{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T11:32:02Z","timestamp":1791977522954,"version":"4.4.0"},"reference-count":48,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2024,12,13]],"date-time":"2024-12-13T00:00:00Z","timestamp":1734048000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004901","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de Minas Gerais","doi-asserted-by":"publisher","award":["APQ 00639\/22"],"award-info":[{"award-number":["APQ 00639\/22"]}],"id":[{"id":"10.13039\/501100004901","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["302069\/2022-4; 400194\/2022-8"],"award-info":[{"award-number":["302069\/2022-4; 400194\/2022-8"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Cutaneous leishmaniasis (CL) is a neglected tropical disease that poses a significant public health challenge in Brazil and worldwide. Miltefosine, the only orally administered drug available for CL, was recently incorporated into Brazil\u2019s treatment protocols following recommendations by the World Health Organization (WHO) and revisions by national health authorities. While this represents an important advancement, miltefosine is associated with frequent gastrointestinal side effects and potential teratogenic risks, necessitating careful patient eligibility assessments and close clinical monitoring throughout treatment. Furthermore, the absence of national effectiveness data underscores the need for careful monitoring during large-scale implementation. This study, part of a broader implementation monitoring process, seeks to estimate the frequency, intensity, and seriousness of adverse events (AEs) associated with miltefosine. It also aims to identify factors linked to treatment discontinuation during the pilot phase of miltefosine distribution in the state of Minas Gerais, Brazil. Descriptive analyses were performed to present measures of central tendency and dispersion for the variables. Additionally, a multivariate analysis was conducted to explore relationships between explanatory variables and outcomes of interest. Between 2021 and 2023, 77.1% of patients treated with miltefosine experienced at least one AE. The rate of serious AEs related to treatment was 1.3%. Gastrointestinal symptoms were the most commonly reported AEs, followed by musculoskeletal manifestations. The most frequent laboratory alteration observed was an increase in serum creatinine, which was significantly associated with hypertension, age, and mucosal involvement of leishmaniasis. No pregnancies were recorded during the implementation period. Early treatment discontinuation rate occurred in 11.8% of cases, with discontinuation associated with age and baseline serum creatinine alterations. Half of the patients required temporary treatment interruptions or irregular dosing, extending the treatment duration beyond the planned 28 days. This pharmacovigilance model provides valuable insights, representing an approach potentially applicable to other neglected disease control programs, especially when introducing new treatment technologies.<\/jats:p>","DOI":"10.1371\/journal.pone.0315710","type":"journal-article","created":{"date-parts":[[2024,12,13]],"date-time":"2024-12-13T18:24:09Z","timestamp":1734114249000},"page":"e0315710","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":15,"title":["Safety profile of miltefosine in the treatment of cutaneous leishmaniasis"],"prefix":"10.1371","volume":"19","author":[{"given":"La\u00eds Raquel","family":"Ribeiro","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1087-9819","authenticated-orcid":true,"given":"Sarah Nascimento","family":"Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mell Ferreira","family":"Saliba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana\u00edna","family":"de Pina Carvalho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gl\u00e1ucia","family":"Cota","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,12,13]]},"reference":[{"key":"pone.0315710.ref001","unstructured":"OMS. 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Lancet Publishing Group; 2018. pp. 951\u2013970.","DOI":"10.1016\/S0140-6736(18)31204-2"},{"key":"pone.0315710.ref004","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.clindermatol.2006.05.008","article-title":"Cutaneous leishmaniasis","volume":"25","author":"MS Bailey","year":"2007","journal-title":"Clin Dermatol"},{"key":"pone.0315710.ref005","unstructured":"Fernandes HJ. AN\u00c1LISE DA TOXICIDADE RELACIONADA AO USO INTRALESIONAL DE ANTIMONIATO DE MEGLUMINA NO TRATAMENTO DA LEISHMANIOSE CUT\u00c2NEA LOCALIZADA. 2019. A [Internet]. 2019 [cited 2024 Jul 8]. https:\/\/www.arca.fiocruz.br\/bitstream\/handle\/icict\/35337\/D_2019_Herbert%20Fernandes.pdf?sequence=2"},{"key":"pone.0315710.ref006","unstructured":"Ramalho DB. Estudo cl\u00ednico para avalia\u00e7\u00e3o da efic\u00e1cia e seguran\u00e7a do uso intralesional de antimoniato de meglumina no tratamento da leishmaniose cut\u00e2nea localizada. 2017. [cited 2024 Jul 8]. https:\/\/www.cpqrr.fiocruz.br\/texto-completo\/D_2018_DarioRamalho.pdf"},{"key":"pone.0315710.ref007","unstructured":"Silva RE. VALIDA\u00c7\u00c3O DA T\u00c9CNICA DE INFILTRA\u00c7\u00c3O INTRALESIONAL DE ANTIMONIATO DE MEGLUMINA PARA TRATAMENTO DE LEISHMANIOSE CUT\u00c2NEA. 2019. (Doctoral dissertation). https:\/\/www.arca.fiocruz.br\/handle\/icict\/35342."},{"key":"pone.0315710.ref008","doi-asserted-by":"crossref","first-page":"e0184777","DOI":"10.1371\/journal.pone.0184777","article-title":"Efficacy of pentavalent antimoniate intralesional infiltration therapy for cutaneous leishmaniasis: A systematic review","volume":"12","author":"NC Brito","year":"2017","journal-title":"PLoS One"},{"key":"pone.0315710.ref009","unstructured":"Minist\u00e9rio da Sa\u00fade. PORTARIA N\u00b0 56, DE 30 DE OUTUBRO DE 2018, Secretaria de Ci\u00eancia, Tecnologia e Insumos Estrat\u00e9gicos. 2018 [cited 30 Mar 2023]. https:\/\/bvsms.saude.gov.br\/bvs\/saudelegis\/sctie\/2018\/prt0056_31_10_2018.html"},{"key":"pone.0315710.ref010","unstructured":"BRASIL. PORTARIA N\u00b0 3.047, DE 28 DE NOVEMBRO DE 2019. In: Di\u00e1rio Oficial da Uni\u00e3o [Internet]. 28 Nov 2019 [cited 27 Jan 2024]. https:\/\/bvsms.saude.gov.br\/bvs\/saudelegis\/gm\/2019\/prt3047_29_11_2019.html"},{"key":"pone.0315710.ref011","unstructured":"BRASIL. Decreto n\u00b0 11.161 de 04\/08\/2022. In: Di\u00e1rio Oficial da Uni\u00e3o [Internet]. 4 Aug 2022 [cited 12 Feb 2024]. https:\/\/legis.senado.leg.br\/norma\/36213911"},{"key":"pone.0315710.ref012","unstructured":"BRASIL. Minist\u00e9rio da Sa\u00fade, Secretaria de Vigil\u00e2ncia em Sa\u00fade. NOTA INFORMATIVA N\u00b0 13\/2020-CGZV\/DEIDT\/SVS\/MS. 2020 [cited 27 Jan 2024]. https:\/\/www.gov.br\/saude\/pt-br\/assuntos\/saude-de-a-a-z\/l\/lt\/arquivos\/nota-informativa-no-13-2020-cgzv-deidt-svs-ms"},{"key":"pone.0315710.ref013","unstructured":"Nascimento Silva S, Ribeiro LR, Borges dos Santos K, Cota G. Promoting safe and appropriate use of miltefosine to treat tegumentary leishmaniasis in Brazil: A best practice quality improvement project. 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NOTA T\u00c9CNICA CONJUNTA SES\/SUBPAS\/SAF\/DMEST\/SES\/SUBVS\/SVE\/DVAT\/CCZVFRB: Orienta\u00e7\u00f5es sobre o uso da Miltefosina, para o tratamento da Leishmaniose Tegumentar (LT) e operacionaliza\u00e7\u00e3o do fluxo de acesso ao medicamento no \u00e2mbito do Sistema \u00danico de Sa\u00fade do Estado de Minas Gerais. 2021."},{"key":"pone.0315710.ref021","unstructured":"ANVISA. RESOLU\u00c7\u00c3O DA DIRETORIA COLEGIADA\u2014RDC N\u00b0 9, DE 20 DE FEVEREIRO DE 2015 (Publicada no DOU n\u00b0 41, de 3 de mar\u00e7o de 2015) Disp\u00f5e sobre o Regulamento para a realiza\u00e7\u00e3o de ensaios cl\u00ednicos com medicamentos no Brasil. 2015."},{"key":"pone.0315710.ref022","unstructured":"Organization WH. Safety monitoring of medicinal products. Reporting System for General Public. 2012."},{"key":"pone.0315710.ref023","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.rmedc.2009.01.004","article-title":"Algorithms for assessing the probability of an Adverse Drug Reaction","volume":"2","author":"MJ Doherty","year":"2009","journal-title":"Respir Med CME"},{"key":"pone.0315710.ref024","unstructured":"ANVISA. MANUAL PARA NOTIFICA\u00c7\u00c3O DE EVENTOS ADVERSOS E MONITORAMENTO DE SEGURAN\u00c7A EM ENSAIOS CL\u00cdNICOS. 2016;1."},{"key":"pone.0315710.ref025","unstructured":"MedDRA. MedDRA\u2014Medical Dictionary for Regulatory Activities. Sep 2023 [cited 21 Dec 2023]. https:\/\/www.meddra.org\/how-to-use\/support-documentation\/portuguese"},{"key":"pone.0315710.ref026","unstructured":"NIH. Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events. 2017 [cited 21 Dec 2023]. https:\/\/rsc.niaid.nih.gov\/sites\/default\/files\/daidsgradingcorrectedv21.pdf"},{"key":"pone.0315710.ref027","unstructured":"World Health Organization (WHO). Statement on miltefosine\u2014Potential ocular disorders in patients treated with miltefosine for post-kala-azar dermal leishmaniasis (PKDL). 10 Feb 2022 [cited 2 Feb 2024]. https:\/\/www.who.int\/news\/item\/10-02-2022-statement-on-miltefosine---potential-ocular-disorders-in-patients-treated-with-miltefosine-for-post-kala-azar-dermal-leishmaniasis-(pkdl)"},{"key":"pone.0315710.ref028","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1007\/s40264-012-0014-6","article-title":"WHO strategy for collecting safety data in public health programmes: complementing spontaneous reporting systems","volume":"36","author":"SN Pal","year":"2013","journal-title":"Drug Saf"},{"key":"pone.0315710.ref029","doi-asserted-by":"crossref","first-page":"1941","DOI":"10.3390\/ijerph18041941","article-title":"Comparative assessment of the pharmacovigilance systems within the neglected tropical diseases programs in East Africa\u2014Ethiopia, Kenya, Rwanda, and Tanzania","volume":"18","author":"A Barry","year":"2021","journal-title":"Int J Environ Res Public Health"},{"key":"pone.0315710.ref030","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1086\/519690","article-title":"Phase 4 trial of miltefosine for the treatment of Indian visceral leishmaniasis","volume":"196","author":"SK Bhattacharya","year":"2007","journal-title":"J Infect Dis"},{"key":"pone.0315710.ref031","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1007\/BF01211805","article-title":"A dose-finding study of miltefosine (hexadecylphosphocholine) in patients with metastatic solid tumours","volume":"118","author":"J Verweij","year":"1992","journal-title":"J Cancer Res Clin Oncol"},{"key":"pone.0315710.ref032","unstructured":"DATASUS. 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D\u00e9cada do Envelhecimento Saud\u00e1vel nas Am\u00e9ricas (2021\u20132030)\u2014OPAS\/OMS | Organiza\u00e7\u00e3o Pan-Americana da Sa\u00fade. 2021 [cited 6 Feb 2024]. https:\/\/www.paho.org\/pt\/decada-do-envelhecimento-saudavel-nas-americas-2021-2030"},{"key":"pone.0315710.ref034","doi-asserted-by":"crossref","DOI":"10.3389\/fphar.2022.1029067","article-title":"Adverse drug reactions in an ageing PopulaTion (ADAPT) study: Prevalence and risk factors associated with adverse drug reaction-related hospital admissions in older patients","volume":"13","author":"C Cahir","year":"2023","journal-title":"Front Pharmacol"},{"key":"pone.0315710.ref035","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1016\/S0959-8049(05)80142-X","article-title":"Phase II study of daily oral miltefosine (hexadecylphosphocholine) in advanced colorectal cancer","volume":"29","author":"AST Planting","year":"1993","journal-title":"Eur J Cancer"},{"key":"pone.0315710.ref036","doi-asserted-by":"crossref","first-page":"e2457","DOI":"10.1093\/cid\/ciaa1238","article-title":"Efficacy and tolerability of miltefosine in the treatment of cutaneous leishmaniasis","volume":"73","author":"JM Ware","year":"2021","journal-title":"Clinical Infectious Diseases"},{"key":"pone.0315710.ref037","unstructured":"FDA. IMPAVIDO (miltefosine) capsules, for oral use. FULL PRESCRIBING INFORMATION. Reference ID: 4790810. 2021."},{"key":"pone.0315710.ref038","first-page":"328","article-title":"Miltefosine induced reduced male fertility capacity after treatment of post kala-azar dermal leishmaniasis, Bangladesh","volume":"28","author":"A Basher","year":"2019","journal-title":"Mymensingh Med J"},{"key":"pone.0315710.ref039","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1177\/0049475519877317","article-title":"Adverse ocular events on miltefosine treatment for post-kala-azar dermal leishmaniasis in India","volume":"50","author":"S Saurabh","year":"2020","journal-title":"Trop Doct"},{"key":"pone.0315710.ref040","doi-asserted-by":"crossref","first-page":"e0006781","DOI":"10.1371\/journal.pntd.0006781","article-title":"Corneal complications following post kala-azar dermal leishmaniasis treatment","volume":"12","author":"S Maruf","year":"2018","journal-title":"PLoS Negl Trop Dis"},{"key":"pone.0315710.ref041","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1046\/j.1365-2125.1998.00713.x","article-title":"Pharmacovigilance in the pharmaceutical industry","volume":"45","author":"JCC Talbot","year":"1998","journal-title":"Br J Clin Pharmacol"},{"key":"pone.0315710.ref042","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.actatropica.2011.02.007","article-title":"Systematic review of the adverse effects of cutaneous leishmaniasis treatment in the New World","volume":"118","author":"LF Oliveira","year":"2011","journal-title":"Acta Trop"},{"key":"pone.0315710.ref043","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1590\/S0037-86822000000400009","article-title":"Estudo comparativo entre estibogluconato de s\u00f3dio BP 88\u00ae e antimoniato de meglumina no tratamento da leishmaniose cut\u00e2nea II. Toxicidade bioqu\u00edmica e card\u00edaca","volume":"33","author":"ACR Saldanha","year":"2000","journal-title":"Rev Soc Bras Med Trop"},{"key":"pone.0315710.ref044","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/j.trstmh.2005.03.012","article-title":"Electrocardiographic and biochemical adverse effects of sodium stibogluconate during treatment of cutaneous and mucosal leishmaniasis among returned travellers","volume":"100","author":"SD Lawn","year":"2006","journal-title":"Trans R Soc Trop Med Hyg"},{"key":"pone.0315710.ref045","unstructured":"Salud OP de la. Leishmaniasis en las Am\u00e9ricas, recomendaciones para el tratamiento. OPS Washington^ eDC DC; 2013."},{"key":"pone.0315710.ref046","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1080\/14787210.2020.1731305","article-title":"Safety profile of meglumine antimoniate intralesional infiltration for cutaneous leishmaniasis","volume":"18","author":"HJ Fernandes","year":"2020","journal-title":"Expert Rev Anti Infect Ther"},{"key":"pone.0315710.ref047","doi-asserted-by":"crossref","first-page":"e57","DOI":"10.1086\/322689","article-title":"Treatment of American Cutaneous Leishmaniasis with Miltefosine, an Oral Agent","volume":"33","author":"J Soto","year":"2001","journal-title":"Clinical Infectious Diseases"},{"key":"pone.0315710.ref048","unstructured":"IMPAVIDO- miltefosine capsule [bule]. 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