Podjanee Jittamala1,2, Wuelton Monteiro3,4, Menno R Smit5,6,7, Belen Pedrique8, Sabine Specht8, Carlos J Chaccour9,10,11,12, Céline Dard13, Pascal Del Giudice14, Virak Khieu15, Annabel Maruani16, Virgilio E Failoc-Rojas17,18, Marimar Sáez-de-Ocariz19, Antoni Soriano-Arandes20, Jaime Piquero-Casals21, Anne Faisant22, Marie-Pierre Brenier-Pinchart23, David Wimmersberger24, Jean T Coulibaly24,25,26, Jennifer Keiser24, Franck Boralevi27,28, Oliver Sokana29, Michael Marks30,31, Daniel Engelman32,33, Lucia Romani32,34, Andrew C Steer32,33, Lorenz von Seidlein2,35, Nicholas J White2,35, Eli Harriss36, Kasia Stepniewska35,37, Georgina S Humphreys37,38, Kalynn Kennon35,37, Philippe J Guerin35,37,39, Kevin C Kobylinski40. 1. Department of Tropical Hygiene, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. 2. Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand. 3. Fundação de Medicina Tropical Dr. Heitor Vieira Dourado, Manaus, Brazil. 4. Universidade do Estado do Amazonas, Manaus, Brazil. 5. Amsterdam Centre for Global Child Health, Emma Children's Hospital, Amsterdam, The Netherlands. 6. University Medical Centres, University of Amsterdam, Amsterdam, The Netherlands. 7. Malaria Epidemiology Unit, Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom. 8. Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland. 9. ISGlobal, Hospital Clínic-Universitat de Barcelona, Barcelona, Spain. 10. Centro de Investigação em Saúde de Manhiça, Maputo, Mozambique. 11. Ifakara Health Institute, Ifakara, United Republic of Tanzania. 12. Instituto de Medicina Tropical Universidad de Navarra, Pamplona, Spain. 13. Laboratoire de Biologie Médicale, Centre Hospitalier de Basse-Terre, Basse-Terre, Guadeloupe, France. 14. Infectious Diseases and Dermatology Unit, Hospital of Fréjus-Saint-Raphaël, Fréjus, France. 15. National Centre for Parasitology, Entomology and Malaria Control, Ministry of Health, Phnom Penh, Cambodia. 16. Unit of Pediatric Dermatology, University Hospital Center of Tours, University of Tours, Tours, France. 17. Unidad de investigacion para la generacion y sintesis de evidencias en salud, Universidad San Ignacio de Loyola, Lima, Peru. 18. Laboratorio de Parasitologia, Metaxenicas y Zoonosis, Hospital Regional Lambayeque, Lambayeque, Peru. 19. Department of Dermatology, National Institute of Pediatrics, Mexico City, Mexico. 20. Pediatric Infectious Diseases and Immunodeficiencies Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute, Barcelona, Spain. 21. Dermik, Multidisciplinary Dermatology Clinic, Barcelona, Spain. 22. Department of Pediatrics, University Hospital Grenoble-Alpes, Grenoble, France. 23. Departement of Parasitology-Mycology, University Hospital Grenoble-Alpes, Grenoble, France. 24. Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, University of Basel, Basel, Switzerland. 25. Unité de Formation et de Recherche Biosciences, Université Félix Houphouët-Boigny, Abidjan, Côte d'Ivoire. 26. Centre Suisse de Recherches Scientifiques en Côte d'Ivoire, Abidjan, Côte d'Ivoire. 27. Paediatric Dermatology Unit, Children hospital, Bordeaux University Hospital, Bordeaux, France. 28. Centre d'investigation clinique pédiatrique 1401 module plurithématique, Bordeaux University, Bordeaux, France. 29. Ministry of Health and Medical Services, Honiara, Solomon Islands. 30. Clinical Research Department, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom. 31. Hospital for Tropical Diseases, London, United Kingdom. 32. Tropical Diseases, Murdoch Children's Research Institute, Melbourne, VIC, Australia. 33. Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia. 34. The Kirby Institute, UNSW, Sydney, NSW, Australia. 35. Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, United Kingdom. 36. The Knowledge Centre, Bodleian Health Care Libraries, University of Oxford, Oxford, United Kingdom. 37. WorldWide Antimalarial Resistance Network (WWARN), Oxford, United Kingdom. 38. Green Templeton College, University of Oxford, United Kingdom. 39. Infectious Diseases Data Observatory (IDDO), Oxford, United Kingdom. 40. Department of Entomology, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.
Abstract
BACKGROUND: Oral ivermectin is a safe broad spectrum anthelminthic used for treating several neglected tropical diseases (NTDs). Currently, ivermectin use is contraindicated in children weighing less than 15 kg, restricting access to this drug for the treatment of NTDs. Here we provide an updated systematic review of the literature and we conducted an individual-level patient data (IPD) meta-analysis describing the safety of ivermectin in children weighing less than 15 kg. METHODOLOGY/PRINCIPAL FINDINGS: A systematic review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) for IPD guidelines by searching MEDLINE via PubMed, Web of Science, Ovid Embase, LILACS, Cochrane Database of Systematic Reviews, TOXLINE for all clinical trials, case series, case reports, and database entries for reports on the use of ivermectin in children weighing less than 15 kg that were published between 1 January 1980 to 25 October 2019. The protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO): CRD42017056515. A total of 3,730 publications were identified, 97 were selected for potential inclusion, but only 17 sources describing 15 studies met the minimum criteria which consisted of known weights of children less than 15 kg linked to possible adverse events, and provided comprehensive IPD. A total of 1,088 children weighing less than 15 kg were administered oral ivermectin for one of the following indications: scabies, mass drug administration for scabies control, crusted scabies, cutaneous larva migrans, myiasis, pthiriasis, strongyloidiasis, trichuriasis, and parasitic disease of unknown origin. Overall a total of 1.4% (15/1,088) of children experienced 18 adverse events all of which were mild and self-limiting. No serious adverse events were reported. CONCLUSIONS/SIGNIFICANCE: Existing limited data suggest that oral ivermectin in children weighing less than 15 kilograms is safe. Data from well-designed clinical trials are needed to provide further assurance.
BACKGROUND: Oral ivermectin is a safe broad spectrum anthelminthic used for treating several neglected tropical diseases (NTDs). Currently, ivermectin use is contraindicated in children weighing less than 15 kg, restricting access to this drug for the treatment of NTDs. Here we provide an updated systematic review of the literature and we conducted an individual-level patient data (IPD) meta-analysis describing the safety of ivermectin in children weighing less than 15 kg. METHODOLOGY/PRINCIPAL FINDINGS: A systematic review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) for IPD guidelines by searching MEDLINE via PubMed, Web of Science, Ovid Embase, LILACS, Cochrane Database of Systematic Reviews, TOXLINE for all clinical trials, case series, case reports, and database entries for reports on the use of ivermectin in children weighing less than 15 kg that were published between 1 January 1980 to 25 October 2019. The protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO): CRD42017056515. A total of 3,730 publications were identified, 97 were selected for potential inclusion, but only 17 sources describing 15 studies met the minimum criteria which consisted of known weights of children less than 15 kg linked to possible adverse events, and provided comprehensive IPD. A total of 1,088 children weighing less than 15 kg were administered oral ivermectin for one of the following indications: scabies, mass drug administration for scabies control, crusted scabies, cutaneous larva migrans, myiasis, pthiriasis, strongyloidiasis, trichuriasis, and parasitic disease of unknown origin. Overall a total of 1.4% (15/1,088) of children experienced 18 adverse events all of which were mild and self-limiting. No serious adverse events were reported. CONCLUSIONS/SIGNIFICANCE: Existing limited data suggest that oral ivermectin in children weighing less than 15 kilograms is safe. Data from well-designed clinical trials are needed to provide further assurance.
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