Serious Adverse Events Associated with Off-Label Use of Azithromycin or Fentanyl in Children in Intensive Care Units: A Retrospective Chart Review

  • Kazeem A. Oshikoya
  • Gerold T. Wharton
  • Debbie Avant
  • Sara L. Van Driest
  • Norman E. FennIII
  • Allison Lardieri
  • Edwin Doe
  • Beena G. Sood
  • Carol Taketomo
  • Phuong Lieu
  • Lilly Yen
  • Ann W. McMahonEmail author
Original Research Article



Half of prescription drugs commonly given to children lack product labeling on pediatric safety, efficacy, and dosing. Two drugs most widely used off-label in pediatrics are azithromycin and fentanyl. We sought to determine the risk of serious adverse events (SAEs) when oral azithromycin or intravenous/intramuscular fentanyl are used off-label compared to on-label in pediatric intensive care units (ICUs).

Study Design

Six pediatric hospitals participated in a retrospective chart review of patients administered oral azithromycin (n = 241) or intravenous/intramuscular fentanyl (n = 367) between January 5, 2013 and December 26, 2014. Outcomes were SAEs by drug and labeling status: off-label compared to on-label by Food and Drug Administration (FDA)-approved age and/or indication. Statistical analysis was performed using logistic regression to estimate odds ratios (ORs) and Cox regression to estimate hazard ratios (HRs).


Twenty-one (9%) children receiving azithromycin experienced SAEs. Off-label use of azithromycin was not associated with a higher risk of SAE (OR 0.87, 95% CI 0.27–2.71, p = 0.81). Ninety-five (26%) children receiving fentanyl experienced SAEs. Fentanyl off-label use by both age and indication was not associated with a higher risk of overall SAEs compared to on-label use (OR 1.99, 95% CI 0.94–4.19, p = 0.07). However, the risk of the SAE respiratory depression was significantly greater when fentanyl was used off-label by both age and indication (OR 5.05, 95% CI 1.08–23.56, p = 0.044). Results based on HRs were similar.


Azithromycin off-label use in pediatric ICUs does not appear to be associated with an increased risk of SAEs. Off-label use of fentanyl appears to be more frequently associated with respiratory depression when used off-label by both age and indication in pediatric ICUs. Prospective studies should be undertaken to assess the safety and efficacy of fentanyl in the pediatric population so that data can be added to the FDA labeling.



We thank Drs. Mark Levenson and Elande Baro for their guidance with the statistical analysis on this project. This work was supported by UL1 TR000445 to Vanderbilt University Medical Center, T32 GM007569 (KAO) and Burroughs Wellcome Fund IRSA 1015006 (SLV).

Compliance with Ethical Standards

Kazeem A. Oshikoya, Gerold T. Wharton, Debbie Avant, Norman E. Fenn, Allison Lardieri, Edwin Doe, Beena G. Sood, Carol Taketomo, Phuong Lieu, Lilly Yen, and Ann W. McMahon have no conflicts of interest. Sara L. Van Driest has been an invited speaker to Merck and received an honorarium. No additional funding was provided for this study. The opinions expressed in this article are those of the authors and should not be interpreted as the position of the US Food and Drug Administration.

Supplementary material

40272_2018_318_MOESM1_ESM.pdf (211 kb)
Supplementary material 1 (PDF 210 kb)


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Copyright information

© This is a U.S. government work and its text is not subject to copyright protection in the United States; however, its text may be subject to foreign copyright protection 2018

Authors and Affiliations

  • Kazeem A. Oshikoya
    • 1
  • Gerold T. Wharton
    • 2
  • Debbie Avant
    • 2
  • Sara L. Van Driest
    • 1
  • Norman E. FennIII
    • 3
  • Allison Lardieri
    • 4
  • Edwin Doe
    • 5
  • Beena G. Sood
    • 6
  • Carol Taketomo
    • 7
  • Phuong Lieu
    • 7
  • Lilly Yen
    • 7
  • Ann W. McMahon
    • 2
    Email author
  1. 1.Vanderbilt University School of MedicineNashvilleUSA
  2. 2.Office of Pediatric Therapeutics, Office of the Commissioner, Food and Drug AdministrationSilver SpringUSA
  3. 3.Children’s National Health SystemWashingtonUSA
  4. 4.University of Maryland Children’s HospitalBaltimoreUSA
  5. 5.INOVA Children’s HospitalFalls ChurchUSA
  6. 6.Children’s Hospital of MichiganDetroitUSA
  7. 7.Children’s Hospital Los AngelesLos AngelesUSA

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