Analysis of post-market adverse events of panitumumab: a real-world study base on FAERS database

Analysis of post-market adverse events of panitumumab: a real-world study base on 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 Article Analysis of post-market adverse events of panitumumab: a real-world study base on FAERS database Huocong He, Hongyu Yu, Yile Liu, Yang Huang, Jianru Pan, Shaoli Wang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4624947/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Colorectal cancer (CRC) is a significant public health issue, with metastatic disease posing a considerable challenge despite therapeutic advancements. Panitumumab, an EGFR inhibitor, has been a ray of hope for patients with chemorefractory metastatic CRC. However, understanding the safety profile of panitumumab is crucial for optimizing patient care. Methods: This study leveraged the FDA's Adverse Event Reporting System (FAERS) to scrutinize ADR reports linked to panitumumab from September 27, 2006, to December 31, 2023. Utilizing statistical methods such as Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayes Geometric Mean (EBGM), the study conducted a disproportionality analysis to identify potential safety signals. Results: The analysis of 5,166 ADR reports revealed a significant association between panitumumab and a spectrum of ADRs. Notable adverse events included skin toxicities, hematologic and lymphatic system disorders, gastrointestinal issues, electrolyte imbalances, and neurological reactions. The study also highlighted the need for close monitoring of serious outcomes like hospitalization, death, and life-threatening conditions. Conclusion: The study presents a comprehensive analysis of ADRs associated with panitumumab, emphasizing the necessity for continuous pharmacovigilance and the implementation of strategies to ensure patient safety. The limitations of spontaneous reporting systems are acknowledged, and the call for further research to refine the safety profile of panitumumab is made. Biological sciences/Cancer Biological sciences/Drug discovery Health sciences/Diseases Health sciences/Medical research Health sciences/Risk factors Colorectal cancer panitumumab Adverse drug reactions Pharmacovigilance FAERS (FDA Adverse Event Reporting System) Figures Figure 1 Introductio Colorectal cancer (CRC) is a major public health problem. 1 Colorectal cancer accounts for approximately 10% of all annually diagnosed cancers and cancer-related deaths worldwide. 2 With the highest rates seen in the most developed countries. 3 The most common sites of metastasis include lymph nodes, liver, lung, and peritoneum. 4 Despite recent advances in the management of colorectal cancer, metastatic disease remains challenging, and patients are rarely cured. However, a better understanding of the pathways implicated in the evolution and proliferation of cancer cells has led to the development of targeted therapies, that is, agents with action directed at these pathways/features." 5 EGFR is a significant target in the treatment of colorectal cancer metastases because cancer cells rely on these pathways. Panitumumab (Vectibix; Amgen, South San Francisco, California), an FDA-approved therapy for metastatic colorectal cancer (mCRC), targets this receptor 6 . This human IgG2 monoclonal antibody binds to the extracellular domain of EGFR. Unlike cetuximab, panitumumab does not activate antibody-dependent cell-mediated cytotoxicity 7 . The introduction of targeted therapies, such as the EGFR inhibitor panitumumab, has enhanced the clinical efficacy of chemotherapy in mCRC patients 8 . Van Cutsem et al. demonstrated that panitumumab is effective as a monotherapy for chemorefractory metastatic colorectal cancer (mCRC), showing significant improvements in both progression-free survival and overall response rate compared to best supportive care. 9 Panitumumab has brought hope to patients with chemorefractory metastatic colorectal cancer (mCRC) and has been widely adopted worldwide; thus, its safety has also received significant attention. The Food and Drug Administration (FDA) is an agency of the United States government, under the Department of Health and Human Services, responsible for protecting and promoting public health. To address difficulties in accessing non-confidential FDA data through various modes, the FDA launched the openFDA project in March 2013 (Reference 4). The first priority was databases with a combination of high general consumer interest, low accessibility on www.fda.gov , and high interest on the part of the FDA organization that stewards the database. The objective of openFDA is to facilitate access and use of important FDA public datasets by developers, researchers, and the public through harmonization of data across disparate FDA datasets provided via application programming interfaces (APIs). Four main data sources are currently available in openFDA, including FAERS (FDA Adverse Event Reporting System) for drugs and selected biological products. This study investigated the panitumumab to the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) that collects adverse event (AE) reports from various sources, including healthcare professionals, pharmaceutical manufacturers, and individual patients. The FAERS database follows ICH E2B guidelines and codes adverse events according to MedDRA (Medical Dictionary for Regulatory Activities) concepts. The frequency of reports involves drugs that can cause adverse drug reactions (ADRs), we explore unexpected ADRs which are not described in the drug’s label to provide some guidance for clinical medication precautions. Materials and methods 1.Data source and collection The FAERS data utilized in this study underwent collection and preprocessing procedures employing SAS and MySQL. Data related to ivabradine in FAERS were subjected to duplicate record removal and drug name standardization, with drug names mapped to RxNorm concepts and adverse drug reaction (ADR) outcomes mapped to Medical Dictionary for Regulatory Activities (MedDRA®) concepts. Panitumumab -related ADRs were collected over a eight-year period, spanning from Sep 27, 2006, to December 31, 2023. All preferred terms (PTs) targeting the system organ class (SOC), the highest level of MedDRA hierarchy, were extracted for analysis. 2.Statistical analysis To identify adverse events (AEs) reported more frequently than expected for panitumumab, multiple algorithms were used, including ROR (Reporting Odds Ratio), PRR (Proportional Reporting Ratio), BCPNN (Bayesian Confidence Propagation Neural Network), and EBGM (Empirical Bayes Geometric Mean). These algorithms helped detect significant ADRs (Adverse Drug Reactions). Disproportionality analysis, a widely employed method in pharmacovigilance studies, was conducted to discern potential signals between Panitumumab and adverse drug reactions (ADRs). The study employed four primary statistical methodologies: Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayes Geometric Mean (EBGM), derived from the Gamma-Poisson Shrinker (GPS) model. These methods were utilized to assess the association between Panitumumab and ADRs, aiming to identify potential safety concerns and contribute to the ongoing pharmacovigilance efforts. To be deemed effective, adverse drug reaction (ADR) results needed to satisfy the selection criteria of yielding a positive signal across all four methods concurrently. Data processing and statistical analyses related to Panitumumab were conducted using SAS, MySQL, WPS EXCEL, and R software. The prerequisites for the study are outlined in Table 1 , and the detailed formulas for the four methods employed are provided below: Table 1 Table matrix. Target ADR Non-target ADR Panitumumab a c Non- panitumumab b d Note: Panitumumab is the target drug in this study, we retrieve ivabradine data for analysis. N = a + b + c + d. ADR: adverse drug reaction. (i) ROR algorithm $$ROR=\left(ad\right)/\left(bc\right)$$ $$95\text{\%} CI={e}^{\text{l}\text{n}\left(ROR\right)\pm 1.96\sqrt{\frac{1}{a}+\frac{1}{b}+\frac{1}{c}+\frac{1}{d}}}$$ The criteria of positive safety signal detection: the lower limit of 95% CI > 1, N ≥ 3; (ii) PRR algorithm $$PRR=\left[a\left(c+d\right)\right]/\left[c\left(a+b\right)\right]$$ $${\chi }2=\frac{\left(a+b+c+d\right){(ad-bc)}^{2}}{(a+b)(c+d)(a+c)(b+d)}$$ The criteria of positive safety signal detection: PRR ≥ 2, χ2 ≥ 4, N ≥ 3; (iii) BPCNN algorithm $$IC={\text{log}}_{2}\frac{a\left(a+b+c+d\right)}{\left(a+b\right)\left(a+c\right)}$$ $$95\text{\%} CI=E\left(IC\right)\pm 2\times \sqrt{V\left(IC\right)}$$ The criteria of positive safety signal detection: IC025 > 0 (IC025: the lower bound of 95% CI); (iv) EBGM algorithm $$EBGM=\left(aN\right)/\left[\left(a+b\right)\left(a+c\right)\right]$$ $$95\text{\%} CI={e}^{\text{l}\text{n}\left(EGBM\right)\pm 1.96\sqrt{\frac{1}{a}+\frac{1}{b}+\frac{1}{c}+\frac{1}{d}}}$$ The criteria of positive safety signal detection: EBGM05 > 2 (EBGM05: the lower bound of 95% CI). Results During the study period from September 27, 2006, to December 31, 2023, a comprehensive dataset comprising 4,772,722 case reports from FAERS was analyzed, identifying 5,166 adverse event reports primarily associated with panitumumab after excluding duplicate entries. Among these, 1,780 adverse events (AEs) and 317 adverse drug reactions (ADRs) specifically linked to panitumumab were identified. The fluctuating trend in adverse event reports related to panitumumab is depicted in Fig. 1 . Since panitumumab was approved on September 27, 2006, it did not have the fewest adverse events (AEs) reported in 2007, possibly due to its widespread early adoption after approval. The overall trend fluctuated around 300 AEs but showed an upward trajectory. Exceptions include 197 AEs reported in 2013 and 177 AEs reported in 2020 (the lowest number of AEs reported since panitumumab was approved by the FDA on September 27, 2006). The years 2022 and 2023 also marked new highs in reported AEs. Therefore, monitoring the safety of panitumumab is of crucial significance. Additionally, detailed clinical characteristics of the events associated with panitumumab are described in Table 2 . Table 2 The features of reports associated with panitumumab from September 2006 to December 2023. Panitumumab Case Number Percentage(%) Total counts 5166 Gender Male 2511 78.37% Female 1459 45.54% Unknown 1196 37.33% Age 80 237 7.40% Unknown 2579 80.50% Reported Counties(the top ranked) US (United States) 1763 55.02% JP(Japan) 1041 32.49% FR(France) 230 7.18% DE(Germany) 228 7.12% IT(Italy) 195 6.09% Poland 147 4.59% Spanis 114 3.56% AU(Australia) 104 3.25% CA(Canada) 90 2.81% Turkey 76 2.37% Brazil 53 1.65% Mexico 44 1.37% Russian Federation 27 0.84% Sweden 22 0.69% Norway 16 0.50% India 13 0.41% Egypt 11 0.34% CN(China) 8 0.25% South Africa 6 0.19% Other 766 23.91% Serious Outcomes Congenital Anomaly 1 0.03% Death 825 25.75% Disability 67 2.09% Hospitalization-initial or Prolonged 1601 49.97% Life-threatening 269 8.40% Requred Intervention to Prevent Permanent Impairmnt Damage 4 0.12% Other 2655 74.88% Among the population experiencing all AEs, males (2511, 78.37%) outnumbered females (1459, 45.54%) by a factor of 1.72. Regarding age distribution, each age group, spanning 10 years, exhibited a gradual incline initially, followed by a subsequent decline. The distribution is as follows: <20 (7, 0.22%), 20–29 (12, 0.37%), 30–39 (87, 2.72%), 40–49 (237, 7.40%), 50–59 (513, 16.01%), and 60–69 (807, 25.19%). Subsequently, there was a gradual decrease in the 70–79 age group (687, 21.44%) and > 80 (237, 7.40%). Additionally, the top-ranked countries for panitumumab consumption were the United States (1763, 55.02%), Japan (1041, 32.49%), France (230, 7.18%), Germany (228, 7.12%), Italy (195, 6.09%), Poland (147, 4.59%), Spain (114, 3.56%), Australia (104, 3.25%), Canada (90, 2.81%), Turkey (76, 2.37%), Brazil (53, 1.65%), Mexico (44, 1.37%), Russian Federation (27, 0.84%), Sweden (22, 0.69%), Norway (16, 0.50%), India (13, 0.41%), Egypt (11, 0.34%), China (8, 0.25%), and South Africa (6, 0.19%). The most prevalent AEs were Hospitalization-initial or Prolonged (1,601, 49.97%), accounting for nearly half of all AEs. Following this, the occurrences were death (825, 25.75%), life-threatening (269, 8.40%), and disability (67, 2.09%). The least prevalent were Required Intervention to Prevent Permanent Impairment Damage (4, 0.12%) and disability (1, 0.03%). 3.2. System Organ Class Level-associated signal detections Table 3 presents the results of signal detection analysis for panitumumab at the System Organ Class (SOC) level. It is evident that adverse events (AEs) associated with panitumumab are widespread across 24 organ systems, indicating a relatively common occurrence of panitumumab-related AEs. Notably, the highest number of AEs was observed in "Skin and subcutaneous tissue disorders" (n = 2165), followed by "Gastrointestinal disorders" (n = 874), "General disorders and administration site conditions" (n = 824), "Metabolism and nutrition disorders" (n = 752), "Blood and lymphatic system disorders" (n = 590), "Neoplasms benign, malignant and unspecified (incl cysts and polyps)" (n = 461), "Infections and infestations" (n = 366), "Investigations" (n = 278), "Injury, poisoning and procedural complications" (n = 267), "Nervous system disorders" (n = 234), and "Vascular disorders" (n = 203). Many of these adverse events (AEs) are closely related to the pharmacological mechanisms of panitumumab, including "Skin and subcutaneous tissue disorders," "Gastrointestinal disorders," and "Neoplasms benign, malignant and unspecified (including cysts and polyps)." 3.3 PT level-associated signal detections Table 4 offers comprehensive statistics regarding 50 Preferred Terms (PTs) delineating adverse drug reactions (ADRs) associated with panitumumab therapy. Comprehensive data are provided in Supplemental Table 1. These ADRs are meticulously ranked based on case numbers, furnishing healthcare professionals with detailed insights to anticipate, identify, and effectively manage potential adverse reactions linked to panitumumab utilization. Such data empowers healthcare practitioners with valuable information essential for optimizing patient care during panitumumab treatment. Table 3 Signal strength of AEs of panitumumab at the System Organ Class (SOC) level in FDA Adverse Event Reporting System (FAERS) source System Organ Class SOC Code Case Number ROR(95%CI) PRR(95%CI) χ2 IC(IC025) EBGM(EBGM05) Skin and subcutaneous tissue disorders 10040785 2165 16.35 (15.47–17.28) 9.92 (9.60-10.24) 18042.45 3.30 (3.13) 9.88 (9.34) Gastrointestinal disorders 10017947 874 5.90 (5.48–6.34) 5.07 (4.77–5.38) 2946.41 2.34 (2.10) 5.06 (4.70) General disorders and administration site conditions 10018065 824 6.97 (6.47–7.51) 6.02 (5.65–6.41) 3530.93 2.59 (2.34) 6.00 (5.57) Metabolism and nutrition disorders 10027433 752 9.29 (8.60-10.04) 8.08 (7.56–8.63) 4734.82 3.01 (2.75) 8.06 (7.46) Blood and lymphatic system disorders 10005329 590 6.16 (5.65–6.71) 5.57 (5.16–6.01) 2252.42 2.47 (2.19) 5.56 (5.10) Neoplasms benign, malignant and unspecified (incl cysts and polyps) 10029104 461 15.15 (13.77–16.68) 13.89 (12.73–15.16) 5514.64 3.79 (3.47) 13.81 (12.54) Infections and infestations 10021881 366 11.14 (10.02–12.39) 10.42 (9.44–11.51) 3124.26 3.38 (3.02) 10.38 (9.33) Investigations 10022891 278 10.20 (9.04–11.51) 9.71 (8.65–10.88) 2173.18 3.27 (2.87) 9.67 (8.56) Injury, poisoning and procedural complications 10022117 267 6.06 (5.35–6.85) 5.80 (5.16–6.51) 1066.26 2.53 (2.12) 5.78 (5.11) Nervous system disorders 10029205 234 10.43 (9.14–11.89) 10.00 (8.82–11.34) 1895.11 3.32 (2.88) 9.96 (8.73) Vascular disorders 10047065 203 5.69 (4.94–6.54) 5.50 (4.81–6.30) 751.29 2.46 (1.99) 5.49 (4.77) Immune system disorders 10021428 184 10.75 (9.28–12.46) 10.40 (9.02–11.99) 1561.87 3.37 (2.88) 10.36 (8.94) Hepatobiliary disorders 10019805 151 9.88 (8.40-11.62) 9.62 (8.22–11.27) 1165.33 3.26 (2.72) 9.59 (8.15) Eye disorders 10015919 96 17.89 (14.61–21.92) 17.58 (14.41–21.45) 1490.84 4.13 (3.46) 17.45 (14.25) Respiratory, thoracic and mediastinal disorders 10038738 84 7.23 (5.83–8.97) 7.13 (5.76–8.82) 442.12 2.83 (2.12) 7.11 (5.73) Surgical and medical procedures 10042613 48 3.64 (2.74–4.84) 3.62 (2.73–4.80) 91.00 1.85 (0.93) 3.61 (2.72) Renal and urinary disorders 10038359 31 5.52 (3.88–7.86) 5.49 (3.87–7.81) 113.75 2.45 (1.32) 5.48 (3.85) Congenital, familial and genetic disorders 10010331 28 33.37 (22.95–48.51) 33.19 (22.88–48.16) 861.27 5.03 (3.83) 32.71 (22.5) Cardiac disorders 10007541 21 3.70 (2.41–5.68) 3.69 (2.41–5.65) 41.12 1.88 (0.53) 3.68 (2.40) Social circumstances 10041244 9 6.69 (3.47–12.87) 6.68 (3.47–12.84) 43.33 2.74 (0.78) 6.66 (3.46) Reproductive system and breast disorders 10038604 6 13.82 (6.19–30.86) 13.81 (6.19–30.79) 70.83 3.78 (1.48) 13.73 (6.15) Product issues 10077536 5 5.85 (2.43–14.08) 5.85 (2.43–14.06) 20.04 2.54 (0.09) 5.83 (2.42) Endocrine disorders 10014698 4 14.34 (5.36–38.36) 14.33 (5.36–38.30) 49.29 3.83 (1.17) 14.25 (5.33) Footnotes: SOC, System Organ Class; ROR, Reporting Odds Ratio; CI, Confidence Interval; PRR, Proportional Reporting Ratio; χ2, Chi-squared; IC, Information Component; EBGM, Empirical Bayesian Geometric Mean Table 4 The top 50 signal strength of AEs of Panitumumab ranked by Case Number at the Preferred Terms level in FDA Adverse Event Reporting System (FAERS) source. System Organ Class PTs Case Number ROR (95%CI) PRR (95%CI) χ2 IC (IC025) EBGM (EBGM05) Skin and subcutaneous tissue disorders rash 675 7.95 (7.33–8.62) 7.04 (6.56–7.56) 3555.39 2.81 (2.54) 7.02 (6.48) Gastrointestinal disorders diarrhoea 482 3.94 (3.59–4.32) 3.66 (3.36–3.99) 956.01 1.87 (1.56) 3.66 (3.33) Metabolism and nutrition disorders hypomagnesaemia 283 111.32 (98.48-125.83) 105.28 (93.74-118.24) 27902.19 6.65 (6.24) 100.49 (88.9) General disorders and administration site conditions disease progression 255 9.52 (8.39–10.80) 9.10 (8.07–10.26) 1839.88 3.18 (2.76) 9.06 (7.99) Skin and subcutaneous tissue disorders dermatitis acneiform 254 261.68 (229.15-298.84) 248.86 (219.21-282.53) 56307.74 7.80(7.36) 223.53 (195.74) Blood and lymphatic system disorders neutropenia 240 8.77 (7.70–9.98) 8.41 (7.43–9.51) 1568.71 3.07 (2.63) 8.38 (7.36) Skin and subcutaneous tissue disorders skin toxicity 231 233.84 (203.65–268.50) 223.43 (195.68-255.11) 46417.15 7.66 (7.20) 202.80 (176.62) Neoplasms benign, malignant and unspecified (incl cysts and polyps) colorectal cancer metastatic 177 685.97 (578.47-813.45) 662.51 (561.20-782.09) 89723.84 8.99 (8.44) 508.65 (428.94) Infections and infestations paronychia 166 242.47 (206.11-285.24) 234.71 (200.46-274.81) 34889.79 7.73 (7.19) 212.05 (180.25) General disorders and administration site conditions pyrexia 164 2.53 (2.17–2.96) 2.48 (2.13–2.89) 146.8 1.31 (0.79) 2.48 (2.12) Metabolism and nutrition disorders decreased appetite 158 3.42 (2.92–4.01) 3.35 (2.87–3.91) 262.3 1.74 (1.22) 3.35 (2.85) Gastrointestinal disorders stomatitis 153 13.35 (11.36–15.68) 12.98 (11.10-15.18) 1685.68 3.69 (3.15) 12.91 (10.99) Nervous system disorders neuropathy peripheral 152 7.89 (6.71–9.27) 7.68 (6.57–8.99) 883.99 2.94 (2.40) 7.66 (6.52) Metabolism and nutrition disorders dehydration 148 6.15 (5.22–7.24) 6.00 (5.12–7.03) 617.85 2.58 (2.04) 5.99 (5.08) Skin and subcutaneous tissue disorders dry skin 136 9.50 (8.01–11.27) 9.28 (7.86–10.95) 1002.75 3.21 (2.64) 9.24 (7.79) Immune system disorders interstitial lung disease 121 13.15 (10.98–15.76) 12.87 (10.78–15.35) 1319.12 3.68 (3.08) 12.80 (10.68) General disorders and administration site conditions febrile neutropenia 120 10.61 (8.85–12.72) 10.39 (8.70–12.40) 1015.62 3.37 (2.77) 10.34 (8.63) Blood and lymphatic system disorders anaemia 120 3.34 (2.79-4.00) 3.28 (2.75–3.92) 191.7 1.71 (1.11) 3.28 (2.74) Skin and subcutaneous tissue disorders skin disorder 119 16.74 (13.95–20.09) 16.38 (13.70-19.58) 1708.05 4.02 (3.42) 16.27 (13.55) Blood and lymphatic system disorders thrombocytopenia 110 5.17 (4.28–6.25) 5.08 (4.22–6.11) 361.15 2.34 (1.72) 5.07 (4.20) Skin and subcutaneous tissue disorders erythema 100 2.99 (2.45–3.65) 2.95 (2.43–3.59) 129.84 1.56 (0.91) 2.95 (2.42) Skin and subcutaneous tissue disorders skin reaction 97 33.51 (27.37–41.03) 32.90 (26.98–40.13) 2957.82 5.02 (4.35) 32.43 (26.49) Neoplasms benign, malignant and unspecified (incl cysts and polyps) colon cancer 96 26.76 (21.84–32.79) 26.28 (21.53–32.08) 2308.45 4.70 (4.03) 25.98 (21.2) General disorders and administration site conditions therapy partial responder 93 39.25 (31.91–48.27) 38.56 (31.47–47.25) 3345.09 5.24 (4.56) 37.91 (30.82) Injury, poisoning and procedural complications product storage error 91 3.83 (3.11–4.71) 3.78 (3.08–4.63) 186.27 1.92 (1.23) 3.77 (3.06) Investigations neutrophil count decreased 90 11.57 (9.39–14.26) 11.39 (9.27–13.98) 849.43 3.50 (2.81) 11.33 (9.19) Vascular disorders pulmonary embolism 86 4.01 (3.24–4.96) 3.96 (3.21–4.88) 190.34 1.98 (1.28) 3.95 (3.19) Hepatobiliary disorders metastases to liver 81 23.24 (18.64–28.98) 22.89 (18.42–28.44) 1679.25 4.50 (3.78) 22.66 (18.18) Skin and subcutaneous tissue disorders rash pustular 78 54.51 (43.47–68.35) 53.70 (42.97–67.11) 3938.51 5.71 (4.97) 52.44 (41.82) Injury, poisoning and procedural complications circumstance or information capable of leading to medication error 78 9.38 (7.50-11.73) 9.25 (7.42–11.54) 572.51 3.2 0(2.47) 9.22 (7.37) General disorders and administration site conditions mucosal inflammation 74 15.43 (12.26–19.43) 15.22 (12.13–19.10) 977.57 3.92 (3.16) 15.13 (12.01) Neoplasms benign, malignant and unspecified (incl cysts and polyps) malignant neoplasm progression 71 3.28 (2.60–4.15) 3.25 (2.58–4.10) 110.88 1.70 (0.93) 3.25 (2.57) General disorders and administration site conditions general physical health deterioration 69 3.30 (2.60–4.19) 3.27 (2.59–4.14) 109.09 1.71 (0.93) 3.27 (2.58) Investigations blood magnesium decreased 68 46.69 (36.67–59.46) 46.09 (36.31–58.51) 2938.52 5.50 (4.70) 45.16 (35.46) Immune system disorders infusion related reaction 63 7.69 (5.99–9.86) 7.61 (5.95–9.72) 360.75 2.92 (2.11) 7.58 (5.91) Skin and subcutaneous tissue disorders acne 61 7.95 (6.18–10.24) 7.87 (6.13–10.11) 365.19 2.97 (2.14) 7.85 (6.09) Metabolism and nutrition disorders hypocalcaemia 60 15.62 (12.10-20.17) 15.45 (12.00-19.89) 805.79 3.94 (3.10) 15.35 (11.89) Metabolism and nutrition disorders hypokalaemia 60 7.18 (5.57–9.27) 7.11 (5.53–9.15) 314.5 2.83 (1.99) 7.09 (5.49) Infections and infestations sepsis 59 2.73 (2.11–3.52) 2.71 (2.10–3.49) 63.63 1.43 (0.60) 2.70 (2.09) Skin and subcutaneous tissue disorders skin fissures 52 20.08 (15.26–26.42) 19.89 (15.16–26.09) 924.73 4.3 (3.41) 19.72 (14.98) Blood and lymphatic system disorders leukopenia 51 5.44 (4.12–7.16) 5.39 (4.10–7.09) 182.33 2.43 (1.53) 5.38 (4.08) Eye disorders conjunctivitis 47 13.12 (9.84–17.50) 13.01 (9.78–17.31) 518.42 3.69 (2.76) 12.94 (9.70) Infections and infestations folliculitis 46 43.27 (32.28–58.01) 42.90 (32.08–57.36) 1846.51 5.40 (4.44) 42.09 (31.4) Skin and subcutaneous tissue disorders palmar-plantar erythrodysaesthesia syndrome 46 8.37 (6.26–11.20) 8.31 (6.23–11.08) 294.75 3.05 (2.10) 8.28 (6.19) Nervous system disorders peripheral sensory neuropathy 43 41.49 (30.65–56.17) 41.15 (30.47–55.58) 1653.83 5.34 (4.35) 40.41 (29.85) Gastrointestinal disorders intestinal obstruction 38 5.55 (4.03–7.64) 5.52 (4.02–7.57) 140.33 2.46 (1.43) 5.50 (4.00) Skin and subcutaneous tissue disorders skin exfoliation 37 3.21 (2.32–4.44) 3.19 (2.32–4.40) 55.8 1.67 (0.63) 3.19 (2.31) Respiratory, thoracic and mediastinal disorders metastases to lung 36 15.43 (11.11–21.44) 15.33 (11.06–21.25) 479.11 3.93 (2.87) 15.23 (10.96) Surgical and medical procedures surgery 36 2.80 (2.02–3.89) 2.79 (2.01–3.86) 41.38 1.48 (0.42) 2.79 (2.01) Skin and subcutaneous tissue disorders dermatitis 34 9.58 (6.84–13.44) 9.53 (6.81–13.33) 258.54 3.25 (2.16) 9.49 (6.77) Footnotes: SOC, System Organ Class; ROR, Reporting Odds Ratio; CI, Confidence Interval; PRR, Proportional Reporting Ratio; χ2, Chi-squared; IC, Information Component; EBGM, Empirical Bayesian Geometric Mean The top five preferred terms (PTs) associated with panitumumab are as follows: rash (n = 675, IC025 = 2.81 (2.54)), diarrhoea (n = 482, IC025 = 1.87 (1.56)), hypomagnesaemia (n = 283, IC025 = 6.65 (6.24)), disease progression (n = 255, IC025 = 3.18 (2.76)), and dermatitis acneiform (n = 254, IC025 = 7.80(7.36)). Additionally, the top five PTs of panitumumab ranked by IC025 value are trichomegaly (n = 13, IC025 = 9.07 (7.15)), colorectal cancer metastatic (n = 177, IC025 = 8.99 (8.44)), colorectal cancer recurrent (n = 10, IC025 = 8.72 (6.62)), dermatitis acneiform (n = 254, IC025 = 7.8 (7.36)) and paronychia (n = 166, IC025 = 7.73 (7.19)). Discussion This real-world evidence study conducted a comprehensive analysis of 317 adverse drug reaction (ADR) reports associated with panitumumab use. Notably, the number of ADR cases in males was significantly higher than in females. This disparity could be attributed to a higher number of males taking panitumumab or to metabolic differences in drug response between genders. Previous studies have not reported a higher overall incidence of ADRs in males compared to females, only noting gender differences in specific symptoms 10,11 or PMIDa higher total number of ADRs in females. Therefore, the finding that males experience more ADRs than females warrants further investigation. The reports indicate that ADRs increase with age up to 70 years, peaking in the 60–69 age group, and then gradually decrease. Overall, the number of ADR reports is significantly higher in individuals over 40 years old compared to those under 40. This trend may be due to the larger population of patients over 40 years old taking the medication, highlighting the need for special monitoring of patients in this age group. In contrast, younger patients are fewer in number and thus have fewer reports of ADRs. The increasing trend of ADRs with age up to 70 years suggests that older age groups are more susceptible to these reactions. The subsequent decline in ADRs after 70 years of age may be due to a slower metabolism in this age group, resulting in fewer ADRs. There were notable differences in ADR reports across countries and regions. For instance, Japan reported the second-highest number of cases after the United States. This may be because panitumumab was introduced in Japan relatively early, in 2009, and the larger patient population in Japan might contribute to the higher number of ADR cases. In contrast, China reported only six ADR cases, possibly because panitumumab is not marketed in China and may not be a first-line treatment option. Among the reported ADRs, "Hospitalization-initial or Prolonged" was the most common, accounting for 1601 cases (49.97%), followed by "Death" with 825 cases (25.75%), and "Life-threatening" with 269 cases. This indicates the severity of the adverse events caused by panitumumab, which is particularly concerning. Additionally, the data presented may be affected by differences in reporting systems and cultural factors. Various countries have differing levels of effectiveness in their systems for reporting medication adverse effects, as well as different degrees of focus on medication safety and the monitoring of adverse reactions by regulatory authorities. Skin toxicities from EGFR inhibitors (EGFRIs) include pruritus, acneiform dermatitis, skin desquamation, paronychia, and pustular rash 12 . These typically manifest early in therapy, with subsequent complications such as skin infections and ulceration 13 . UV radiation exacerbates these effects by heightening keratinocyte apoptosis sensitivity in sun-exposed areas 14–16 . Due to their frequent occurrence in adverse event reports from FAERS, monitoring is particularly crucial 17–19 . 18 Panitumumab has been associated with adverse reactions in the blood and lymphatic systems, including hypomagnesemia (283 cases), hypocalcemia (60 cases), and hypokalemia (60 cases). Additionally, numerous specific adverse reactions have been reported in the hematologic system, such as neutropenia (240 cases), febrile neutropenia (120 cases), anemia (120 cases), thrombocytopenia (110 cases), and leukopenia (51 cases). Febrile neutropenia (FN) is particularly notable as a severe adverse reaction, defined as an oral temperature > 38.3°C or two consecutive readings > 38.0°C for 2 hours, with an absolute neutrophil count (ANC) < 0.5 × 10 9 /L 20 . The use of anti-EGFR monoclonal antibodies has been associated with a significant increase in grades 3–4 infections or febrile neutropenia 21 . Chemotherapy-induced neutropenia and FN are also critical dose-limiting side effects, often necessitating treatment adjustments that may impact outcomes 22,23 . FN is known for its substantial morbidity, mortality, and healthcare costs 20,24,25 . Therefore, clinicians must be vigilant about this serious adverse effect and implement appropriate prevention and monitoring measures. In the real world, various adverse reactions related to the digestive system have also been reported, as detailed in drug labeling, including diarrhea (482 cases), oral mucositis (153 cases), and anorexia (158 cases). Specific instances observed include intestinal obstruction (38 cases), ileus (25 cases), intestinal perforation (20 cases), small intestinal obstruction (16 cases), and gastrointestinal perforation (15 cases). Ascites (21 cases) is also documented. Special attention should be given to intestinal obstruction, intestinal perforation, and gastrointestinal perforation, as these are serious clinical symptoms that may occur during the course of rectal cancer. Research has reported that panitumumab can cause the serious complication of intestinal obstruction 26 . However, there are no specific reports of panitumumab causing intestinal perforation or gastrointestinal perforation. Additionally, although the use of targeted therapies can potentially reduce metastases, these agents can also affect the normal adjacent liver parenchyma, leading to hepatotoxicity 27 . Adverse reactions affecting the hepatic and biliary systems in the real world include hepatic failure (25 cases), veno-occlusive liver disease (8 cases), hepatic fibrosis (5 cases), liver abscess (5 cases), cholestatic jaundice (5 cases), and biliary obstruction (4 cases). Special emphasis is warranted for hepatic failure (25 cases), veno-occlusive liver disease (8 cases), and liver abscess (5 cases). Polyneuropathy is a disabling condition of the peripheral nerves, characterized by symmetrical distal numbness, paresthesia, pain, and weakness, primarily in the arms and legs. It negatively impacts quality of life 28 . Elderly individuals are at higher risk for developing polyneuropathy and related injuries from falls 29 . Therefore, special attention should be given to this adverse drug reaction. Among the side effects of panitumumab treatment, a significant number of neurological adverse reactions have been reported, including peripheral neuropathy (152 cases), polyneuropathy (30 cases), and peripheral sensory neuropathy (43 cases). Notably, polyneuropathy, which is a severe condition affecting multiple nerves, warrants further investigation to determine the drug's role in this adverse reaction. The occurrence of these adverse reactions serves as a reminder and warning for users of panitumumab, especially in countries or regions where the drug has recently been introduced. It aims to alert healthcare providers and patients about potential risks associated with its use. It's important to note limitations in the FAERS (FDA Adverse Event Reporting System) as a spontaneous reporting system, which may have inherent biases in the reported data. Conclusion This study conducted a comprehensive analysis of adverse drug reactions (ADRs) associated with panitumumab, revealing predominant effects on the skin, hematologic and lymphatic systems, digestive system, electrolyte imbalances, systemic reactions, respiratory system, cardiovascular system, and nervous system. Common adverse reactions included serious events such as intestinal obstruction, intestinal perforation, and hepatic failure, underscoring the critical need for vigilance in monitoring and managing these risks. The study relied on data from the FDA Adverse Event Reporting System (FAERS), acknowledging limitations inherent to spontaneous reporting databases. Future research is essential to accurately assess panitumumab's safety profile, ensuring patients receive effective and safe treatment. Declarations CRediT authorship contribution statement Huocong He : Writing – review & editing, Writing – original draft, Supervision. Hongyu Yu : Writing – original draft, Formal analysis. Yile Liu : Writing – review & editing, Validation, Data curation. Yang Huang : Validation, Data curation. Jianru Pan : Validation, Data curation. Shaoli Wang : Supervision, Methodology. Declaration of competing 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. Author Contribution H.H. and Y.L. wrote the main manuscript text. H.Y. performed formal analysis. Y.L. conducted validation and data curation. Y.H. and J.P. contributed to validation and data curation. S.W. supervised the project and contributed to methodology. All authors reviewed the manuscript. Data Availability The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. References Siegel, R. L. et al. Colorectal cancer statistics, 2020. CA Cancer J Clin 70 , 145-164, doi:10.3322/caac.21601 (2020). Bray, F. et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68 , 394-424, doi:10.3322/caac.21492 (2018). Dekker, E., Tanis, P. J., Vleugels, J. L. A., Kasi, P. M. & Wallace, M. B. Colorectal cancer. Lancet 394 , 1467-1480, doi:10.1016/s0140-6736(19)32319-0 (2019). Riihimäki, M., Hemminki, A., Sundquist, J. & Hemminki, K. Patterns of metastasis in colon and rectal cancer. Sci Rep 6 , 29765, doi:10.1038/srep29765 (2016). Piawah, S. & Venook, A. P. Targeted therapy for colorectal cancer metastases: A review of current methods of molecularly targeted therapy and the use of tumor biomarkers in the treatment of metastatic colorectal cancer. Cancer 125 , 4139-4147, doi:10.1002/cncr.32163 (2019). Chan, D. L. H. et al. Epidermal growth factor receptor (EGFR) inhibitors for metastatic colorectal cancer. Cochrane Database Syst Rev 6 , Cd007047, doi:10.1002/14651858.CD007047.pub2 (2017). Yarom, N. & Jonker, D. J. The role of the epidermal growth factor receptor in the mechanism and treatment of colorectal cancer. Discov Med 11 , 95-105 (2011). Chu, E. An update on the current and emerging targeted agents in metastatic colorectal cancer. Clin Colorectal Cancer 11 , 1-13, doi:10.1016/j.clcc.2011.05.005 (2012). Van Cutsem, E. et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 25 , 1658-1664, doi:10.1200/jco.2006.08.1620 (2007). Heinrich, K. et al. Impact of sex on the efficacy and safety of panitumumab plus fluorouracil and folinic acid versus fluorouracil and folinic acid alone as maintenance therapy in RAS WT metastatic colorectal cancer (mCRC). Subgroup analysis of the PanaMa-study (AIO-KRK-0212). ESMO Open 8 , 101568, doi:10.1016/j.esmoop.2023.101568 (2023). Raimondi, A. et al. Early onset metastatic colorectal cancer in patients receiving panitumumab-based upfront strategy: Overall and sex-specific outcomes in the Valentino trial. Int J Cancer 151 , 1760-1769, doi:10.1002/ijc.34156 (2022). Cunningham, D. et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351 , 337-345, doi:10.1056/NEJMoa033025 (2004). Busam, K. J. et al. Cutaneous side-effects in cancer patients treated with the antiepidermal growth factor receptor antibody C225. Br J Dermatol 144 , 1169-1176, doi:10.1046/j.1365-2133.2001.04226.x (2001). Luu, M., Lai, S. E., Patel, J., Guitart, J. & Lacouture, M. E. Photosensitive rash due to the epidermal growth factor receptor inhibitor erlotinib. Photodermatol Photoimmunol Photomed 23 , 42-45, doi:10.1111/j.1600-0781.2007.00273.x (2007). Jost, M., Gasparro, F. P., Jensen, P. J. & Rodeck, U. Keratinocyte apoptosis induced by ultraviolet B radiation and CD95 ligation -- differential protection through epidermal growth factor receptor activation and Bcl-x(L) expression. J Invest Dermatol 116 , 860-866, doi:10.1046/j.1523-1747.2001.01356.x (2001). Jacot, W. et al. Acneiform eruption induced by epidermal growth factor receptor inhibitors in patients with solid tumours. Br J Dermatol 151 , 238-241, doi:10.1111/j.1365-2133.2004.06026.x (2004). Wagner, L. I. & Lacouture, M. E. Dermatologic toxicities associated with EGFR inhibitors: the clinical psychologist's perspective. Impact on health-related quality of life and implications for clinical management of psychological sequelae. Oncology (Williston Park) 21 , 34-36 (2007). Eilers, R. E., Jr. et al. Dermatologic infections in cancer patients treated with epidermal growth factor receptor inhibitor therapy. J Natl Cancer Inst 102 , 47-53, doi:10.1093/jnci/djp439 (2010). Boone, S. L. et al. Impact and management of skin toxicity associated with anti-epidermal growth factor receptor therapy: survey results. Oncology 72 , 152-159, doi:10.1159/000112795 (2007). Lyman, G. H. et al. Risk of mortality in patients with cancer who experience febrile neutropenia. Cancer 116 , 5555-5563, doi:10.1002/cncr.25332 (2010). Funakoshi, T., Suzuki, M. & Tamura, K. Infectious complications in cancer patients treated with anti-EGFR monoclonal antibodies cetuximab and panitumumab: a systematic review and meta-analysis. Cancer Treat Rev 40 , 1221-1229, doi:10.1016/j.ctrv.2014.09.002 (2014). Crawford, J. et al. Risk and timing of neutropenic events in adult cancer patients receiving chemotherapy: the results of a prospective nationwide study of oncology practice. J Natl Compr Canc Netw 6 , 109-118, doi:10.6004/jnccn.2008.0012 (2008). Chang, J. Chemotherapy dose reduction and delay in clinical practice. evaluating the risk to patient outcome in adjuvant chemotherapy for breast cancer. Eur J Cancer 36 Suppl 1 , S11-14, doi:10.1016/s0959-8049(99)00259-2 (2000). Crawford, J., Dale, D. C. & Lyman, G. H. Chemotherapy-induced neutropenia: risks, consequences, and new directions for its management. Cancer 100 , 228-237, doi:10.1002/cncr.11882 (2004). Kuderer, N. M., Dale, D. C., Crawford, J., Cosler, L. E. & Lyman, G. H. Mortality, morbidity, and cost associated with febrile neutropenia in adult cancer patients. Cancer 106 , 2258-2266, doi:10.1002/cncr.21847 (2006). Piringer, G. et al. LM02 trial Perioperative treatment with panitumumab and FOLFIRI in patients with wild-type RAS, potentially resectable colorectal cancer liver metastases-a phase II study. Front Oncol 13 , 1231600, doi:10.3389/fonc.2023.1231600 (2023). Di Fiore, F. & Van Cutsem, E. Acute and long-term gastrointestinal consequences of chemotherapy. Best Pract Res Clin Gastroenterol 23 , 113-124, doi:10.1016/j.bpg.2008.11.016 (2009). Teunissen, L. L., Eurelings, M., Notermans, N. C., Hop, J. W. & van Gijn, J. Quality of life in patients with axonal polyneuropathy. J Neurol 247 , 195-199, doi:10.1007/s004150050562 (2000). England, J. D. & Asbury, A. K. Peripheral neuropathy. Lancet 363 , 2151-2161, doi:10.1016/s0140-6736(04)16508-2 (2004). Additional Declarations No competing interests reported. Supplementary Files SupplementalTable1.xlsx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4624947","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":329375622,"identity":"a06de573-13cb-4ac8-919a-fab3e2ce46c7","order_by":0,"name":"Huocong He","email":"","orcid":"","institution":"Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital","correspondingAuthor":false,"prefix":"","firstName":"Huocong","middleName":"","lastName":"He","suffix":""},{"id":329375623,"identity":"69f2ebe2-6bd6-4b7f-acc7-35f4453b1693","order_by":1,"name":"Hongyu Yu","email":"","orcid":"","institution":"Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Hongyu","middleName":"","lastName":"Yu","suffix":""},{"id":329375624,"identity":"27c659e8-5fce-49e6-8c35-7b578e7f2a03","order_by":2,"name":"Yile Liu","email":"","orcid":"","institution":"HuiHua College of Hebei Normal University","correspondingAuthor":false,"prefix":"","firstName":"Yile","middleName":"","lastName":"Liu","suffix":""},{"id":329375625,"identity":"91a2cc29-7bc2-49db-b886-d93f73eb90e7","order_by":3,"name":"Yang Huang","email":"","orcid":"","institution":"Chinese Academy of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Yang","middleName":"","lastName":"Huang","suffix":""},{"id":329375626,"identity":"87fca188-f658-4d14-ab37-5681df4eaf75","order_by":4,"name":"Jianru Pan","email":"","orcid":"","institution":"Fuzhou University","correspondingAuthor":false,"prefix":"","firstName":"Jianru","middleName":"","lastName":"Pan","suffix":""},{"id":329375627,"identity":"fe737b70-2553-474b-86a9-d32e26bf8da6","order_by":5,"name":"Shaoli Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyElEQVRIiWNgGAWjYNCCAgYGfmbmgw9I0GLAwCDZzpZsQJoWg/M8ZgLEKT5+9vDLHwZ1iZsPM5gxMNTYRBPWciYvzZrHgC1x22GGtAcMx9JyGwhpMTuQY2bMYMAD0nLcgLHhMBFazr8xM/xhIJG4uZmxTYI4LTdyjB/wGBgkbmBmZiNOi/2NN2bMPAYJxjMOszEbJBDjF8n+HOOPPyrqZPv7z3988KHGhrAWIGCTABKOYJUJRCgHAeYPIAcSqXgUjIJRMApGIgAAN14+Uwygl6gAAAAASUVORK5CYII=","orcid":"","institution":"Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital","correspondingAuthor":true,"prefix":"","firstName":"Shaoli","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2024-06-23 11:02:02","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4624947/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4624947/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":60811559,"identity":"1eb7663f-3013-4798-89b2-7d010923ca0b","added_by":"auto","created_at":"2024-07-22 10:56:50","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":49071,"visible":true,"origin":"","legend":"\u003cp\u003eTrend of annual adverse event reports of panitumumab\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4624947/v1/8d79fd2ca1a59c2af099fcc6.png"},{"id":67618317,"identity":"21dcf759-014c-4b14-ab50-55f6cdc1eace","added_by":"auto","created_at":"2024-10-28 06:47:09","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1083667,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4624947/v1/fc1b6071-eb8b-451d-9401-3f884cf86a7a.pdf"},{"id":60811560,"identity":"29e53aaa-0363-478b-8624-f9ac289c16a7","added_by":"auto","created_at":"2024-07-22 10:56:50","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":82978,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalTable1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-4624947/v1/24ac3b29326d8446b7595f1a.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Analysis of post-market adverse events of panitumumab: a real-world study base on FAERS database","fulltext":[{"header":"Introductio","content":"\u003cp\u003eColorectal cancer (CRC) is a major public health problem. \u003csup\u003e1\u003c/sup\u003eColorectal cancer accounts for approximately 10% of all annually diagnosed cancers and cancer-related deaths worldwide. \u003csup\u003e2\u003c/sup\u003eWith the highest rates seen in the most developed countries. \u003csup\u003e3\u003c/sup\u003eThe most common sites of metastasis include lymph nodes, liver, lung, and peritoneum. \u003csup\u003e4\u003c/sup\u003eDespite recent advances in the management of colorectal cancer, metastatic disease remains challenging, and patients are rarely cured. However, a better understanding of the pathways implicated in the evolution and proliferation of cancer cells has led to the development of targeted therapies, that is, agents with action directed at these pathways/features.\" \u003csup\u003e5\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eEGFR is a significant target in the treatment of colorectal cancer metastases because cancer cells rely on these pathways. Panitumumab (Vectibix; Amgen, South San Francisco, California), an FDA-approved therapy for metastatic colorectal cancer (mCRC), targets this receptor \u003csup\u003e6\u003c/sup\u003e. This human IgG2 monoclonal antibody binds to the extracellular domain of EGFR. Unlike cetuximab, panitumumab does not activate antibody-dependent cell-mediated cytotoxicity\u003csup\u003e7\u003c/sup\u003e. The introduction of targeted therapies, such as the EGFR inhibitor panitumumab, has enhanced the clinical efficacy of chemotherapy in mCRC patients\u003csup\u003e8\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eVan Cutsem et al. demonstrated that panitumumab is effective as a monotherapy for chemorefractory metastatic colorectal cancer (mCRC), showing significant improvements in both progression-free survival and overall response rate compared to best supportive care. \u003csup\u003e\u003cb\u003e9\u003c/b\u003e\u003c/sup\u003ePanitumumab has brought hope to patients with chemorefractory metastatic colorectal cancer (mCRC) and has been widely adopted worldwide; thus, its safety has also received significant attention.\u003c/p\u003e \u003cp\u003eThe Food and Drug Administration (FDA) is an agency of the United States government, under the Department of Health and Human Services, responsible for protecting and promoting public health. To address difficulties in accessing non-confidential FDA data through various modes, the FDA launched the openFDA project in March 2013 (Reference 4). The first priority was databases with a combination of high general consumer interest, low accessibility on \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e\u003ca href=\"http://www.fda.gov\" target=\"_blank\"\u003ewww.fda.gov\u003c/a\u003e\u003c/span\u003e\u003cspan address=\"http://www.fda.gov\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e, and high interest on the part of the FDA organization that stewards the database. The objective of openFDA is to facilitate access and use of important FDA public datasets by developers, researchers, and the public through harmonization of data across disparate FDA datasets provided via application programming interfaces (APIs). Four main data sources are currently available in openFDA, including FAERS (FDA Adverse Event Reporting System) for drugs and selected biological products.\u003c/p\u003e \u003cp\u003eThis study investigated the panitumumab to the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) that collects adverse event (AE) reports from various sources, including healthcare professionals, pharmaceutical manufacturers, and individual patients. The FAERS database follows ICH E2B guidelines and codes adverse events according to MedDRA (Medical Dictionary for Regulatory Activities) concepts. The frequency of reports involves drugs that can cause adverse drug reactions (ADRs), we explore unexpected ADRs which are not described in the drug\u0026rsquo;s label to provide some guidance for clinical medication precautions.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003e1.Data source and collection\u003c/p\u003e \u003cp\u003eThe FAERS data utilized in this study underwent collection and preprocessing procedures employing SAS and MySQL. Data related to ivabradine in FAERS were subjected to duplicate record removal and drug name standardization, with drug names mapped to RxNorm concepts and adverse drug reaction (ADR) outcomes mapped to Medical Dictionary for Regulatory Activities (MedDRA\u0026reg;) concepts. Panitumumab -related ADRs were collected over a eight-year period, spanning from Sep 27, 2006, to December 31, 2023. All preferred terms (PTs) targeting the system organ class (SOC), the highest level of MedDRA hierarchy, were extracted for analysis.\u003c/p\u003e \u003cp\u003e2.Statistical analysis\u003c/p\u003e \u003cp\u003eTo identify adverse events (AEs) reported more frequently than expected for panitumumab, multiple algorithms were used, including ROR (Reporting Odds Ratio), PRR (Proportional Reporting Ratio), BCPNN (Bayesian Confidence Propagation Neural Network), and EBGM (Empirical Bayes Geometric Mean). These algorithms helped detect significant ADRs (Adverse Drug Reactions).\u003c/p\u003e \u003cp\u003eDisproportionality analysis, a widely employed method in pharmacovigilance studies, was conducted to discern potential signals between Panitumumab and adverse drug reactions (ADRs). The study employed four primary statistical methodologies: Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayes Geometric Mean (EBGM), derived from the Gamma-Poisson Shrinker (GPS) model. These methods were utilized to assess the association between Panitumumab and ADRs, aiming to identify potential safety concerns and contribute to the ongoing pharmacovigilance efforts. To be deemed effective, adverse drug reaction (ADR) results needed to satisfy the selection criteria of yielding a positive signal across all four methods concurrently. Data processing and statistical analyses related to Panitumumab were conducted using SAS, MySQL, WPS EXCEL, and R software.\u003c/p\u003e \u003cp\u003eThe prerequisites for the study are outlined in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, and the detailed formulas for the four methods employed are provided below:\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\u003eTable matrix.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTarget ADR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNon-target ADR\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePanitumumab\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\u003ec\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon- panitumumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eb\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ed\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eNote: Panitumumab is the target drug in this study, we retrieve ivabradine data for analysis.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;a\u0026thinsp;+\u0026thinsp;b\u0026thinsp;+\u0026thinsp;c\u0026thinsp;+\u0026thinsp;d.\u003c/p\u003e \u003cp\u003eADR: adverse drug reaction.\u003c/p\u003e \u003cp\u003e(i) ROR algorithm\u003cdiv id=\"Equa\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equa\" name=\"EquationSource\"\u003e\n$$ROR=\\left(ad\\right)/\\left(bc\\right)$$\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Equb\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equb\" name=\"EquationSource\"\u003e\n$$95\\text{\\%} CI={e}^{\\text{l}\\text{n}\\left(ROR\\right)\\pm 1.96\\sqrt{\\frac{1}{a}+\\frac{1}{b}+\\frac{1}{c}+\\frac{1}{d}}}$$\u003c/div\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003eThe criteria of positive safety signal detection: the lower limit of 95% CI\u0026thinsp;\u0026gt;\u0026thinsp;1, N\u0026thinsp;\u0026ge;\u0026thinsp;3;\u003c/p\u003e \u003cp\u003e(ii) PRR algorithm\u003cdiv id=\"Equc\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equc\" name=\"EquationSource\"\u003e\n$$PRR=\\left[a\\left(c+d\\right)\\right]/\\left[c\\left(a+b\\right)\\right]$$\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Equd\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equd\" name=\"EquationSource\"\u003e\n$${\\chi }2=\\frac{\\left(a+b+c+d\\right){(ad-bc)}^{2}}{(a+b)(c+d)(a+c)(b+d)}$$\u003c/div\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003eThe criteria of positive safety signal detection: PRR\u0026thinsp;\u0026ge;\u0026thinsp;2, χ2\u0026thinsp;\u0026ge;\u0026thinsp;4, N\u0026thinsp;\u0026ge;\u0026thinsp;3;\u003c/p\u003e \u003cp\u003e(iii) BPCNN algorithm\u003cdiv id=\"Eque\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Eque\" name=\"EquationSource\"\u003e\n$$IC={\\text{log}}_{2}\\frac{a\\left(a+b+c+d\\right)}{\\left(a+b\\right)\\left(a+c\\right)}$$\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Equf\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equf\" name=\"EquationSource\"\u003e\n$$95\\text{\\%} CI=E\\left(IC\\right)\\pm 2\\times \\sqrt{V\\left(IC\\right)}$$\u003c/div\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003eThe criteria of positive safety signal detection: IC025\u0026thinsp;\u0026gt;\u0026thinsp;0 (IC025: the lower bound of 95% CI);\u003c/p\u003e \u003cp\u003e(iv) EBGM algorithm\u003cdiv id=\"Equg\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equg\" name=\"EquationSource\"\u003e\n$$EBGM=\\left(aN\\right)/\\left[\\left(a+b\\right)\\left(a+c\\right)\\right]$$\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Equh\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equh\" name=\"EquationSource\"\u003e\n$$95\\text{\\%} CI={e}^{\\text{l}\\text{n}\\left(EGBM\\right)\\pm 1.96\\sqrt{\\frac{1}{a}+\\frac{1}{b}+\\frac{1}{c}+\\frac{1}{d}}}$$\u003c/div\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003eThe criteria of positive safety signal detection: EBGM05\u0026thinsp;\u0026gt;\u0026thinsp;2 (EBGM05: the lower bound of 95% CI).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eDuring the study period from September 27, 2006, to December 31, 2023, a comprehensive dataset comprising 4,772,722 case reports from FAERS was analyzed, identifying 5,166 adverse event reports primarily associated with panitumumab after excluding duplicate entries. Among these, 1,780 adverse events (AEs) and 317 adverse drug reactions (ADRs) specifically linked to panitumumab were identified. The fluctuating trend in adverse event reports related to panitumumab is depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eSince panitumumab was approved on September 27, 2006, it did not have the fewest adverse events (AEs) reported in 2007, possibly due to its widespread early adoption after approval. The overall trend fluctuated around 300 AEs but showed an upward trajectory. Exceptions include 197 AEs reported in 2013 and 177 AEs reported in 2020 (the lowest number of AEs reported since panitumumab was approved by the FDA on September 27, 2006). The years 2022 and 2023 also marked new highs in reported AEs. Therefore, monitoring the safety of panitumumab is of crucial significance.\u003c/p\u003e \u003cp\u003eAdditionally, detailed clinical characteristics of the events associated with panitumumab are described in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe features of reports associated with panitumumab from September 2006 to December 2023.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003ePanitumumab\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCase Number\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePercentage(%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal counts\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5166\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\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 \u003cp\u003e2511\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e78.37%\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 \u003cp\u003e1459\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e45.54%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1196\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37.33%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;20\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\u003e0.22%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e20\u0026ndash;29\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\u003e0.37%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e30\u0026ndash;39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.72%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e40\u0026ndash;49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e237\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.40%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e50\u0026ndash;59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e513\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16.01%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e60\u0026ndash;69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e807\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25.19%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e70\u0026ndash;79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e687\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21.44%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e237\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.40%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2579\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e80.50%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReported Counties(the top ranked)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUS (United States)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1763\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e55.02%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJP(Japan)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1041\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32.49%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFR(France)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e230\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.18%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDE(Germany)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e228\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.12%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIT(Italy)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e195\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.09%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePoland\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e147\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.59%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpanis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e114\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.56%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAU(Australia)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e104\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.25%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCA(Canada)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.81%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTurkey\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.37%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBrazil\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.65%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMexico\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.37%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRussian Federation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.84%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSweden\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.69%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNorway\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\u003e0.50%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIndia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.41%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEgypt\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\u003e0.34%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCN(China)\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\u003e0.25%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSouth Africa\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\u003e0.19%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e766\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23.91%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerious Outcomes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCongenital Anomaly\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.03%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDeath\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e825\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25.75%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisability\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.09%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHospitalization-initial or Prolonged\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1601\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e49.97%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLife-threatening\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e269\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.40%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRequred Intervention to Prevent Permanent Impairmnt Damage\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\u003e0.12%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2655\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e74.88%\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\u003eAmong the population experiencing all AEs, males (2511, 78.37%) outnumbered females (1459, 45.54%) by a factor of 1.72. Regarding age distribution, each age group, spanning 10 years, exhibited a gradual incline initially, followed by a subsequent decline. The distribution is as follows: \u0026lt;20 (7, 0.22%), 20\u0026ndash;29 (12, 0.37%), 30\u0026ndash;39 (87, 2.72%), 40\u0026ndash;49 (237, 7.40%), 50\u0026ndash;59 (513, 16.01%), and 60\u0026ndash;69 (807, 25.19%). Subsequently, there was a gradual decrease in the 70\u0026ndash;79 age group (687, 21.44%) and \u0026gt;\u0026thinsp;80 (237, 7.40%).\u003c/p\u003e \u003cp\u003eAdditionally, the top-ranked countries for panitumumab consumption were the United States (1763, 55.02%), Japan (1041, 32.49%), France (230, 7.18%), Germany (228, 7.12%), Italy (195, 6.09%), Poland (147, 4.59%), Spain (114, 3.56%), Australia (104, 3.25%), Canada (90, 2.81%), Turkey (76, 2.37%), Brazil (53, 1.65%), Mexico (44, 1.37%), Russian Federation (27, 0.84%), Sweden (22, 0.69%), Norway (16, 0.50%), India (13, 0.41%), Egypt (11, 0.34%), China (8, 0.25%), and South Africa (6, 0.19%).\u003c/p\u003e \u003cp\u003eThe most prevalent AEs were Hospitalization-initial or Prolonged (1,601, 49.97%), accounting for nearly half of all AEs. Following this, the occurrences were death (825, 25.75%), life-threatening (269, 8.40%), and disability (67, 2.09%). The least prevalent were Required Intervention to Prevent Permanent Impairment Damage (4, 0.12%) and disability (1, 0.03%).\u003c/p\u003e \u003cp\u003e3.2. System Organ Class Level-associated signal detections\u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e presents the results of signal detection analysis for panitumumab at the System Organ Class (SOC) level. It is evident that adverse events (AEs) associated with panitumumab are widespread across 24 organ systems, indicating a relatively common occurrence of panitumumab-related AEs. Notably, the highest number of AEs was observed in \"Skin and subcutaneous tissue disorders\" (n\u0026thinsp;=\u0026thinsp;2165), followed by \"Gastrointestinal disorders\" (n\u0026thinsp;=\u0026thinsp;874), \"General disorders and administration site conditions\" (n\u0026thinsp;=\u0026thinsp;824), \"Metabolism and nutrition disorders\" (n\u0026thinsp;=\u0026thinsp;752), \"Blood and lymphatic system disorders\" (n\u0026thinsp;=\u0026thinsp;590), \"Neoplasms benign, malignant and unspecified (incl cysts and polyps)\" (n\u0026thinsp;=\u0026thinsp;461), \"Infections and infestations\" (n\u0026thinsp;=\u0026thinsp;366), \"Investigations\" (n\u0026thinsp;=\u0026thinsp;278), \"Injury, poisoning and procedural complications\" (n\u0026thinsp;=\u0026thinsp;267), \"Nervous system disorders\" (n\u0026thinsp;=\u0026thinsp;234), and \"Vascular disorders\" (n\u0026thinsp;=\u0026thinsp;203). Many of these adverse events (AEs) are closely related to the pharmacological mechanisms of panitumumab, including \"Skin and subcutaneous tissue disorders,\" \"Gastrointestinal disorders,\" and \"Neoplasms benign, malignant and unspecified (including cysts and polyps).\"\u003c/p\u003e \u003cp\u003e3.3 PT level-associated signal detections\u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e offers comprehensive statistics regarding 50 Preferred Terms (PTs) delineating adverse drug reactions (ADRs) associated with panitumumab therapy. Comprehensive data are provided in \u003cb\u003eSupplemental Table\u0026nbsp;1.\u003c/b\u003e These ADRs are meticulously ranked based on case numbers, furnishing healthcare professionals with detailed insights to anticipate, identify, and effectively manage potential adverse reactions linked to panitumumab utilization. Such data empowers healthcare practitioners with valuable information essential for optimizing patient care during panitumumab treatment.\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\u003eSignal strength of AEs of panitumumab at the System Organ Class (SOC) level in FDA Adverse Event Reporting System (FAERS) source\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" 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=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSystem Organ Class\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSOC Code\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCase Number\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eROR(95%CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePRR(95%CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eχ2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIC(IC025)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eEBGM(EBGM05)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSkin and subcutaneous tissue disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10040785\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2165\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e16.35 (15.47\u0026ndash;17.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9.92 (9.60-10.24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e18042.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.30 (3.13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e9.88 (9.34)\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=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10017947\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e874\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.90 (5.48\u0026ndash;6.34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.07 (4.77\u0026ndash;5.38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2946.41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.34 (2.10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e5.06 (4.70)\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=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10018065\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e824\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6.97 (6.47\u0026ndash;7.51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.02 (5.65\u0026ndash;6.41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3530.93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.59 (2.34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e6.00 (5.57)\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=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10027433\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e752\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9.29 (8.60-10.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8.08 (7.56\u0026ndash;8.63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e4734.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.01 (2.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e8.06 (7.46)\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=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10005329\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e590\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6.16 (5.65\u0026ndash;6.71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.57 (5.16\u0026ndash;6.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2252.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.47 (2.19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e5.56 (5.10)\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=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10029104\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e461\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e15.15 (13.77\u0026ndash;16.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13.89 (12.73\u0026ndash;15.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e5514.64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.79 (3.47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e13.81 (12.54)\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=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10021881\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e366\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e11.14 (10.02\u0026ndash;12.39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10.42 (9.44\u0026ndash;11.51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3124.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.38 (3.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e10.38 (9.33)\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=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10022891\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e278\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e10.20 (9.04\u0026ndash;11.51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9.71 (8.65\u0026ndash;10.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2173.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.27 (2.87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e9.67 (8.56)\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=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10022117\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e267\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6.06 (5.35\u0026ndash;6.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.80 (5.16\u0026ndash;6.51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1066.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.53 (2.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e5.78 (5.11)\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=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10029205\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e234\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e10.43 (9.14\u0026ndash;11.89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10.00 (8.82\u0026ndash;11.34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1895.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.32 (2.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e9.96 (8.73)\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=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10047065\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e203\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.69 (4.94\u0026ndash;6.54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.50 (4.81\u0026ndash;6.30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e751.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.46 (1.99)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e5.49 (4.77)\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=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10021428\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e184\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e10.75 (9.28\u0026ndash;12.46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e10.40 (9.02\u0026ndash;11.99)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1561.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.37 (2.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e10.36 (8.94)\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=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10019805\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e151\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9.88 (8.40-11.62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9.62 (8.22\u0026ndash;11.27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1165.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.26 (2.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e9.59 (8.15)\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=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10015919\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e17.89 (14.61\u0026ndash;21.92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e17.58 (14.41\u0026ndash;21.45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1490.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e4.13 (3.46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e17.45 (14.25)\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=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10038738\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7.23 (5.83\u0026ndash;8.97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7.13 (5.76\u0026ndash;8.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e442.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.83 (2.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e7.11 (5.73)\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=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10042613\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.64 (2.74\u0026ndash;4.84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.62 (2.73\u0026ndash;4.80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e91.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.85 (0.93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e3.61 (2.72)\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=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10038359\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.52 (3.88\u0026ndash;7.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.49 (3.87\u0026ndash;7.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e113.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.45 (1.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e5.48 (3.85)\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=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10010331\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e33.37 (22.95\u0026ndash;48.51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e33.19 (22.88\u0026ndash;48.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e861.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e5.03 (3.83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e32.71 (22.5)\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=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10007541\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.70 (2.41\u0026ndash;5.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.69 (2.41\u0026ndash;5.65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e41.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.88 (0.53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e3.68 (2.40)\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=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10041244\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6.69 (3.47\u0026ndash;12.87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.68 (3.47\u0026ndash;12.84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e43.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.74 (0.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e6.66 (3.46)\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=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10038604\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e13.82 (6.19\u0026ndash;30.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13.81 (6.19\u0026ndash;30.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e70.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.78 (1.48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e13.73 (6.15)\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=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10077536\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.85 (2.43\u0026ndash;14.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.85 (2.43\u0026ndash;14.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e20.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.54 (0.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e5.83 (2.42)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEndocrine disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10014698\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e14.34 (5.36\u0026ndash;38.36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e14.33 (5.36\u0026ndash;38.30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e49.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.83 (1.17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e14.25 (5.33)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003eFootnotes: SOC, System Organ Class; ROR, Reporting Odds Ratio; CI, Confidence Interval; PRR, Proportional Reporting Ratio; χ2, Chi-squared; IC, Information Component; EBGM, Empirical Bayesian Geometric Mean\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe top 50 signal strength of AEs of Panitumumab ranked by Case Number at the Preferred Terms level in FDA Adverse Event Reporting System (FAERS) source.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\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=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSystem Organ Class\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePTs\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCase Number\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eROR\u003c/p\u003e \u003cp\u003e(95%CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePRR\u003c/p\u003e \u003cp\u003e(95%CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eχ2\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIC\u003c/p\u003e \u003cp\u003e(IC025)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eEBGM\u003c/p\u003e \u003cp\u003e(EBGM05)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\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\u003erash\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e675\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7.95 (7.33\u0026ndash;8.62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e7.04 (6.56\u0026ndash;7.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3555.39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.81 (2.54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e7.02 (6.48)\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\u003ediarrhoea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e482\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.94 (3.59\u0026ndash;4.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.66 (3.36\u0026ndash;3.99)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e956.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.87 (1.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e3.66 (3.33)\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\u003ehypomagnesaemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e283\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e111.32 (98.48-125.83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e105.28 (93.74-118.24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e27902.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e6.65 (6.24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e100.49 (88.9)\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\u003edisease progression\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e255\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9.52 (8.39\u0026ndash;10.80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e9.10 (8.07\u0026ndash;10.26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1839.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.18 (2.76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e9.06 (7.99)\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\u003edermatitis acneiform\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e254\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e261.68 (229.15-298.84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e248.86 (219.21-282.53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e56307.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e7.80(7.36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e223.53 (195.74)\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\u003eneutropenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e240\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8.77 (7.70\u0026ndash;9.98)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e8.41 (7.43\u0026ndash;9.51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1568.71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.07 (2.63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e8.38 (7.36)\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\u003eskin toxicity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e231\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e233.84 (203.65\u0026ndash;268.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e223.43 (195.68-255.11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e46417.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e7.66 (7.20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e202.80 (176.62)\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\u003ecolorectal cancer metastatic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e177\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e685.97 (578.47-813.45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e662.51 (561.20-782.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e89723.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e8.99 (8.44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e508.65 (428.94)\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\u003eparonychia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e166\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e242.47 (206.11-285.24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e234.71 (200.46-274.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e34889.79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e7.73 (7.19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e212.05 (180.25)\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\u003epyrexia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e164\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.53 (2.17\u0026ndash;2.96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.48 (2.13\u0026ndash;2.89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e146.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.31 (0.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e2.48 (2.12)\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\u003edecreased appetite\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e158\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.42 (2.92\u0026ndash;4.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.35 (2.87\u0026ndash;3.91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e262.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.74 (1.22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e3.35 (2.85)\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\u003estomatitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e153\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e13.35 (11.36\u0026ndash;15.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e12.98 (11.10-15.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1685.68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.69 (3.15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e12.91 (10.99)\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\u003eneuropathy peripheral\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e152\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7.89 (6.71\u0026ndash;9.27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e7.68 (6.57\u0026ndash;8.99)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e883.99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.94 (2.40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e7.66 (6.52)\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\u003edehydration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e148\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6.15 (5.22\u0026ndash;7.24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6.00 (5.12\u0026ndash;7.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e617.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.58 (2.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e5.99 (5.08)\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\u003edry skin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e136\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9.50 (8.01\u0026ndash;11.27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e9.28 (7.86\u0026ndash;10.95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1002.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.21 (2.64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e9.24 (7.79)\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\u003einterstitial lung disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e121\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e13.15 (10.98\u0026ndash;15.76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e12.87 (10.78\u0026ndash;15.35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1319.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.68 (3.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e12.80 (10.68)\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\u003efebrile neutropenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e120\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e10.61 (8.85\u0026ndash;12.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e10.39 (8.70\u0026ndash;12.40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1015.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.37 (2.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e10.34 (8.63)\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\u003eanaemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e120\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.34 (2.79-4.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.28 (2.75\u0026ndash;3.92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e191.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.71 (1.11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e3.28 (2.74)\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\u003eskin disorder\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e119\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e16.74 (13.95\u0026ndash;20.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e16.38 (13.70-19.58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1708.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e4.02 (3.42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e16.27 (13.55)\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\u003ethrombocytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e110\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.17 (4.28\u0026ndash;6.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5.08 (4.22\u0026ndash;6.11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e361.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.34 (1.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e5.07 (4.20)\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\u003eerythema\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.99 (2.45\u0026ndash;3.65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.95 (2.43\u0026ndash;3.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e129.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.56 (0.91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e2.95 (2.42)\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\u003eskin reaction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e33.51 (27.37\u0026ndash;41.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e32.90 (26.98\u0026ndash;40.13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2957.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e5.02 (4.35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e32.43 (26.49)\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\u003ecolon cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e26.76 (21.84\u0026ndash;32.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e26.28 (21.53\u0026ndash;32.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2308.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e4.70 (4.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e25.98 (21.2)\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\u003etherapy partial responder\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e39.25 (31.91\u0026ndash;48.27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e38.56 (31.47\u0026ndash;47.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3345.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e5.24 (4.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e37.91 (30.82)\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\u003eproduct storage error\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.83 (3.11\u0026ndash;4.71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.78 (3.08\u0026ndash;4.63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e186.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.92 (1.23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e3.77 (3.06)\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\u003eneutrophil count decreased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e11.57 (9.39\u0026ndash;14.26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e11.39 (9.27\u0026ndash;13.98)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e849.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.50 (2.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e11.33 (9.19)\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\u003epulmonary embolism\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.01 (3.24\u0026ndash;4.96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.96 (3.21\u0026ndash;4.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e190.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.98 (1.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e3.95 (3.19)\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\u003emetastases to liver\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e23.24 (18.64\u0026ndash;28.98)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e22.89 (18.42\u0026ndash;28.44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1679.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e4.50 (3.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e22.66 (18.18)\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\u003erash pustular\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e54.51 (43.47\u0026ndash;68.35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e53.70 (42.97\u0026ndash;67.11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3938.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e5.71 (4.97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e52.44 (41.82)\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\u003ecircumstance or information capable of leading to medication error\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9.38 (7.50-11.73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e9.25 (7.42\u0026ndash;11.54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e572.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.2 0(2.47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e9.22 (7.37)\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\u003emucosal inflammation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e15.43 (12.26\u0026ndash;19.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e15.22 (12.13\u0026ndash;19.10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e977.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.92 (3.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e15.13 (12.01)\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\u003emalignant neoplasm progression\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.28 (2.60\u0026ndash;4.15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.25 (2.58\u0026ndash;4.10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e110.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.70 (0.93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e3.25 (2.57)\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\u003egeneral physical health deterioration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.30 (2.60\u0026ndash;4.19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.27 (2.59\u0026ndash;4.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e109.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.71 (0.93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e3.27 (2.58)\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\u003eblood magnesium decreased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e46.69 (36.67\u0026ndash;59.46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e46.09 (36.31\u0026ndash;58.51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2938.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e5.50 (4.70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e45.16 (35.46)\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\u003einfusion related reaction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7.69 (5.99\u0026ndash;9.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e7.61 (5.95\u0026ndash;9.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e360.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.92 (2.11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e7.58 (5.91)\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\u003eacne\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7.95 (6.18\u0026ndash;10.24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e7.87 (6.13\u0026ndash;10.11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e365.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.97 (2.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e7.85 (6.09)\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\u003ehypocalcaemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e15.62 (12.10-20.17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e15.45 (12.00-19.89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e805.79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.94 (3.10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e15.35 (11.89)\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\u003ehypokalaemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7.18 (5.57\u0026ndash;9.27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e7.11 (5.53\u0026ndash;9.15)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e314.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.83 (1.99)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e7.09 (5.49)\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\u003esepsis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.73 (2.11\u0026ndash;3.52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.71 (2.10\u0026ndash;3.49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e63.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.43 (0.60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e2.70 (2.09)\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\u003eskin fissures\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e20.08 (15.26\u0026ndash;26.42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e19.89 (15.16\u0026ndash;26.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e924.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e4.3 (3.41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e19.72 (14.98)\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\u003eleukopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.44 (4.12\u0026ndash;7.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5.39 (4.10\u0026ndash;7.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e182.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.43 (1.53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e5.38 (4.08)\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\u003econjunctivitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e13.12 (9.84\u0026ndash;17.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e13.01 (9.78\u0026ndash;17.31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e518.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.69 (2.76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e12.94 (9.70)\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\u003efolliculitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e43.27 (32.28\u0026ndash;58.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e42.90 (32.08\u0026ndash;57.36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1846.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e5.40 (4.44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e42.09 (31.4)\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\u003epalmar-plantar erythrodysaesthesia syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8.37 (6.26\u0026ndash;11.20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e8.31 (6.23\u0026ndash;11.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e294.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.05 (2.10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e8.28 (6.19)\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\u003eperipheral sensory neuropathy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e41.49 (30.65\u0026ndash;56.17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e41.15 (30.47\u0026ndash;55.58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1653.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e5.34 (4.35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e40.41 (29.85)\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\u003eintestinal obstruction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.55 (4.03\u0026ndash;7.64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5.52 (4.02\u0026ndash;7.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e140.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.46 (1.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e5.50 (4.00)\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\u003eskin exfoliation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.21 (2.32\u0026ndash;4.44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.19 (2.32\u0026ndash;4.40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e55.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.67 (0.63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e3.19 (2.31)\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\u003emetastases to lung\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e15.43 (11.11\u0026ndash;21.44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e15.33 (11.06\u0026ndash;21.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e479.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.93 (2.87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e15.23 (10.96)\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\u003esurgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.80 (2.02\u0026ndash;3.89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.79 (2.01\u0026ndash;3.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e41.38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.48 (0.42)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e2.79 (2.01)\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\u003edermatitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9.58 (6.84\u0026ndash;13.44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e9.53 (6.81\u0026ndash;13.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e258.54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.25 (2.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e9.49 (6.77)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"8\"\u003eFootnotes: SOC, System Organ Class; ROR, Reporting Odds Ratio; CI, Confidence Interval; PRR, Proportional Reporting Ratio; χ2, Chi-squared; IC, Information Component; EBGM, Empirical Bayesian Geometric Mean\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe top five preferred terms (PTs) associated with panitumumab are as follows: rash (n\u0026thinsp;=\u0026thinsp;675, IC025\u0026thinsp;=\u0026thinsp;2.81 (2.54)), diarrhoea (n\u0026thinsp;=\u0026thinsp;482, IC025\u0026thinsp;=\u0026thinsp;1.87 (1.56)), hypomagnesaemia (n\u0026thinsp;=\u0026thinsp;283, IC025\u0026thinsp;=\u0026thinsp;6.65 (6.24)), disease progression (n\u0026thinsp;=\u0026thinsp;255, IC025\u0026thinsp;=\u0026thinsp;3.18 (2.76)), and dermatitis acneiform (n\u0026thinsp;=\u0026thinsp;254, IC025\u0026thinsp;=\u0026thinsp;7.80(7.36)). Additionally, the top five PTs of panitumumab ranked by IC025 value are trichomegaly (n\u0026thinsp;=\u0026thinsp;13, IC025\u0026thinsp;=\u0026thinsp;9.07 (7.15)), colorectal cancer metastatic (n\u0026thinsp;=\u0026thinsp;177, IC025\u0026thinsp;=\u0026thinsp;8.99 (8.44)), colorectal cancer recurrent (n\u0026thinsp;=\u0026thinsp;10, IC025\u0026thinsp;=\u0026thinsp;8.72 (6.62)), dermatitis acneiform (n\u0026thinsp;=\u0026thinsp;254, IC025\u0026thinsp;=\u0026thinsp;7.8 (7.36)) and paronychia (n\u0026thinsp;=\u0026thinsp;166, IC025\u0026thinsp;=\u0026thinsp;7.73 (7.19)).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis real-world evidence study conducted a comprehensive analysis of 317 adverse drug reaction (ADR) reports associated with panitumumab use. Notably, the number of ADR cases in males was significantly higher than in females. This disparity could be attributed to a higher number of males taking panitumumab or to metabolic differences in drug response between genders. Previous studies have not reported a higher overall incidence of ADRs in males compared to females, only noting gender differences in specific symptoms \u003csup\u003e10,11\u003c/sup\u003e or PMIDa higher total number of ADRs in females. Therefore, the finding that males experience more ADRs than females warrants further investigation.\u003c/p\u003e \u003cp\u003eThe reports indicate that ADRs increase with age up to 70 years, peaking in the 60\u0026ndash;69 age group, and then gradually decrease. Overall, the number of ADR reports is significantly higher in individuals over 40 years old compared to those under 40. This trend may be due to the larger population of patients over 40 years old taking the medication, highlighting the need for special monitoring of patients in this age group. In contrast, younger patients are fewer in number and thus have fewer reports of ADRs. The increasing trend of ADRs with age up to 70 years suggests that older age groups are more susceptible to these reactions. The subsequent decline in ADRs after 70 years of age may be due to a slower metabolism in this age group, resulting in fewer ADRs.\u003c/p\u003e \u003cp\u003eThere were notable differences in ADR reports across countries and regions. For instance, Japan reported the second-highest number of cases after the United States. This may be because panitumumab was introduced in Japan relatively early, in 2009, and the larger patient population in Japan might contribute to the higher number of ADR cases. In contrast, China reported only six ADR cases, possibly because panitumumab is not marketed in China and may not be a first-line treatment option.\u003c/p\u003e \u003cp\u003eAmong the reported ADRs, \"Hospitalization-initial or Prolonged\" was the most common, accounting for 1601 cases (49.97%), followed by \"Death\" with 825 cases (25.75%), and \"Life-threatening\" with 269 cases. This indicates the severity of the adverse events caused by panitumumab, which is particularly concerning.\u003c/p\u003e \u003cp\u003eAdditionally, the data presented may be affected by differences in reporting systems and cultural factors. Various countries have differing levels of effectiveness in their systems for reporting medication adverse effects, as well as different degrees of focus on medication safety and the monitoring of adverse reactions by regulatory authorities.\u003c/p\u003e \u003cp\u003eSkin toxicities from EGFR inhibitors (EGFRIs) include pruritus, acneiform dermatitis, skin desquamation, paronychia, and pustular rash\u003csup\u003e12\u003c/sup\u003e. These typically manifest early in therapy, with subsequent complications such as skin infections and ulceration \u003csup\u003e13\u003c/sup\u003e. UV radiation exacerbates these effects by heightening keratinocyte apoptosis sensitivity in sun-exposed areas \u003csup\u003e14\u0026ndash;16\u003c/sup\u003e. Due to their frequent occurrence in adverse event reports from FAERS, monitoring is particularly crucial\u003csup\u003e17\u0026ndash;19\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e \u003csup\u003e18\u003c/sup\u003e \u003c/p\u003e \u003cp\u003ePanitumumab has been associated with adverse reactions in the blood and lymphatic systems, including hypomagnesemia (283 cases), hypocalcemia (60 cases), and hypokalemia (60 cases). Additionally, numerous specific adverse reactions have been reported in the hematologic system, such as neutropenia (240 cases), febrile neutropenia (120 cases), anemia (120 cases), thrombocytopenia (110 cases), and leukopenia (51 cases).\u003c/p\u003e \u003cp\u003eFebrile neutropenia (FN) is particularly notable as a severe adverse reaction, defined as an oral temperature\u0026thinsp;\u0026gt;\u0026thinsp;38.3\u0026deg;C or two consecutive readings\u0026thinsp;\u0026gt;\u0026thinsp;38.0\u0026deg;C for 2 hours, with an absolute neutrophil count (ANC)\u0026thinsp;\u0026lt;\u0026thinsp;0.5 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e /L\u003csup\u003e20\u003c/sup\u003e. The use of anti-EGFR monoclonal antibodies has been associated with a significant increase in grades 3\u0026ndash;4 infections or febrile neutropenia\u003csup\u003e21\u003c/sup\u003e. Chemotherapy-induced neutropenia and FN are also critical dose-limiting side effects, often necessitating treatment adjustments that may impact outcomes\u003csup\u003e22,23\u003c/sup\u003e. FN is known for its substantial morbidity, mortality, and healthcare costs\u003csup\u003e20,24,25\u003c/sup\u003e. Therefore, clinicians must be vigilant about this serious adverse effect and implement appropriate prevention and monitoring measures.\u003c/p\u003e \u003cp\u003eIn the real world, various adverse reactions related to the digestive system have also been reported, as detailed in drug labeling, including diarrhea (482 cases), oral mucositis (153 cases), and anorexia (158 cases). Specific instances observed include intestinal obstruction (38 cases), ileus (25 cases), intestinal perforation (20 cases), small intestinal obstruction (16 cases), and gastrointestinal perforation (15 cases). Ascites (21 cases) is also documented.\u003c/p\u003e \u003cp\u003eSpecial attention should be given to intestinal obstruction, intestinal perforation, and gastrointestinal perforation, as these are serious clinical symptoms that may occur during the course of rectal cancer. Research has reported that panitumumab can cause the serious complication of intestinal obstruction \u003csup\u003e26\u003c/sup\u003e. However, there are no specific reports of panitumumab causing intestinal perforation or gastrointestinal perforation.\u003c/p\u003e \u003cp\u003eAdditionally, although the use of targeted therapies can potentially reduce metastases, these agents can also affect the normal adjacent liver parenchyma, leading to hepatotoxicity\u003csup\u003e27\u003c/sup\u003e. Adverse reactions affecting the hepatic and biliary systems in the real world include hepatic failure (25 cases), veno-occlusive liver disease (8 cases), hepatic fibrosis (5 cases), liver abscess (5 cases), cholestatic jaundice (5 cases), and biliary obstruction (4 cases). Special emphasis is warranted for hepatic failure (25 cases), veno-occlusive liver disease (8 cases), and liver abscess (5 cases).\u003c/p\u003e \u003cp\u003ePolyneuropathy is a disabling condition of the peripheral nerves, characterized by symmetrical distal numbness, paresthesia, pain, and weakness, primarily in the arms and legs. It negatively impacts quality of life\u003csup\u003e28\u003c/sup\u003e. Elderly individuals are at higher risk for developing polyneuropathy and related injuries from falls \u003csup\u003e29\u003c/sup\u003e. Therefore, special attention should be given to this adverse drug reaction.\u003c/p\u003e \u003cp\u003eAmong the side effects of panitumumab treatment, a significant number of neurological adverse reactions have been reported, including peripheral neuropathy (152 cases), polyneuropathy (30 cases), and peripheral sensory neuropathy (43 cases). Notably, polyneuropathy, which is a severe condition affecting multiple nerves, warrants further investigation to determine the drug's role in this adverse reaction.\u003c/p\u003e \u003cp\u003eThe occurrence of these adverse reactions serves as a reminder and warning for users of panitumumab, especially in countries or regions where the drug has recently been introduced. It aims to alert healthcare providers and patients about potential risks associated with its use. It's important to note limitations in the FAERS (FDA Adverse Event Reporting System) as a spontaneous reporting system, which may have inherent biases in the reported data.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study conducted a comprehensive analysis of adverse drug reactions (ADRs) associated with panitumumab, revealing predominant effects on the skin, hematologic and lymphatic systems, digestive system, electrolyte imbalances, systemic reactions, respiratory system, cardiovascular system, and nervous system. Common adverse reactions included serious events such as intestinal obstruction, intestinal perforation, and hepatic failure, underscoring the critical need for vigilance in monitoring and managing these risks. The study relied on data from the FDA Adverse Event Reporting System (FAERS), acknowledging limitations inherent to spontaneous reporting databases. Future research is essential to accurately assess panitumumab's safety profile, ensuring patients receive effective and safe treatment.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003eCRediT authorship contribution statement\u003c/p\u003e \u003cp\u003e \u003cb\u003eHuocong He\u003c/b\u003e: Writing \u0026ndash; review \u0026amp; editing, Writing \u0026ndash; original draft, Supervision. \u003cb\u003eHongyu Yu\u003c/b\u003e: Writing \u0026ndash; original draft, Formal analysis. \u003cb\u003eYile Liu\u003c/b\u003e: Writing \u0026ndash; review \u0026amp; editing, Validation, Data curation. \u003cb\u003eYang Huang\u003c/b\u003e: Validation, Data curation. \u003cb\u003eJianru Pan\u003c/b\u003e: Validation, Data curation. \u003cb\u003eShaoli Wang\u003c/b\u003e: Supervision, Methodology.\u003c/p\u003e\u003cp\u003e \u003ch2\u003eDeclaration of competing interest\u003c/h2\u003e \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 \u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eH.H. and Y.L. wrote the main manuscript text. H.Y. performed formal analysis. Y.L. conducted validation and data curation. Y.H. and J.P. contributed to validation and data curation. S.W. supervised the project and contributed to methodology. All authors reviewed the manuscript.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSiegel, R. 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Peripheral neuropathy. \u003cem\u003eLancet\u003c/em\u003e\u003cstrong\u003e363\u003c/strong\u003e, 2151-2161, doi:10.1016/s0140-6736(04)16508-2 (2004).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Colorectal cancer, panitumumab, Adverse drug reactions, Pharmacovigilance, FAERS (FDA Adverse Event Reporting System)","lastPublishedDoi":"10.21203/rs.3.rs-4624947/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4624947/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eColorectal cancer (CRC) is a significant public health issue, with metastatic disease posing a considerable challenge despite therapeutic advancements. Panitumumab, an EGFR inhibitor, has been a ray of hope for patients with chemorefractory metastatic CRC. However, understanding the safety profile of panitumumab is crucial for optimizing patient care.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study leveraged the FDA's Adverse Event Reporting System (FAERS) to scrutinize ADR reports linked to panitumumab from September 27, 2006, to December 31, 2023. Utilizing statistical methods such as Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayes Geometric Mean (EBGM), the study conducted a disproportionality analysis to identify potential safety signals.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe analysis of 5,166 ADR reports revealed a significant association between panitumumab and a spectrum of ADRs. Notable adverse events included skin toxicities, hematologic and lymphatic system disorders, gastrointestinal issues, electrolyte imbalances, and neurological reactions. The study also highlighted the need for close monitoring of serious outcomes like hospitalization, death, and life-threatening conditions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study presents a comprehensive analysis of ADRs associated with panitumumab, emphasizing the necessity for continuous pharmacovigilance and the implementation of strategies to ensure patient safety. The limitations of spontaneous reporting systems are acknowledged, and the call for further research to refine the safety profile of panitumumab is made.\u003c/p\u003e","manuscriptTitle":"Analysis of post-market adverse events of panitumumab: a real-world study base on FAERS database","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-22 10:56:46","doi":"10.21203/rs.3.rs-4624947/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5386f55b-a010-48a3-8f51-63176ba0d3d1","owner":[],"postedDate":"July 22nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":34871932,"name":"Biological sciences/Cancer"},{"id":34871933,"name":"Biological sciences/Drug discovery"},{"id":34871934,"name":"Health sciences/Diseases"},{"id":34871935,"name":"Health sciences/Medical research"},{"id":34871936,"name":"Health sciences/Risk factors"}],"tags":[],"updatedAt":"2024-10-28T06:39:00+00:00","versionOfRecord":[],"versionCreatedAt":"2024-07-22 10:56:46","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4624947","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4624947","identity":"rs-4624947","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}