Skip to main content
SpringerLink
Log in

Two decades of off-label prescribing in children: a literature review

  • Review Article
  • Published:
World Journal of Pediatrics Aims and scope Submit manuscript

Abstract

Background

In the past two decades, many legislative and regulatory initiatives were taken globally to improve drug use in children. However, children are still found to be prescribed with off-label drugs. This study was conducted to provide an overview of the worldwide trend in off-label prescribing in children from the year 1996 to 2016.

Data sources

The articles published in PubMed, MEDLINE and Google Scholar were searched using text words: off-label, unlicensed, paediatric and children. Additional articles were identified by reviewing the bibliography of the retrieved articles. Full-text articles published in English which reported on the prevalence of off-label prescribing in children between January 1996 and December 2016 were included.

Results

A total of 101 studies met the inclusion criteria. Off-label prescribing definition included four main categories: age, indication, dose and route of administration. The three most common reference sources used in the studies were summary of product characteristics, national formularies and package inserts. Overall, the off-label prescribing rates in children ranged from 1.2 to 99.7%. The most common category of off-label prescribing in children was dose and age.

Conclusions

This review highlighted that off-label prescribing in children was found to be highly prevalent throughout the past two decades, persistently in the neonatal intensive care units. This suggests that besides legislative and regulatory initiatives, behavioural, knowledge aspects and efforts to integrate evidence into practice related to off-label prescribing also need to be evaluated and consolidated as part of the concerted efforts to narrow the gaps in prescribing for children.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Riedel C, Lehmann B, Broich K, Sudhop T. Improving drug licensing for children and adolescents: position paper from the More Medicines for Minors Symposion 8 June 2015 in Bonn. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2016;59:1587–92 (in Germany).

    PubMed  Google Scholar 

  2. Coté CJ, Kauffman RE, Troendle GJ, Lambert GH. Is the “therapeutic orphan” about to be adopted? Pediatrics. 1996;98:118–23.

    PubMed  Google Scholar 

  3. Rocchi F, Tomasi P. The development of medicines for children. Part of a series on Pediatric Pharmacology, guest edited by Gianvincenzo Zuccotti, Emilio Clementi, and Massimo Molteni. Pharmacol Res. 2011;64:169–75.

    PubMed  Google Scholar 

  4. Brill MJ, Diepstraten J, van Rongen A, van Kralingen S, van den Anker JN, Knibbe CA. Impact of obesity on drug metabolism and elimination in adults and children. Clin Pharmacokinet. 2012;51:277–304.

    CAS  PubMed  Google Scholar 

  5. Oshikoya KA, Sammons HM, Choonara I. A systematic review of pharmacokinetics studies in children with protein-energy malnutrition. Eur J Clin Pharmacol. 2010;66:1025–35.

    CAS  PubMed  Google Scholar 

  6. Pandolfini C, Bonati M. A literature review on off-label drug use in children. Eur J Pediatr. 2005;164:552–8.

    PubMed  Google Scholar 

  7. Cuzzolin L, Atzei A, Fanos V. 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. 2006;5:703–18.

    PubMed  Google Scholar 

  8. Magalhães J, Rodrigues AT, Roque F, Figueiras A, Falcão A, Herdeiro MT. Use of off-label and unlicenced drugs in hospitalised paediatric patients: a systematic review. Eur J Clin Pharmacol. 2015;71:1–13.

    PubMed  Google Scholar 

  9. Souza A, Santos D, Fonseca S, Medeiros M, Batista L, Turner M, et al. Toxic excipients in medications for neonates in Brazil. Eur J Pediatr. 2014;173:935–45.

    CAS  PubMed  Google Scholar 

  10. Yewale VN, Dharmapalan D. Promoting appropriate use of drugs in children. Int J Pediatr. 2012;2012:906570.

    PubMed  PubMed Central  Google Scholar 

  11. Ufer M, Rane A, Karlsson Å, Kimland E, Bergman U. Widespread off-label prescribing of topical but not systemic drugs for 350,000 paediatric outpatients in Stockholm. Eur J Clin Pharmacol. 2003;58:779–83.

    PubMed  Google Scholar 

  12. Manthripragada AD, Pinheiro SP, MaCurdy TE, Saneinejad S, Worrall CM, Kelman JA, et al. Off-label topical calcineurin inhibitor use in children. Pediatrics. 2013;132:e1327–32.

    PubMed  Google Scholar 

  13. Man SC, Primejdie DP, Sarkozi IK, Popa A. Off-label and unlicensed prescribing in hospitalized children: prevalence and reasons. Farmacia. 2017;65:460–6.

    Google Scholar 

  14. Balan S, Hassali MA, Mak VSL. Non-regulatory related factors leading to off-label prescribing in children: a concept map. Res Soc Adm Pharm. 2017;13:1219–21.

    CAS  Google Scholar 

  15. Mathis L, Rodriguez W. Drug therapy in pediatrics: a developing field. Dermatol Ther. 2009;22:257–61.

    PubMed  Google Scholar 

  16. Nahata MC. New regulations for pediatric labeling of prescription drugs. Ann Pharmacother. 1996;30:1032–3.

    CAS  PubMed  Google Scholar 

  17. Suydam LA, Kubic MJ. FDA’s implementation of FDAMA: an interim balance sheet. Food Drug Law J. 2001;56:131–5.

    CAS  PubMed  Google Scholar 

  18. Ward RM, Kauffman R. Future of pediatric therapeutics: reauthorization of BPCA and PREA. Clin Pharmacol Ther. 2007;81:477–9.

    CAS  PubMed  Google Scholar 

  19. Fain K, Daubresse M, Alexander GC. The Food and Drug Administration Amendments Act and postmarketing commitments. JAMA. 2013;310:202–4.

    CAS  PubMed  Google Scholar 

  20. Hoppu K, Anabwani G, Garcia-Bournissen F, Gazarian M, Kearns GL, Nakamura H, et al. The status of paediatric medicines initiatives around the world—what has happened and what has not? Eur J Clin Pharmacol. 2012;68:1–10.

    PubMed  Google Scholar 

  21. Dunne J. The European Regulation on medicines for paediatric use. Paediatr Respir Rev. 2007;8:177–83.

    PubMed  Google Scholar 

  22. Hawcutt DB, Smyth RL. The new European Regulation on pediatric medicines: regulatory perspective. Paediatr Drugs. 2008;10:143–6.

    PubMed  Google Scholar 

  23. Uchiyama A. Pediatric clinical studies in Japan: regulations and current status. Appl Clin Trials. 2002;11:57.

    Google Scholar 

  24. Yang Y, Su GC. A comparative study between WHO essential medicines for children and pediatric medicines in the national essential drug list of China. China Pharm. 2011;22:2994–8.

    Google Scholar 

  25. Yang BM, Bae EY, Kim J. Economic evaluation and pharmaceutical reimbursement reform in South Korea’s National Health Insurance. Health Aff (Millwood). 2008;27:179–87.

    PubMed  Google Scholar 

  26. Hoppu K, Sn Ranganathan SS, Dodoo AN. Realities of paediatric pharmacotherapy in the developing world. Arch Dis Child. 2011;96:764–8.

    PubMed  Google Scholar 

  27. Corny J, Lebel D, Bailey B, Bussières JF. Unlicensed and off-label drug use in children before and after pediatric governmental initiatives. J Pediatr Pharmacol Ther. 2015;20:316–28.

    PubMed  PubMed Central  Google Scholar 

  28. Braun V, Clarke V. Using thematic analysis in psychology. Qual Res Psychol. 2006;3:77–101.

    Google Scholar 

  29. Conroy S, McIntyre J, Choonara I. Unlicensed and off label drug use in neonates. Arch Dis Child Fetal Neonatal Ed. 1999;80:F142–4 (discussion F144–5).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. O’Donnell CP, Stone RJ, Morley CJ. Unlicensed and off-label drug use in an Australian neonatal intensive care unit. Pediatrics. 2002;110:e52.

    PubMed  Google Scholar 

  31. Carvalho PR, Carvalho CG, Alievi PT, Martinbiancho J, Trotta EA. Prescription of drugs not appropriate for children in a Pediatric Intensive Care Unit. J Pediatr (Rio J). 2003;79:397–402 (in Portuguese).

    Google Scholar 

  32. Gavrilov V, Berkovitch M, Ling G, Brenner-Zadda G, Lifshitz M, Gorodischer R. Unapproved prescriptions in two pediatric intensive care units in Israel. Curr Ther Res Clin Exp. 2003;64:734–42.

    PubMed  PubMed Central  Google Scholar 

  33. Gavrilov V, Lifshitz M, Levy J, Gorodischer R. Unlicensed and off-label medication use in a general pediatrics ambulatory hospital unit in Israel. Isr Med Assoc J. 2000;2:595–7.

    CAS  PubMed  Google Scholar 

  34. Lifshitz M, Gavrilov V, Grossman Z, Binsthok M, Hornik D, Rosemblum H, et al. Unapproved prescription practices in primary pediatric clinics in Israel: a prospective analysis. Curr Ther Res. 2002;63:830–7.

    Google Scholar 

  35. Ekins-Daukes S, Helms PJ, Simpson CR, Taylor MW, McLay JS. Off-label prescribing to children in primary care: retrospective observational study. Eur J Clin Pharmacol. 2004;60:349–53.

    PubMed  Google Scholar 

  36. Turner S, Gill A, Nunn T, Hewitt B, Choonara I. Use of “off-label” and unlicensed drugs in paediatric intensive care unit. Lancet. 1996;347:549–50.

    CAS  PubMed  Google Scholar 

  37. Chalumeau M, Tréluyer J, Salanave B, Assathiany R, Chéron G, Crocheton N, et al. Off label and unlicensed drug use among French office based paediatricians. Arch Dis Child. 2000;83:502–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. McIntyre J, Conroy S, Avery A, Corns H, Choonara I. Unlicensed and off label prescribing of drugs in general practice. Arch Dis Child. 2000;83:498–501.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. ‘t Jong GW, Vulto AG, de Hoog M, Schimmel KJ, Tibboel D, van den Anker JN. A survey of the use of off-label and unlicensed drugs in a Dutch children’s hospital. Pediatrics. 2001;108:1089–93.

    PubMed  Google Scholar 

  40. ‘t Jong GW, van der Linden PD, Bakker EM, van der Lely N, Eland IA, Stricker BH, et al. Unlicensed and off-label drug use in a paediatric ward of a general hospital in the Netherlands. Eur J Clin Pharmacol. 2002;58:293–7.

    PubMed  Google Scholar 

  41. McKinzie JP, Wright SW, Wrenn KD. Pediatric drug therapy in the emergency department: does it meet FDA-approved prescribing guidelines? Am J Emerg Med. 1997;15:118–21.

    CAS  PubMed  Google Scholar 

  42. Schirm E, Tobi H, de Jong-van den Berg LT. Unlicensed and off label drug use by children in the community: cross sectional study. BMJ. 2002;324:1312–3.

    PubMed  PubMed Central  Google Scholar 

  43. Schirm E, Tobi H, de Jong-van den Berg LT. Risk factors for unlicensed and off-label drug use in children outside the hospital. Pediatrics. 2003;111:291–5.

    PubMed  Google Scholar 

  44. ‘t Jong GW, Eland IA, Sturkenboom MC, van den Anker JN, Stricker BH. Determinants for drug prescribing to children below the minimum licensed age. Eur J Clin Pharmacol. 2003;58:701–5.

    PubMed  Google Scholar 

  45. Turner S, Longworth A, Nunn AJ, Choonara I. Unlicensed and off label drug use in paediatric wards: prospective study. BMJ. 1998;316:343–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Neubert A, Dormann H, Weiss J, Egger T, Criegee-Rieck M, Rascher W, et al. The impact of unlicensed and off-label drug use on adverse drug reactions in paediatric patients. Drug Saf. 2004;27:1059–67.

    PubMed  Google Scholar 

  47. Turner S. Unregistered and off-label drug use in paediatric inpatients. Aust J Hosp Pharm. 1999;29:265–8.

    Google Scholar 

  48. Conroy S, Choonara I, Impicciatore P, Mohn A, Arnell H, Rane A, et al. Survey of unlicensed and off label drug use in paediatric wards in European countries. European Network for Drug Investigation in Children. BMJ. 2000;320:79–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Barr J, Brenner-Zada G, Heiman E, Pareth G, Bulkowstein M, Greenberg R, et al. Unlicensed and off-label medication use in a neonatal intensive care unit: a prospective study. Am J Perinatol. 2002;19:67–72.

    PubMed  Google Scholar 

  50. Eiland LS, Knight P. Evaluating the off-label use of medications in children. Am J Health Syst Pharm. 2006;63:1062–5.

    PubMed  Google Scholar 

  51. Di Paolo ER, Stoetter H, Cotting J, Frey P, Gehri M, Beck-Popovic M, et al. Unlicensed and off-label drug use in a Swiss paediatric university hospital. Swiss Med Wkly. 2006;136:218–22.

    PubMed  Google Scholar 

  52. Pandolfini C, Impicciatore P, Provasi D, Rocchi F, Campi R, Bonati M, et al. Off-label use of drugs in Italy: a prospective, observational and multicentre study. Acta Paediatr. 2002;91:339–47.

    CAS  PubMed  Google Scholar 

  53. Bücheler R, Schwab M, Mörike K, Kalchthaler B, Mohr H, Schröder H, et al. Off label prescribing to children in primary care in Germany: retrospective cohort study. BMJ. 2002;324:1311–2.

    PubMed  PubMed Central  Google Scholar 

  54. Horen B, Montastruc JL, Lapeyre-Mestre M. Adverse drug reactions and off-label drug use in paediatric outpatients. Br J Clin Pharmacol. 2002;54:665–70.

    PubMed  PubMed Central  Google Scholar 

  55. Kieran EA, O’Callaghan N, O’Donnell CP. Unlicensed and off-label drug use in an Irish neonatal intensive care unit: a prospective cohort study. Acta Paediatr. 2014;103:e139–42.

    CAS  PubMed  Google Scholar 

  56. Carvalho CG, Ribeiro MR, Bonilha MM, Fernandes M Jr, Procianoy RS, Silveira RC. Use of off-label and unlicensed drugs in the neonatal intensive care unit and its association with severity scores. J Pediatr (Rio J). 2012;88:465–70.

    Google Scholar 

  57. Mesquita M, Godoy G, Cabral MS, Zavala R, Espínola E, Genes L. Prescription of off-label and unlicensed drugs in hospitalized newborns: a multicenter study in five hospitals in Greater Asuncion, Paraguay. Pediatría (Asunción). 2014;41:208–14.

    Google Scholar 

  58. Silva J, Flor-de-Lima F, Soares H, Guimarães H. Off-label and unlicensed drug use in neonatology: reality in a Portuguese university hospital. Acta Med Port. 2015;28:297–306.

    PubMed  Google Scholar 

  59. Ferreira Lde A, Ibiapina Cda C, Machado MG, Fagundes ED. High prevalence of off-label and unlicensed drug prescribing in a Brazilian intensive care unit. Rev Assoc Med Bras. 1992;2012:82–7 (in Portuguese).

    Google Scholar 

  60. Jobanputra N, Save SU, Bavdekar SB. Off-label and unlicensed drug use in children admitted to Pediatric Intensive Care Units (PICU). Int J Risk Saf Med. 2015;27:113–21.

    PubMed  Google Scholar 

  61. García-López I, Fuentes-Ríos JE, Manrique-Rodríguez S, Fernández-Llamazares CM. Off-label and unlicensed drug use: results from a pilot study in a paediatric intensive care unit. An Pediatr (Barc). 2017;86:28–36 (in Spanish).

    PubMed  Google Scholar 

  62. Hsien L, Breddemann A, Frobel AK, Heusch A, Schmidt KG, Läer S. Off-label drug use among hospitalised children: identifying areas with the highest need for research. Pharm World Sci. 2008;30:497–502.

    PubMed  Google Scholar 

  63. Santos DB, Clavenna A, Bonati M, Coelho HL. Off-label and unlicensed drug utilization in hospitalized children in Fortaleza, Brazil. Eur J Clin Pharmacol. 2008;64:1111–8.

    PubMed  Google Scholar 

  64. Dos Santos L, Heineck I. Drug utilization study in pediatric prescriptions of a university hospital in southern Brazil: off-label, unlicensed and high-alert medications. Farm Hosp. 2012;36:180–6.

    PubMed  Google Scholar 

  65. Ballard CD, Peterson GM, Thompson AJ, Beggs SA. Off-label use of medicines in paediatric inpatients at an Australian teaching hospital. J Paediatr Child Health. 2013;49:38–42.

    PubMed  Google Scholar 

  66. Saiyed MM, Lalwani T, Rana D. Off-label medicine use in pediatric inpatients: a prospective observational study at a tertiary care hospital in India. Int J Pediatr. 2014;2014:415815.

    PubMed  PubMed Central  Google Scholar 

  67. Joret-Descout P, Prot-Labarthe S, Brion F, Bataille J, Hartmann JF, Bourdon O. Off-label and unlicensed utilisation of medicines in a French paediatric hospital. Int J Clin Pharm. 2015;37:1222–7.

    PubMed  Google Scholar 

  68. Corny J, Bailey B, Lebel D, Bussières JF. Unlicensed and off-label drug use in paediatrics in a mother-child tertiary care hospital. Paediatr Child Health. 2016;21:83–7.

    PubMed  PubMed Central  Google Scholar 

  69. Teigen A, Wang S, Truong BT, Bjerknes K. Off-label and unlicensed medicines to hospitalised children in Norway. J Pharm Pharmacol. 2017;69:432–8.

    CAS  PubMed  Google Scholar 

  70. Phan H, Leder M, Fishley M, Moeller M, Nahata M. Off-label and unlicensed medication use and associated adverse drug events in a pediatric emergency department. Pediatr Emerg Care. 2010;26:424–30.

    PubMed  Google Scholar 

  71. McD Taylor D, Joffe P, Taylor SE, Jones A, Cheek JA, Craig SS, et al. Off-label and unlicenced medicine administration to paediatric emergency department patients. Emerg Med Australas. 2015;27:440–6.

    PubMed  Google Scholar 

  72. Knopf H, Wolf IK, Sarganas G, Zhuang W, Rascher W, Neubert A. Off-label medicine use in children and adolescents: results of a population-based study in Germany. BMC Public Health. 2013;13:631.

    PubMed  PubMed Central  Google Scholar 

  73. Abdulah R, Khairinisa MA, Pratiwi AA, Barliana MI, Pradipta IS, Halimah E, et al. Off-label paediatric drug use in an Indonesian community setting. J Clin Pharm Ther. 2015;40:409–12.

    CAS  PubMed  Google Scholar 

  74. Ariati AL, Kartinah N, Intannia D. Description of the use of off-label drugs in pediatric patients outpatient in Ulin Banjarmasin public hospital period January–December 2013. J Pharmasci. 2015;2:58–64 (in Indonesian).

    Google Scholar 

  75. Ellul IC, Grech V, Attard-Montalto S. Paediatric off-label and unlicensed prescribing in primary care in Malta: prospective observational drug utilisation study. Int J Risk Saf Med. 2015;27:123–34.

    PubMed  Google Scholar 

  76. Gonçalves MG, Heineck I. Frequency of prescriptions of off-label drugs and drugs not approved for pediatric use in primary health care in a southern municipality of Brazil. Rev Paul Pediatr. 2016;34:11–7 (in Portuguese).

    PubMed  PubMed Central  Google Scholar 

  77. Lindell-Osuagwu L, Korhonen MJ, Saano S, Helin-Tanninen M, Naaranlahti T, Kokki H. Off-label and unlicensed drug prescribing in three paediatric wards in Finland and review of the international literature. J Clin Pharm Ther. 2009;34:277–87.

    CAS  PubMed  Google Scholar 

  78. Khdour MR, Hallak HO, Alayasa KS, AlShahed QN, Hawwa AF, McElnay JC. Extent and nature of unlicensed and off-label medicine use in hospitalised children in Palestine. Int J Clin Pharm. 2011;33:650–5.

    PubMed  Google Scholar 

  79. Palčevski G, Skočibušić N, Vlahović-Palčevski V. Unlicensed and off-label drug use in hospitalized children in Croatia: a cross-sectional survey. Eur J Clin Pharmacol. 2012;68:1073–7.

    PubMed  Google Scholar 

  80. Czarniak P, Bint L, Favié L, Parsons R, Hughes J, Sunderland B. Clinical setting influences off-label and unlicensed prescribing in a paediatric teaching hospital. PLoS One. 2015;10:e0120630.

    PubMed  PubMed Central  Google Scholar 

  81. Blanco-Reina E, Medina-Claros AF, Vega-Jiménez MA, Ocaña-Riola R, Márquez-Romero EI, Ruiz-Extremera Á. Drug utilization pattern in children and off-label use of medicines in a pediatric intensive care unit. Med Intensiva. 2016;40:1–8 (in English, Spanish).

    CAS  PubMed  Google Scholar 

  82. Berdkan S, Rabbaa L, Hajj A, Eid B, Jabbour H, Osta NE, et al. Comparative assessment of off-label and unlicensed drug prescriptions in children: FDA versus ANSM Guidelines. Clin Ther. 2016;38:1833–44.

    PubMed  Google Scholar 

  83. Palmaro A, Bissuel R, Renaud N, Durrieu G, Escourrou B, Oustric S, et al. Off-label prescribing in pediatric outpatients. Pediatrics. 2015;135:49–58.

    PubMed  Google Scholar 

  84. Bellis JR, Kirkham JJ, Thiesen S, Conroy EJ, Bracken LE, Mannix HL, et al. Adverse drug reactions and off-label and unlicensed medicines in children: a nested case? Control study of inpatients in a pediatric hospital. BMC Med. 2013;11:238.

    PubMed  PubMed Central  Google Scholar 

  85. Bellis JR, Kirkham JJ, Nunn AJ, Pirmohamed M. Adverse drug reactions and off-label and unlicensed medicines in children: a prospective cohort study of unplanned admissions to a paediatric hospital. Br J Clin Pharmacol. 2014;77:545–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Kimland E, Nydert P, Odlind V, Böttiger Y, Lindemalm S. Paediatric drug use with focus on off-label prescriptions at Swedish hospitals—a nationwide study. Acta Paediatr. 2012;101:772–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Lindell-Osuagwu L, Hakkarainen M, Sepponen K, Vainio K, Naaranlahti T, Kokki H. Prescribing for off-label use and unauthorized medicines in three paediatric wards in Finland, the status before and after the European Union Paediatric Regulation. J Clin Pharm Ther. 2014;39:144–53.

    CAS  PubMed  Google Scholar 

  88. Dell’Aera M, Gasbarro AR, Padovano M, Laforgia N, Capodiferro D, Solarino B, et al. Unlicensed and off-label use of medicines at a neonatology clinic in Italy. Pharm World Sci. 2007;29:361–7.

    PubMed  Google Scholar 

  89. Dessì A, Salemi C, Fanos V, Cuzzolin L. Drug treatments in a neonatal setting: focus on the off-label use in the first month of life. Pharm World Sci. 2010;32:120–4.

    PubMed  Google Scholar 

  90. Neubert A, Lukas K, Leis T, Dormann H, Brune K, Rascher W. Drug utilisation on a preterm and neonatal intensive care unit in Germany: a prospective, cohort-based analysis. Eur J Clin Pharmacol. 2010;66:87–95.

    PubMed  Google Scholar 

  91. Thomas A. The use of unlicensed and off label drugs in Tygerberg Hospital neonatal intensive care unit. Stellenbosch: Stellenbosch University; 2014.

    Google Scholar 

  92. Cuzzolin L, Agostino R. Off-label and unlicensed drug treatments in Neonatal Intensive Care Units: an Italian multicentre study. Eur J Clin Pharmacol. 2016;72:117–23.

    CAS  PubMed  Google Scholar 

  93. Ribeiro M, Jorge A, Macedo AF. Off-label drug prescribing in a Portuguese paediatric emergency unit. Int J Clin Pharm. 2013;35:30–6.

    PubMed  Google Scholar 

  94. Morales-Carpi C, Estañ L, Rubio E, Lurbe E, Morales-Olivas FJ. Drug utilization and off-label drug use among Spanish emergency room paediatric patients. Eur J Clin Pharmacol. 2010;66:315–20.

    CAS  PubMed  Google Scholar 

  95. Zhang L, Li Y, Liu Y, Zeng L, Hu D, Huang L, et al. Pediatric off-label drug use in China: risk factors and management strategies. J Evid Based Med. 2013;6:4–18.

    PubMed  Google Scholar 

  96. Shah SS, Hall M, Goodman DM, Feuer P, Sharma V, Fargason C Jr, et al. Off-label drug use in hospitalized children. Arch Pediatr Adolesc Med. 2007;161:282–90.

    PubMed  Google Scholar 

  97. Mühlbauer B, Janhsen K, Pichler J, Schoettler P. Off-label use of prescription drugs in childhood and adolescence: an analysis of prescription patterns in Germany. Dtsch Arztebl Int. 2009;106:25–31.

    PubMed  PubMed Central  Google Scholar 

  98. Langerová P, Vrtal J, Urbánek K. Incidence of unlicensed and off-label prescription in children. Ital J Pediatr. 2014;40:12.

    PubMed  PubMed Central  Google Scholar 

  99. Czaja AS, Reiter PD, Schultz ML, Valuck RJ. Patterns of off-label prescribing in the pediatric intensive care unit and prioritizing future research. J Pediatr Pharmacol Ther. 2015;20:186–96.

    PubMed  PubMed Central  Google Scholar 

  100. Jain SS, Bavdekar SB, Gogtay NJ, Sadawarte PA. Off-label drug use in children. Indian J Pediatr. 2008;75:1133–6.

    PubMed  Google Scholar 

  101. Okechukwu RC, Aghom OE. Prescription pattern of unlicensed and off-label medicines for children aged 0–5 years in a tertiary hospital and a primary health care centre in Nigeria. S Afr J Bioeth Law. 2009;2:62–6.

    Google Scholar 

  102. Nguyen KA, Claris O, Kassai B. Unlicensed and off-label drug use in a neonatal unit in France. Acta Paediatr. 2011;100:615–7.

    PubMed  Google Scholar 

  103. Riou S, Plaisant F, Maucort Boulch D, Kassai B, Claris O, Nguyen KA. Unlicensed and off-label drug use: a prospective study in French NICU. Acta Paediatr. 2015;104:e228–31.

    PubMed  Google Scholar 

  104. de Souza AS Jr, Santos DB, Rey LC, Medeiros MG, Vieira MG, Coelho HLL. Off-label use and harmful potential of drugs in a NICU in Brazil: a descriptive study. BMC Pediatr. 2016;16:13.

    PubMed  PubMed Central  Google Scholar 

  105. Slažneva J, Kovács L, Kuželová M. Off-label drug use among hospitalized children: identifying extent and nature. Eur Pharm J. 2012;59:621–5.

    Google Scholar 

  106. Luedtke KE, Buck ML. Evaluation of off-label prescribing at a children’s rehabilitation center. J Pediatr Pharmacol Ther. 2014;19:296–301.

    PubMed  PubMed Central  Google Scholar 

  107. Bazzano AT, Mangione-Smith R, Schonlau M, Suttorp MJ, Brook RH. Off-label prescribing to children in the United States outpatient setting. Acad Pediatr. 2009;9:81–8.

    PubMed  Google Scholar 

  108. Sturkenboom M, Felisi M, Manfredi C, Neubert A, Cantarutti L, Padula R, et al. Paediatric status and off-label use of drugs in children in Italy, United Kingdom and the Netherlands. Pharm Policy Law. 2009;11:51–9.

    Google Scholar 

  109. Oguz SS, Kanmaz HG, Dilmen U. Off-label and unlicensed drug use in neonatal intensive care units in Turkey: the old-inn study. Int J Clin Pharm. 2012;34:136–41.

    PubMed  Google Scholar 

  110. Schweigertova J, Durisova A, Dolnikova D, Ondriasova E, Balazova M, Slezakova V, et al. Off-label and unlicensed use of medicinal products in the neonatal setting in the Slovak Republic. Pediatr Int. 2016;58:126–31.

    PubMed  Google Scholar 

  111. Jain S, Saini SS, Chawla D, Kumar P, Dhir S. Off-label use of drugs in neonatal intensive care units. Indian Pediatr. 2014;51:644–6.

    PubMed  Google Scholar 

  112. Olsson J, Kimland E, Pettersson S, Odlind V. Paediatric drug use with focus on off-label prescriptions in Swedish outpatient care—a nationwide study. Acta Paediatr. 2011;100:1272–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Carnovale C, Conti V, Perrone V, Antoniazzi S, Pozzi M, Merlino L, et al. Paediatric drug use with focus on off-label prescriptions in Lombardy and implications for therapeutic approaches. Eur J Pediatr. 2013;172:1679–85.

    PubMed  Google Scholar 

  114. Bensouda-Grimaldi L, Sarraf N, Doisy F, Jonville-Béra AP, Pivette J, Autret-Leca E. Prescription of drugs contraindicated in children: a national community survey. Eur J Clin Pharmacol. 2007;63:99–101.

    PubMed  Google Scholar 

  115. Doherty DR, Pascuet E, Ni A, Stewart P, Splinter W, Vaillancourt R. Off-label drug use in pediatric anesthesia and intensive care according to official and pediatric reference formularies. Can J Anaesth. 2010;57:1078–88.

    PubMed  Google Scholar 

  116. Ellul IC, Grech V. Off-label and unlicensed paediatric prescribing in a community setting: a prospective longitudinal cohort study in Malta. Paediatr Int Child Health. 2014;34:12–8.

    PubMed  Google Scholar 

  117. Lass J, Käär R, Jõgi K, Varendi H, Metsvaht T, Lutsar I. Drug utilisation pattern and off-label use of medicines in Estonian neonatal units. Eur J Clin Pharmacol. 2011;67:1263–71.

    PubMed  Google Scholar 

  118. Lass J, Irs A, Pisarev H, Leinemann T, Lutsar I. Off label use of prescription medicines in children in outpatient setting in Estonia is common. Pharmacoepidemiol Drug Saf. 2011;20:474–81.

    PubMed  Google Scholar 

  119. Yang CP, Veltri MA, Anton B, Yaster M, Berkowitz ID. Food and Drug Administration approval for medications used in the pediatric intensive care unit: a continuing conundrum. Pediatr Crit Care Med. 2011;12:e195–9.

    PubMed  Google Scholar 

  120. Kumar P, Walker JK, Hurt KM, Bennett KM, Grosshans N, Fotis MA. Medication use in the neonatal intensive care unit: current patterns and off-label use of parenteral medications. J Pediatr. 2008;152:412–5.

    PubMed  Google Scholar 

  121. Oreagba IA, Omotoso KS, Sonibare AJT, Sonibare T, Oshikoya KA. Off-label prescription for paediatric in- and out-patients at a tertiary hospital in Lagos, Nigeria. W Afr J Pharmacol Drug Res. 2015;30:18–27.

    Google Scholar 

  122. Bhadiyadara SN, Rana DA, Malhotra SD, Patel VJ. Off-label and unlicensed drug use in paediatric outpatient department—a prospective study at a tertiary care teaching hospital. J Young Pharm. 2015;7:164–70.

    Google Scholar 

  123. Laforgia N, Nuccio MM, Schettini F, Dell’Aera M, Gasbarro AR, Dell’Erba A, et al. Off-label and unlicensed drug use among neonatal intensive care units in Southern Italy. Pediatr Int. 2014;56:57–9.

    PubMed  Google Scholar 

  124. Bavdekar SB, Sadawarte PA, Gogtay NJ, Jain SS, Jadhav S. Off-label drug use in a Pediatric Intensive Care Unit. Indian J Pediatr. 2009;76:1113–8.

    CAS  PubMed  Google Scholar 

  125. Roldán T, Villamañán E, Ruano M, Larrubia Y, Gómez-Salcedo P, Herrero A. Analysis of clinical trials and off-label drug use in hospitalized pediatric patients. Arch Argent Pediatr. 2014;112:249–53.

    PubMed  Google Scholar 

  126. ‘t Jong GW, Eland IA, Sturkenboom MC, van den Anker JN, Stricker BH. Unlicensed and off label prescription of drugs to children: population based cohort study. BMJ. 2002;324:1313–4.

    PubMed  PubMed Central  Google Scholar 

  127. Turner S, Nunn A, Fielding K, Choonara I. Adverse drug reactions to unlicensed and off-label drugs on paediatric wards: a prospective study. Acta Paediatr. 1999;88:965–8.

    CAS  PubMed  Google Scholar 

  128. Lee JL, Redzuan AM, Shah NM. Unlicensed and off-label use of medicines in children admitted to the intensive care units of a hospital in Malaysia. Int J Clin Pharm. 2013;35:1025–9.

    PubMed  Google Scholar 

  129. Warrier I, Du W, Natarajan G, Salari V, Aranda J. Patterns of drug utilization in a neonatal intensive care unit. J Clin Pharmacol. 2006;46:449–55.

    PubMed  Google Scholar 

  130. Al Balushi KA, Al-Sawafi F, Al-Ghafri F, Al-Zakwani I. Drug utilization pattern in an Omani pediatric population. J Basic Clin Pharm. 2013;4:68–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Ku LC, Smith PB. Dosing in neonates: special considerations in physiology and trial design. Pediatr Res. 2015;77:2–9.

    PubMed  Google Scholar 

  132. Schirm E, Tobi H, van Puijenbroek EP, Monster-Simons MH, de Jong-van den Berg LT. Reported adverse drug reactions and their determinants in Dutch children outside the hospital. Pharmacoepidemiol Drug Saf. 2004;13:159–65.

    CAS  PubMed  Google Scholar 

  133. Jonville-Bera AP, Bera F, Autret-Leca E. Are incorrectly used drugs more frequently involved in adverse drug reactions? A prospective study. Eur J Clin Pharmacol. 2005;61:231–6.

    CAS  PubMed  Google Scholar 

  134. Aagaard L, Hansen EH. Prescribing of medicines in the Danish paediatric population outwith the licensed age group: characteristics of adverse drug reactions. Br J Clin Pharmacol. 2011;71:751–7.

    PubMed  PubMed Central  Google Scholar 

  135. Wallerstedt SM, Brunlof G, Sundstrom A. Rates of spontaneous reports of adverse drug reactions for drugs reported in children: a cross-sectional study with data from the Swedish adverse drug reaction database and the Swedish Prescribed Drug Register. Drug Saf. 2011;34:669–82.

    PubMed  Google Scholar 

  136. Clarkson A, Conroy S, Burroughs K, Choonara I. Surveillance for adverse drug reactions in children: a paediatric regional monitoring centre. Paediatr Perinat Drug Ther. 2004;6:20–3.

    Google Scholar 

  137. Carnovale C, Brusadelli T, Zuccotti G, Beretta S, Sullo MG, Capuano A, et al. The importance of monitoring adverse drug reactions in pediatric patients: the results of a national surveillance program in Italy. Expert Opin Drug Saf. 2014;13(Suppl 1):S1–8.

    PubMed  Google Scholar 

  138. Neubert A, Wong IC, Bonifazi A, Catapano M, Felisi M, Baiardi P, et al. Defining off-label and unlicensed use of medicines for children: results of a Delphi survey. Pharmacol Res. 2008;58:316–22.

    PubMed  Google Scholar 

  139. Rylance GW. Drug availability and dose information for children. J Clin Pharm Ther. 1979;4:153–8.

    Google Scholar 

  140. Tan E, Cranswick NE, Rayner CR, Chapman CB. Dosing information for paediatric patients: are they really “therapeutic orphans”? Med J Aust. 2003;179:195–8.

    PubMed  Google Scholar 

  141. Sachs AN, Avant D, Lee CS, Rodriguez W, Murphy MD. Pediatric information in drug product labeling. JAMA. 2012;307:1914–5.

    CAS  PubMed  Google Scholar 

  142. Thompson DF, Rains C. A comparison of licensed indications for equivalent drugs in the United Kingdom and the United States. Ther Innov Regul Sci. 1993;27:529–36.

    Google Scholar 

  143. Young L, Lawes F, Tordoff J, Norris P, Reith D. Access to prescribing information for paediatric medicines in the USA: post-modernization. Br J Clin Pharmacol. 2009;67:341–6.

    PubMed  PubMed Central  Google Scholar 

  144. Neville KA, Frattarelli DA, Galinkin JL, Green TP, Johnson TD, Paul IM, et al. Off-label use of drugs in children. Pediatrics. 2014;133:563–7.

    PubMed  Google Scholar 

  145. Riordan FA. Use of unlabelled and off licence drugs in children. BMJ. 2000;320:1210.

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Shoulders BR, Smithburger PL, Tchen S, Buckley M, Lat I, Kane-Gill SL. Characterization of guideline evidence for off-label medication use in the intensive care unit. Ann Pharmacother. 2017;51:529–42.

    PubMed  Google Scholar 

  147. Ng H, Thomas T. Paediatric Protocols for Malaysian Hospitals. Malaysia: Ministry of Health of Malaysia; 2012.

    Google Scholar 

  148. Pieścik-Lech M, Shamir R, Guarino A, Szajewska H. The management of acute gastroenteritis in children. Aliment Pharmacol Ther. 2013;37:289–303.

    PubMed  Google Scholar 

  149. Szajewska H. What are the indications for using probiotics in children? Arch Dis Child. 2016;101:398–403.

    PubMed  Google Scholar 

  150. Mukattash T, Hawwa AF, Trew K, McElnay JC. Healthcare professional experiences and attitudes on unlicensed/off-label paediatric prescribing and paediatric clinical trials. Eur J Clin Pharmacol. 2011;67:449–61.

    PubMed  Google Scholar 

  151. Kontou A, Sarafidis K, Roilides E. Antimicrobial dosing in neonates. Expert Rev Clin Pharmacol. 2017;10:239–42.

    CAS  PubMed  Google Scholar 

  152. Ansani N, Sirio C, Smitherman T, Fedutes-Henderson B, Skledar S, Weber RJ, et al. Designing a strategy to promote safe, innovative off-label use of medications. Am J Med Qual. 2006;21:255–61.

    PubMed  Google Scholar 

  153. Gazarian M, Kelly M, McPhee JR, Graudins LV, Ward RL, Campbell TJ. Off-label use of medicines: consensus recommendations for evaluating appropriateness. Med J Aust. 2006;185:544–8.

    PubMed  Google Scholar 

  154. Hemminki E. Review of literature on the factors affecting drug prescribing. Soc Sci Med. 1975;9:111–6.

    CAS  PubMed  Google Scholar 

  155. Bradley CP. Factors which influence the decision whether or not to prescribe: the dilemma facing general practitioners. Br J Gen Pract. 1992;42:454–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Caamaño-Isorna F, Montes A, Takkouche B, Gestal-Otero J. Do pharmacists’ opinions affect their decision to dispense or recommend a visit to a doctor? Pharmacoepidemiol Drug Saf. 2005;14:659–64.

    PubMed  Google Scholar 

  157. Ljungberg C, Lindblad ÅK, Tully MP. Hospital doctors’ views of factors influencing their prescribing. J Eval Clin Pract. 2007;13:765–71.

    PubMed  Google Scholar 

  158. Cutts C, Tett SE. Influences on doctors’ prescribing: is geographical remoteness a factor? Aust J Rural Health. 2003;11:124–30.

    PubMed  Google Scholar 

  159. Drummond MF, Schwartz JS, Jönsson B, Luce BR, Neumann PJ, Siebert U, et al. Key principles for the improved conduct of health technology assessments for resource allocation decisions. Int J Technol Assess Health Care. 2008;24:244–58.

    PubMed  Google Scholar 

  160. Largent EA, Pearson SD. Which orphans will find a home? The rule of rescue in resource allocation for rare diseases. Hastings Cent Rep. 2012;42:27–34.

    PubMed  Google Scholar 

Download references

Funding

No financial or non-financial benefits have been received or will be received from any party related directly or indirectly to the subject of this article.

Author information

Authors and Affiliations

  1. Discipline of Social and Administrative Pharmacy, School of Pharmaceutical Sciences, University Sains Malaysia, 11800, Gelugor, Penang, Malaysia

    Shamala Balan & Mohamed Azmi Ahmad Hassali

  2. Center for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Melbourne, Australia

    Vivienne S. L. Mak

Authors
  1. Shamala Balan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mohamed Azmi Ahmad Hassali
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vivienne S. L. Mak
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SB contributed in the conception of the review, acquisition of review articles, analysis and interpretation of data for the review and writing of the review. MAAH and VM provided the supervision, critical revision of intellectual content of the review and final approval of the version to be published.

Corresponding author

Correspondence to Shamala Balan.

Ethics declarations

Ethical approval

This literature review is exempted from ethical review as it involves the use of existing data or records that contains only de-identifiable data about human beings.

Conflict of interest

All the authors of this study declare that they have no competing interest.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Balan, S., Hassali, M.A.A. & Mak, V.S.L. Two decades of off-label prescribing in children: a literature review. World J Pediatr 14, 528–540 (2018). https://doi.org/10.1007/s12519-018-0186-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12519-018-0186-y

Keywords

Search

Navigation