Skip to main content
SpringerLink
Log in

Off-label and unlicensed drug treatments in Neonatal Intensive Care Units: an Italian multicentre study

  • Pharmacoepidemiology and Prescription
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

The use of medicines among newborns admitted to intensive care units is characterized by a high prevalence of off-label/unlicensed use and a wide variability in the absence of international guidelines. A prospective cross-sectional study was organized with the aim to analyse drug prescriptions among all 107 Italian level III neonatal intensive care units.

Methods

An online questionnaire was used to collect detailed information for each newborn, and a classification was made about the license status of all prescriptions. In addition, prescriptions were analysed taking into account a practical guide prepared by the Italian Society of Neonatology (ISN).

Results

The 1-day survey (May–July 2014) regarded 220 newborn infants admitted to 36/107 Italian neonatal intensive care units: 191 prematures and 29 born at term. In total, 720 prescriptions (corresponding to 79 different drugs) were analysed: 191 (26.5 %) followed the terms of the product license, 529 (73.5 %) were off-label or unlicensed: 193/220 newborns (87.7 %) received at least one off-label/unlicensed prescription. Antiinfectives were the most common medicine used, followed by respiratory drugs and antianaemics; in an off-label manner, the most common was cardiovascular and central nervous system (CNS) drugs, gastrointestinals and antiinfectives. The most common categories of off-label use were age (34.4 %) and dosing frequency (20.6 %). Compared to ISN practical guide, prescriptions adhered more frequently to indications (100 % for ampicillin/sulbactam, >80 % for ampicillin, fluconazole, fentanyl, ranitidine and vancomicin).

Conclusions

Our results confirm the high prevalence of off-label/unlicensed drug use in the neonatal population and underline a better adherence to indications based on clinical practice, suggesting the need to update information contained in the data sheets of medicines.

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. Cuzzolin L (2014) Variability in drug use among newborns admitted to NICUs: a proposal for a European multicentre study. J Pediatr Neonatal Individual Med 3(1), e030122. doi:10.7363/030122

    Google Scholar 

  2. Van Riet-Nales DA, de Jager KE, Schobben AF, Egberts TC, Rademaker CM (2011) The availability and age-appropriateness of medicines authorized for children in the Netherlands. Br J Clin Pharmacol 72:465–473. doi:10.1111/j.1365-2125.2011.03982.x

    Article  PubMed  PubMed Central  Google Scholar 

  3. Mason J, Pirmohamed M, Nunn T (2012) Off-label and unlicensed medicine use and adverse drug reactions in children: a narrative review of the literature. Eur J Clin Pharmacol 68:21–28. doi:10.1007/s00228-011-1097-1

    Article  PubMed  Google Scholar 

  4. Conroy S (2011) Association between licence status and medication errors. Arch Dis Child 96:305–306. doi:10.1136/adc.2010.191940

    Article  PubMed  Google Scholar 

  5. Agostino R, Braguglia A, Caccamo ML, Dotta A, Massenzi L, Messner H, Sorrentino E (2009) Farmacoterapia neonatale: guida pratica (con software interattivo). Biomedia Ed, Milan

  6. American Academy of Pediatrics (2014) Policy statement: off-label use of drugs in children. Pediatrics 133(3):563–567. doi:10.1542/peds.2013-4060

    Article  Google Scholar 

  7. 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

    Article  PubMed  Google Scholar 

  8. EMA document (2013) Successes of the paediatric regulation after 5 years. EMA/250577/2013. Available at: http://www.ema.europa.eu/ema/index.jsp?curl-pages/news_and_events/news/2013/06/news_detail_001823.jsp&mid-WC0b01ac058004d5c1 Accessed 19 Aug 2013

  9. Pansieri C, Bonati M, Choonara I, Jacqz-Aigrain E (2014) Neonatal drug trials: impact of EU and US paediatric regulations. Arch Dis Child Fetal Neonatal Ed (online first). doi:10.1136/archdischild-2013-305900

    Google Scholar 

  10. Cuzzolin L (2014) Off-label drug in the newborn. J Pediatr Neonat Individual Med 3(2), e030224. doi:10.7363/030224

    Google Scholar 

  11. Conroy S, McIntyre J, Choonara I (1999) Unlicensed and off label drug use in neonates. Arch Dis Child Fetal Neonat Ed 80:F142–F145. doi:10.1136/fn.80.2.F142

    Article  CAS  Google Scholar 

  12. Avenel S, Bomkratz A, Dassieu G, Janaud JC, Danan C (2000) The incidence of prescriptions without marketing product license in a neonatal intensive care unit. Arch Pediatr 7:143–147. doi:10.1016/S0929-693x(00)88083-5

    Article  PubMed  CAS  Google Scholar 

  13. T’ Jong GW, Vulto AG, De Hoog M, Schimmel JM, Tibboel D, Van den Anker JN (2001) A survey of the use of off-label and unlicensed drugs in a Dutch Children’s Hospital. Pediatrics 108:1089–1093. doi:10.1542/peds.108.5.1089

    Article  Google Scholar 

  14. Lopez-Martinez R, Cabanas Poy MJ, Oliveras Arenas M, Clemente Bautista S (2005) Utilizacion de medicamentos en una UCI neonatal: studio prospectivo. Farm Hosp 29:26–29

    Article  PubMed  CAS  Google Scholar 

  15. Di Paolo ER, Stoetter H, Cotting J, Frey P, Gehri M, Beck-Popovic M, Tolsa J, Fanconi S, Pannatier A (2006) Unlicensed and off-label drug use in a Swiss paediatric university hospital. Swiss Med Wkly 136:218–222

    PubMed  Google Scholar 

  16. Prandstetter C, Tamesberger M, Wagner O, Weissensteiner M, Wiesinger-Eidenberger G, Weidinger I, Lechner E (2009) Medical prescriptions to premature and newborn infants in an Austrian neonatal intensive care unit. Klin Pediatr 221:312–317. doi:10.1055/s-0029-1220903

    Article  CAS  Google Scholar 

  17. Lindell-Osuagwu L, Korhonen MJ, Saano S, Helin-Tanninen M, Naaranlahti T, Kokki H (2009) Off-label and unlicensed drug prescribing in three paediatric wards in Finland and review of the international literature. J Clin Pharm Ther 34:277–287. doi:10.1111/j.1365-2710.2008.01005.x

    Article  PubMed  CAS  Google Scholar 

  18. Neubert A, Lukas K, Leis T, Dormann H, Brune K, Rascher W (2010) Drug utilization on a preterm and neonatal intensive care unit in Germany: a prospective, cohort-based analysis. Eur J Clin Pharmacol 66:87–95. doi:10.1007/s00228-009-0722-8

    Article  PubMed  Google Scholar 

  19. Nguyen KA, Claris O, Kassai B (2011) Unlicensed and off-label drug use in a neonatal unit in France. Acta Paediatr 100:615–617. doi:10.1111/j.1651-2227.2010.02103.x

    Article  PubMed  Google Scholar 

  20. Lass J, Käär R, Jõgi K, Varendi H, Metsvaht T, Lutsar I (2011) Drug utilization pattern and off-label use of medicines in Estonian neonatal units. Eur J Clin Pharmacol 67:1263–1271. doi:10.1007/s00228-011-1072-x

    Article  PubMed  Google Scholar 

  21. Kimland E, Nydert P, Odlind V, Böttiger Y, Lindemalm S (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

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  22. Oguz SS, Kanmaz HG, Dilmen U (2012) Off-label and unlicensed drug use in neonatal intensive care units in Turkey: the old-inn study. Int J Clin Pharm 34:136–141. doi:10.1007/s11096-011-9604-0

    Article  PubMed  Google Scholar 

  23. Palčevski G, Skočibušić N, Vlahović-Palčevski V (2012) Unlicensed and off-label drug use in hospitalized children in Croatia: a cross-sectional survey. Eur J Clin Pharmacol 68:1073–1077. doi:10.1007/s00228-012-1221-x

    Article  PubMed  Google Scholar 

  24. Kieran EA, O’Callaghan N, O’Donnell CPF (2014) Unlicensed and off-label drug use in an Irish neonatal intensive care unit: a prospective cohort study. Acta Paediatr 103:e139–e142. doi:10.1111/apa.12541

    Article  PubMed  CAS  Google Scholar 

  25. Lindell-Osuagwu L, Hakkarainen M, Sepponen K, Vainio K, Naaranlahti T, Kokki H (2014) 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 39:144–153. doi:10.1111/jcpt.12119

    Article  PubMed  CAS  Google Scholar 

  26. Dell’Aera M, Gasbarro AR, Padovano M, Laforgia N, Capodiferro D, Solarino B, Quaranta R, Dell’Erba AS (2007) Unlicensed and off-label use of medicines at a neonatology clinic in Italy. Pharm World Sci 29:361–367. doi:10.1007/s11096-006-9081-z

    Article  PubMed  Google Scholar 

  27. Dessì A, Salemi C, Fanos V, Cuzzolin L (2010) Drug treatments in a neonatal setting: focus on the off-label use in the first month of life. Pharm World Sci 32:120–124. doi:10.1007/s11096-009-9356-2

    Article  PubMed  Google Scholar 

  28. Laforgia N, Nuccio MM, Schettini F, Dell’Aera M, Gasbarro AR, Dell’Erba A, Solarino B (2014) Off-label and unlicensed drug use among neonatal intensive care units in Southern Italy. Pediatr Int 56:57–59. doi:10.1111/ped.12190

    Article  PubMed  Google Scholar 

  29. Porta A, Esposito S, Menson E, Spyridis N, Tsolia M, Sharland M, Principi N (2010) Off-label antibiotic use in children in three European countries. Eur J Clin Pharmacol 66(9):919–927. doi:10.1007/s00228-010-0842-1

    Article  PubMed  Google Scholar 

  30. Manzoni P, Mostert M, Jacqz-Aigrain E, Farina D (2009) The use of fluconazole in neonatal intensive care units. Arch Dis Child 94:983–987. doi:10.1136/ adc.2008.154385

    Article  PubMed  CAS  Google Scholar 

  31. Benjamin DK, Hudak ML, Duara S et al (2014) Effect of fluconazole prophylaxis on candidiasis and mortality in premature infants: a randomized clinical trial. JAMA 311(17):1742–1749. doi:10.1001/jama.2014.2624

    Article  PubMed  PubMed Central  Google Scholar 

  32. Pansieri C, Pandolfini C, Jacqz-Aigrain E, van den Anker J, Bonati M (2015) Fluconazole prophylaxis in neonates. Arch Dis Child 100(1):75–76. doi:10.1136/ archdischild-2014-306771

    Article  PubMed  Google Scholar 

  33. Pappas PG, Kauffman CA, Andes D et al (2009) Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis 48:503–535. doi:10.1086/596757

    Article  PubMed  CAS  Google Scholar 

  34. Kaguelidou F, Pandolfini C, Manzoni P, Choonara I, Bonati M, Jacqz-Aigrain E (2012) European survey on the use of prophylactic fluconazole in neonatal intensive care units. Eur J Pediatr 171:439–445. doi:10.1007/s00431-011-1565-8

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  35. Pandolfini C, Sequi M, Manzoni P, Bonati M (2013) The use of ciprofloxacin and fluconazole in Italian neonatal intensive care units: a nationwide survey. BMC Pediatr 13:5. doi:10.1186/1471-2431-13-5

    Article  PubMed  PubMed Central  Google Scholar 

  36. Malcom WF, Cotton CM (2012) Metoclopramide, H2 blockers, and proton pump inhibitors: pharmacotherapy for gastroesophageal reflux in neonates. Clin Perinatol 39(1):99–109. doi:10.1016/j.clp.2011.12.015

    Article  Google Scholar 

  37. Laughon MM, Avant D, Tripathi N, Hornik CP, Cohen-Wolkowiez M, Clark RH, Smth PB, Rodriguez W (2014) Drug labelling and exposure in neonates. JAMA Pediatr 168(2):130–136. doi:10.1001/jamapediatrics.2013.4208

    Article  PubMed  PubMed Central  Google Scholar 

  38. Terrin G, Passariello A, De Curtis M, Manguso F, Salvia G, Lega L, Messina F, Paludetto R, Berni Canani R (2012) Ranitidine is associated with infections, necrotizing enterocolitis, and fatal outcome in newborns. Pediatrics 129:e40–e45. doi:10.1542/peds.2011-0796

    Article  PubMed  Google Scholar 

  39. Tighe M, Afzal NA, Bevan A, Hayen A, Munro A, Beattie RM (2014) Pharmacological treatment of children with gastro-oesophageal reflux. Cochrane Database Syst Rev 11, CD008550. doi:10.1002/14651858.CD008550.pub2

    PubMed  Google Scholar 

  40. Haiden N, Klebermass K, Cardona F, Schwindt J, Berger A, Kohlhauser-Vollmuth C, Jilma B, Pollak A (2006) A randomized, controlled trial of the effects of adding vitamin B12 and folate to erythropoietin for the treatment of anemia of prematurity. Pediatrics 118:180–188. doi:10.1542/peds.2005-2475

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

Special thanks to all neonatologists who collaborated to the collection of the data (in alphabetical order): Domenico Antonio Agostino (AO San Giovanni Addolorata, Roma), Antonietta Auriemma (AO Bolognini, Seriate, Bergamo), Adriano Azzali (Ospedale San Giovanni di Dio, Agrigento), Manuela Bedetta (Policlinico Casilino, Roma), Tatiana Boetti (Ospedale Sant’Anna, Torino), Lina Bollani (Policlinico San Matteo, Pavia), Raffaele Borrelli (AOU Parma), Angela Bossi (Ospedale Del Ponte, Varese), Roberto Bottino (Fondazione Poliambulanza, Brescia), Matteo Bruschettini (Istituto Gaslini, Genova), Elsa Buffone (AO San Camillo-Forlanini, Roma), Anna Casani (AO Rummo, Benevento), Alessandra Casati (Ospedale Belcolle, Viterbo), Giacomo Cavallaro (Fondazione IRCCS Ca’ Granda Ospedale Maggiore, Milano), Roksana Chakrokh (Ospedale Maggiore, Bologna), Natalia Chukhlantseva (Ospedale Bambin Gesù, Roma), Elena Ciarmoli (Fondazione Monza e Brianza, Monza), Gloria Cristofori (Fondazione IRCCS Ca’ Granda Ospedale Maggiore, Milano), Angelica Dessì (AOU Cagliari), Beatrice Gambi (Ospedale San Giovanni di Dio, Firenze), Giancarlo Gargano (Arcispedale Santa Maria Nuova, Reggio Emilia), Valeria Ghiglione (Ospedale Spalto, Marengo, Alessandria), Paolo Ghirri (AOU Pisana, Pisa), Nicola Laforgia (AOU Policlinico, Bari), Stefania Liguori (Ospedale Maria Vittoria, Torino), Valeria Anna Manfredini (Ospedale di Rho, Milano), Luca Massenzi (Fatebenefratelli-Isola Tiberina, Roma), Anna Claudia Massolo (Ospedale Bambin Gesù, Roma), Federico Matina (Spedali Civili, Brescia), Fabio Natale (Azienda Policlinico Umberto I, Roma), Emilia Parodi (AO Ordine Mauriziano, Torino), Luisa Pieragostini (Ospedale San Filippo Neri, Roma), Matteo Rinaldi (Ospedali Riuniti di Foggia), Daniele Roncati (AOU Careggi, Firenze), Cristina Ruspaggiati (AOU Parma), Vincenzo Salvo (AOU Policlinico G. Martino, Messina), Maria Cristina Siviero (Ospedale Sant’Eugenio, Roma), Elena Sorrentino (Fatebenefratelli-Ospedale San Pietro, Roma) and Paolo Tagliabue (Ospedale San Gerardo, Monza).

Some data of this study have been presented as a poster at the 11th International Workshop on Neonatology on October 2015, Cagliari (Italy).

Contributions of author statement

Rocco Agostino and Laura Cuzzolin defined the study and the online questionnaire. Laura Cuzzolin performed the analysis of the data and wrote the first draft of the manuscript. Rocco Agostino critically reviewed the manuscript.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Diagnostics & Public Health-Section of Pharmacology, University of Verona, Policlinico G.B. Rossi, Piazzale L.A. Scuro, 37134, Verona, Italy

    Laura Cuzzolin

  2. Fatebenefratelli-ricerca, Isola Tiberina, Rome, Italy

    Rocco Agostino

Authors
  1. Laura Cuzzolin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rocco Agostino
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Laura Cuzzolin.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cuzzolin, L., Agostino, R. Off-label and unlicensed drug treatments in Neonatal Intensive Care Units: an Italian multicentre study. Eur J Clin Pharmacol 72, 117–123 (2016). https://doi.org/10.1007/s00228-015-1962-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-015-1962-4

Keywords

Search

Navigation