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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
  • 36 Downloads

Abstract

Objectives

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).

Results

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.

Conclusions

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.

Notes

Acknowledgements

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)

References

  1. 1.
    Sachs A, Avant D, Lee C, Rodriguez W, Murphy D. Research letter: pediatric information in drug product labeling. JAMA. 2012;307(18):1914–5.CrossRefGoogle Scholar
  2. 2.
    Ufer M, Kimland E, Bergman U. Adverse drug reactions and off-label prescribing for paediatric outpatients: a one-year survey of spontaneous reports in Sweden. Pharmacoepidemiol Drug Saf. 2004;13:147–52.CrossRefGoogle Scholar
  3. 3.
    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.CrossRefGoogle Scholar
  4. 4.
    Aagaard L. Off-label and unlicensed prescribing of medicines in pediatric populations: occurrence and safety aspects. Basic Clin Pharmacol Toxicol. 2015;117(4):215–8.CrossRefGoogle Scholar
  5. 5.
    Food and Drug Administration, HHS. 21 CFR 314.80: Post marketing reporting of adverse drug experiences 2017. https://www.gpo.gov/fdsys/pkg/CFR-2011-title21-vol5/pdf/CFR-2011-title21-vol5-sec314-80.pdf. Accessed 30 Jul 2017.
  6. 6.
    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;7(11):238.  https://doi.org/10.1186/1741-7015-11-238.CrossRefGoogle Scholar
  7. 7.
    Alamu JO. Evaluation of antimicrobial use in a pediatric intensive care unit. Ph.D. (Doctor of Philosophy) thesis, University of Iowa. 2009. http://ir.uiowa.edu/etd/277. Accessed 06 Jun 2017.
  8. 8.
    Tobias JD. Sedation in the intensive care unit: challenges, outcomes, and failure strategies. In: Manson KP, editor. Pediatric sedation outside of the operating room: a multispecialty international collaboration. New York: Springer; 2015. p. 125–49.Google Scholar
  9. 9.
    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(3):282–90.CrossRefGoogle Scholar
  10. 10.
    Zithromax (azithromycin) [package insert]. Pfizer, Inc. New York, NY; March 30, 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/050670s032,050710s046,050711s043,050784s030lbl.pdf. Accessed 8 Jun 2017.
  11. 11.
    Tiwari T, Murphy TV, Moran J. Recommended antimicrobial agents for the treatment and post-exposure prophylaxis of pertussis: 2005 CDC Guidelines. MMWR Recomm Rep. 2005;54(RR-14):1–16.PubMedGoogle Scholar
  12. 12.
    Fentanyl citrate [package insert]. Hospira Inc. Pfizer Inc. Lake Forest, IL; December 2016. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/019115s030s031lbl.pdf. Accessed 8 Jun 2017.
  13. 13.
    Prescilla RP. The pharmacology and clinical application of sedatives, analgesics, and adjuncts. In: Manson KP, editor. Pediatric sedation outside of the operating room: a multispecialty international collaboration. New York: Springer; 2015. p. 125–49.Google Scholar
  14. 14.
    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(2):83–7.CrossRefGoogle Scholar
  15. 15.
    Institute for Safe Medication Practices. QuarterWatch (special report, 2014): Adverse drug events in children less than 18 years old. 2017. https://www.ismp.org/newsletters/acutecare/showarticle.aspx?id=67. Accessed 01 Aug 2017.
  16. 16.
    Silva DCB, Araujo OR, Arduini RG, Alonso CFR, Shibata ARO, Troster EJ. Adverse drug events in a paediatric intensive care unit: a prospective cohort. BMJ Open. 2013;3(2):e001868.  https://doi.org/10.1136/bmjopen-2012-001868.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Agarwal S, Classen D, Larsen G, Tofil NM, Hayes LW, Sullivan JE, et al. Prevalence of adverse events in pediatric intensive care units in the United States. Pediatr Crit Care Med. 2010;11(5):568–78.  https://doi.org/10.1097/PCC.0b013e3181d8e405.CrossRefPubMedGoogle Scholar
  18. 18.
    U.S. Food and Drug Administration. CFR—Code of Federal Regulations Title 21. 2017. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=201.57. Accessed 30 Dec 2017.
  19. 19.
    Brunton LL, Knollmann BC, Hilal-Dandan R. Goodman and Gilman’s the pharmacological basis of therapeutics. 13th ed. New York: McGraw Hill Medical; 2018.Google Scholar
  20. 20.
    Khan LM, Al-Harthi SE, Saadah OI. Adverse drug reactions in hospitalized pediatric patients of Saudi Arabian university hospital and impact of pharmacovigilance in reporting ADR. Saudi Pharm J. 2013;21(3):261–6.CrossRefGoogle Scholar
  21. 21.
    Priyadharsini R, Surendiran A, Adithan C, Sreenivasan S, Sahoo FK. A study of adverse drug reactions in pediatric patients. J Pharmacol Pharmacother. 2011;2(4):277–80.CrossRefGoogle Scholar
  22. 22.
    Vázquez-Alvarez AO, Brennan-Bourdon LM, Rincón-Sánchez AR, Islas-Carbajal MC, Huerta-Olvera SG. Improved drug safety through intensive pharmacovigilance in hospitalized pediatric patients. BMC Pharmacol Toxicol. 2017;18(1):79.CrossRefGoogle Scholar
  23. 23.
    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(3):186–96.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Institute for Safe Medication Practices List of High-Alert Medication. 2017. http://www.ismp.org/Tools/institutionalhighAlert.asp. Accessed 6 Jun 2017.
  25. 25.
    BPCA priority list of pediatric therapeutic needs. 2017. http://bpca.nichd.nih.gov/prioritization/status.cfm. Accessed 6 Jun 2017.
  26. 26.
    Rhoney DH, Murry KR. National survey on the use of sedatives and neuromuscular blocking agents in the pediatric intensive care unit. Pediatr Crit Care Med. 2002;3:129–33.CrossRefGoogle Scholar
  27. 27.
    Horen B, Montastruc JL, Lapeyre-Mestre M. Adverse drug reactions and off-label drug use in pediatric outpatients. Br J Clin Pharmacol. 2002;54(6):665–70.CrossRefGoogle Scholar
  28. 28.
    Gill AM, Cousins A, Nunn AJ, Choonara IA. Opiate-induced respiratory depression in pediatric patients. Ann Pharmacother. 1996;30(2):125–9.CrossRefGoogle Scholar
  29. 29.
    Rashed AN, Wong IC, Cranswick N, Hefele B, Tomlin S, Jackman J, et al. Adverse drug reactions in children–international surveillance and evaluation (ADVISE): a multicentre cohort study. Drug Saf. 2012;35(6):481–94.CrossRefGoogle Scholar
  30. 30.
    Kabara S, Kagawa T, Ikejima N, Takatsuji S, Sueda A. Side effects of continuous fentanyl infusion for postoperative pain relief in children. Masui. 2015;64(8):799–803.PubMedGoogle Scholar

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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