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<journal-id journal-id-type="publisher-id">Front. Pharmacol.</journal-id>
<journal-title>Frontiers in Pharmacology</journal-title>
<abbrev-journal-title abbrev-type="pubmed">Front. Pharmacol.</abbrev-journal-title>
<issn pub-type="epub">1663-9812</issn>
<publisher>
<publisher-name>Frontiers Media S.A.</publisher-name>
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<article-meta>
<article-id pub-id-type="publisher-id">1259908</article-id>
<article-id pub-id-type="doi">10.3389/fphar.2023.1259908</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Pharmacology</subject>
<subj-group>
<subject>Original Research</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>A pharmacovigilance study of etoposide in the FDA adverse event reporting system (FAERS) database, what does the real world say?</article-title>
<alt-title alt-title-type="left-running-head">Cui et al.</alt-title>
<alt-title alt-title-type="right-running-head">
<ext-link ext-link-type="uri" xlink:href="https://doi.org/10.3389/fphar.2023.1259908">10.3389/fphar.2023.1259908</ext-link>
</alt-title>
</title-group>
<contrib-group>
<contrib contrib-type="author" equal-contrib="yes">
<name>
<surname>Cui</surname>
<given-names>Zhiwei</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<xref ref-type="author-notes" rid="fn001">
<sup>&#x2020;</sup>
</xref>
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<contrib contrib-type="author" equal-contrib="yes">
<name>
<surname>Cheng</surname>
<given-names>Feiyan</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<xref ref-type="author-notes" rid="fn001">
<sup>&#x2020;</sup>
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<contrib contrib-type="author">
<name>
<surname>Wang</surname>
<given-names>Lihui</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
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<contrib contrib-type="author">
<name>
<surname>Zou</surname>
<given-names>Fan</given-names>
</name>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
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<contrib contrib-type="author">
<name>
<surname>Pan</surname>
<given-names>Rumeng</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
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<contrib contrib-type="author">
<name>
<surname>Tian</surname>
<given-names>Yuhan</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
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<contrib contrib-type="author">
<name>
<surname>Zhang</surname>
<given-names>Xiyuan</given-names>
</name>
<xref ref-type="aff" rid="aff3">
<sup>3</sup>
</xref>
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<contrib contrib-type="author">
<name>
<surname>She</surname>
<given-names>Jing</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
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<contrib contrib-type="author">
<name>
<surname>Zhang</surname>
<given-names>Yidan</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
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<contrib contrib-type="author" corresp="yes">
<name>
<surname>Yang</surname>
<given-names>Xinyuan</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<xref ref-type="corresp" rid="c001">&#x2a;</xref>
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<aff id="aff1">
<sup>1</sup>
<institution>Department of Obstetrics and Gynecology</institution>, <institution>The First Affiliated Hospital of Xi&#x2019;an Jiaotong University</institution>, <addr-line>Xi&#x2019;an</addr-line>, <country>China</country>
</aff>
<aff id="aff2">
<sup>2</sup>
<institution>Department of Respiratory and Critical Care Medicine</institution>, <institution>Affiliated Hospital of Zunyi Medical University</institution>, <addr-line>Zunyi</addr-line>, <country>China</country>
</aff>
<aff id="aff3">
<sup>3</sup>
<institution>Department of General Medicine</institution>, <institution>Yanan University Affiliated Hospital</institution>, <addr-line>Yan&#x2019;an</addr-line>, <country>China</country>
</aff>
<author-notes>
<fn fn-type="edited-by">
<p>
<bold>Edited by:</bold> <ext-link ext-link-type="uri" xlink:href="https://loop.frontiersin.org/people/888500/overview">Eugene Van Puijenbroek</ext-link>, Netherlands Pharmacovigilance Centre Lareb, Netherlands</p>
</fn>
<fn fn-type="edited-by">
<p>
<bold>Reviewed by:</bold> <ext-link ext-link-type="uri" xlink:href="https://loop.frontiersin.org/people/1144472/overview">Weimin Zhong</ext-link>, Xiamen Fifth Hospital, China</p>
<p>
<ext-link ext-link-type="uri" xlink:href="https://loop.frontiersin.org/people/816664/overview">Anoop Kumar</ext-link>, Delhi Pharmaceutical Sciences and Research University, India</p>
</fn>
<corresp id="c001">&#x2a;Correspondence: Xinyuan Yang, <email>xinyuanyang2022@163.com</email>
</corresp>
<fn fn-type="equal" id="fn001">
<label>
<sup>&#x2020;</sup>
</label>
<p>These authors share first authorship</p>
</fn>
</author-notes>
<pub-date pub-type="epub">
<day>26</day>
<month>10</month>
<year>2023</year>
</pub-date>
<pub-date pub-type="collection">
<year>2023</year>
</pub-date>
<volume>14</volume>
<elocation-id>1259908</elocation-id>
<history>
<date date-type="received">
<day>17</day>
<month>07</month>
<year>2023</year>
</date>
<date date-type="accepted">
<day>10</day>
<month>10</month>
<year>2023</year>
</date>
</history>
<permissions>
<copyright-statement>Copyright &#xa9; 2023 Cui, Cheng, Wang, Zou, Pan, Tian, Zhang, She, Zhang and Yang.</copyright-statement>
<copyright-year>2023</copyright-year>
<copyright-holder>Cui, Cheng, Wang, Zou, Pan, Tian, Zhang, She, Zhang and Yang</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/">
<p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</p>
</license>
</permissions>
<abstract>
<p>
<bold>Introduction:</bold> Etoposide is a broad-spectrum antitumor drug that has been extensively studied in clinical trials. However, limited information is available regarding its real-world adverse reactions. Therefore, this study aimed to assess and evaluate etoposide-related adverse events in a real-world setting by using data mining method on the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database.</p>
<p>
<bold>Methods:</bold> Through the analysis of 16,134,686 reports in the FAERS database, a total of 9,892 reports of etoposide-related adverse drug events (ADEs) were identified. To determine the significance of these ADEs, various disproportionality analysis algorithms were applied, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS) algorithms.</p>
<p>
<bold>Results:</bold> As a result, 478 significant disproportionality preferred terms (PTs) that were identified by all four algorithms were retained. These PTs included commonly reported adverse events such as thrombocytopenia, leukopenia, anemia, stomatitis, and pneumonitis, which align with those documented in the drug&#x2019;s instructions and previous clinical trials. However, our analysis also uncovered unexpected and significant ADEs, including thrombotic microangiopathy, ototoxicity, second primary malignancy, nephropathy toxic, and ovarian failure. Furthermore, we examined the time-to-onset (TTO) of these ADEs using the Weibull distribution test and found that the median TTO for etoposide-associated ADEs was 10&#xa0;days (interquartile range [IQR] 2&#x2013;32&#xa0;days). The majority of cases occurred within the first month (73.8%) after etoposide administration. Additionally, our analysis revealed specific high-risk signals for males, such as pneumonia and cardiac infarction, while females showed signals for drug resistance and ototoxicity.</p>
<p>
<bold>Discussion:</bold> These findings provide valuable insight into the occurrence of ADEs following etoposide initiation, which can potentially support clinical monitoring and risk identification efforts.</p>
</abstract>
<kwd-group>
<kwd>etoposide</kwd>
<kwd>real-word analysis</kwd>
<kwd>pharmacovigilance</kwd>
<kwd>adverse drug event</kwd>
<kwd>FAERS</kwd>
</kwd-group>
<custom-meta-wrap>
<custom-meta>
<meta-name>section-at-acceptance</meta-name>
<meta-value>Pharmacoepidemiology</meta-value>
</custom-meta>
</custom-meta-wrap>
</article-meta>
</front>
<body>
<sec id="s1">
<title>1 Introduction</title>
<p>Etoposide (VP-16) is a semi-synthetic derivative of the natural antibiotic podophyllotoxin, acting as a potent inhibitor of topoisomerase-II (<xref ref-type="bibr" rid="B12">Cheema et al., 2011</xref>). This inhibition leads to DNA strand breaks and the induction of apoptosis, triggering mutagenic and cell death pathways (<xref ref-type="bibr" rid="B55">Meresse et al., 2004</xref>; <xref ref-type="bibr" rid="B44">Le and Wang, 2023</xref>). Upon entry into the human body, etoposide predominantly binds to serum albumin (93%&#x2013;98%) and undergoes elimination via the kidneys and biliary tract following glucuronidation (<xref ref-type="bibr" rid="B44">Le and Wang, 2023</xref>). The recommended oral dose of etoposide for monotherapy or combination therapy is 100&#x2013;200&#xa0;mg/m2/day on days 1&#x2013;5, or 200&#xa0;mg/m2/day on days 1, 3, and 5 every 3&#x2013;4&#xa0;weeks. Since its approval by the FDA in 1983, etoposide has been widely utilized in the treatment of various solid and hematologic tumors, such as small cell lung cancer, germ cell tumors, and lymphoma (<xref ref-type="bibr" rid="B52">McHugh et al., 2020</xref>; <xref ref-type="bibr" rid="B70">Rudin et al., 2020</xref>; <xref ref-type="bibr" rid="B34">Jeha et al., 2021</xref>; <xref ref-type="bibr" rid="B95">Torka et al., 2023</xref>). When combined with other chemotherapeutic agents, it has achieved a remission rate of over 80% (<xref ref-type="bibr" rid="B55">Meresse et al., 2004</xref>). In a clinical study involving patients with nonseminomatous germ cell tumors, adjuvant etoposide plus cisplatin for 2 cycles demonstrated prolonged disease-specific and relapse-free survival, along with acceptable toxicity and lower drug costs (<xref ref-type="bibr" rid="B52">McHugh et al., 2020</xref>).</p>
<p>Adverse drug events (ADEs) are crucial concerns in modern healthcare as they have a significant impact on patient safety, treatment outcomes, and overall public health (<xref ref-type="bibr" rid="B57">Montan&#xe9; and Santesmases, 2020</xref>). Given the outstanding efficacy and widespread use of etoposide in the treatment of tumors, it is important to understand its adverse effects to improve patient care (<xref ref-type="bibr" rid="B19">Edwards and Aronson, 2000</xref>). Common adverse reactions reported in association with etoposide dosing include myelosuppression, gastrointestinal toxicity, and hypersensitivity reactions (<xref ref-type="bibr" rid="B30">Henwood and Brogden, 1990</xref>; <xref ref-type="bibr" rid="B112">Zhu et al., 2016</xref>). However, unknown adverse reactions of etoposide are expected to be identified in post-marketing studies due to the limitations of clinical trials, such as restricted populations, limited follow-up time, and complications (<xref ref-type="bibr" rid="B106">Yan et al., 2022</xref>; <xref ref-type="bibr" rid="B33">Javed and Kumar, 2023</xref>). Therefore, searching for potential ADEs of etoposide through post-marketing surveillance using data mining algorithms is highly warranted.</p>
<p>The pharmacovigilance of drugs relies on the identification of statistical signals derived from diverse data sources (<xref ref-type="bibr" rid="B103">Vogel et al., 2020</xref>). Signals in pharmacovigilance refer to novel or known connections between adverse events and drugs (<xref ref-type="bibr" rid="B33">Javed and Kumar, 2023</xref>). Disproportionality analysis, a widely utilized method, is employed to detect signals using pharmacovigilance databases (<xref ref-type="bibr" rid="B32">Jain et al., 2023</xref>). This type of analysis considers the distribution of all drugs and events in the database, calculates statistical associations between drugs and ADEs, and is frequently employed in post-market safety assessments of drugs (<xref ref-type="bibr" rid="B3">Almenoff et al., 2007</xref>; <xref ref-type="bibr" rid="B103">Vogel et al., 2020</xref>; <xref ref-type="bibr" rid="B80">Sharma et al., 2023</xref>). The FDA Adverse Event Reporting System (FAERS) is a publicly accessible database that collects reports of ADEs from healthcare professionals, patients, and drug manufacturers. It serves as a crucial tool for the FDA&#x2019;s post-marketing safety monitoring of drugs and medical products, and it is one of the largest pharmacovigilance databases worldwide (<xref ref-type="bibr" rid="B54">Meng et al., 2019</xref>). Additionally, due to the large sample size of the FAERS database, data mining techniques possess sufficient statistical power to detect rare adverse reactions that are challenging to identify in traditional epidemiological studies (<xref ref-type="bibr" rid="B17">Duggirala et al., 2016</xref>; <xref ref-type="bibr" rid="B36">Jiao et al., 2020</xref>; <xref ref-type="bibr" rid="B79">Sharma and Kumar, 2022</xref>). Given that etoposide-related adverse reaction reports primarily originate from clinical trials, with a focus on specific organ systems, we utilized the FAERS database to conduct disproportionality analyses. This assessment aimed to evaluate the long-term safety of etoposide through post-marketing surveillance, providing a comprehensive and valuable reference for its real-world safety.</p>
</sec>
<sec sec-type="materials|methods" id="s2">
<title>2 Material and methods</title>
<sec id="s2-1">
<title>2.1 Data source and pre-processing</title>
<p>To systematically evaluate the safety of etoposide in the post-marketing period, we conducted a retrospective pharmacovigilance study using data obtained from the FAERS database. The FAERS database covers data from the first quarter of 2004 to the fourth quarter of 2022 and can be accessed at (<ext-link ext-link-type="uri" xlink:href="https://fis.fda.gov/extensions/FPD-QDE-FAERS/">https://fis.fda.gov/extensions/FPD-QDE-FAERS/</ext-link>FPD-QDE-FAERS.html). The FAERS data consists of seven datasets: demographic and administrative information (DEMO), drug information (DRUG), adverse drug reaction information (REAC), patient outcomes information (OUCT), reported sources (RPSR), drug therapy start dates and end dates (THER), and indications for drug administration (INDI) (<xref ref-type="bibr" rid="B83">Shu et al., 2022b</xref>). We imported all the downloaded data from the FAERS database into SAS software (version 9.4) for further collation and analysis. We acquired a total of 19,494,698 reports. Since the database is updated on a quarterly basis, there will unavoidably be duplication of previous public reports. According to the FDA&#x2019;s recommendations, we operated deduplication process before statistical analyses, following the criteria: (1) If the CASEIDs were the same, the latest FDA_DT were selected. (2) If the CASEIDs and the FDA_DT were the same, the higher PRIMARYIDs were selected (<xref ref-type="bibr" rid="B83">Shu et al., 2022b</xref>). The removing the duplicate records led to a decrease in the number of reports to 16,134,686 (<xref ref-type="fig" rid="F1">Figure 1</xref>). The 3D structure of etoposide is derived from the PubChem (<ext-link ext-link-type="uri" xlink:href="https://pubchem.ncbi.nlm.nih.gov/">https://pubchem.ncbi.nlm.nih.gov/</ext-link>) (<xref ref-type="bibr" rid="B39">Kim et al., 2023</xref>).</p>
<fig id="F1" position="float">
<label>FIGURE 1</label>
<caption>
<p>The flow diagram of selecting etoposide-related ADEs from FAERS database.</p>
</caption>
<graphic xlink:href="fphar-14-1259908-g001.tif"/>
</fig>
</sec>
<sec id="s2-2">
<title>2.2 Drug identification and adverse events</title>
<p>As FAERS had two variables including DRUGNAME and PROD_AI, both the brand names and common names were employed to recognize records related to etoposide. In this study, &#x201c;ETOPOSIDE&#x201d;, &#x201c;VP-16,&#x201d; &#x201c;LASTET,&#x201d; &#x201c;TOPOSAR,&#x201d; &#x201c;VEPESID,&#x201d; and &#x201c;CELLTOP&#x201d; were used to search. The reported drugs in FAERS were classified into four modalities: PS (primary suspect), SS (second suspect), C (concomitant), and I (interacting). To enhance accuracy, the role code of ADEs was retained only as the PS drug (<xref ref-type="bibr" rid="B110">Zhang et al., 2023</xref>). During the period of this research, we identified totally 9892 ADEs reports of etoposide as the PS drug. System Organ Class (SOC) was the highest level of the Medical Dictionary for Regulatory Activities (MedDRA, version 26.0. Available from <ext-link ext-link-type="uri" xlink:href="https://www.meddra.org/">https://www.meddra.org/</ext-link>) terminology, by which all ADEs in reports were coded of Preferred Terms (PTs) (<xref ref-type="bibr" rid="B93">Tieu and Breder, 2018</xref>). Then, 29,723 etoposide-related PTs were screened out (<xref ref-type="fig" rid="F1">Figure 1</xref>). We performed case/non-case analyses to determine whether the ADEs reported for etoposide were statistically significant at the PT and SOC levels compared to other drugs in the complete FAERS database.</p>
<p>Furthermore, the time-to-onset (TTO) of ADEs caused by etoposide were defined as the interval between EVENT_DT (ADEs onset date, in DEMO file) and START_DT (start date of etoposide use, in THER file). Input errors including inaccurate or missing date entries and EVENT_DT earlier than START_DT were eliminated. For exhaustively evaluating the TTO, we incorporated median, quartile, and Weibull shape parameter test in our research (<xref ref-type="bibr" rid="B40">Kinoshita et al., 2020</xref>; <xref ref-type="bibr" rid="B85">Shu et al., 2022d</xref>). The varying risk incidence increase or decrease of the ADEs over time could be determined and predicted by the Weibull distribution, with scale (&#x3b1;) and shape (<italic>&#x3b2;</italic>) being two parameters used to describe the Weibull distribution shape (<xref ref-type="bibr" rid="B51">Mazhar et al., 2021</xref>).</p>
</sec>
<sec id="s2-3">
<title>2.3 Subgroup analysis</title>
<p>Subgroup analyses were conducted to investigate the association between etoposide dosing and adverse effects in subgroups based on age (&#x3c;18 [child and adolescent], 18&#x2013;64 [adult], and &#x3e;64 [elder]), gender (male and female), weight (&#x3c;80&#xa0;kg, 80&#x2013;100&#xa0;kg, and &#x3e;100&#xa0;kg), and reporting person (consumer and health professional).</p>
</sec>
<sec id="s2-4">
<title>2.4 Data mining algorithm and statistical analysis</title>
<p>Disproportionality analysis is primarily used as a tool for hypothesizing possible causal relationships between drugs and adverse events. It is based on comparing the observed and expected number of reports for each specific combination of drug and adverse event (<xref ref-type="bibr" rid="B58">Montastruc et al., 2011</xref>; <xref ref-type="bibr" rid="B11">Caster et al., 2020</xref>; <xref ref-type="bibr" rid="B31">Hu et al., 2020</xref>; <xref ref-type="bibr" rid="B80">Sharma et al., 2023</xref>). Consequently, in our research, we conducted a disproportionality analysis to determine the potential correlation between etoposide and all ADEs. Considering that separate methods of detecting signals may be insufficient, the four algorithms including reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS) were implied (<xref ref-type="bibr" rid="B46">Lindquist et al., 2000</xref>; <xref ref-type="bibr" rid="B100">van Puijenbroek et al., 2002</xref>; <xref ref-type="bibr" rid="B77">Shao et al., 2021</xref>; <xref ref-type="bibr" rid="B111">Zhou et al., 2021</xref>). PRR and ROR are frequencyist (non-Bayesian), while BCPNN and MGPS are Bayesian (<xref ref-type="bibr" rid="B74">Sakaeda et al., 2013</xref>). Information Components (IC) are used in the tool BCPNN to measure disproportionality (<xref ref-type="bibr" rid="B28">Hauben and Zhou, 2003</xref>; <xref ref-type="bibr" rid="B7">Bate, 2007</xref>). MGPS analysis is a well-established technique for reducing the rate of false-positive reports by applying a Bayesian shrinkage estimator to the observed/expected ratio to give smaller risk estimates with narrower confidence intervals, even if the event counts are small (<xref ref-type="bibr" rid="B61">Napoli et al., 2014</xref>; <xref ref-type="bibr" rid="B98">Trippe et al., 2017</xref>). The two Bayesian methods (BCPNN and MGPS) were considered useful because each detected unique signal even when there were few reports of ADE for a particular drug (<xref ref-type="bibr" rid="B64">Nomura et al., 2015</xref>). Overall, the higher the value of the four parameters, the stronger the signal value. The specific formulas and the criteria of positive safety signal detection of the four algorithms were shown in <xref ref-type="table" rid="T1">Table 1</xref>. Only the signals that had at a minimum of three targeted drug ADEs records were counted. To assure the reliability of the results, we selected ADEs signals that satisfy the above four algorithm criteria simultaneously for the study (<xref ref-type="bibr" rid="B74">Sakaeda et al., 2013</xref>; <xref ref-type="bibr" rid="B108">Yin et al., 2022</xref>). We also excluded the indications for etoposide from the ADEs to avoid unclear presentation (<xref ref-type="bibr" rid="B92">Tang et al., 2022</xref>). The drug label of etoposide was obtained from the DailyMed (<ext-link ext-link-type="uri" xlink:href="https://dailymed.nlm.nih.gov/dailymed/index.cfm">https://dailymed.nlm.nih.gov/dailymed/index.cfm</ext-link>)(<xref ref-type="bibr" rid="B107">Yao et al., 2017</xref>), and Summary of Product Characteristics (SmPC) (<ext-link ext-link-type="uri" xlink:href="https://www.ema.europa.eu/en/glossary/summary-product-characteristics">https://www.ema.europa.eu/en/glossary/summary-product-characteristics</ext-link>) (<xref ref-type="bibr" rid="B62">Nezvalova-Henriksen et al., 2023</xref>). Novelty/unexpectedness signal is defined as any significant ADEs detected without being outlined in the drug label (<xref ref-type="bibr" rid="B82">Shu et al., 2022a</xref>). All processing of data and statistical analyses were carried out using SAS 9.4, Microsoft EXCEL 2019, and R (version 4.2.1).</p>
<table-wrap id="T1" position="float">
<label>TABLE 1</label>
<caption>
<p>Four major algorithms used to assess potential associations between etoposide and ADEs. a, Number of reports that contain both targeted drug and targeted drug adverse reactions; b, Number of reports of other drug adverse reactions that contain the targeted drug; c, Number of reports of targeted drug adverse reactions that contain other drugs; d, Number of reports that contain other drugs and other drug adverse reactions. 95% CI, 95% confidence interval; N, the number of reports; &#x3c7;2, chi-squared; IC, information component; IC025, the lower limit of 95% CI of the IC; E (IC), the IC expectations; V(IC), the variance of IC; EBGM, empirical Bayesian geometric mean; EBGM05, the lower limit of 95% CI of EBGM.</p>
</caption>
<table>
<thead valign="top">
<tr>
<th align="left">Algorithms</th>
<th align="center">Equation</th>
<th align="center">Criteria</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td rowspan="2" align="left">ROR</td>
<td align="left">ROR &#x3d; (ad/bc)</td>
<td rowspan="2" align="center">lower limit of 95% CI &#x3e; 1</td>
</tr>
<tr>
<td align="left">95%CI &#x3d; eln (ROR)&#xb1;1.96 (1/a&#x2b;1/b&#x2b;1/c&#x2b;1/d)&#x5e;0.5</td>
</tr>
<tr>
<td rowspan="2" align="left">PRR</td>
<td align="left">PRR &#x3d; a (c&#x2b;d)/c/(a&#x2b;b)</td>
<td rowspan="2" align="center">N &#x2265; 3 PRR&#x2265;2, &#x3c7;2&#x2265;4, N &#x2265; 3</td>
</tr>
<tr>
<td align="left">&#x3c7;2 &#x3d; [(ad-bc)&#x5e;2](a&#x2b;b&#x2b;c&#x2b;d)/[(a&#x2b;b)(c&#x2b;d)(a&#x2b;c)(b&#x2b;d)]</td>
</tr>
<tr>
<td rowspan="2" align="left">BCPNN</td>
<td align="left">IC &#x3d; log2a (a&#x2b;b&#x2b;c&#x2b;d)/((a&#x2b;c)(a&#x2b;b))</td>
<td rowspan="2" align="center">IC025 &#x3e; 0</td>
</tr>
<tr>
<td align="left">95%CI &#x3d; E (IC) &#xb1; 2V(IC)&#x5e;0.5</td>
</tr>
<tr>
<td rowspan="2" align="left">MGPS</td>
<td align="left">EBGM &#x3d; a (a&#x2b;b&#x2b;c&#x2b;d)/(a&#x2b;c)/(a&#x2b;b)</td>
<td rowspan="2" align="center">EBGM05 &#x3e; 2</td>
</tr>
<tr>
<td align="left">95%CI &#x3d; eln (EBGM)&#xb1;1.96 (1/a&#x2b;1/b&#x2b;1/c&#x2b;1/d)&#x5e;0.5</td>
</tr>
</tbody>
</table>
</table-wrap>
</sec>
</sec>
<sec sec-type="results" id="s3">
<title>3 Results</title>
<sec id="s3-1">
<title>3.1 Annual distribution of etoposide-related ADE reports</title>
<p>According to the data from the FAERS database, there were a total of 9892 ADEs reports for etoposide between January 2004 and December 2022. From an overall perspective, the number of ADE reports has been increasing over the years, as depicted in <xref ref-type="fig" rid="F2">Figure 2</xref>. The lowest and highest number of reports were observed in 2005 (114 reports) and 2020 (1230 reports), respectively. Notably, there was a substantial increase in the number of reports in 2015. More detailed information on the annual distribution can be found in <xref ref-type="fig" rid="F2">Figure 2</xref>.</p>
<fig id="F2" position="float">
<label>FIGURE2</label>
<caption>
<p>The annual distribution of etoposide-related ADE reports from 2004 to 2022.</p>
</caption>
<graphic xlink:href="fphar-14-1259908-g002.tif"/>
</fig>
</sec>
<sec id="s3-2">
<title>3.2 General characteristics in the real-world population</title>
<p>
<xref ref-type="table" rid="T2">Table 2</xref> displayed the population characteristics of the ADEs reports associated with etoposide. It is notable that there were more male patients reported (49.6%) compared to female patients (34.3%), potentially due to specific indications of the drug such as testicular cancer. The reported proportions of body weight in the categories of &#x3c;80&#xa0;kg, 80&#x2013;100&#xa0;kg, and &#x3e;100&#xa0;kg was 15.7%, 4.5%, and 1.3%, respectively. A higher occurrence of etoposide-related ADEs was observed in young (22.5%) and middle-aged patients (39.4%) compared to elderly patients (14.1%).</p>
<table-wrap id="T2" position="float">
<label>TABLE 2</label>
<caption>
<p>Clinical characteristics of reports with etoposide from the FAERS Database (January 2004&#x2013;December 2022).</p>
</caption>
<table>
<thead valign="top">
<tr>
<th align="center">Characteristics</th>
<th align="center">Case number, n</th>
<th align="center">Case proportion, %</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td align="center">
<bold>Number of events</bold>
</td>
<td align="center">9892</td>
<td align="left"/>
</tr>
<tr>
<td align="center">
<bold>Gender</bold>
</td>
<td align="left"/>
<td align="left"/>
</tr>
<tr>
<td align="center">Female</td>
<td align="center">3392</td>
<td align="center">34.3</td>
</tr>
<tr>
<td align="center">Male</td>
<td align="center">4903</td>
<td align="center">49.6</td>
</tr>
<tr>
<td align="center">Unknown</td>
<td align="center">1597</td>
<td align="center">16.1</td>
</tr>
<tr>
<td align="center">
<bold>Weight (kg)</bold>
</td>
<td align="left"/>
<td align="left"/>
</tr>
<tr>
<td align="center">&#x3c;80</td>
<td align="center">1553</td>
<td align="center">15.7</td>
</tr>
<tr>
<td align="center">80&#x2013;100</td>
<td align="center">449</td>
<td align="center">4.5</td>
</tr>
<tr>
<td align="center">&#x3e;100</td>
<td align="center">127</td>
<td align="center">1.3</td>
</tr>
<tr>
<td align="center">Unknown</td>
<td align="center">7763</td>
<td align="center">78.5</td>
</tr>
<tr>
<td align="center">
<bold>Age (years)</bold>
</td>
<td align="left"/>
<td align="left"/>
</tr>
<tr>
<td align="center">&#x3c;18</td>
<td align="center">2228</td>
<td align="center">22.5</td>
</tr>
<tr>
<td align="center">18&#x2013;64</td>
<td align="center">3893</td>
<td align="center">39.4</td>
</tr>
<tr>
<td align="center">&#x3e;64</td>
<td align="center">1399</td>
<td align="center">14.1</td>
</tr>
<tr>
<td align="center">Unknown</td>
<td align="center">2372</td>
<td align="center">24.0</td>
</tr>
<tr>
<td align="center">
<bold>Reported Countries (top five)</bold>
</td>
<td align="left"/>
<td align="left"/>
</tr>
<tr>
<td align="center">America</td>
<td align="center">2694</td>
<td align="center">27.2</td>
</tr>
<tr>
<td align="center">France</td>
<td align="center">1100</td>
<td align="center">11.1</td>
</tr>
<tr>
<td align="center">Japan</td>
<td align="center">912</td>
<td align="center">9.2</td>
</tr>
<tr>
<td align="center">Canada</td>
<td align="center">858</td>
<td align="center">8.7</td>
</tr>
<tr>
<td align="center">Italy</td>
<td align="center">494</td>
<td align="center">5.0</td>
</tr>
<tr>
<td align="center">
<bold>Reported Person</bold>
</td>
<td align="left"/>
<td align="left"/>
</tr>
<tr>
<td align="center">Health professional</td>
<td align="center">8779</td>
<td align="center">88.7</td>
</tr>
<tr>
<td align="center">Consumer</td>
<td align="center">608</td>
<td align="center">6.2</td>
</tr>
<tr>
<td align="center">Unknown</td>
<td align="center">505</td>
<td align="center">5.1</td>
</tr>
<tr>
<td align="center">
<bold>Serious Outcomes</bold>
</td>
<td align="left"/>
<td align="left"/>
</tr>
<tr>
<td align="center">Death (DE)</td>
<td align="center">1937</td>
<td align="center">15.5</td>
</tr>
<tr>
<td align="center">Life-threatening (LF)</td>
<td align="center">1041</td>
<td align="center">8.3</td>
</tr>
<tr>
<td align="center">Hospitalization (HO)</td>
<td align="center">3065</td>
<td align="center">24.6</td>
</tr>
<tr>
<td align="center">Disability (DS)</td>
<td align="center">133</td>
<td align="center">1.1</td>
</tr>
<tr>
<td align="center">Other serious outcomes</td>
<td align="center">6308</td>
<td align="center">50.5</td>
</tr>
<tr>
<td align="center">
<bold>Indications (top five)</bold>
</td>
<td align="left"/>
<td align="left"/>
</tr>
<tr>
<td align="center">Product used for unknown indication</td>
<td align="center">661</td>
<td align="center">6.7</td>
</tr>
<tr>
<td align="center">Acute myeloid leukaemia</td>
<td align="center">456</td>
<td align="center">4.6</td>
</tr>
<tr>
<td align="center">Small cell lung cancer</td>
<td align="center">370</td>
<td align="center">3.7</td>
</tr>
<tr>
<td align="center">Hodgkin&#x2019;s disease</td>
<td align="center">360</td>
<td align="center">3.6</td>
</tr>
<tr>
<td align="center">Acute lymphocytic leukaemia</td>
<td align="center">344</td>
<td align="center">3.5</td>
</tr>
</tbody>
</table>
</table-wrap>
<p>The majority of ADE reports were from the United States (27.2%), followed by France (11.1%), Japan (9.2%), Canada (8.7%), and Italy (5.0%). Interestingly, health professionals accounted for the highest proportion (88.7%) of these reports. Among the serious outcomes reported, 50.5% were classified as &#x201c;other serious outcomes,&#x201d; while the most frequently reported serious outcome was hospitalization (24.6%). Additionally, the percentages of death and life-threatening outcomes were 15.5% and 8.3%, respectively. These outcomes may be more closely associated with the progression of the underlying tumor.</p>
<p>The top five indications for etoposide use included cases where the product was used for an unknown indication (6.7%), acute myeloid leukemia (4.6%), small cell lung cancer (3.7%), Hodgkin&#x2019;s disease (3.6%), and acute lymphocytic leukemia (3.5%).</p>
</sec>
<sec id="s3-3">
<title>3.3 Signals detection at the system organ class level</title>
<p>
<xref ref-type="table" rid="T3">Table 3</xref> presented the signal strength and number of reports for etoposide at the System Organ Class (SOC) level. Our statistical analysis identified a total of 27 organ systems that were implicated in etoposide-induced ADEs. The SOC that met all four criteria simultaneously and showed significant association with etoposide ADEs was blood and lymphatic system disorders (SOC code: 10005329, 3745 reports).</p>
<table-wrap id="T3" position="float">
<label>TABLE 3</label>
<caption>
<p>Signal strength of ADEs of etoposide at the System Organ Class (SOC) level in FAERS database. An asterisk indicates a positive signal value under this algorithm. ROR, reporting odds ratio; CI, confidence interval; PRR, proportional reporting ratio; &#x3c7;2, chi-squared; IC, information component; EBGM, empirical Bayesian geometric mean.</p>
</caption>
<table>
<thead valign="top">
<tr>
<th align="left">SOC name</th>
<th align="center">Case number</th>
<th align="center">ROR (95%CI)</th>
<th align="center">PRR (&#x3c7;2)</th>
<th align="center">IC(IC025)</th>
<th align="center">EBGM(EBGM05)</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td align="left">Blood and lymphatic system disorders</td>
<td align="center">3745</td>
<td align="center">8.53 (8.24&#x2013;8.83)&#x2a;</td>
<td align="center">7.58 (21665.64)&#x2a;</td>
<td align="center">2.92 (1.25)&#x2a;</td>
<td align="center">7.55 (7.34)&#x2a;</td>
</tr>
<tr>
<td align="left">Infections and infestations</td>
<td align="center">3641</td>
<td align="center">2.57 (2.48&#x2013;2.66)&#x2a;</td>
<td align="center">2.37 (3050.51)&#x2a;</td>
<td align="center">1.25 (-0.42)</td>
<td align="center">2.37 (2.30)&#x2a;</td>
</tr>
<tr>
<td align="left">General disorders and administration site conditions</td>
<td align="center">3106</td>
<td align="center">0.56 (0.54&#x2013;0.58)</td>
<td align="center">0.60 (985.15)</td>
<td align="center">&#x2212;0.73 (-2.40)</td>
<td align="center">0.60 (0.58)</td>
</tr>
<tr>
<td align="left">Injury, poisoning and procedural complications</td>
<td align="center">2500</td>
<td align="center">0.85 (0.82&#x2013;0.89)</td>
<td align="center">0.86 (60.59)</td>
<td align="center">&#x2212;0.21 (-1.88)</td>
<td align="center">0.86 (0.83)</td>
</tr>
<tr>
<td align="left">Gastrointestinal disorders</td>
<td align="center">2249</td>
<td align="center">0.87 (0.84&#x2013;0.91)</td>
<td align="center">0.88 (38.71)</td>
<td align="center">&#x2212;0.18 (-1.85)</td>
<td align="center">0.88 (0.85)</td>
</tr>
<tr>
<td align="left">Respiratory, thoracic and mediastinal disorders</td>
<td align="center">2075</td>
<td align="center">1.51 (1.44&#x2013;1.58)&#x2a;</td>
<td align="center">1.47 (328.26)</td>
<td align="center">0.56 (-1.11)</td>
<td align="center">1.47 (1.42)</td>
</tr>
<tr>
<td align="left">Neoplasms benign, malignant and unspecified (incl cysts and polyps)</td>
<td align="center">1852</td>
<td align="center">2.34 (2.23&#x2013;2.45)&#x2a;</td>
<td align="center">2.25 (1327.28)&#x2a;</td>
<td align="center">1.17 (-0.49)</td>
<td align="center">2.25 (2.17)&#x2a;</td>
</tr>
<tr>
<td align="left">Nervous system disorders</td>
<td align="center">1724</td>
<td align="center">0.65 (0.62&#x2013;0.68)</td>
<td align="center">0.67 (305.59)</td>
<td align="center">&#x2212;0.58 (-2.24)</td>
<td align="center">0.67 (0.64)</td>
</tr>
<tr>
<td align="left">Investigations</td>
<td align="center">1406</td>
<td align="center">0.74 (0.70&#x2013;0.78)</td>
<td align="center">0.75 (119.71)</td>
<td align="center">&#x2212;0.41 (-2.07)</td>
<td align="center">0.75 (0.72)</td>
</tr>
<tr>
<td align="left">Cardiac disorders</td>
<td align="center">995</td>
<td align="center">1.24 (1.16&#x2013;1.32)&#x2a;</td>
<td align="center">1.23 (43.13)</td>
<td align="center">0.30 (-1.37)</td>
<td align="center">1.23 (1.16)</td>
</tr>
<tr>
<td align="left">Vascular disorders</td>
<td align="center">976</td>
<td align="center">1.52 (1.43&#x2013;1.62)&#x2a;</td>
<td align="center">1.50 (167.46)</td>
<td align="center">0.59 (-1.08)</td>
<td align="center">1.50 (1.42)</td>
</tr>
<tr>
<td align="left">Skin and subcutaneous tissue disorders</td>
<td align="center">856</td>
<td align="center">0.52 (0.49&#x2013;0.56)</td>
<td align="center">0.54 (361.48)</td>
<td align="center">&#x2212;0.90 (-2.56)</td>
<td align="center">0.54 (0.51)</td>
</tr>
<tr>
<td align="left">Renal and urinary disorders</td>
<td align="center">854</td>
<td align="center">1.47 (1.37&#x2013;1.57)&#x2a;</td>
<td align="center">1.46 (124.1)</td>
<td align="center">0.54 (-1.12)</td>
<td align="center">1.46 (1.37)</td>
</tr>
<tr>
<td align="left">Metabolism and nutrition disorders</td>
<td align="center">808</td>
<td align="center">1.25 (1.16&#x2013;1.34)&#x2a;</td>
<td align="center">1.24 (38.53)</td>
<td align="center">0.31 (-1.36)</td>
<td align="center">1.24 (1.17)</td>
</tr>
<tr>
<td align="left">Hepatobiliary disorders</td>
<td align="center">566</td>
<td align="center">2.10 (1.93&#x2013;2.28)&#x2a;</td>
<td align="center">2.08 (318.85)&#x2a;</td>
<td align="center">1.05 (-0.61)</td>
<td align="center">2.08 (1.94)</td>
</tr>
<tr>
<td align="left">Musculoskeletal and connective tissue disorders</td>
<td align="center">441</td>
<td align="center">0.27 (0.25&#x2013;0.30)</td>
<td align="center">0.28 (855.40)</td>
<td align="center">&#x2212;1.83 (-3.50)</td>
<td align="center">0.28 (0.26)</td>
</tr>
<tr>
<td align="left">Immune system disorders</td>
<td align="center">441</td>
<td align="center">1.36 (1.24&#x2013;1.50)&#x2a;</td>
<td align="center">1.36 (41.95)</td>
<td align="center">0.44 (-1.23)</td>
<td align="center">1.36 (1.25)</td>
</tr>
<tr>
<td align="left">Psychiatric disorders</td>
<td align="center">292</td>
<td align="center">0.16 (0.14&#x2013;0.18)</td>
<td align="center">0.17 (1246.38)</td>
<td align="center">&#x2212;2.55 (-4.21)</td>
<td align="center">0.17 (0.16)</td>
</tr>
<tr>
<td align="left">Surgical and medical procedures</td>
<td align="center">231</td>
<td align="center">0.61 (0.53&#x2013;0.69)</td>
<td align="center">0.61 (58.82)</td>
<td align="center">&#x2212;0.72 (-2.38)</td>
<td align="center">0.61 (0.55)</td>
</tr>
<tr>
<td align="left">Eye disorders</td>
<td align="center">217</td>
<td align="center">0.37 (0.32&#x2013;0.42)</td>
<td align="center">0.37 (235.75)</td>
<td align="center">&#x2212;1.43 (-3.10)</td>
<td align="center">0.37 (0.33)</td>
</tr>
<tr>
<td align="left">Ear and labyrinth disorders</td>
<td align="center">184</td>
<td align="center">1.42 (1.23&#x2013;1.64)&#x2a;</td>
<td align="center">1.42 (22.70)</td>
<td align="center">0.50 (-1.16)</td>
<td align="center">1.42 (1.26)</td>
</tr>
<tr>
<td align="left">Reproductive system and breast disorders</td>
<td align="center">149</td>
<td align="center">0.54 (0.46&#x2013;0.63)</td>
<td align="center">0.54 (59.52)</td>
<td align="center">&#x2212;0.89 (-2.56)</td>
<td align="center">0.54 (0.47)</td>
</tr>
<tr>
<td align="left">Congenital, familial and genetic disorders</td>
<td align="center">143</td>
<td align="center">1.53 (1.29&#x2013;1.80)&#x2a;</td>
<td align="center">1.52 (25.73)</td>
<td align="center">0.61 (-1.06)</td>
<td align="center">1.52 (1.33)</td>
</tr>
<tr>
<td align="left">Endocrine disorders</td>
<td align="center">114</td>
<td align="center">1.54 (1.28&#x2013;1.85)&#x2a;</td>
<td align="center">1.54 (21.63)</td>
<td align="center">0.62 (-1.04)</td>
<td align="center">1.54 (1.32)</td>
</tr>
<tr>
<td align="left">Pregnancy, puerperium and perinatal conditions</td>
<td align="center">96</td>
<td align="center">0.72 (0.59&#x2013;0.89)</td>
<td align="center">0.73 (10.00)</td>
<td align="center">&#x2212;0.46 (-2.13)</td>
<td align="center">0.73 (0.61)</td>
</tr>
<tr>
<td align="left">Product issues</td>
<td align="center">48</td>
<td align="center">0.11 (0.08&#x2013;0.14)</td>
<td align="center">0.11 (363.25)</td>
<td align="center">&#x2212;3.22 (-4.89)</td>
<td align="center">0.11 (0.08)</td>
</tr>
<tr>
<td align="left">Social circumstances</td>
<td align="center">14</td>
<td align="center">0.10 (0.06&#x2013;0.17)</td>
<td align="center">0.10 (112.74)</td>
<td align="center">&#x2212;3.31 (-4.97)</td>
<td align="center">0.10 (0.07)</td>
</tr>
</tbody>
</table>
</table-wrap>
<p>Additionally, other significant SOCs that met three criteria at the same time included infections and infestations (SOC code: 10021881, 3641 reports), and neoplasms benign, malignant, and unspecified (including cysts and polyps) (SOC code: 10029104, 1852 reports). Furthermore, there were several other significant SOCs that met at least one of the criteria. These included respiratory, thoracic, and mediastinal disorders (SOC code: 10038738, 2075 reports), cardiac disorders (SOC code: 10007541, 995 reports), vascular disorders (SOC code: 10047065, 976 reports), renal and urinary disorders (SOC code: 10038359, 854 reports), metabolism and nutrition disorders (SOC code: 10027433, 808 reports), hepatobiliary disorders (SOC code: 10019805, 566 reports), immune system disorders (SOC code: 10021428, 441 reports), ear and labyrinth disorders (SOC code: 10013993, 184 reports), congenital, familial, genetic disorders (SOC code: 10010331, 143 reports), and endocrine disorders (SOC code: 10014698, 114 reports).</p>
</sec>
<sec id="s3-4">
<title>3.4 Signals detection at the preferred terms level</title>
<p>A total of 478 etoposide-induced ADEs that covering 26 SOCs at the PT level were detected after compliance with all four algorithms simultaneously. The full results were listed in <xref ref-type="sec" rid="s11">Supplementary Table S1</xref>. We then ranked all the PTs with ADEs case number exceeding 30 (a&#x3e;30) according to the value of EBGM05 (the most stringent algorithm) from largest to smallest, and selected a total of 68 ADEs that met the screening criteria (<xref ref-type="bibr" rid="B74">Sakaeda et al., 2013</xref>). They were grouped by SOC and the result was shown in <xref ref-type="table" rid="T4">Table 4</xref>.</p>
<table-wrap id="T4" position="float">
<label>TABLE 4</label>
<caption>
<p>Signal strength of ADEs of etoposide at the Preferred terms (PTs) level in FAERS database. Asterisks indicate new and significant signals of etoposide-associated ADEs from FAERS database. ROR, reporting odds ratio; CI, confidence interval; PRR, proportional reporting ratio; &#x3c7;2, chi-squared; IC, information component; EBGM, empirical Bayesian geometric mean.</p>
</caption>
<table>
<thead valign="top">
<tr>
<th align="left">SOC name</th>
<th align="left">Preferred terms (PTs)</th>
<th align="center">Case numbers</th>
<th align="center">ROR(95%Cl)</th>
<th align="center">PRR</th>
<th align="center">&#x3c7;2</th>
<th align="center">IC (IC025)</th>
<th align="center">EBGM (EBGM05)</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td align="left">Blood and lymphatic system disorders</td>
<td align="left">Febrile bone marrow aplasia&#x2a;</td>
<td align="center">80</td>
<td align="center">42.49 (34.03&#x2013;53.07)</td>
<td align="center">42.38</td>
<td align="center">3150.61</td>
<td align="center">5.37 (3.70)</td>
<td align="center">41.33 (34.32)</td>
</tr>
<tr>
<td align="left">Blood and lymphatic system disorders</td>
<td align="left">Febrile neutropenia</td>
<td align="center">874</td>
<td align="center">30.34 (28.35&#x2013;32.47)</td>
<td align="center">29.48</td>
<td align="center">23639.47</td>
<td align="center">4.86 (3.19)</td>
<td align="center">28.97 (27.37)</td>
</tr>
<tr>
<td align="left">Blood and lymphatic system disorders</td>
<td align="left">Bone marrow failure&#x2a;</td>
<td align="center">248</td>
<td align="center">22.15 (19.53&#x2013;25.12)</td>
<td align="center">21.98</td>
<td align="center">4901.18</td>
<td align="center">4.44 (2.77)</td>
<td align="center">21.70 (19.53)</td>
</tr>
<tr>
<td align="left">Blood and lymphatic system disorders</td>
<td align="left">Haematotoxicity</td>
<td align="center">87</td>
<td align="center">23.16 (18.74&#x2013;28.63)</td>
<td align="center">23.10</td>
<td align="center">1813.81</td>
<td align="center">4.51 (2.84)</td>
<td align="center">22.79 (19.09)</td>
</tr>
<tr>
<td align="left">Blood and lymphatic system disorders</td>
<td align="left">Aplastic anaemia</td>
<td align="center">60</td>
<td align="center">23.97 (18.57&#x2013;30.94)</td>
<td align="center">23.93</td>
<td align="center">1299.08</td>
<td align="center">4.56 (2.89)</td>
<td align="center">23.59 (19.06)</td>
</tr>
<tr>
<td align="left">Blood and lymphatic system disorders</td>
<td align="left">Pancytopenia</td>
<td align="center">386</td>
<td align="center">14.89 (13.46&#x2013;16.47)</td>
<td align="center">14.71</td>
<td align="center">4893.66</td>
<td align="center">3.87 (2.20)</td>
<td align="center">14.59 (13.41)</td>
</tr>
<tr>
<td align="left">Blood and lymphatic system disorders</td>
<td align="left">Neutropenia</td>
<td align="center">561</td>
<td align="center">9.43 (8.67&#x2013;10.25)</td>
<td align="center">9.27</td>
<td align="center">4123.11</td>
<td align="center">3.21 (1.54)</td>
<td align="center">9.22 (8.60)</td>
</tr>
<tr>
<td align="left">Blood and lymphatic system disorders</td>
<td align="left">Thrombocytopenia</td>
<td align="center">417</td>
<td align="center">7.96 (7.23&#x2013;8.77)</td>
<td align="center">7.86</td>
<td align="center">2490.27</td>
<td align="center">2.97 (1.30)</td>
<td align="center">7.83 (7.22)</td>
</tr>
<tr>
<td align="left">Blood and lymphatic system disorders</td>
<td align="left">Disseminated intravascular coagulation&#x2a;</td>
<td align="center">62</td>
<td align="center">8.42 (6.56&#x2013;10.80)</td>
<td align="center">8.40</td>
<td align="center">402.2</td>
<td align="center">3.06 (1.40)</td>
<td align="center">8.36 (6.78)</td>
</tr>
<tr>
<td align="left">Blood and lymphatic system disorders</td>
<td align="left">Leukopenia</td>
<td align="center">176</td>
<td align="center">7.36 (6.34&#x2013;8.54)</td>
<td align="center">7.32</td>
<td align="center">957.31</td>
<td align="center">2.87 (1.20)</td>
<td align="center">7.29 (6.44)</td>
</tr>
<tr>
<td align="left">Blood and lymphatic system disorders</td>
<td align="left">Thrombotic microangiopathy&#x2a;</td>
<td align="center">35</td>
<td align="center">8.41 (6.04&#x2013;11.73)</td>
<td align="center">8.41</td>
<td align="center">227.22</td>
<td align="center">3.06 (1.40)</td>
<td align="center">8.37 (6.34)</td>
</tr>
<tr>
<td align="left">Blood and lymphatic system disorders</td>
<td align="left">Lymphopenia</td>
<td align="center">50</td>
<td align="center">7.66 (5.80&#x2013;10.11)</td>
<td align="center">7.64</td>
<td align="center">287.48</td>
<td align="center">2.93 (1.26)</td>
<td align="center">7.61 (6.03)</td>
</tr>
<tr>
<td align="left">Blood and lymphatic system disorders</td>
<td align="left">Cytopenia</td>
<td align="center">34</td>
<td align="center">7.84 (5.59&#x2013;10.98)</td>
<td align="center">7.83</td>
<td align="center">201.58</td>
<td align="center">2.96 (1.30)</td>
<td align="center">7.80 (5.88)</td>
</tr>
<tr>
<td align="left">Blood and lymphatic system disorders</td>
<td align="left">Myelosuppression</td>
<td align="center">47</td>
<td align="center">6.32 (4.74&#x2013;8.41)</td>
<td align="center">6.31</td>
<td align="center">209.16</td>
<td align="center">2.65 (0.99)</td>
<td align="center">6.29 (4.95)</td>
</tr>
<tr>
<td align="left">Blood and lymphatic system disorders</td>
<td align="left">Agranulocytosis</td>
<td align="center">45</td>
<td align="center">5.60 (4.18&#x2013;7.51)</td>
<td align="center">5.59</td>
<td align="center">169.21</td>
<td align="center">2.48 (0.81)</td>
<td align="center">5.58 (4.37)</td>
</tr>
<tr>
<td align="left">Blood and lymphatic system disorders</td>
<td align="left">Anaemia</td>
<td align="center">345</td>
<td align="center">3.64 (3.27&#x2013;4.04)</td>
<td align="center">3.61</td>
<td align="center">650.42</td>
<td align="center">1.85 (0.18)</td>
<td align="center">3.60 (3.29)</td>
</tr>
<tr>
<td align="left">Cardiac disorders</td>
<td align="left">Cardiotoxicity&#x2a;</td>
<td align="center">73</td>
<td align="center">19.62 (15.57&#x2013;24.71)</td>
<td align="center">19.57</td>
<td align="center">1271.21</td>
<td align="center">4.27 (2.61)</td>
<td align="center">19.35 (15.95)</td>
</tr>
<tr>
<td align="left">Cardiac disorders</td>
<td align="left">Acute myocardial infarction</td>
<td align="center">53</td>
<td align="center">3.37 (2.58&#x2013;4.42)</td>
<td align="center">3.37</td>
<td align="center">88.13</td>
<td align="center">1.75 (0.08)</td>
<td align="center">3.36 (2.68)</td>
</tr>
<tr>
<td align="left">Congenital, familial and genetic disorders</td>
<td align="left">Aplasia</td>
<td align="center">61</td>
<td align="center">52.62 (40.77&#x2013;67.92)</td>
<td align="center">52.52</td>
<td align="center">2986.25</td>
<td align="center">5.67 (4.00)</td>
<td align="center">50.90 (41.11)</td>
</tr>
<tr>
<td align="left">Ear and labyrinth disorders</td>
<td align="left">Ototoxicity&#x2a;</td>
<td align="center">37</td>
<td align="center">44.18 (31.86&#x2013;61.25)</td>
<td align="center">44.12</td>
<td align="center">1518.22</td>
<td align="center">5.43 (3.76)</td>
<td align="center">42.98 (32.70)</td>
</tr>
<tr>
<td align="left">Ear and labyrinth disorders</td>
<td align="left">Deafness&#x2a;</td>
<td align="center">51</td>
<td align="center">4.10 (3.12&#x2013;5.40)</td>
<td align="center">4.10</td>
<td align="center">119.16</td>
<td align="center">2.03 (0.37)</td>
<td align="center">4.09 (3.25)</td>
</tr>
<tr>
<td align="left">Gastrointestinal disorders</td>
<td align="left">Neutropenic colitis&#x2a;</td>
<td align="center">42</td>
<td align="center">51.05 (37.54&#x2013;69.42)</td>
<td align="center">50.98</td>
<td align="center">1995.59</td>
<td align="center">5.63 (3.96)</td>
<td align="center">49.46 (38.25)</td>
</tr>
<tr>
<td align="left">Gastrointestinal disorders</td>
<td align="left">Oesophagitis</td>
<td align="center">45</td>
<td align="center">8.31 (6.20&#x2013;11.14)</td>
<td align="center">8.30</td>
<td align="center">287.4</td>
<td align="center">3.05 (1.38)</td>
<td align="center">8.26 (6.46)</td>
</tr>
<tr>
<td align="left">Gastrointestinal disorders</td>
<td align="left">Colitis&#x2a;</td>
<td align="center">72</td>
<td align="center">4.23 (3.36&#x2013;5.34)</td>
<td align="center">4.23</td>
<td align="center">176.96</td>
<td align="center">2.08 (0.41)</td>
<td align="center">4.22 (3.47)</td>
</tr>
<tr>
<td align="left">Gastrointestinal disorders</td>
<td align="left">Stomatitis</td>
<td align="center">109</td>
<td align="center">3.83 (3.17&#x2013;4.62)</td>
<td align="center">3.82</td>
<td align="center">226.59</td>
<td align="center">1.93 (0.27)</td>
<td align="center">3.81 (3.26)</td>
</tr>
<tr>
<td align="left">General disorders and administration site conditions</td>
<td align="left">Mucosal inflammation</td>
<td align="center">256</td>
<td align="center">20.84 (18.41&#x2013;23.58)</td>
<td align="center">20.67</td>
<td align="center">4732.89</td>
<td align="center">4.35 (2.69)</td>
<td align="center">20.42 (18.41)</td>
</tr>
<tr>
<td align="left">General disorders and administration site conditions</td>
<td align="left">Multiple organ dysfunction syndrome&#x2a;</td>
<td align="center">165</td>
<td align="center">7.53 (6.46&#x2013;8.78)</td>
<td align="center">7.50</td>
<td align="center">925.24</td>
<td align="center">2.90 (1.23)</td>
<td align="center">7.47 (6.57)</td>
</tr>
<tr>
<td align="left">General disorders and administration site conditions</td>
<td align="left">Drug resistance&#x2a;</td>
<td align="center">46</td>
<td align="center">3.92 (2.94&#x2013;5.24)</td>
<td align="center">3.92</td>
<td align="center">99.84</td>
<td align="center">1.97 (0.30)</td>
<td align="center">3.91 (3.07)</td>
</tr>
<tr>
<td align="left">Hepatobiliary disorders</td>
<td align="left">Venoocclusive liver disease&#x2a;</td>
<td align="center">107</td>
<td align="center">48.75 (40.21&#x2013;59.11)</td>
<td align="center">48.58</td>
<td align="center">4841.96</td>
<td align="center">5.56 (3.89)</td>
<td align="center">47.20 (40.17)</td>
</tr>
<tr>
<td align="left">Hepatobiliary disorders</td>
<td align="left">Hepatotoxicity</td>
<td align="center">41</td>
<td align="center">4.00 (2.94&#x2013;5.44)</td>
<td align="center">4.00</td>
<td align="center">91.88</td>
<td align="center">2.00 (0.33)</td>
<td align="center">3.99 (3.09)</td>
</tr>
<tr>
<td align="left">Hepatobiliary disorders</td>
<td align="left">Hepatic failure&#x2a;</td>
<td align="center">52</td>
<td align="center">3.39 (2.58&#x2013;4.46)</td>
<td align="center">3.39</td>
<td align="center">87.43</td>
<td align="center">1.76 (0.09)</td>
<td align="center">3.38 (2.69)</td>
</tr>
<tr>
<td align="left">Immune system disorders</td>
<td align="left">Haemophagocytic lymphohistiocytosis&#x2a;</td>
<td align="center">80</td>
<td align="center">19.91 (15.97&#x2013;24.83)</td>
<td align="center">19.86</td>
<td align="center">1415.83</td>
<td align="center">4.30 (2.63)</td>
<td align="center">19.63 (16.32)</td>
</tr>
<tr>
<td align="left">Immune system disorders</td>
<td align="left">Anaphylactic reaction</td>
<td align="center">94</td>
<td align="center">3.83 (3.13&#x2013;4.70)</td>
<td align="center">3.82</td>
<td align="center">195.81</td>
<td align="center">1.93 (0.27)</td>
<td align="center">3.82 (3.22)</td>
</tr>
<tr>
<td align="left">Infections and infestations</td>
<td align="left">Neutropenic sepsis&#x2a;</td>
<td align="center">104</td>
<td align="center">28.74 (23.67&#x2013;34.90)</td>
<td align="center">28.65</td>
<td align="center">2727.12</td>
<td align="center">4.82 (3.15)</td>
<td align="center">28.17 (23.94)</td>
</tr>
<tr>
<td align="left">Infections and infestations</td>
<td align="left">Aspergillus infection&#x2a;</td>
<td align="center">57</td>
<td align="center">15.77 (12.14&#x2013;20.47)</td>
<td align="center">15.74</td>
<td align="center">779.22</td>
<td align="center">3.96 (2.30)</td>
<td align="center">15.60 (12.54)</td>
</tr>
<tr>
<td align="left">Infections and infestations</td>
<td align="left">Bacteraemia&#x2a;</td>
<td align="center">69</td>
<td align="center">12.95 (10.21&#x2013;16.41)</td>
<td align="center">12.92</td>
<td align="center">753.03</td>
<td align="center">3.68 (2.01)</td>
<td align="center">12.83 (10.52)</td>
</tr>
<tr>
<td align="left">Infections and infestations</td>
<td align="left">Septic shock&#x2a;</td>
<td align="center">216</td>
<td align="center">10.82 (9.46&#x2013;12.38)</td>
<td align="center">10.75</td>
<td align="center">1899.2</td>
<td align="center">3.42 (1.75)</td>
<td align="center">10.69 (9.55)</td>
</tr>
<tr>
<td align="left">Infections and infestations</td>
<td align="left">Bronchopulmonary aspergillosis&#x2a;</td>
<td align="center">36</td>
<td align="center">10.13 (7.30&#x2013;14.06)</td>
<td align="center">10.12</td>
<td align="center">294.15</td>
<td align="center">3.33 (1.66)</td>
<td align="center">10.07 (7.65)</td>
</tr>
<tr>
<td align="left">Infections and infestations</td>
<td align="left">Cytomegalovirus infection&#x2a;</td>
<td align="center">71</td>
<td align="center">8.98 (7.11&#x2013;11.35)</td>
<td align="center">8.96</td>
<td align="center">499.8</td>
<td align="center">3.16 (1.49)</td>
<td align="center">8.92 (7.34)</td>
</tr>
<tr>
<td align="left">Infections and infestations</td>
<td align="left">Pneumocystis jirovecii pneumonia&#x2a;</td>
<td align="center">51</td>
<td align="center">8.85 (6.72&#x2013;11.66)</td>
<td align="center">8.84</td>
<td align="center">352.82</td>
<td align="center">3.14 (1.47)</td>
<td align="center">8.80 (6.99)</td>
</tr>
<tr>
<td align="left">Infections and infestations</td>
<td align="left">Sepsis&#x2a;</td>
<td align="center">379</td>
<td align="center">6.97 (6.29&#x2013;7.71)</td>
<td align="center">6.89</td>
<td align="center">1904.02</td>
<td align="center">2.78 (1.11)</td>
<td align="center">6.87 (6.31)</td>
</tr>
<tr>
<td align="left">Infections and infestations</td>
<td align="left">
<italic>Clostridium difficile</italic> colitis&#x2a;</td>
<td align="center">38</td>
<td align="center">7.41 (5.38&#x2013;10.19)</td>
<td align="center">7.40</td>
<td align="center">209.34</td>
<td align="center">2.88 (1.22)</td>
<td align="center">7.37 (5.64)</td>
</tr>
<tr>
<td align="left">Infections and infestations</td>
<td align="left">
<italic>Candida</italic> infection&#x2a;</td>
<td align="center">49</td>
<td align="center">4.94 (3.73&#x2013;6.54)</td>
<td align="center">4.93</td>
<td align="center">153.24</td>
<td align="center">2.30 (0.63)</td>
<td align="center">4.92 (3.89)</td>
</tr>
<tr>
<td align="left">Infections and infestations</td>
<td align="left">Bacterial infection&#x2a;</td>
<td align="center">39</td>
<td align="center">4.60 (3.36&#x2013;6.30)</td>
<td align="center">4.59</td>
<td align="center">109.38</td>
<td align="center">2.20 (0.53)</td>
<td align="center">4.58 (3.52)</td>
</tr>
<tr>
<td align="left">Infections and infestations</td>
<td align="left">Fungal infection&#x2a;</td>
<td align="center">62</td>
<td align="center">3.86 (3.01&#x2013;4.96)</td>
<td align="center">3.86</td>
<td align="center">131.03</td>
<td align="center">1.95 (0.28)</td>
<td align="center">3.85 (3.13)</td>
</tr>
<tr>
<td align="left">Infections and infestations</td>
<td align="left">
<italic>Clostridium difficile</italic> infection&#x2a;</td>
<td align="center">32</td>
<td align="center">3.24 (2.29&#x2013;4.58)</td>
<td align="center">3.24</td>
<td align="center">49.34</td>
<td align="center">1.69 (0.03)</td>
<td align="center">3.23 (2.42)</td>
</tr>
<tr>
<td align="left">Injury, poisoning and procedural complications</td>
<td align="left">Infusion related reaction&#x2a;</td>
<td align="center">161</td>
<td align="center">5.53 (4.74&#x2013;6.46)</td>
<td align="center">5.51</td>
<td align="center">592.5</td>
<td align="center">2.46 (0.79)</td>
<td align="center">5.49 (4.82)</td>
</tr>
<tr>
<td align="left">Injury, poisoning and procedural complications</td>
<td align="left">Off label use</td>
<td align="center">1143</td>
<td align="center">3.47 (3.27&#x2013;3.69)</td>
<td align="center">3.38</td>
<td align="center">1932.16</td>
<td align="center">1.75 (0.09)</td>
<td align="center">3.37 (3.21)</td>
</tr>
<tr>
<td align="left">Investigations</td>
<td align="left">Ejection fraction decreased&#x2a;</td>
<td align="center">31</td>
<td align="center">4.07 (2.86&#x2013;5.79)</td>
<td align="center">4.06</td>
<td align="center">71.48</td>
<td align="center">2.02 (0.35)</td>
<td align="center">4.06 (3.02)</td>
</tr>
<tr>
<td align="left">Metabolism and nutrition disorders</td>
<td align="left">Tumour lysis syndrome</td>
<td align="center">145</td>
<td align="center">37.61 (31.89&#x2013;44.36)</td>
<td align="center">37.43</td>
<td align="center">5026.69</td>
<td align="center">5.19 (3.53)</td>
<td align="center">36.61 (31.89)</td>
</tr>
<tr>
<td align="left">Neoplasms benign, malignant and unspecified (incl cysts and polyps)</td>
<td align="left">Myelodysplastic syndrome&#x2a;</td>
<td align="center">189</td>
<td align="center">26.49 (22.94&#x2013;30.60)</td>
<td align="center">26.33</td>
<td align="center">4533.37</td>
<td align="center">4.70 (3.03)</td>
<td align="center">25.93 (22.98)</td>
</tr>
<tr>
<td align="left">Neoplasms benign, malignant and unspecified (incl cysts and polyps)</td>
<td align="left">Second primary malignancy&#x2a;</td>
<td align="center">43</td>
<td align="center">10.32 (7.64&#x2013;13.93)</td>
<td align="center">10.30</td>
<td align="center">358.96</td>
<td align="center">3.36 (1.69)</td>
<td align="center">10.24 (7.97)</td>
</tr>
<tr>
<td align="left">Neoplasms benign, malignant and unspecified (incl cysts and polyps)</td>
<td align="left">Malignant neoplasm progression&#x2a;</td>
<td align="center">203</td>
<td align="center">4.45 (3.87&#x2013;5.11)</td>
<td align="center">4.42</td>
<td align="center">537.25</td>
<td align="center">2.14 (0.48)</td>
<td align="center">4.41 (3.93)</td>
</tr>
<tr>
<td align="left">Nervous system disorders</td>
<td align="left">Posterior reversible encephalopathy syndrome&#x2a;</td>
<td align="center">102</td>
<td align="center">21.69 (17.84&#x2013;26.38)</td>
<td align="center">21.62</td>
<td align="center">1980.34</td>
<td align="center">4.42 (2.75)</td>
<td align="center">21.35 (18.13)</td>
</tr>
<tr>
<td align="left">Nervous system disorders</td>
<td align="left">Peripheral sensory neuropathy</td>
<td align="center">33</td>
<td align="center">12.22 (8.67&#x2013;17.21)</td>
<td align="center">12.20</td>
<td align="center">336.95</td>
<td align="center">3.60 (1.93)</td>
<td align="center">12.12 (9.10)</td>
</tr>
<tr>
<td align="left">Nervous system disorders</td>
<td align="left">Encephalopathy&#x2a;</td>
<td align="center">102</td>
<td align="center">8.98 (7.39&#x2013;10.91)</td>
<td align="center">8.95</td>
<td align="center">716.68</td>
<td align="center">3.15 (1.49)</td>
<td align="center">8.91 (7.57)</td>
</tr>
<tr>
<td align="left">Nervous system disorders</td>
<td align="left">Neurotoxicity</td>
<td align="center">32</td>
<td align="center">4.23 (2.99&#x2013;5.99)</td>
<td align="center">4.23</td>
<td align="center">78.76</td>
<td align="center">2.08 (0.41)</td>
<td align="center">4.22 (3.16)</td>
</tr>
<tr>
<td align="left">Renal and urinary disorders</td>
<td align="left">Nephropathy toxic&#x2a;</td>
<td align="center">72</td>
<td align="center">14.88 (11.79&#x2013;18.77)</td>
<td align="center">14.84</td>
<td align="center">921.35</td>
<td align="center">3.88 (2.21)</td>
<td align="center">14.72 (12.12)</td>
</tr>
<tr>
<td align="left">Reproductive system and breast disorders</td>
<td align="left">Ovarian failure&#x2a;</td>
<td align="center">43</td>
<td align="center">179.93 (131.29&#x2013;246.60)</td>
<td align="center">179.67</td>
<td align="center">6879.7</td>
<td align="center">7.34 (5.67)</td>
<td align="center">161.89 (124.36)</td>
</tr>
<tr>
<td align="left">Respiratory, thoracic and mediastinal disorders</td>
<td align="left">Pulmonary toxicity</td>
<td align="center">37</td>
<td align="center">12.61 (9.12&#x2013;17.43)</td>
<td align="center">12.59</td>
<td align="center">391.94</td>
<td align="center">3.64 (1.98)</td>
<td align="center">12.51 (9.54)</td>
</tr>
<tr>
<td align="left">Respiratory, thoracic and mediastinal disorders</td>
<td align="left">Acute respiratory distress syndrome&#x2a;</td>
<td align="center">77</td>
<td align="center">8.88 (7.10&#x2013;11.11)</td>
<td align="center">8.86</td>
<td align="center">534.06</td>
<td align="center">3.14 (1.47)</td>
<td align="center">8.82 (7.31)</td>
</tr>
<tr>
<td align="left">Respiratory, thoracic and mediastinal disorders</td>
<td align="left">Pulmonary haemorrhage&#x2a;</td>
<td align="center">34</td>
<td align="center">8.32 (5.94&#x2013;11.66)</td>
<td align="center">8.32</td>
<td align="center">217.77</td>
<td align="center">3.05 (1.38)</td>
<td align="center">8.28 (6.24)</td>
</tr>
<tr>
<td align="left">Respiratory, thoracic and mediastinal disorders</td>
<td align="left">Pneumonitis</td>
<td align="center">67</td>
<td align="center">5.61 (4.41&#x2013;7.13)</td>
<td align="center">5.60</td>
<td align="center">252.21</td>
<td align="center">2.48 (0.81)</td>
<td align="center">5.58 (4.57)</td>
</tr>
<tr>
<td align="left">Respiratory, thoracic and mediastinal disorders</td>
<td align="left">Respiratory failure&#x2a;</td>
<td align="center">183</td>
<td align="center">5.02 (4.34&#x2013;5.80)</td>
<td align="center">4.99</td>
<td align="center">583.1</td>
<td align="center">2.32 (0.65)</td>
<td align="center">4.98 (4.41)</td>
</tr>
<tr>
<td align="left">Respiratory, thoracic and mediastinal disorders</td>
<td align="left">Respiratory distress&#x2a;</td>
<td align="center">70</td>
<td align="center">5.05 (3.99&#x2013;6.39)</td>
<td align="center">5.04</td>
<td align="center">226.08</td>
<td align="center">2.33 (0.66)</td>
<td align="center">5.03 (4.13)</td>
</tr>
<tr>
<td align="left">Respiratory, thoracic and mediastinal disorders</td>
<td align="left">Hypoxia&#x2a;</td>
<td align="center">68</td>
<td align="center">4.09 (3.22&#x2013;5.19)</td>
<td align="center">4.08</td>
<td align="center">157.79</td>
<td align="center">2.03 (0.36)</td>
<td align="center">4.07 (3.34)</td>
</tr>
<tr>
<td align="left">Surgical and medical procedures</td>
<td align="left">Stem cell transplant</td>
<td align="center">33</td>
<td align="center">28.65 (20.31&#x2013;40.43)</td>
<td align="center">28.62</td>
<td align="center">864.50</td>
<td align="center">4.81 (3.15)</td>
<td align="center">28.14 (21.10)</td>
</tr>
<tr>
<td align="left">Vascular disorders</td>
<td align="left">Venoocclusive disease</td>
<td align="center">41</td>
<td align="center">34.97 (25.66&#x2013;47.66)</td>
<td align="center">34.93</td>
<td align="center">1322.82</td>
<td align="center">5.10 (3.43)</td>
<td align="center">34.21 (26.41)</td>
</tr>
<tr>
<td align="left">Vascular disorders</td>
<td align="left">Flushing</td>
<td align="center">196</td>
<td align="center">3.69 (3.20&#x2013;4.24)</td>
<td align="center">3.67</td>
<td align="center">380.31</td>
<td align="center">1.87 (0.21)</td>
<td align="center">3.66 (3.26)</td>
</tr>
<tr>
<td align="left">Vascular disorders</td>
<td align="left">Cyanosis</td>
<td align="center">34</td>
<td align="center">4.26 (3.04&#x2013;5.97)</td>
<td align="center">4.26</td>
<td align="center">84.58</td>
<td align="center">2.09 (0.42)</td>
<td align="center">4.25 (3.21)</td>
</tr>
</tbody>
</table>
</table-wrap>
<p>In our study, some PTs including thrombocytopenia (PT:10043555, case number 417), leukopenia (PT:10024384, case number 176), myelosuppression (PT:10028584, n &#x3d; 47), febrile neutropenia (PT:10016288, n &#x3d; 874), anaemia (PT:10002034, case number 345), oesophagitis (PT:10030216, n &#x3d; 45), stomatitis (PT:10042128, n &#x3d; 109), hepatotoxicity (PT:10019851, n &#x3d; 41), peripheral sensory neuropathy (PT:10034620, n &#x3d; 33), neurotoxicity (PT:10029350, n &#x3d; 32), and pneumonitis (PT:10035742, n &#x3d; 67) were complied with warnings in instructions and drug labels. Of particular note, more than 40 unexpected significant ADEs were uncovered in drug labels, including disseminated intravascular coagulation (PT:10013442, n &#x3d; 62), thrombotic microangiopathy (PT:10043645, n &#x3d; 35), cardiotoxicity (PT:10048610, n &#x3d; 73), ototoxicity (PT:10033109, n &#x3d; 37), deafness (PT:10011878, n &#x3d; 51), multiple organ dysfunction syndrome (PT:10077361, n &#x3d; 165), drug resistance (PT:10059866, n &#x3d; 46), hepatic failure (PT:10019663, n &#x3d; 52), bacteraemia (PT:10003997, n &#x3d; 69), sepsis (PT:10040047, n &#x3d; 379), <italic>clostridium difficile</italic> infection (PT:10054236, n &#x3d; 32), second primary malignancy (PT:10039801, n &#x3d; 43), malignant neoplasm progression (PT:10051398, n &#x3d; 203), encephalopathy (PT:10014625, n &#x3d; 102), nephropathy toxic (PT:10029155, n &#x3d; 72), ovarian failure (PT:10033165, n &#x3d; 43), acute respiratory distress syndrome (PT:10001052, n &#x3d; 77), respiratory failure (PT:10038695, n &#x3d; 183), hypoxia (PT:10021143, n &#x3d; 68), and so on. Furthermore, although there were some PTs with a small number of cases, the signal value intensity was high, such as Erythema ab igne (n &#x3d; 4, EBGM 722.84 [240.57]), primary hypogonadism (n &#x3d; 16, EBGM 194.20 [125.44]), hypertensive hydrocephalus (n &#x3d; 3, EBGM 232.34 [88.55]), genotoxicity (n &#x3d; 4, EBGM 191.34 [79.92]), renal salt-wasting syndrome (n &#x3d; 19, EBGM 105.11 [71.23]). This suggested that the occurrence of these ADEs and etoposide administration were also closely related and deserved clinical attention. <xref ref-type="sec" rid="s11">Supplementary Table S1</xref> provided the EGBM 05 rankings of all the 478&#xa0;PTs. <xref ref-type="sec" rid="s11">Supplementary Table S2</xref> summarizes all the adverse reactions mentioned in the DailyMed and SmPC instructions. <xref ref-type="sec" rid="s11">Supplementary Figures S1A, S1B</xref> intersects the positive signals found in this study with the adverse drug reactions mentioned in DailyMed and SmPC. To sum up, the ADEs analysis of real-world data based on the FAERS database could also provide a great reference for the revision of etoposide instructions.</p>
</sec>
<sec id="s3-5">
<title>3.5 Time-to-onset analysis of etoposide-related ADEs</title>
<p>The onset times of etoposide-related ADEs were extracted and analyzed from the FAERS database. After removing any missing or incorrect onset time reports, a total of 2138 ADEs with available onset times were included in the analysis. The median onset time was found to be 10 days, with an interquartile range (IQR) of 2&#x2013;32&#xa0;days.</p>
<p>Regarding the distribution of ADEs over time, <xref ref-type="fig" rid="F3">Figure 3</xref> illustrates that the majority of ADEs occurred within the first month after etoposide administration (n &#x3d; 1579, 73.8%). The number of ADEs decreased with a time delay, with 196 ADEs (9.2%) occurring in the second month and 137 ADEs (6.4%) occurring in the third month. Notably, our data showed that adverse events may still occur after 1&#xa0;year of etoposide treatment, accounting for 3.2% of cases.</p>
<fig id="F3" position="float">
<label>FIGURE 3</label>
<caption>
<p>Time-to-onset of etoposide-related ADEs.</p>
</caption>
<graphic xlink:href="fphar-14-1259908-g003.tif"/>
</fig>
<p>In the evaluation of the Weibull Shape Parameter analysis (<xref ref-type="table" rid="T5">Table 5</xref>), the shape parameter (<italic>&#x3b2;</italic>) was calculated to be 0.55, and the upper limit of its 95% confidence interval (CI) was 0.57. The value of <italic>&#x3b2;</italic> &#x3c; 1 suggested that the incidence of ADEs was considered to decrease over time, indicating an early failure type.</p>
<table-wrap id="T5" position="float">
<label>TABLE 5</label>
<caption>
<p>Time-to-onset analysis for etoposide-related signals using the Weibull distribution test. n, number of cases with available time-to-onset; IQR, interquartile range; TTO, Time-to-onset. A TTO of 0 days means that the adverse event happens within the day of treatment.</p>
</caption>
<table>
<thead valign="top">
<tr>
<th rowspan="3" align="center">Casesn</th>
<th rowspan="2" colspan="2" align="center">TTO (days)</th>
<th colspan="4" align="center">Weibull distribution</th>
<th rowspan="3" align="center">Failure type</th>
</tr>
<tr>
<th colspan="2" align="center">Scale parameter</th>
<th colspan="2" align="center">Shape parameter</th>
</tr>
<tr>
<th align="center">Media (IQR) </th>
<th align="center">Min-Max</th>
<th align="center">&#x3b1; </th>
<th align="center">95% CI</th>
<th align="center">&#x3b2; </th>
<th align="center">95% CI</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td align="center">2138</td>
<td align="center">10 (2&#x2013;32)</td>
<td align="center">0&#x2013;4900</td>
<td align="center">38.56</td>
<td align="center">35.05&#x2013;42.07</td>
<td align="center">0.55</td>
<td align="left">0.53&#x2013;0.57</td>
<td align="center">Early failure</td>
</tr>
</tbody>
</table>
</table-wrap>
</sec>
<sec id="s3-6">
<title>3.6 Subgroup analysis</title>
<p>
<xref ref-type="fig" rid="F4">Figure 4</xref> illustrates the findings of the disproportionate analysis stratified by patient age. Among the two subgroups aged &#x3c;18 and 18&#x2013;64&#xa0;years, the highest number of cases were associated with the positive signal of &#x201c;off-label use.&#x201d; Conversely, in the &#x3e;64 age subgroup, &#x201c;febrile neutropenia&#x201d; had the highest number of cases. Furthermore, when analyzing the number of top 10 ADEs in each subgroup, it was found that cough and flushing signals were only reported in the subgroup of age &#x3c;18. On the other hand, acute kidney injury and pneumonia were found to be more common in the other two age subgroups (18&#x2013;64, and &#x3e;64).</p>
<fig id="F4" position="float">
<label>FIGURE 4</label>
<caption>
<p>Age-based subgroup analysis of etoposide-related ADEs.</p>
</caption>
<graphic xlink:href="fphar-14-1259908-g004.tif"/>
</fig>
<p>Likewise, this subgroup disparity in ADEs was also evaluated across weight (<xref ref-type="sec" rid="s11">Supplementary Figure S2</xref>), gender (<xref ref-type="sec" rid="s11">Supplementary Figure S3</xref>), and reporting person (<xref ref-type="sec" rid="s11">Supplementary Figure S4</xref>). These subgroup analyses provide a way to compare signal values between different subgroups, allowing for the identification of similarities and differences. This information is crucial for more detailed clinical management and can help healthcare professionals tailor their approach based on specific subgroup characteristics.</p>
</sec>
<sec id="s3-7">
<title>3.7 Gender differences in etoposide-related ADEs</title>
<p>At the PT level, using the ROR algorithm, we identified 58 signals that showed disproportionality in the occurrence of ADEs between males and females. Some of the major ADEs that were more likely to occur in women included cardiac failure congestive, primary hypogonadism, nausea, oesophagitis, death, disease progression, drug resistance, fatigue, multiple organ dysfunction syndrome, hepatic function abnormality, haemophagocytic lymphohistiocytosis, staphylococcal infection, and urinary tract infection. On the other hand, high-risk ADEs in males included leukopenia, thrombocytopenia, pneumonia, hyponatremia, neoplasm progression, peripheral neuropathy, confusional state, acute kidney injury, and pulmonary embolism (<xref ref-type="fig" rid="F5">Figure 5</xref>). You could find all the detailed results in <xref ref-type="sec" rid="s11">Supplementary Table S3</xref>.</p>
<fig id="F5" position="float">
<label>FIGURE 5</label>
<caption>
<p>Reporting odds ratios (ROR) with 95% CI for all positive gender-related ADEs. CI, confidence interval; ROR, Reporting odds ratio.</p>
</caption>
<graphic xlink:href="fphar-14-1259908-g005.tif"/>
</fig>
<p>To further differentiate etoposide-related ADEs in terms of gender, we generated a &#x201c;volcano plot&#x201d; in <xref ref-type="fig" rid="F6">Figure 6</xref> to visualize the results. Each point in the plot represented an etoposide-related ADE, and ADEs with significant Log2ROR and -log10 (adjusted <italic>p</italic>-value) were labeled. In males, three significant signals were observed, including pneumonia, myocardial infarction, and atrial fibrillation. In females, five significant signals were found including drug resistance, cardiac failure congestive, fatigue, ototoxicity, and multiple organ dysfunction syndrome (<xref ref-type="fig" rid="F6">Figure 6</xref>).</p>
<fig id="F6" position="float">
<label>FIGURE 6</label>
<caption>
<p>Volcano map of gender difference risk signal for etoposide. ROR, reporting odds ratios; <italic>P</italic>.adj, the <italic>p</italic>-value is adjusted with false discovery rate (FDR) method.</p>
</caption>
<graphic xlink:href="fphar-14-1259908-g006.tif"/>
</fig>
</sec>
</sec>
<sec sec-type="discussion" id="s4">
<title>4 Discussion</title>
<p>We conducted a post-marketing pharmacovigilance analysis of etoposide by collecting and evaluating real-world data from the largest sample, with the aim of identifying potential, new adverse reactions to etoposide and analyzing the onset time of adverse reactions as well as gender differences. These findings may help guide updates to the SmPC and provide new evidence for the rational use of etoposide in clinical practice.</p>
<sec id="s4-1">
<title>4.1 Baseline data description</title>
<p>Our study uncovered a yearly increase in the number of reported adverse event reports associated with etoposide, beginning in 2004 and maintaining a relatively high level since 2016. This upward trend suggests not only the effectiveness of etoposide treatment, leading to its increased use in various indications and patient populations, but also emphasizes the importance of analyzing these adverse reactions. Another significant finding was that etoposide-related adverse events occurred more commonly in males (49.6%) compared to females (34.3%). This observation aligns with the higher incidence of etoposide usage in men for major indications such as acute myeloid leukemia (AML), acute lymphocytic leukemia, Hodgkin&#x2019;s lymphoma, small cell lung cancer, and specific indications like testicular cancer (<xref ref-type="bibr" rid="B75">Sant et al., 2010</xref>; <xref ref-type="bibr" rid="B96">Townsend and Linch, 2012</xref>; <xref ref-type="bibr" rid="B29">Helles&#xf8;y et al., 2021</xref>; <xref ref-type="bibr" rid="B71">Rudin et al., 2021</xref>; <xref ref-type="bibr" rid="B13">Chovanec et al., 2023</xref>). Furthermore, our study highlighted that approximately 90% (88.7%) of adverse event reports were provided by health professionals, which adds credibility to the results of our analysis.</p>
</sec>
<sec id="s4-2">
<title>4.2 Blood and infection-related adverse reactions</title>
<p>Based on disproportionality analysis, we found that the most common and significant ADEs at the SOC levels included &#x201c;blood and lymphatic system disorders,&#x201d; and &#x201c;infections and infestations&#x201d;. One of the most frequent dose-limiting adverse reactions in cancer therapy is hematotoxicity (n &#x3d; 87, ROR 23.16 [18.74&#x2013;28.63]). The fast blood cell turnover renders them a potential target for conventional chemotherapy, and such toxicity can contribute to a range of blood disorders (<xref ref-type="bibr" rid="B26">Haglund et al., 2010</xref>). Furthermore, there were many previous clinical studies that also confirmed the hematological toxicity of etoposide. Tonder&#x2019;s research suggested that 8 of 12 high-grade glioma patients occurred hematotoxicity of World Health Organization (WHO) grade 3 or 4 after administration of carboplatin and etoposide (<xref ref-type="bibr" rid="B94">Tonder et al., 2014</xref>). In another multicenter phase II trial in small cell lung cancer (SCLC), treatment with etoposide resulted in grade 3 to 4 leukopenia and grade 3 thrombocytopenia in 74% and 10% of patients, respectively (<xref ref-type="bibr" rid="B9">Bremnes et al., 2001</xref>). A meta-analysis bringing together the results of three randomized controlled trail in SCLC showed that etoposide/cisplatin was more likely to have blood-related side effects than irinotecan/cisplatin (<xref ref-type="bibr" rid="B35">Jeremi&#x107; and Mili&#x107;i&#x107;, 2007</xref>). Through a real-world analysis of etoposide, we had also identified a number of significant hematologic adverse signals including anemia (n &#x3d; 345, ROR 3.64 [3.27&#x2013;4.04]), leukopenia (n &#x3d; 176, ROR 7.36 [6.34&#x2013;8.54]), thrombocytopenia (n &#x3d; 417, ROR 7.96 [7.23&#x2013;8.77]), and myelosuppression (n &#x3d; 47, ROR 6.32 [4.74&#x2013;8.41]), which were consistent with the results of previous clinical trials and the drug&#x2019;s instructions. Furthermore, we have identified novel, unlabeled signals in the instructions, such as thrombotic microangiopathy (n &#x3d; 35, ROR 8.41 [6.04&#x2013;11.73]). Although the risk of thrombotic microangiopathy has been reported to increase significantly with etoposide after autologous stem cell transplantation in neuroblastoma patients, the specific role of etoposide in causing vascular endothelial injury requires further investigation (<xref ref-type="bibr" rid="B101">Vantelon et al., 2001</xref>; <xref ref-type="bibr" rid="B37">Jodele et al., 2018</xref>).</p>
<p>In addition to hematologic toxicity, various opportunistic infections are considered to be strongly associated with increased patient mortality, reduced chemotherapy doses, treatment delays, and increased healthcare costs (<xref ref-type="bibr" rid="B68">Peretz et al., 2016</xref>; <xref ref-type="bibr" rid="B65">Nordvig et al., 2018</xref>; <xref ref-type="bibr" rid="B1">Abdel-Azim et al., 2019</xref>). The reported incidence of infections associated with etoposide use in different clinical trials of SCLC ranged from 6% to 33% (<xref ref-type="bibr" rid="B72">Saito et al., 2006</xref>; <xref ref-type="bibr" rid="B60">Morabito et al., 2017</xref>; <xref ref-type="bibr" rid="B88">Socinski et al., 2017</xref>; <xref ref-type="bibr" rid="B81">Shimokawa et al., 2023</xref>). Additionally, similar infections have been reported in the treatment of tumors of blood, ovarian, prostate and breast origin (<xref ref-type="bibr" rid="B14">Dahl et al., 2000</xref>; <xref ref-type="bibr" rid="B67">Papandreou et al., 2002</xref>; <xref ref-type="bibr" rid="B47">Lu et al., 2015</xref>; <xref ref-type="bibr" rid="B49">Matsumoto et al., 2015</xref>). The myelosuppressive effect of etoposide, particularly its impact on neutrophil production, is likely the main contributing factor to the development of various aggressive infections. These infections, in turn, can further impair neutrophil production and hasten their depletion. Therefore, prophylactic administration of colony-stimulating factor injections is necessary (<xref ref-type="bibr" rid="B99">Urban et al., 1996</xref>; <xref ref-type="bibr" rid="B42">Kuderer et al., 2007</xref>; <xref ref-type="bibr" rid="B56">Mhaskar et al., 2014</xref>; <xref ref-type="bibr" rid="B104">Wang et al., 2015</xref>). In conclusion, it is imperative for clinicians to closely monitor patients&#x2019; coagulation function following the administration of etoposide. Antiplatelet agents should be used with caution, particularly in patients identified as high-risk for thrombosis during pre-treatment evaluation. Furthermore, timely intervention is crucial for managing various potential infections.</p>
</sec>
<sec id="s4-3">
<title>4.3 Neoplasms-related adverse reactions</title>
<p>At the neoplasm level, we also identified a number of ADEs with strong signal values. Second primary malignancy (SPM) (n &#x3d; 43, ROR 10.32 [7.64&#x2013;13.93]) is defined as a second, distinct pathological diagnosis of the same or different origin as the first primary malignancy, and chemotherapy also increases the risk of secondary hematologic or solid malignancies (<xref ref-type="bibr" rid="B45">Lenzi et al., 2020</xref>; <xref ref-type="bibr" rid="B23">Geng et al., 2023</xref>). The mechanism of etoposide-induced second primary malignancy (SPM) can be attributed to two possible explanations. Firstly, it can cause translocation rearrangement of the MLL gene on chromosome 11q23 (<xref ref-type="bibr" rid="B21">Ezoe, 2012</xref>). Secondly, the formation of catechol during drug metabolism can contribute to SPM development (<xref ref-type="bibr" rid="B27">Hartmann and Lipp, 2006</xref>; <xref ref-type="bibr" rid="B109">Zahnreich and Schmidberger, 2021</xref>). In addition, our study revealed that tumor lysis syndrome (TLS) also has strong signal value (n &#x3d; 145, ROR 37.61). TLS occurs due to the rapid breakdown of malignant cells, leading to the release of cellular contents, such as electrolytes, nucleic acids, and metabolites, into the bloodstream. This phenomenon typically happens spontaneously or after treatment in patients with malignancies (<xref ref-type="bibr" rid="B18">Durani and Hogan, 2020</xref>; <xref ref-type="bibr" rid="B25">Grewal et al., 2023</xref>). TLS is characterized by its high lethality and is often associated with the administration of cytotoxic chemotherapy. Clinical manifestations of TLS primarily include hyperuricemia, hyperkalemia, and hyperphosphatemia, which can result in acute respiratory distress, disseminated intravascular coagulation, and renal failure (<xref ref-type="bibr" rid="B10">Calvo Villas, 2019</xref>; <xref ref-type="bibr" rid="B91">Tambaro and Wierda, 2020</xref>). We came across a case report which described a patient with testicular cancer who developed TLS and eventually succumbed to an infection and respiratory distress syndrome after receiving etoposide chemotherapy (<xref ref-type="bibr" rid="B41">Kobatake et al., 2015</xref>). It is therefore essential to assess the risk before chemotherapy and closely monitor electrolyte levels after treatment in patients with high-risk factors for TLS, such as those with highly proliferative hematologic tumors or pre-existing renal dysfunction (<xref ref-type="bibr" rid="B18">Durani and Hogan, 2020</xref>). In conclusion, our study alerts clinical decision makers that they should be aware of these lethal tumor-related signals during etoposide administration.</p>
</sec>
<sec id="s4-4">
<title>4.4 Adverse reactions at other SOC level</title>
<p>ADEs associated with etoposide administration may also involve other organs or tissues based on our disproportionality analysis. The observed cardiac disorders of etoposide use in our research included cardiotoxicity (n &#x3d; 73, ROR 319.62 [15.57&#x2013;24.71]) and acute myocardial infarction (n &#x3d; 53, ROR 3.37 [2.58&#x2013;4.42]).The metabolic disturbances caused by chemotherapy drugs and the oxidative damage by the oxygen radicals they produce might be reasonable explanations for its cardiotoxicity (<xref ref-type="bibr" rid="B66">Pai and Nahata, 2000</xref>; <xref ref-type="bibr" rid="B87">Simbre et al., 2005</xref>). As for the nephropathy toxic (n &#x3d; 72, ROR 14.88 [11.79&#x2013;18.77]) associated with etoposide administration, in addition to the above-mentioned TLS that might trigger renal failure, other possible explanations include delayed clearance of the drug in the kidney or an increased burden on the kidney from microthrombosis. Other than the more common adverse reactions listed above, there are a number of less commonly reported toxicities involving the ear and reproductive system that require caution. Ear and labyrinth disorders associated with etoposide administration were identified in our study including ototoxicity (n &#x3d; 37, ROR 44.18 [31.86&#x2013;61.25]) and deafness (n &#x3d; 51, ROR 4.10 [3.12&#x2013;5.40]), which may be related to drug-induced damage to cochlear hair cells (<xref ref-type="bibr" rid="B43">Kushner et al., 2006</xref>). Notably, an analysis of adverse drug reaction (ADR) reports describing drug-induced ototoxicity from the Italian spontaneous reporting system also identified a potential role for etoposide in the development of tinnitus, which is also in agreement with our results (<xref ref-type="bibr" rid="B6">Barbieri et al., 2019</xref>). Regarding the relationship between etoposide and ovarian failure (n &#x3d; 43, ROR 179.93 [131.29&#x2013;246.60]), it was reported that Anti-Muller hormone (an indicator of ovarian reserve function) was significantly lower in patients receiving etoposide-containing chemotherapy compared to the general population, and reduced ovarian function was difficult to restore after discontinuation of the drug (<xref ref-type="bibr" rid="B53">Meissner et al., 2015</xref>; <xref ref-type="bibr" rid="B5">Anderson et al., 2018</xref>). Prior to chemotherapy with etoposide, female patients should be informed of the potential gonadal toxicity. Age-specific discussions and fertility preservation procedures should also be considered, such as the use of gonadotropin-releasing hormone agonist prior to chemotherapy to reduce the number of primordial follicles entering the differentiation phase and to reduce follicular apoptosis, thereby protecting ovarian reserve function (<xref ref-type="bibr" rid="B8">Blumenfeld, 2007</xref>; <xref ref-type="bibr" rid="B59">Moore et al., 2015</xref>). In conclusion, the above newly identified signals in different organs may need to be specified in subsequent updates of the drug specification.</p>
</sec>
<sec id="s4-5">
<title>4.5 Time-to-onset and gender difference of ADEs</title>
<p>The findings of our study indicate that the majority of ADEs following etoposide treatment occur within 3&#xa0;months, with the highest incidence observed in the first month (73.8%). In total, 89.4% of ADEs were reported within the first 3&#xa0;months. Given this information, it is crucial to pay close attention to ADEs within the first month following etoposide administration. Timely identification and management of adverse events caused by etoposide therapy at an early stage are essential. It is noteworthy that there is a lack of comprehensive studies focusing on the specific timing of adverse reactions after etoposide administration, making our study a valuable contribution in this area. Gender differences have been shown to affect the bioavailability, distribution, metabolism, and elimination of drugs, leading to variations in ADEs between males and females (<xref ref-type="bibr" rid="B113">Zopf et al., 2009</xref>; <xref ref-type="bibr" rid="B15">de Vries et al., 2020</xref>; <xref ref-type="bibr" rid="B22">Farkouh et al., 2020</xref>). However, there is a lack of reported gender-specific ADEs associated with etoposide treatment. In our study, we observed that females had a higher number of positive signal values for ADEs compared to males. This finding aligns with previous research indicating that females are more prone to experiencing ADEs (<xref ref-type="bibr" rid="B97">Tran et al., 1998</xref>; <xref ref-type="bibr" rid="B4">Anderson, 2005</xref>). Interestingly, in males, we identified pneumonia as a high-risk signal, which may be attributed to their longer airways compared to females (<xref ref-type="bibr" rid="B90">Talaminos Barroso et al., 2018</xref>). Enhancing our understanding of gender-related ADEs will contribute to improving drug safety, efficacy, and optimizing drug therapy for both males and females (<xref ref-type="bibr" rid="B78">Sharifi et al., 2021</xref>). Subsequent clinical trials and mechanistic studies are necessary to validate and provide explanations for these ADEs with gender differences. This will guide better drug regimens for both males and females.</p>
<p>The present research, although suggesting a potentially significant relationship between the use of etoposide and the likelihood of reporting ADEs in FAERS, is not without limitations. First, it is important to acknowledge that FAERS is a spontaneous reporting system, and information collected from various countries and professionals may be incomplete or inaccurate, which can introduce bias into the analysis results. Second, despite our detailed explanation in the discussion section, FAERS alone cannot provide sufficient evidence to establish a causal relationship between drug use and ADEs (<xref ref-type="bibr" rid="B84">Shu et al., 2022c</xref>). Therefore, our findings should be viewed more as a warning to clinicians and pharmacists to remain vigilant regarding potential adverse events. Third, it is worth noting that monotherapy is uncommon in cancer treatment. Although etoposide was identified as the primary suspect in the reported adverse events in our analysis, it is challenging to determine the adverse effects solely caused by etoposide (<xref ref-type="bibr" rid="B21">Ezoe, 2012</xref>). Finally, it is also worth exploring how these ADEs impact across races, or across regions (<xref ref-type="bibr" rid="B73">Sabblah et al., 2017</xref>)? It is crucial to consider these limitations when interpreting the findings of our research and to encourage further investigations, including clinical trials and self-testing cohort data of clinical dosing information, to validate and expand upon our observations.</p>
</sec>
</sec>
<sec sec-type="conclusion" id="s5">
<title>5 Conclusion</title>
<p>In conclusion, this study conducted a scientific and systematic analysis of adverse reactions linked to etoposide dosing, including their onset times and potential gender differences using the FAERS database. It is crucial that clinicians maintain a high level of vigilance regarding these potentially serious ADEs. Additionally, considering the potential gender differences is important for optimizing drug selection and closely monitoring patients. Further prospective clinical studies are required to confirm and enhance our understanding of the association between etoposide and these ADEs.</p>
</sec>
</body>
<back>
<sec sec-type="data-availability" id="s6">
<title>Data availability statement</title>
<p>The original contributions presented in the study are included in the article/<xref ref-type="sec" rid="s11">Supplementary material</xref>, further inquiries can be directed to the corresponding author.</p>
</sec>
<sec id="s7">
<title>Author contributions</title>
<p>ZC: Conceptualization, Visualization, Writing&#x2013;original draft. FC: Conceptualization, Writing&#x2013;original draft. LW: Formal Analysis, Writing&#x2013;original draft. FZ: Formal Analysis, Writing&#x2013;original draft. RP: Visualization, Writing&#x2013;original draf. YT: Visualization, Writing&#x2013;original draf. XZ: Writing&#x2013;review and editing. JZ: Writing&#x2013;review and editing. YZ: Writing&#x2013;review and editing. XY: Funding acquisition, Supervision, Writing&#x2013;original draft, Writing&#x2013;review and editing.</p>
</sec>
<sec id="s8">
<title>Funding</title>
<p>The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research was supported by the fund of &#x201c;Project A of the First affiliated Hospital of Xi&#x2019;an Jiaotong University (XJTU-2021-01)&#x201d;.</p>
</sec>
<ack>
<p>We would like to thank everyone who participated in this study.</p>
</ack>
<sec sec-type="COI-statement" id="s9">
<title>Conflict of interest</title>
<p>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.</p>
</sec>
<sec sec-type="disclaimer" id="s10">
<title>Publisher&#x2019;s note</title>
<p>All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.</p>
</sec>
<sec id="s11">
<title>Supplementary material </title>
<p>The Supplementary Material for this article can be found online at: <ext-link ext-link-type="uri" xlink:href="https://www.frontiersin.org/articles/10.3389/fphar.2023.1259908/full#supplementary-material">https://www.frontiersin.org/articles/10.3389/fphar.2023.1259908/full&#x23;supplementary-material</ext-link>
</p>
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