Download PDF
Planta Med
DOI: 10.1055/a-2294-5259
Perspectives

Rationalising Optimal Dosing of Phytotherapeutics For Use In Children: Current Status – Potential Solutions – Actions Needed

Andreas Hensel 
1   Institute of Pharmaceutical Biology and Phytochemistry, University of Münster, Germany
,
Rudolf Bauer 
2   Institut für Pharmazeutische Wissenschaften, Pharmakognosie, Universitaet Graz, Austria
,
Michael Heinrich 
3   School of Pharmacy, University College London, United Kingdom of Great Britain and Northern Ireland
,
Georg Hempel
4   Pharmaceutical and Medical Chenistry, University of Münster, Germany
,
Olaf Kelber
5   Research and Development, Bayer Consumer Health, Steigerwald Arzneimittelwerk GmbH, Darmstadt, Germany
,
Karin Kraft
6   Centre of Internal Medicine, University Medicine Rostock, Germany
,
Birka Lehmann
7   University of Bonn, Germany
,
Montserrat Mesegué Medà
8   Hospital Sant Joan de Déu, Barcelona, Spain
,
Karen Nieber
9   University of Leipzig, Germany
,
Bernd Roether
10   Bionorica SE, Neumarkt, Germany
,
Judith Maria Rollinger 
11   Department of Pharmaceutical Sciences, University of Vienna, Austria
,
Rüdiger Wiebelitz
12   Practice for Pediatric and Adolescent Medicine, Perleberg, Germany
› Author Affiliations
› Further Information
   Permissions and Reprints

Abstract

“Children are not small adults with respect to the treatment with medicinal products.” This statement of the WHO was the basis for the initiative of the European Commission for the establishment of a paediatric regulation in 2007 to improve the health of children by facilitating the development of medicines for children and adolescents. Seventeen years later, in the field of herbal medicinal products, results are still sobering. Therefore, the Foundation Plants for Health, Society for Medicinal Plants and Natural Products Research, and German Society for Phytotherapy organised a symposium to assess the status quo for the paediatric use of herbal medicinal products (HMPs), to analyse the causes of the current situation, and to discuss strategies for establishing the proof of safe and efficacious HMPs for children.

The current situation for HMPs and their use in children is not fulfilling the requirements of legislation. HMPs in paediatrics are effective and safe, but considering the needs of children is necessary. In European countries, the use, registration, and marketing of HMPs are different, depending on the respective national regulations and specific traditions. EU herbal monographs are the best common denominator for such procedures. Emerging safety discussions must be considered. New approaches with real-world data might be a solution. The regulatory framework is to be adapted. Defining rationalised dosing for HMPs can be achieved by the extrapolation of data from adults, by using existing clinical data for children, and by using RWD. Therefore, a strong need for revising restrictions for the use of HMPs in children and rationalising defined dosage regimes is obvious.

Keywords

children - dosage - extrapolation - herbal medicinal products - phytotherapeutics - real world data


Publication History

Received: 13 February 2024

Accepted: 25 March 2024

Accepted Manuscript online:
25 March 2024

Article published online:
11 April 2024

© 2024. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Ferro A. Paediatric prescribing: why children are not small adults. Br J Clin Pharmacol 2015; 79: 351-353 DOI: 10.1111/bcp.12540.
    Google Scholar
  • 2 Joseph PD, Craig JC, Caldwell PHY. Clinical trials in children. Br J Clin Pharmacol 2015; 79: 357-369 DOI: 10.1111/bcp.12305.
    Google Scholar
  • 3 Petkova V, Hadzhieva B, Nedialkov P. Phytotherapeutic approaches to treatment and prophylaxis in pediatric practice. PHAR 2019; 66: 115-119 DOI: 10.3897/pharmacia.66.e37954.
    Google Scholar
  • 4 Freire CdJ, Da Barbosa LRS, Da Costa JG, Santos RGdA, Santos AFD. Phytotherapy in pediatrics: the production of knowledge and practices in Primary Care. Rev Bras Enferm 2018; 71: 637-645 DOI: 10.1590/0034-7167-2017-0436.
    Google Scholar
  • 5 Ullah H, Filippis A de Baldi A, Dacrema M, Esposito C, Garzarella EU, Santarcangelo C, Tantipongpiradet A, Daglia M. Beneficial Effects of Plant Extracts and Bioactive Food Components in Childhood Supplementation. Nutrients 2021; 13 DOI: 10.3390/nu13093157.
    Google Scholar
  • 6 Shim SB, Lee HH, Ahn HL, Lee JA, Lee HL. Effectiveness and safety of herbal medicine on children with simple obesity. Medicine: Case Reports and Study Protocols 2021; 2: e0132 DOI: 10.1097/MD9.0000000000000132.
    Google Scholar
  • 7 Anheyer D, Cramer H, Lauche R, Saha FJ, Dobos G. Herbal Medicine in Children With Respiratory Tract Infection: Systematic Review and Meta-Analysis. Acad Pediatr 2018; 18: 8-19 DOI: 10.1016/j.acap.2017.06.006.
    Google Scholar
  • 8 Anheyer D, Dobos G, Cramer H. Evidenzlage pflanzlicher Präparate in der Anwendung bei Kindern und Jugendlichen. Z Phytother 2017; 37: 236-241 DOI: 10.1055/s-0042-119174.
    Google Scholar
  • 9 Anheyer D, Frawley J, Koch AK, Lauche R, Langhorst J, Dobos G, Cramer H. Herbal Medicines for Gastrointestinal Disorders in Children and Adolescents: A Systematic Review. Pediatrics 2017; 139 DOI: 10.1542/peds.2017-0062.
    Google Scholar
  • 10 Anheyer D, Lauche R, Schumann D, Dobos G, Cramer H. Herbal medicines in children with attention deficit hyperactivity disorder (ADHD): A systematic review. Complement Ther Med 2017; 30: 14-23 DOI: 10.1016/j.ctim.2016.11.004.
    Google Scholar
  • 11 Nieber K. Klinische Studien zur Anwendung pflanzlicher Arzneimittel bei Kindern – ein Überblick zur vorliegenden Literatur. Swiss J Integrat Med 2016; 28: 5-7 DOI: 10.1159/000442756.
    Google Scholar
  • 12 Commission of the EU. ed. Report from the Commission to the European Parliament and the Council State of Paediatric Medicines in the EU: 10 years of the EU Paediatric Regulation; 2017.
    Google Scholar
  • 13 Permanand G, Mossialos E, McKee M. The EUʼs new paediatric medicines legislation: serving childrenʼs needs?. Arch Dis Child 2007; 92: 808-811 DOI: 10.1136/adc.2006.105692.
    Google Scholar
  • 14 European Parliament – Council on Medicinal Products for Paediatric Use. Regulation (EC) No 1901/2006 of the European Parliament and of the Council on medicinal products for paediatric use, amended by Regulation (EC) No 1902/2006. vom 2006.
    Google Scholar
  • 15 European Medicines Agency EMA, Committee on Herbal Medicinal Products HMPC. Reflection paper on the necessity of initiatives to stimulate the conduct of clinical studies with herbal medicinal products in the pediatric population. EMA/HMPC/833398/2009.
    Google Scholar
  • 16 European Parliament. Regulation of the European Parliament and of the concil laying down Union procedures for the authorisation and supervision of medicinal products for human use and establishing rules governing the European Medicines Agency, amending Regulation (EC) No 1394/2007 and Regulation (EU) No 536/2014 and repealing Regulation (EC) No 726/2004, Regulation (EC) No 141/2000 and Regulation (EC) No 1901/2006 vom 2023.
    Google Scholar
  • 17 Welz AN, Emberger-Klein A, Menrad K. The importance of herbal medicine use in the German health-care system: prevalence, usage pattern, and influencing factors. BMC Health Serv Res 2019; 19: 952 DOI: 10.1186/s12913-019-4739-0.
    Google Scholar
  • 18 Lazarou R, Heinrich M. Herbal medicine: Who cares? The changing views on medicinal plants and their roles in British lifestyle. Phytother Res 2019; 33: 2409-2420 DOI: 10.1002/ptr.6431.
    Google Scholar
  • 19 Tugume P, Nyakoojo C. Ethno-pharmacological survey of herbal remedies used in the treatment of paediatric diseases in Buhunga parish, Rukungiri District, Uganda. BMC Complement Altern Med 2019; 19: 353 DOI: 10.1186/s12906-019-2763-6.
    Google Scholar
  • 20 Wegener T. Herbal medicinal products in the paediatric population – status quo and perspectives. Wiener Med Wochenschr 2013; 163: 46-51 DOI: 10.1007/s10354-013-0175-7.
    Google Scholar
  • 21 Du Y, Wolf I-K, Zhuang W, Bodemann S, Knöss W, Knopf H. Use of herbal medicinal products among children and adolescents in Germany. BMC Complement Altern Med 2014; 14: 218 DOI: 10.1186/1472-6882-14-218.
    Google Scholar
  • 22 Tomassoni AJ, Simone K. Herbal medicines for children: an illusion of safety?. Curr Opin Pediatr 2001; 13: 162-169 DOI: 10.1097/00008480-200104000-00014.
    Google Scholar
  • 23 Hümer M, Scheller G, Kapellen T, Gebauer C, Schmidt H, Kiess W. Phytotherapie in der Kinderheilkunde – Prävalenz, Indikationen und Motivation. Dtsch Med Wochenschr 2010; 135: 959-964 DOI: 10.1055/s-0030-1253683.
    Google Scholar
  • 24 Gardiner P, Adams D, Filippelli AC, Nasser H, Saper R, White L, Vohra S. A systematic review of the reporting of adverse events associated with medical herb use among children. Glob Adv Health Med 2013; 2: 46-55 DOI: 10.7453/gahmj.2012.071.
    Google Scholar
  • 25 Polat S, Gürol A. Safety of Herbal Medicines in Children. In:: Akram M, ed. Alternative Medicine – Update. IntechOpen; 2021
    Google Scholar
  • 26 Snodgrass WR. Herbal products: Risks and benefits of use in children. Curr Ther Res Clin Exp 2001; 62: 724-737 DOI: 10.1016/S0011-393X(01)80079-5.
    Google Scholar
  • 27 Çiftçi S, Samur FG. Use of Botanical Dietary Supplements in Infants and Children and Their Effects on Health. Hacettepe University Faculty of Health Sciences Journal 2017; 4: 30-45 DOI: 10.21020/husbfd.303011.
    Google Scholar
  • 28 Tachjian A, Maria V, Jahangir A. Use of herbal products and potential interactions in patients with cardiovascular diseases. J Am Coll Cardiol 2010; 55: 515-525 DOI: 10.1016/j.jacc.2009.07.074.
    Google Scholar
  • 29 Ekor M. The growing use of herbal medicines: issues relating to adverse reactions and challenges in monitoring safety. Front Pharmacol 2014; 4 DOI: 10.3389/fphar.2013.00177.
    Google Scholar
  • 30 Rietbrock N, Staib H, Loew D. ed. Klinische Pharmakologie: Enzymentwicklung während der Fetalperiode und Kindheit. 4th ed. Darmstadt: Steinkopff Verlag; 2001
    Google Scholar
  • 31 van den Anker J, Reed MD, Allegaert K, Kearns GL. Developmental Changes in Pharmacokinetics and Pharmacodynamics. J Clin Pharmacol 2018; 58 Suppl 10: S10-S25 DOI: 10.1002/jcph.1284.
    Google Scholar
  • 32 Schrier L, Hadjipanayis A, Stiris T, Ross-Russell RI, Valiulis A, Turner MA, Zhao W, Cock P de Wildt SN de Allegaert K, van den Anker J. Off-label use of medicines in neonates, infants, children, and adolescents: a joint policy statement by the European Academy of Paediatrics and the European society for Developmental Perinatal and Pediatric Pharmacology. Eur J Pediatr 2020; 179: 839-847 DOI: 10.1007/s00431-019-03556-9.
    Google Scholar
  • 33 van Rongen A, Krekels EH, Calvier E am Wildt SN de an Vermeulen. Knibbe CA. An Update on the Use of Allometric and Other Scaling Methods to Scale Drug Clearance in Children: Towards Decision Tables. Expert Opin Dug MetabToxicol 2022; 18: 99-113 DOI: 10.1080/17425255.2021.2027907.
    Google Scholar
  • 34 Schilcher H DW. Phytotherapie in der Kinderheilkunde. 4th ed. Stuttgart: Wissenschaftl. Verlagsgesellschaft; 2006
    Google Scholar
  • 35 European Parliament and EC Council. Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for pediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004 vom 12. 12. 2006.
    Google Scholar
  • 36 Diaz M, Soler A, Altemira A. Alto uso de terapias complementarias en pacientes pediátricos hospitalizados en un hospital de tercer nivel. High use of complementary therapies in paediatric inpatients in a tertiary hospital. Spanish Pediatric Asociation (AEPED) Congress 2019; 2019
    Google Scholar
  • 37 Güemes Heras I, Santamaría-Orleans A, Colinas Herrero JF, Gómez Sorrigueta P, Ortiz González L, La Iglesia-Arnaez R de. Canals Baeza A. Use of Dietary Supplements among Spanish Pediatricians in Daily Practice: A Cross-Sectional Survey Study. J Nutr Metab 2019; 2019: 5819305 DOI: 10.1155/2019/5819305.
    Google Scholar
  • 38 Santamaría-Orleans A, La Iglesia-Arnáez Rd. Alonso-Osorio MJ. Use recommendation of pediatric infusions by health professional. Revista de Fiitoterapia; 2017: 27-35
    Google Scholar
  • 39 Kersting G, Willmann S, Würthwein G, Lippert J, Boos J, Hempel G. Physiologically based pharmacokinetic modelling of high- and low-dose etoposide: from adults to children. Cancer Chemother Pharmacol 2012; 69: 397-405 DOI: 10.1007/s00280-011-1706-9.
    Google Scholar
  • 40 Marquardt P, Kaft K, Nieber K. Clinical trials with herbal medicinal products in children: a literature analysis. Wien Med Wochenschr 2015; 165: 236-242 DOI: 10.1007/s10354-015-0373-6.
    Google Scholar
  • 41 Farrington R, Musgrave I, Byard RW. Potential adverse outcomes of herbal preparation use in childhood. Acta Paediatr 2019; 108: 419-422 DOI: 10.1111/apa.14595.
    Google Scholar
  • 42 Conroy S, McIntyre J, Choonara I. Unlicensed and off label drug use in neonates. Arch Dis Child Fetal Neonatal Ed 1999; 80: F142-144 DOI: 10.1136/fn.80.2.F142. discussion F144–F145
    Google Scholar
  • 43 Zipursky J, Juurlink DN. Studying Drug Safety in the Real World. JAMA Intern Med 2018; 178: 1533-1534 DOI: 10.1001/jamainternmed.2018.5766.
    Google Scholar
  • 44 Zuzak TJ, Rauber-Lüthy C, Simões-Wüst AP. Accidental intakes of remedies from complementary and alternative medicine in children–analysis of data from the Swiss Toxicological Information Centre. Eur J Pediatr 2010; 169: 681-688 DOI: 10.1007/s00431-009-1087-9.
    Google Scholar
  • 45 Bie S de Ferrajolo C, Straus SMJM, Verhamme KMC, Bonhoeffer J, Wong ICK, Sturkenboom MCJM. Pediatric Drug Safety Surveillance in FDA-AERS: A Description of Adverse Events from GRiP Project. PLoS One 2015; 10: e0130399 DOI: 10.1371/journal.pone.0130399.
    Google Scholar
  • 46 Busner J, Targum SD. The clinical global impressions scale: applying a research tool in clinical practice. Psychiatry 2007; 4: 28-37
    Google Scholar
  • 47 Nieber K, Raskopf E, Möller J, Kelber O, Fürst R, Shah-Hosseini K, Singh J, Kraft K, Mösgens R. Pharmaco-epidemiological research on herbal medicinal products in the paediatric population: data from the PhytoVIS study. Eur J Pediatr 2020; 179: 507-512 DOI: 10.1007/s00431-019-03532-3.
    Google Scholar