{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T02:02:31Z","timestamp":1789696951160,"version":"4.0.1"},"reference-count":26,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["DARU J Pharm Sci"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Risk management plans (RMPs) support lifecycle management of drug-related risks. In Japan, however, their use in clinical practice remains limited, and healthcare professionals often rely on the package insert for safety information. After RMP termination at re-examination, healthcare professionals may no longer readily identify unresolved risks absent from the package insert through either the package insert or the Pharmaceuticals and Medical Devices Agency (PMDA) RMP source.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>We investigated the extent to which important potential risks in RMPs are reflected in the package insert and considered the implications of RMP termination when such risks remain undocumented.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We analyzed RMPs publicly available as of May 2023 using data from the PMDA website. For each important potential risk, we examined whether it was documented in the package insert and summarized the results descriptively by risk type.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Among 772 important potential risks in 330 RMPs, 134 (17.4%) were not documented in the package insert. Non-documentation proportions were relatively high for \u201cInfections and infestations\u201d (32.7%), \u201cGastrointestinal disorders\u201d (32.4%), and \u201cNeoplasms benign, malignant and unspecified (incl cysts and polyps)\u201d (28.4%), whereas a relatively low proportion was observed for \u201cVascular disorders\u201d (2.3%).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Some important potential risks in active Japanese RMPs were not documented in the package insert. This may create gaps in risk communication after RMP termination, although clinical outcomes and patient harm were not assessed. Allowing RMP continuation beyond re-examination when necessary may help maintain awareness of unresolved safety concerns.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s40199-026-00661-7","type":"journal-article","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T01:18:18Z","timestamp":1789694298000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Important potential risks not reflected in Japanese drug labeling: implications for risk management plan termination"],"prefix":"10.1007","volume":"34","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-9815-1910","authenticated-orcid":false,"given":"Natsuko","family":"Kameyama","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayana","family":"Ide","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0117-3961","authenticated-orcid":false,"given":"Hideki","family":"Maeda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,18]]},"reference":[{"key":"661_CR1","unstructured":"Pharmaceuticals and Medical Devices Agency. Pharmaceuticals and medical devices safety information, no. 300. In: Pharmaceuticals and medical devices agency. 2013. https:\/\/www.pmda.go.jp\/files\/000153064.pdf. Accessed 28 May 2025."},{"key":"661_CR2","unstructured":"Pharmaceuticals and medical devices agency. Pharmaceuticals and Medical Devices Agency. Risk management plan (RMP). https:\/\/www.pmda.go.jp\/english\/safety\/info-services\/drugs\/rmp\/0001.html. Accessed 28 May 2025."},{"key":"661_CR3","unstructured":"International Council for Harmonisation. ICH harmonised tripartite guideline: Pharmacovigilance planning E2E. In: International council for harmonisation. 2004. https:\/\/www.pmda.go.jp\/files\/000156732.pdf. Accessed 19 Apr 2025."},{"key":"661_CR4","unstructured":"Ministry of Health, Labor and Welfare. Risk management plan guidance (PFSB\/SD notification no. 0411\u20131, PFSB\/ELD notification no. 0411\u20132). 2012. https:\/\/www.pmda.go.jp\/files\/000153333.pdf. Accessed 28 May 2025."},{"key":"661_CR5","unstructured":"Pharmaceuticals and Medical Devices Agency. Pharmaceuticals and medical devices safety information, no. 401. 2023. https:\/\/www.pmda.go.jp\/files\/000252814.pdf. Accessed 28 May 2023."},{"key":"661_CR6","doi-asserted-by":"publisher","first-page":"1387652","DOI":"10.3389\/fmed.2024.1387652","volume":"11","author":"N Kameyama","year":"2024","unstructured":"Kameyama N, Hosaka A, Maeda H. Current situation and issues regarding termination of risk management plans in Japan. Front Med. 2024;11:1387652. https:\/\/doi.org\/10.3389\/fmed.2024.1387652.","journal-title":"Front Med"},{"key":"661_CR7","doi-asserted-by":"publisher","first-page":"e01110","DOI":"10.1002\/prp2.1110","volume":"11","author":"R Saito","year":"2023","unstructured":"Saito R, Miyazaki S. Analysis of safety specifications in risk management plan at the time of drug approval and addition of clinically significant adverse reactions in the package insert post-approval in Japan. Pharmacol Res Perspect. 2023;11:e01110. https:\/\/doi.org\/10.1002\/prp2.1110.","journal-title":"Pharmacol Res Perspect"},{"key":"661_CR8","doi-asserted-by":"publisher","first-page":"1265","DOI":"10.1002\/pds.4662","volume":"27","author":"K Watanabe","year":"2018","unstructured":"Watanabe K, Murakami M, Masuyama K, Ishiguro C, Matsuda T. The association between concerns toward adverse reactions during pre-approval drug reviews and the post-approval addition of clinically significant adverse reactions to package inserts: a retrospective analysis. Pharmacoepidemiol Drug Saf. 2018;27:1265\u201376. https:\/\/doi.org\/10.1002\/pds.4662.","journal-title":"Pharmacoepidemiol Drug Saf"},{"key":"661_CR9","doi-asserted-by":"publisher","first-page":"1117","DOI":"10.1007\/s43441-025-00818-7","volume":"59","author":"S Sawada","year":"2025","unstructured":"Sawada S, Asao K, Kobayashi R, Bosco J, Maeda H. Characterization of Japanese risk management plans after 10 years of implementation: 2013-2023. Ther Innov Regul Sci. 2025;59:1117\u201328. https:\/\/doi.org\/10.1007\/s43441-025-00818-7.","journal-title":"Ther Innov Regul Sci"},{"key":"661_CR10","doi-asserted-by":"publisher","first-page":"815","DOI":"10.1080\/14740338.2021.1909569","volume":"20","author":"D Butler","year":"2021","unstructured":"Butler D, Vucic K, Straus S, Cupelli A, Micallef B, Serracino-Inglott A, et al. Regulatory experience of handling Risk Management Plans (RMPs) for medicinal products in the EU. Expert Opin Drug Saf. 2021;20:815\u201326. https:\/\/doi.org\/10.1080\/14740338.2021.1909569.","journal-title":"Expert Opin Drug Saf"},{"key":"661_CR11","unstructured":"Pharmaceuticals and Medical Devices Agency. List of submitted J-RMPs. https:\/\/www.pmda.go.jp\/safety\/info-services\/drugs\/items-information\/rmp\/0001.html. Accessed 28 May 2025."},{"key":"661_CR12","unstructured":"MedDRA. Medical dictionary for regulatory activities (MedDRA). https:\/\/www.meddra.org\/. Accessed 28 May 2025."},{"key":"661_CR13","unstructured":"Pharmaceuticals and Medical Devices Agency. Medical drug information search: Information search for prescription drugs. https:\/\/www.pmda.go.jp\/PmdaSearch\/iyakuSearch\/. Accessed 28 May 2025."},{"key":"661_CR14","unstructured":"Ministry of Internal Affairs and Communications. Japanese standard classification of products. In: Ministry of internal affairs and communications. 1990. https:\/\/www.soumu.go.jp\/toukei_toukatsu\/index\/seido\/syouhin\/2index.htm. Accessed 28 May 2025."},{"key":"661_CR15","doi-asserted-by":"publisher","first-page":"205","DOI":"10.11256\/jjdi.17.205","volume":"17","author":"H Sato","year":"2016","unstructured":"Sato H, Ohira E, Murakami T, Kanetaka Y, Murakami T, Izumi H, et al. Comparison between risk listed in the risk management plan and the product labeling of the drug package insert. Jpn J Drug Inform. 2016;17:205\u20138. https:\/\/doi.org\/10.11256\/jjdi.17.205.","journal-title":"Jpn J Drug Inform."},{"key":"661_CR16","unstructured":"Ministry of Health, Labour and Welfare. Guidelines for the description of electronic package inserts for prescription drugs. In: Ministry of health, labour and welfare. 2021. https:\/\/www.pmda.go.jp\/files\/000247606.pdf. Accessed 28 May 2025."},{"key":"661_CR17","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1097\/EDE.0b013e3181577511","volume":"18","author":"JP Vandenbroucke","year":"2007","unstructured":"Vandenbroucke JP, von Elm E, Altman DG, G\u00f8tzsche PC, Mulrow CD, Pocock SJ, et al. Strengthening the reporting of observational studies in epidemiology (STROBE): explanation and elaboration. Epidemiology. 2007;18:805\u201335. https:\/\/doi.org\/10.1097\/EDE.0b013e3181577511.","journal-title":"Epidemiology"},{"key":"661_CR18","doi-asserted-by":"publisher","first-page":"750857","DOI":"10.5402\/2013\/750857","volume":"2013","author":"DL Nadler","year":"2013","unstructured":"Nadler DL, Zurbenko IG. Developing a Weibull model extension to estimate cancer latency. ISRN Epidemiol. 2013;2013:750857. https:\/\/doi.org\/10.5402\/2013\/750857.","journal-title":"ISRN Epidemiol"},{"key":"661_CR19","doi-asserted-by":"publisher","first-page":"1072864","DOI":"10.3389\/fpubh.2023.1072864","volume":"11","author":"JR Jhuang","year":"2023","unstructured":"Jhuang JR, Chiu PC, Hsieh TC, Chen CH, Pu YS, Lee WC. Latency period of aristolochic acid-induced upper urinary tract urothelial carcinoma. Front Public Health. 2023;11:1072864. https:\/\/doi.org\/10.3389\/fpubh.2023.1072864.","journal-title":"Front Public Health"},{"key":"661_CR20","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/j.ccc.2020.09.001","volume":"37","author":"SK Seo","year":"2021","unstructured":"Seo SK, Liu C, Dadwal SS. Infectious disease complications in patients with cancer. Crit Care Clin. 2021;37:69\u201384. https:\/\/doi.org\/10.1016\/j.ccc.2020.09.001.","journal-title":"Crit Care Clin"},{"key":"661_CR21","unstructured":"Japan Pharmaceutical Manufacturers Association. Maintenance of Japanese risk management plan seen from company cases: Suggestions for appropriate pharmaceutical risk management. 2022. https:\/\/www.jpma.or.jp\/information\/evaluation\/results\/allotment\/rfcmr000000010il-att\/rfcmr000000010s9.pdf. Accessed 16 Apr 2025."},{"key":"661_CR22","unstructured":"European Medicines Agency. Risk management plans. https:\/\/www.ema.europa.eu\/en\/human-regulatory\/marketing-authorisation\/pharmacovigilance\/risk-management\/risk-management-plans. Accessed 16 Apr 2025."},{"key":"661_CR23","unstructured":"European Medicines Agency. Guideline on good pharmacovigilance practices (GVP) module V - risk management systems (Rev 2). 2017. https:\/\/www.ema.europa.eu\/en\/documents\/scientific-guideline\/guideline-good-pharmacovigilance-practices-module-v-risk-management-systems-rev-2_en.pdf. Accessed 5 Sep 2023."},{"key":"661_CR24","unstructured":"Food and Drug Administration, Guidance: Medication guides \u2013 distribution requirements and inclusion in risk evaluation and mitigation strategies (REMS). 2011. https:\/\/www.fda.gov\/media\/79776\/download. Accessed 8 Jan 2024."},{"key":"661_CR25","unstructured":"Ministry of Health, Labour and Welfare, Pharmaceutical Affairs and Medical Devices System Subcommittee, Health Science Council. Summary of the revisions to the pharmaceutical and medical device act and related systems. 2025. https:\/\/www.mhlw.go.jp\/content\/11120000\/001371285.pdf. Accessed 16 Apr 2025."},{"key":"661_CR26","unstructured":"Ministry of Health, Labour and Welfare. The act partially amending the act on securing quality, efficacy and safety of products including pharmaceuticals and medical devices, and other acts. 2025. https:\/\/www.mhlw.go.jp\/content\/11120000\/001491539.pdf. Accessed 29 May 2025."}],"container-title":["DARU Journal of Pharmaceutical Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s40199-026-00661-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s40199-026-00661-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s40199-026-00661-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T01:18:25Z","timestamp":1789694305000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s40199-026-00661-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,18]]},"references-count":26,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["661"],"URL":"https:\/\/doi.org\/10.1007\/s40199-026-00661-7","relation":{},"ISSN":["2008-2231"],"issn-type":[{"value":"2008-2231","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,18]]},"assertion":[{"value":"26 June 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 September 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 September 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"This study used publicly available data and did not require ethics approval or informed consent.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"As this research does not include human subjects, informed consent was not applicable.","order":3,"name":"Ethics","label":"Informed consent","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"NK is an employee of CMIC Co., Ltd. The study was conducted independently of the employer. The other authors declare that they have no conflicts of interest.","order":4,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study does not involve human participants or animals.","order":5,"name":"Ethics","label":"Research involving human participants and\/or animals","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"80"}}