Drug Safety

, Volume 27, Issue 13, pp 1059–1067 | Cite as

The Impact of Unlicensed and Off-Label Drug Use on Adverse Drug Reactions in Paediatric Patients

  • Antje Neubert
  • Harald Dormann
  • Jutta Weiss
  • Tobias Egger
  • Manfred Criegee-Rieck
  • Wolfgang Rascher
  • Kay Brune
  • Burkhard Hinz
Original Research Article


Background and objective: Many drugs that are used to treat children are either not licensed for use in paediatric patients (unlicensed) or prescribed outside the terms of the product licence (off label). The incidence of adverse drug reactions (ADRs) associated with the use of such drugs is yet to be established. This study investigates, for the first time in a German patient population, the impact of unlicensed and off-label drug use on ADRs in paediatric patients.

Patients and methods: An 8-month prospective pharmacoepidemiological cohort-based survey was conducted on a ten-bed paediatric isolation ward at the University Hospital Erlangen-Nüremberg, Germany. All patients were intensively monitored for ADRs by a pharmacoepidemiological team. ADRs were characterised according to international classification methods. All drug prescriptions were evaluated retrospectively as to unlicensed or off-label use on the basis of the product information.

Results: A total of 178 patients were included in the study and 740 drug prescriptions were given to 156 patients (median three prescriptions per patient). In 198 cases (27.7% of all prescriptions) drugs were used in either an unlicensed (n = 3) or off-label (n = 195) manner. A total of 46 ADRs were observed in 31 patients (17.4%). Patients receiving at least one unlicensed or off-label drug prescription during hospitalisation (n = 92) experienced an ADR significantly more frequently (n = 26 patients) than patients receiving only licensed drugs (n = 64 vs 5 patients). ADRs were associated with 29 (5.6%) of the 517 licensed drug prescriptions and with 12 (6.1%) of the 198 unlicensed or off-label drug prescriptions. The majority of ADRs caused by unlicensed and off-label drug use were recognised by the attending physician. However, statistical analysis revealed no significant difference in the number of licensed and unlicensed/off-label drug prescriptions causing ADRs.

Conclusion: This study demonstrated that at a paediatric isolation ward the incidence of ADRs caused by unlicensed or off-label drug use was not significantly more than that caused by the licensed drug use. However, patients treated with unlicensed or off-label drugs were shown to possess a significantly increased risk for developing ADRs.


Adverse Drug Reaction Drug Prescription Licence Status Paediatric Outpatient Product Licence 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This study was supported by grants from the Bundesministerium für Bildung und Forschung (BMBF Nr. 01EC98030), the German-Israeli-Foundation (GIF No G 690 221.9/2000), the Doerenkamp Professorship for Innovations in Animal and Consumer Protection and the Bayerisches Staatsministerium “Bayern aktiv”.


  1. 1.
    Choonara I, Conroy S. Unlicensed and off-label drug use in children: implications for safety. Drug Saf 2002; 25: 1–5PubMedCrossRefGoogle Scholar
  2. 2.
    Chalumeau M, Treluyer JM, Salanave B, et al. Off label and unlicensed drug use among French office based paediatricians. Arch Dis Child 2000; 83: 502–5PubMedCrossRefGoogle Scholar
  3. 3.
    Conroy S, Choonara I, Impicciatore P, 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: 79–82PubMedCrossRefGoogle Scholar
  4. 4.
    Gavrilov V, Lifshitz M, Levy J, et al. Unlicensed and off-label medication use in a general pediatrics ambulatory hospital unit in Israel. Isr Med Assoc J 2000; 2: 595–7PubMedGoogle Scholar
  5. 5.
    McIntyre J, Conroy S, Avery A, et al. Unlicensed and off label prescribing of drugs in general practice. Arch Dis Child 2000; 83: 498–501PubMedCrossRefGoogle Scholar
  6. 6.
    Schirm E, Tobi H, Jong-van den Berg LT. Unlicensed and off label drug use by children in the community: cross sectional study. BMJ 2002; 324: 1312–3PubMedCrossRefGoogle Scholar
  7. 7.
    Turner S, Longworth A, Nunn AJ, et al. Unlicensed and off label drug use in paediatric wards: prospective study. BMJ 1998; 316: 343–5PubMedCrossRefGoogle Scholar
  8. 8.
    Impicciatore P, Choonara I, Clarkson A, et al. Incidence of adverse drug reactions in paediatric in/out-patients: a systematic review and meta-analysis of prospective studies. Br J Clin Pharmacol 2001; 52: 77–83PubMedCrossRefGoogle Scholar
  9. 9.
    Weiss J, Krebs S, Hoffmann C, et al. Survey of adverse drug reactions on a pediatric ward: a strategy for early and detailed detection. Pediatrics 2002; 110: 254–7PubMedCrossRefGoogle Scholar
  10. 10.
    Christensen ML, Helms RA, Chesney RW. Is pediatric labeling really necessary? Pediatrics 1999; 104: 593–7PubMedGoogle Scholar
  11. 11.
    Seyberth HW. Problems of drug safety in children [in German]. Monatsschr Kinderheilkd 1982; 130: 529–35PubMedGoogle Scholar
  12. 12.
    Shirkey H. Therapeutic orphans. Pediatrics 1999; 104: 583–4PubMedGoogle Scholar
  13. 13.
    Turner S, Nunn AJ, Fielding K, et al. Adverse drug reactions to unlicensed and off-label drugs on paediatric wards: a prospective study. Acta Paediatr 1999; 88: 965–8PubMedCrossRefGoogle Scholar
  14. 14.
    Horen B, Montastruc JL, Lapeyre-Mestre M. Adverse drug reactions and off-label drug use in paediatric outpatients. Br J Clin Pharmacol 2002; 54: 665–70PubMedCrossRefGoogle Scholar
  15. 15.
    The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Clinical investigation on medicinal products in the paediatric population (efficacy guideline II), July 2000 [online]. Available from URL: [Accessed 2004 Sep 4]Google Scholar
  16. 16.
    BPI Service GmbH, Frankfurt. Fachinfo-Fachinformationsverzeichnis Deutschland [CD version 2001/1]. Berlin: Satz-Rechen-Zentrum, 2001Google Scholar
  17. 17.
    Rote Liste 2001: Arzneimittelverzeichnis Deutschland ECV. Aulendorf: Rote Liste Service GmbH, 2001Google Scholar
  18. 18.
    World Health Organization. International drug monitoring: the role of the hospital. World Health Organ Tech Rep Ser 1969; 425: 5–24Google Scholar
  19. 19.
    Naranj CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981; 30: 239–45CrossRefGoogle Scholar
  20. 20.
    Schumock GT, Thornton JP. Focusing on the preventability of adverse drug reactions [letter]. Hosp Pharm 1992; 27: 538PubMedGoogle Scholar
  21. 21.
    WHO. The adverse reaction terminology [online]. Available from URL: [Accessed 2004 Aug 18]
  22. 22.
    Conroy S, McIntyre J, Choonara I. Unlicensed and off label drug use in neonates. Arch Dis Child Fetal Neonatal Ed 1999; 80: F142–4PubMedCrossRefGoogle Scholar
  23. 23.
    Turner S, Gill A, Nunn T, et al. Use of “off-label” and unlicensed drugs in paediatric intensive care unit. Lancet 1996; 347: 549–50PubMedCrossRefGoogle Scholar
  24. 24.
    ’t Jong GW, Vulto AG, de Hoo M, et al. A survey of the use of off-label and unlicensed drugs in a Dutch children’s hospital. Pediatrics 2001; 108: 1089–93PubMedCrossRefGoogle Scholar
  25. 25.
    Azaz-Livshits T, Levy M, Sadan B, et al. Computerized survelliance of adverse drug reactions in hospital: pilot study. Br J Clin Pharmacol 1998; 45: 309–14PubMedCrossRefGoogle Scholar
  26. 26.
    Bates DW, O’Neil AC, Boyle D, et al. Potential identifiability and preventability of adverse events using information systems. J Am Med Inform Assoc 1994; 1: 404–11PubMedCrossRefGoogle Scholar
  27. 27.
    Classen DC, Pestotnik SL, Evans RS, et al. Computerized surveillance of adverse drug events in hospital patients. JAMA 1991; 266: 2847–51PubMedCrossRefGoogle Scholar
  28. 28.
    Dormann H, Muth-Selbach U, Krebs S, et al. Incidence and costs of adverse drug reactions during hospitalisation: computerised monitoring versus stimulated spontaneous reporting. Drug Saf 2000; 22: 161–8PubMedCrossRefGoogle Scholar
  29. 29.
    Evans RS, Pestotnik SL, Classen DC, et al. Development of a computerized adverse drug event monitor. Proc Annu Symp Comput Appl Med Care 1991; 23–7Google Scholar
  30. 30.
    Honigman B, Lee J, Rothschild J, et al. Using computerized data to identify adverse drug events in outpatients. J Am Med Inform Assoc 2001; 8: 254–66PubMedCrossRefGoogle Scholar
  31. 31.
    Lanctot KL, Naranjo CA. Computer-assisted evaluation of adverse events using a Bayesian approach. J Clin Pharmacol 1994; 34: 142–7PubMedGoogle Scholar

Copyright information

© Adis Data Information BV 2004

Authors and Affiliations

  • Antje Neubert
    • 1
  • Harald Dormann
    • 1
  • Jutta Weiss
    • 2
  • Tobias Egger
    • 1
  • Manfred Criegee-Rieck
    • 1
  • Wolfgang Rascher
    • 2
  • Kay Brune
    • 1
  • Burkhard Hinz
    • 1
  1. 1.Department of Experimental and Clinical Pharmacology and ToxicologyFriedrich Alexander University Erlangen-NürembergErlangenGermany
  2. 2.Department of Paediatrics and Adolescent MedicineFriedrich Alexander University Erlangen-NürembergErlangenGermany

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