{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T13:26:59Z","timestamp":1768570019907,"version":"3.49.0"},"posted":{"date-parts":[[2025,5,9]]},"group-title":"Pediatrics","reference-count":55,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T00:00:00Z","timestamp":1746748800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,5,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Purpose<\/jats:title>\n                  <jats:p>\n                    Acetaminophen (\n                    <jats:bold>APAP<\/jats:bold>\n                    ) is a ubiquitous antipyretic and analgesic used in children in the United States (\n                    <jats:bold>US<\/jats:bold>\n                    ), including those with cancer. The effects of US Food &amp; Drug Administration (\n                    <jats:bold>FDA<\/jats:bold>\n                    ) guidance on APAP prescribing have been described for healthy adults and children; however, APAP use patterns in children with cancer are unknown. Considering their increased risk of liver injury, APAP\u2019s potential for causing hepatoxicity, and FDA guidance changes, this study examined the recent evolution of APAP use in children with cancer.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    This retrospective, multi-center analysis extracted APAP prescribing data from the Pediatric Health Information System\u00ae (\n                    <jats:bold>PHIS<\/jats:bold>\n                    ). Eligible children were aged 0-26 years, had a cancer diagnosis per International Classification of Diseases (\n                    <jats:bold>ICD<\/jats:bold>\n                    ) codes, and were prescribed a chemotherapeutic. APAP and APAP-opioid combination prescribing were assessed at hospital, regional, and national levels. Changes in APAP and APAP-opioid combination use rates were assessed using the non-parametric Mann-Kendall test.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Findings<\/jats:title>\n                  <jats:p>PHIS records for the complete years of 2004-2021 yielded 388,364 inpatient encounters for 50,779 unique patients. Of these, 87.3% of patients received APAP. Although APAP-opioid combination use was infrequent overall, children receiving APAP were more likely to receive an APAP-opioid combination medication (N=25,880, 13.4%, p &lt; 0.001) compared to those who did not receive APAP. Among specialty children\u2019s hospitals, national APAP use was stable over the study period. Regionally, APAP use increased among hospitals in the Northeast. APAP-opioid combination use decreased nationally with regional variation. In contrast to the steady decline in other regions, Southern APAP-opioid combination use was consistently elevated before declining in 2014.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Implications<\/jats:title>\n                  <jats:p>This article describes acetaminophen and acetaminophen-opioid prescribing trends among children with cancer in the United States. These trends are key to help clinicians assess changes in pain management strategies over time, contextualize analgesic exposure and efficacy, and provide a foundation for future studies in drug safety. Extensive acetaminophen use can affect liver health, and further work is needed to evaluate acetaminophen exposure in children with cancer.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Data Statement<\/jats:title>\n                  <jats:p>Deidentified data were obtained and evaluated under an IRB-approved protocol. Due to privacy requirements, the data are not available to be shared.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.05.08.25327260","type":"posted-content","created":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T20:30:16Z","timestamp":1746822616000},"source":"Crossref","is-referenced-by-count":0,"title":["Acetaminophen and Acetaminophen-Opioid Combination Prescribing Trends Among Hospitalized Children, Adolescents, and Young Adults with Cancer"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4738-3240","authenticated-orcid":false,"given":"Cheryl L.","family":"Mathis","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huong D.","family":"Meeks","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin M.","family":"Watt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luke D.","family":"Maese","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan E.","family":"Constance","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025051301200977000_2025.05.08.25327260v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(99)01310-0"},{"key":"2025051301200977000_2025.05.08.25327260v1.2","doi-asserted-by":"publisher","DOI":"10.1177\/1043454214563751"},{"key":"2025051301200977000_2025.05.08.25327260v1.3","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.33289"},{"key":"2025051301200977000_2025.05.08.25327260v1.4","doi-asserted-by":"publisher","DOI":"10.3390\/cancers15030591"},{"key":"2025051301200977000_2025.05.08.25327260v1.5","doi-asserted-by":"publisher","DOI":"10.1080\/10428194.2020.1749604"},{"key":"2025051301200977000_2025.05.08.25327260v1.6","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2023.1080"},{"key":"2025051301200977000_2025.05.08.25327260v1.7","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2710.2012.01371.x"},{"key":"2025051301200977000_2025.05.08.25327260v1.8","doi-asserted-by":"publisher","DOI":"10.1080\/08998280.2016.11929431"},{"key":"2025051301200977000_2025.05.08.25327260v1.9","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.33639"},{"key":"2025051301200977000_2025.05.08.25327260v1.10","doi-asserted-by":"publisher","DOI":"10.1200\/edbk_100020"},{"key":"2025051301200977000_2025.05.08.25327260v1.11","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2011-3035"},{"key":"2025051301200977000_2025.05.08.25327260v1.12","doi-asserted-by":"publisher","DOI":"10.1111\/j.1526-4637.2010.00811.x"},{"issue":"4","key":"2025051301200977000_2025.05.08.25327260v1.13","first-page":"50","article-title":"Drug interactions in cancer patients requiring concomitant chemotherapy and analgesics","volume":"13","year":"2013","journal-title":"Pract Pain Manag"},{"key":"2025051301200977000_2025.05.08.25327260v1.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.cld.2013.07.005"},{"key":"2025051301200977000_2025.05.08.25327260v1.15","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-642-00663-0_12"},{"key":"2025051301200977000_2025.05.08.25327260v1.16","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-012-1410-7"},{"key":"2025051301200977000_2025.05.08.25327260v1.17","doi-asserted-by":"publisher","DOI":"10.1002\/jcph.1442"},{"key":"2025051301200977000_2025.05.08.25327260v1.18","doi-asserted-by":"publisher","DOI":"10.1080\/15563650600907165"},{"key":"2025051301200977000_2025.05.08.25327260v1.19","doi-asserted-by":"publisher","DOI":"10.1002\/hep.20948"},{"key":"2025051301200977000_2025.05.08.25327260v1.20","doi-asserted-by":"publisher","DOI":"10.1111\/j.1572-0241.2007.01388.x"},{"key":"2025051301200977000_2025.05.08.25327260v1.21","unstructured":"Food Drug Administration Center for Drugs Evaluation Research (2010). Guidance for Industry: Organ-Specific Warnings: Internal Analgesic, Antipyretic, and Antirheumatic Drug Products for Over-the-Counter Human Use \u2014 Small Entity Compliance Guide. FDA, Maryland, accessed Jan. 31, 2025."},{"key":"2025051301200977000_2025.05.08.25327260v1.22","unstructured":"Food Drug Administration Center for Drugs Evaluation Research (2011). FDA Drug Safety Communication: Prescription Acetaminophen Products to be Limited to 325 mg Per Dosage Unit; Boxed Warning Will Highlight Potential for Severe Liver Failure. FDA, Maryland, accessed Jan. 31, 2025."},{"key":"2025051301200977000_2025.05.08.25327260v1.23","unstructured":"Food Drug Administration Center for Drugs Evaluation Research (2015). Guidance for Industry: Organ-Specific Warnings: Internal Analgesic, Antipyretic, and Antirheumatic Drug Products for Over-the-Counter Human Use \u2014 Labeling for Products That Contain Acetaminophen. FDA, Maryland, accessed Jan. 31, 2025."},{"key":"2025051301200977000_2025.05.08.25327260v1.24","unstructured":"Food Drug Administration Center for Drugs Evaluation Research (2017). Guidance for Industry: Recommended Warning for Over-the-Counter Acetaminophen-Containing Drug Products and Labeling Statements Regarding Serious Skin Reactions. FDA, Maryland, accessed Jan. 31, 2025."},{"key":"2025051301200977000_2025.05.08.25327260v1.25","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.22265"},{"key":"2025051301200977000_2025.05.08.25327260v1.26","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD008205.pub3"},{"key":"2025051301200977000_2025.05.08.25327260v1.27","doi-asserted-by":"publisher","DOI":"10.1016\/j.anpede.2019.08.001"},{"key":"2025051301200977000_2025.05.08.25327260v1.28","doi-asserted-by":"publisher","DOI":"10.1097\/MPG.0000000000002767"},{"key":"2025051301200977000_2025.05.08.25327260v1.29","doi-asserted-by":"publisher","DOI":"10.1177\/0269216311428528"},{"key":"2025051301200977000_2025.05.08.25327260v1.30","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD012637.pub2"},{"key":"2025051301200977000_2025.05.08.25327260v1.31","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12352"},{"key":"2025051301200977000_2025.05.08.25327260v1.32","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD006601.pub4"},{"key":"2025051301200977000_2025.05.08.25327260v1.33","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD012508.pub2"},{"key":"2025051301200977000_2025.05.08.25327260v1.34","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2022.3744"},{"key":"2025051301200977000_2025.05.08.25327260v1.35","unstructured":"Food Drug Administration Center for Drugs Evaluation Research (2010). Drug Approval Package: Ofirmev (acetaminophen) Injection, 10 mg\/mL. 2010. < https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2010\/022450_ofirmev_toc.cfm> FDA, Maryland, accessed Feb 24, 2025."},{"key":"2025051301200977000_2025.05.08.25327260v1.36","unstructured":"Food Drug Administration Center for Drugs Evaluation Research (2013). FDA Drug Safety Communication: FDA warns of rare but serious skin reactions with the pain reliever\/fever reducer acetaminophen. FDA, Maryland, accessed Jan. 31, 2025."},{"key":"2025051301200977000_2025.05.08.25327260v1.37","unstructured":"United States Department of Justice (2014). 21 CFR Part 1308: Schedules of Controlled Substances: Rescheduling of Hydrocodone Combination Products From Schedule III to Schedule II. Federal Register, 79 (163), accessed Jan. 31, 2025."},{"key":"2025051301200977000_2025.05.08.25327260v1.38","unstructured":"Mann, B. 4 U.S. companies will pay $26 billion to settle claims they fueled the opioid crisis. 2022. <https:\/\/www.npr.org\/2022\/02\/25\/1082901958\/opioid-settlement-johnson-26-billion> National Public Radio, accessed Jan. 31, 2025."},{"key":"2025051301200977000_2025.05.08.25327260v1.39","doi-asserted-by":"publisher","DOI":"10.1016\/j.surg.2021.04.002"},{"key":"2025051301200977000_2025.05.08.25327260v1.40","unstructured":"National Institute on Drug Abuse. Drug Overdose Deaths: Facts and Figures. 2024. <https:\/\/nida.nih.gov\/research-topics\/trends-statistics\/overdose-death-rates> accessed Jan. 31, 2025."},{"key":"2025051301200977000_2025.05.08.25327260v1.41","unstructured":"Association, C. s. H. Leverage Your Data With CHA\u2019s Pediatric Health Information System (PHIS). < https:\/\/www.childrenshospitals.org\/content\/analytics\/product-program\/pediatric-health-information-system> (accessed February 13, 2025)."},{"key":"2025051301200977000_2025.05.08.25327260v1.42","doi-asserted-by":"publisher","DOI":"10.1001\/jamasurg.2021.0549"},{"key":"2025051301200977000_2025.05.08.25327260v1.43","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.0040297"},{"key":"2025051301200977000_2025.05.08.25327260v1.44","unstructured":"Center for Disease Control. Geographic division or region. https:\/\/www.cdc.gov\/nchs\/hus\/sources-definitions\/geographic-region.htm (accessed February 13, 2025)."},{"key":"2025051301200977000_2025.05.08.25327260v1.45","unstructured":"R Core Team (2024). _R: A Language and Environment for Statistical Computing_. R Foundation for Statistical Computing, Vienna, Austria. <https:\/\/www.R-project.org\/> (accessed Feb. 13, 2025)."},{"key":"2025051301200977000_2025.05.08.25327260v1.46","doi-asserted-by":"publisher","DOI":"10.21105\/joss.01686"},{"key":"2025051301200977000_2025.05.08.25327260v1.47","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djad115"},{"key":"2025051301200977000_2025.05.08.25327260v1.48","doi-asserted-by":"publisher","DOI":"10.15585\/mmwr.mm6725a2"},{"key":"2025051301200977000_2025.05.08.25327260v1.49","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2431-14-199"},{"key":"2025051301200977000_2025.05.08.25327260v1.50","doi-asserted-by":"publisher","DOI":"10.1093\/oncolo\/oyad292"},{"key":"2025051301200977000_2025.05.08.25327260v1.51","doi-asserted-by":"publisher","DOI":"10.1016\/j.pmedr.2020.101184"},{"key":"2025051301200977000_2025.05.08.25327260v1.52","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(08)70279-1"},{"key":"2025051301200977000_2025.05.08.25327260v1.53","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(08)70307-3"},{"key":"2025051301200977000_2025.05.08.25327260v1.54","doi-asserted-by":"publisher","DOI":"10.14218\/jcth.2014.00011"},{"key":"2025051301200977000_2025.05.08.25327260v1.55","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2006-0069"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.05.08.25327260","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:35:45Z","timestamp":1768509345000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.1101\/2025.05.08.25327260"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,9]]},"references-count":55,"URL":"https:\/\/doi.org\/10.1101\/2025.05.08.25327260","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1016\/j.prerep.2025.100047","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2025,5,9]]},"subtype":"preprint"}}