European Journal of Clinical Pharmacology

, Volume 70, Issue 4, pp 445–452 | Cite as

The impact of legislation on drug substances used off-label in paediatric wards—a nationwide study

  • Sissel Haslund-Krog
  • René Mathiasen
  • Hanne Rolighed Christensen
  • Helle Holst
Pharmacoepidemiology and Prescription

Abstract

Purpose

This nationwide study is aimed at describing to what extent the European Paediatric Regulation has met therapeutic needs in children.

Methods

Data for each drug substance in defined daily doses (DDD) were extracted from the national Danish data base. We evaluated if drug substances were used off-label and whether they had a paediatric investigation plan (PIP). This study did not include drug prescriptions for individual paediatric patients; thus, it was not possible to make use of all off-label categories previously used. Additionally, paediatric standard assortments (SA) were compared to the European survey on paediatric medicinal products.

Results

Thirteen percent of the 100 most used drug substances were determined as being used off-label, four of which had a PIP and one had a full waiver. Only one of the three drug substances used off-label most often, accounting for 85 % of such use, had a PIP. Neonates were included in one-third of PIPs and adolescents in 15. Nineteen out of 21 PIPs had a waiver and 14 PIPs were deferred. In line with the European survey, carbapenems, corticosteroids and proton pump inhibitors were frequent found in SAs.

Conclusion

PIPs only cover a small proportion of the drugs found to be used off-label in this study. Despite waivers granted, drug substances were used nonetheless. Unmet regulatory needs are still considerable in some therapeutic areas in neonates as well as in children.

Keywords

Children Paediatric investigation plan Off-label Paediatric regulation Standard assortments 

Supplementary material

228_2013_1626_MOESM1_ESM.docx (15 kb)
ESM 1(DOCX 15 kb)

References

  1. 1.
    Kimland E, Nydert P, Odlind V et al (2012) Paediatric drug use with focus on off-label prescriptions at Swedish hospitals—a nationwide study. Acta Paediatr 101:772–778. doi:10.1111/j.1651-2227.2012.02656.x CrossRefPubMedCentralPubMedGoogle Scholar
  2. 2.
    Cuzzolin L, Atzei A, Fanos V (2006) Off-label and unlicensed prescribing for newborns and children in different settings: a review of the literature and a consideration about drug safety. Expert Opin Drug Saf 5:703–718. doi:10.1517/14740338.5.5.703 CrossRefPubMedGoogle Scholar
  3. 3.
    ’t Jong GW, van der Linden PD, Bakker EM et al (2002) Unlicensed and off-label drug use in a paediatric ward of a general hospital in the Netherlands. Eur J Clin Pharmacol 58:293–297. doi:10.1007/s00228-002-0479-9 CrossRefPubMedGoogle Scholar
  4. 4.
    Lindell-Osuagwu L, Korhonen MJ, Saano S et al (2009) Off-label and unlicensed drug prescribing in three paediatric wards in Finland and review of the international literature. J Clin Pharm Ther 34:277–287CrossRefPubMedGoogle Scholar
  5. 5.
    Conroy S, Choonara I, Impicciatore P et al (2000) Survey of unlicensed and off-label drug use in paediatric wards in European countries. European Network for Drug Investigation in Children. BMJ 320:79–82CrossRefPubMedCentralPubMedGoogle Scholar
  6. 6.
    Cohen E, Uleryk E, Jasuja M, Parkin PC (2007) An absence of pediatric randomized controlled trials in general medical journals, 1985–2004. J Clin Epidemiol 60:118–123. doi:10.1016/j.jclinepi.2006.03.015 CrossRefPubMedGoogle Scholar
  7. 7.
    EMA document (2006) Official Journal of the European Union. Paediatric Regulation (EC) No 1901/2006. http://ec.europa.eu/health/files/eudralex/vol-1/reg_2006_1901/reg_2006_1901_en.pdf. Accessed 4 Mar 2013
  8. 8.
    Olski TM, Lampus SF, Gherarducci G, Saint Raymond A (2011) Three years of paediatric regulation in the European Union. Eur J Clin Pharmacol 67:245–252. doi:10.1007/s00228-011-0997-4 CrossRefPubMedGoogle Scholar
  9. 9.
    Knellwolf A-L, Bauzon S, Alberighi ODC et al (2011) Framework conditions facilitating paediatric clinical research. Ital J Pediatr 37:12. doi:10.1186/1824-7288-37-12 CrossRefPubMedCentralPubMedGoogle Scholar
  10. 10.
    EMA document (2010) Report on the survey of all paediatric uses of medicinal products in Europe. http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000096.jsp. Accessed 9 Sep 2013
  11. 11.
    Data base (2012) BIWeb. http://bihost.dk/amgros/login.aspx?ReturnUrl=%2famgros%2fdefault.aspx. Accessed 20 Nov 2012
  12. 12.
    WHOCC - ATC/DDD Index. http://www.whocc.no/atc_ddd_index/. Accessed 8 Mar 2013
  13. 13.
    EMA Website (2012) European Medicines Agency - Find medicine - European public assessment reports. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search.jsp&mid=WC0b01ac058001d124. Accessed 8 Mar 2013
  14. 14.
    Danish Health and Medicine Authority (2012) Summary of product characteristics. http://www.produktresume.dk/docushare/dsweb/View/Collection-96. Accessed Dec 2012
  15. 15.
    Kimland E, Odlind V (2012) Off-label drug use in pediatric patients. Clin Pharmacol Ther 91:796–801. doi:10.1038/clpt.2012.26 CrossRefPubMedGoogle Scholar
  16. 16.
    WHO document (2013) WHOCC - Use of ATC/DDD. http://www.whocc.no/use_of_atc_ddd/. Accessed 22 Feb 2013
  17. 17.
    European Commission document (2013) Better medicines for children from concept to reality. http://ec.europa.eu/health/files/paediatrics/2013_com443/paediatric_report-com(2013)443_en.pdf. Accessed 14 Oct 2013
  18. 18.
    Teutonico D, Montanari S, Ponchel G (2012) Leuprolide acetate: pharmaceutical use and delivery potentials. Expert Opin Drug Deliv 9:343–354. doi:10.1517/17425247.2012.662484 CrossRefPubMedGoogle Scholar
  19. 19.
    Fuqua JS (2013) Treatment and outcomes of precocious puberty: an update. J Clin Endocrinol Metab 98:2198–2207. doi:10.1210/jc.2013-1024 CrossRefPubMedGoogle Scholar
  20. 20.
    Dupuis LL, Nathan PC (2010) Optimizing emetic control in children receiving antineoplastic therapy: beyond the guidelines. Paediatr Drugs 12:51–61. doi:10.2165/11316190-000000000-00000 CrossRefPubMedGoogle Scholar
  21. 21.
    Nathan PC, Tomlinson G, Dupuis LL et al (2006) A pilot study of ondansetron plus metopimazine vs. ondansetron monotherapy in children receiving highly emetogenic chemotherapy: a Bayesian randomized serial N-of-1 trials design. Support Care Cancer 14:268–276. doi:10.1007/s00520-005-0875-7 CrossRefPubMedGoogle Scholar
  22. 22.
  23. 23.
  24. 24.
    Broe J, Platz MA, Nielsen S et al (2013) Off-label use and adverse events of biologic agents in paediatric patients with juvenile idiopathic arthritis. Clin Ther 35:1-2 supplGoogle Scholar
  25. 25.
    Garazzino S, Lutsar I, Bertaina C et al (2013) New antibiotics for paediatric use: a review of a decade of regulatory trials submitted to the European Medicines Agency from 2000–why aren’t we doing better? Int J Antimicrob Agents 42:99–118. doi:10.1016/j.ijantimicag.2013.05.001 CrossRefPubMedGoogle Scholar
  26. 26.
    Kemper EM, Merkus M, Wierenga PC et al (2011) Towards evidence-based pharmacotherapy in children. Paediatr Anaesth 21:183–189. doi:10.1111/j.1460-9592.2010.03493.x CrossRefPubMedGoogle Scholar
  27. 27.
    Tynjälä P, Lindahl P, Honkanen V et al (2007) Infliximab and etanercept in the treatment of chronic uveitis associated with refractory juvenile idiopathic arthritis. Ann Rheum Dis 66:548–550. doi:10.1136/ard.2006.058248 CrossRefPubMedCentralPubMedGoogle Scholar
  28. 28.
    Foeldvari I, Nielsen S, Kümmerle-Deschner J et al (2007) Tumor necrosis factor-alpha blocker in treatment of juvenile idiopathic arthritis-associated uveitis refractory to second-line agents: results of a multinational survey. J Rheumatol 34:1146–1150PubMedGoogle Scholar
  29. 29.
    European Medicines Agency with its Paediatric Committee (2012) 5-year Report to the European Commission. http://ec.europa.eu/health/files/paediatrics/2012-09_pediatric_report-annex1-2_en.pdf. Accessed 19 Feb 2013
  30. 30.
    EMA document (2013) Successes of the paediatric regulation after 5 years. http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/06/news_detail_001823.jsp&mid=WC0b01ac058004d5c1. Accessed 19 Jun 2013
  31. 31.
    European Medicines Agency - EMEA-000130-PIP01-07 - Paracetamol. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/pips/EMEA-000130-PIP01-07/pip_000279.jsp&mid=WC0b01ac058001d129. Accessed 2 Oct 2013
  32. 32.
    EMA document Paediatric Medicines Section (2013) Report to the European Commission. http://ec.europa.eu/health/human-use/paediatric-medicines/developments/. Accessed 2 Oct 2013
  33. 33.
    Allegaert K, Naulaers G, Vanhaesebrouck S, Anderson BJ (2013) The paracetamol concentration-effect relation in neonates. Paediatr Anaesth 23:45–50. doi:10.1111/pan.12076 CrossRefPubMedGoogle Scholar
  34. 34.
    Allegaert K, Palmer GM, Anderson BJ (2011) The pharmacokinetics of intravenous paracetamol in neonates: size matters most. Arch Dis Child 96:575–580. doi:10.1136/adc.2010.204552 CrossRefPubMedGoogle Scholar
  35. 35.
  36. 36.
    Fortinguerra F, Maschi S, Clavenna A, Bonati M (2010) Pain management in the paediatric population: the regulatory situation in Europe. Arch Dis Child 95:749–753. doi:10.1136/adc.2009.179549 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Sissel Haslund-Krog
    • 1
  • René Mathiasen
    • 2
  • Hanne Rolighed Christensen
    • 1
  • Helle Holst
    • 1
  1. 1.Department of Clinical PharmacologyBispebjerg HospitalCopenhagenDenmark
  2. 2.Pediatric and Adolescent MedicineUniversity Hospital RigshospitaletCopenhagenDenmark

Personalised recommendations