 Musculoskeletal and connective tissue disorders 1 1 1 2 1 36 1.00 Surgical and medical procedures 1 1 1 4 1 14 0.39 Neoplasms benign, malignant and unspecified 1 1 1 2 1 14 0.39 Reproductive system and breast disorders 0 0 0 1 0 7 0.19 Product issues 0 0 0 0 0 6 0.17 Congenital, familial and genetic disorders 1 1 1 2 1 5 0.14 Ear and labyrinth disorders 0 0 0 2 0 4 0.11 Social circumstances 0 0 0 1 0 3 0.08 Endocrine disorders 0 0 0 0 0 2 0.06 190 184 165 249 129 3602 100.00 Abbreviations: SOC, system organ class; PT, preferred term; AE, adverse events，ROR, reporting odds ratio; CI, confidence interval; PRR, proportional reporting ratio; χ 2 , chi-information component; IC, information component; IC025, the lower limit of 95% CI of the IC; EBGM, empirical Bayesian geometric mean; EBGM05, the lower limit of 95% CI of EBGM. Table 3 Top 30 PTs for the positive signal strength of Pegasparagase. Axillary vein thrombosis 5 268.52(91.73-786.01) 268.15(887.19) 7.48(1.16) 179.10(61.19) Cerebral mass effect 7 163.54(70.13-381.36) 163.22(865.27) 6.97(1.77) 125.37(53.76) Superior sagittal sinus thrombosis 21 105.87(66.24-169.21) 105.26(1812.90) 6.46(3.48) 88.15(55.15) Leukaemic infiltration 4 165.20(53.84-506.89) 165.02(498.66) 6.98(0.81) 126.42(41.20) Cavernous sinus thrombosis 5 116.75(44.36-307.26) 116.59(470.67) 6.58(1.21) 95.95(36.46) Thalamic infarction 3 134.19(37.85-475.72) 134.07(317.00) 6.75(0.34) 107.46(30.31) Hepatobiliary disease 3 100.64(29.31-345.54) 100.56(249.01) 6.41(0.37) 84.84(24.71) Cellulitis orbital 5 72.57(28.51-184.76) 72.47(310.48) 6.00(1.22) 63.96(25.13) Pancreatitis necrotizing 10 47.17(24.69-90.11) 47.04(414.33) 5.44(2.25) 43.33(22.68) Bacillus test positive 3 73.19(21.90-244.65) 73.13(187.83) 6.01(0.38) 64.48(19.29) Pancreatic pseudocyst 6 50.36(21.80-116.36) 50.28(264.96) 5.53(1.48) 46.05(19.93) Febrile bone marrow aplasia 24 25.91(17.18-39.07) 25.74(544.76) 4.62(3.07) 24.61(16.32) Jugular vein thrombosis 6 38.83(16.95-88.98) 38.77(205.89) 5.18(1.45) 36.22(15.81) Ischaemic cerebral infarction 4 45.69(16.45-126.89) 45.64(160.96) 5.40(0.84) 42.14(15.18) Venous thrombosis 8 33.33(16.31-68.13) 33.26(235.71) 4.97(1.85) 31.38(15.35) Pyomyositis 3 50.32(15.40-164.40) 50.28(132.48) 5.53(0.38) 46.05(14.10) Pancreatitis haemorrhagic 4 42.11(15.21-116.57) 42.06(148.69) 5.29(0.83) 39.08(14.12) Hypofibrinogenaemia 9 29.32(14.98-57.40) 29.25(232.90) 4.80(1.98) 27.79(14.20) Anaphylactic reaction 96 17.32(14.10-21.28) 16.89(1393.19) 4.04(3.52) 16.40(13.35) Transverse sinus thrombosis 4 35.79(13.00-98.53) 35.75(126.68) 5.07(0.82) 33.58(12.20) Pancreatitis 49 16.96(12.73-22.57) 16.74(703.73) 4.02(3.22) 16.26(12.21) Cerebral thrombosis 5 31.22(12.67-76.97) 31.18(138.04) 4.88(1.14) 29.52(11.98) Antithrombin III decreased 4 34.64(12.59-95.26) 34.60(122.61) 5.03(0.81) 32.56(11.84) No reaction on exposure to drug 3 40.26(12.45-130.19) 40.22(106.74) 5.23(0.38) 37.49(11.59) Bacillus infection 4 30.68(11.19-84.07) 30.65(108.52) 4.86(0.80) 29.04(10.60) Peroneal nerve palsy 4 29.42(10.75-80.53) 29.39(103.99) 4.80(0.79) 27.91(10.20) Blood culture positive 11 19.53(10.69-35.67) 19.47(186.01) 4.23(2.07) 18.82(10.30) Subclavian vein thrombosis 3 33.55(10.44-107.75) 33.52(89.08) 4.98(0.37) 31.61(9.84) Mycobacterium chelonae infection 4 27.53(10.07-75.24) 27.50(97.18) 4.71(0.79) 26.21(9.59) Cerebral infarction 13 17.10(9.84-29.74) 17.05(190.36) 4.05(2.18) 16.55(9.52) Note: Data in bold indicates AEs associated with Pancreatitis. Abbreviations: PT, preferred term; ROR, reporting odds ratio; CI, confidence interval; PRR, proportional reporting ratio; χ 2 , chi-information component; IC, information component; IC025, the lower limit of 95% CI of the IC; EBGM, empirical Bayesian geometric mean; EBGM05, the lower limit of 95% CI of EBGM. Table 4 Top 30 PTs for the frequency of the positive signal of Pegasparagase. Anaphylactic reaction 96 17.32(14.10-21.28) 16.89(1393.19) 4.04(3.52) 16.40(13.35) Urticaria 66 4.47(3.50-5.70) 4.40(172.83) 2.13(1.70) 4.37(3.43) Hypersensitivity 59 5.10(3.94-6.61) 5.04(189.74) 2.32(1.85) 5.00(3.86) Hypotension 57 4.78(3.67-6.22) 4.72(166.20) 2.23(1.76) 4.69(3.60) Dyspnoea 56 3.03(2.33-3.95) 3.00(74.77) 1.58(1.14) 2.99(2.30) Infusion related reaction 54 10.87(8.29-14.26) 10.72(467.36) 3.40(2.77) 10.53(8.03) Febrile neutropenia 52 4.96(3.76-6.53) 4.90(160.40) 2.28(1.78) 4.86(3.69) Cough 50 3.23(2.44-4.28) 3.20(75.65) 1.67(1.20) 3.19(2.41) Pancreatitis 49 16.96(12.73-22.57) 16.74(703.73) 4.02(3.22) 16.26(12.21) Tachycardia 38 3.45(2.51-4.76) 3.43(65.10) 1.77(1.22) 3.41(2.48) Swelling face 35 5.87(4.20-8.20) 5.82(138.40) 2.53(1.86) 5.77(4.13) Hyperglycaemia 34 11.88(8.45-16.72) 11.78(328.44) 3.53(2.65) 11.55(8.21) Lip swelling 28 9.76(6.70-14.20) 9.69(214.46) 3.25(2.34) 9.53(6.55) Febrile bone marrow aplasia* 24 25.91(17.18-39.07) 25.74(544.76) 4.62(3.07) 24.61(16.32) Sepsis 24 3.44(2.30-5.15) 3.43(41.03) 1.77(1.06) 3.41(2.28) Oxygen saturation decreased 24 3.97(2.66-5.95) 3.95(52.67) 1.98(1.23) 3.93(2.63) Hepatocellular injury 22 13.98(9.14-21.37) 13.90(256.78) 3.76(2.52) 13.57(8.88) Brain oedema 21 9.34(6.06-14.40) 9.29(152.85) 3.19(2.12) 9.15(5.94) Superior sagittal sinus thrombosis 21 105.87(66.24-169.21) 105.26(1812.90) 6.46(3.48) 88.15(55.15) Coagulopathy 20 9.15(5.87-14.25) 9.11(141.98) 3.17(2.06) 8.97(5.76) Wheezing 20 5.42(3.49-8.43) 5.40(71.03) 2.42(1.51) 5.35(3.44) Pleural effusion* 19 6.19(3.93-9.74) 6.16(81.34) 2.61(1.63) 6.11(3.88) Drug hypersensitivity 18 3.34(2.10-5.31) 3.32(29.11) 1.73(0.89) 3.31(2.08) Cerebral haemorrhage 18 13.40(8.38-21.41) 13.33(200.45) 3.70(2.32) 13.03(8.16) Angioedema 18 5.01(3.15-7.98) 4.99(56.94) 2.31(1.37) 4.95(3.11) Hypertriglyceridaemia 17 15.71(9.69-25.47) 15.64(226.41) 3.93(2.39) 15.22(9.39) Cardio-respiratory arrest 16 4.11(2.51-6.73) 4.10(37.20) 2.03(1.08) 4.07(2.49) Ascites* 16 7.94(4.84-13.02) 7.91(95.21) 2.96(1.77) 7.81(4.76) Blood bilirubin increased 16 6.75(4.12-11.06) 6.72(76.98) 2.73(1.61) 6.65(4.06) Mental status changes* 16 5.92(3.61-9.70) 5.90(64.41) 2.55(1.48) 5.84(3.57) Note: Data in bold indicates AEs which were not included in labels with Pegasparagase. Abbreviations: PT, preferred term; ROR, reporting odds ratio; CI, confidence interval; PRR, proportional reporting ratio; χ2, chi-information component; IC, information component; IC025, the lower limit of 95% CI of the IC; EBGM, empirical Bayesian geometric mean; EBGM05, the lower limit of 95% CI of EBGM. Supplementary Material File (table.docx) Download 36.34 KB Information & Authors Information Version history V1 Version 1 20 January 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Authors Affiliations Wenwen Zhang 0000-0002-0511-4651 Xi'an Jiaotong University View all articles by this author Bin Luo AirForce Medical University View all articles by this author Zhuo Liu Xi'an Jiaotong University View all articles by this author Jie Mi Xi'an Jiaotong University View all articles by this author Yanping Yang AirForce Medical University View all articles by this author Yuan Li 0009-0009-8488-7553 [email protected] Xi'an Jiaotong University View all articles by this author Metrics & Citations Metrics Article Usage 231 views 119 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Wenwen Zhang, Bin Luo, Zhuo Liu, et al. Pancreatitis induced by Pegaspargase in children: a real-world pharmacovigilance analysis based on Food and Drug Administration Adverse Event Reporting System. Authorea . 20 January 2025. 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