{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T19:38:16Z","timestamp":1790969896629,"version":"4.1.0"},"reference-count":51,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T00:00:00Z","timestamp":1759276800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["accpjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacotherapy"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Drug safety has historically been understudied in pediatric populations, rendering them \u201ctherapeutic orphans.\u201d Pediatric drug indications and dosages are often inferred by extrapolating safety, efficacy, and dosing data from adult studies, leading to widespread off\u2010label use. However, this approach fails to account for age\u2010specific differences in disease pathophysiology and developmental pharmacokinetics (PK). Despite evidence that adverse drug events (ADEs) manifest with greater severity in pediatric populations than in adults, fewer than 50% of drugs have been systematically studied for pediatric use. The lack of robust drug safety data may result in suboptimal or harmful treatment strategies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used a data\u2010driven approach that integrated three databases \u2014including Merative MarketScan claims, the Maternal and Pediatric Precision in Therapeutics (MPRINT) Knowledgebase (including 670,185 pediatric pharmacoepidemiology, PK, and clinical trial publications on 5062 drugs), the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS, a postmarketing safety surveillance database), and FDA drug label data\u2014 to identify high\u2010impact target. High\u2010impact targets were defined as drugs that have a high prescription volume, limited safety evidence and high risk of serious ADEs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>With 229,550 prescriptions in MarketScan, only 9 studies, and almost 50 high risk serious ADEs benzonatate was identified as a high\u2010impact drug of concern. Serious ADEs included seizure, death, and arrhythmia with proportional reportion ratios (PRRs) ranging from 4.3 to 477.8.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Approved in 1958, Benzonatate, a nonnarcotic antitussive agent has a limited safety evidence with only nine PE\/PK publications in six decades. Moreover, it is frequently prescribed off\u2010label for cough relief despite questionable effectiveness, and high\u2010risk of serious ADEs. Our findings reveal a disconnect between clinical practice and suppporting safety evidence. As such, there is critical need to study the safety of this drug using emerging real\u2010world data for real\u2010world evidence. In summary, this study presents an approach that is systematic, objective, reproducible, and data driven to identify and prioritize drug\u2010ADE combinations with limited evidence.<\/jats:p><\/jats:sec>","DOI":"10.1002\/phar.70061","type":"journal-article","created":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T12:20:47Z","timestamp":1759321247000},"page":"667-676","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Identifying Pediatric Drug Safety Knowledge Gaps: An Integrated Approach Leveraging Real\u2010World Data, a Biomedical Knowledge Base, and Postmarketing Surveillance Data"],"prefix":"10.1002","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8597-3087","authenticated-orcid":false,"given":"Saurabh","family":"Rahurkar","sequence":"first","affiliation":[{"name":"Department of Biomedical Informatics College of Medicine, The Ohio State University  Columbus Ohio USA"},{"name":"Center for the Advancement of Team Science, Analytics, and Systems Thinking in Health Services and Implementation Science Research (CATALYST) The Ohio State University  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9618-8226","authenticated-orcid":false,"given":"Jiayi","family":"Ouyang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics College of Medicine, The Ohio State University  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2322-3229","authenticated-orcid":false,"given":"Pallavi","family":"Jonnalagadda","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics College of Medicine, The Ohio State University  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5721-091X","authenticated-orcid":false,"given":"Xiaofu","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics College of Medicine, The Ohio State University  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4780-8416","authenticated-orcid":false,"given":"Shijun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics College of Medicine, The Ohio State University  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0988-8478","authenticated-orcid":false,"given":"Chien\u2010Wei","family":"Chiang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics College of Medicine, The Ohio State University  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1904-1737","authenticated-orcid":false,"given":"Lei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics College of Medicine, The Ohio State University  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4123-7613","authenticated-orcid":false,"given":"Aditi","family":"Shendre","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics College of Medicine, The Ohio State University  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0746-1809","authenticated-orcid":false,"given":"Lang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics College of Medicine, The Ohio State University  Columbus Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,10]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0022\u20103476(68)80414\u20107"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.5863\/1551\u20106776\u201020.3.186"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMp0802107"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2019\u20100896"},{"issue":"8","key":"e_1_2_8_6_1","first-page":"776","article-title":"Off\u2010Label Medication Use in Children, More Common Than We Think: A Systematic Review of the Literature","volume":"111","author":"Allen H. 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