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Product Substitution as a Way Forward in Avoiding Potentially Harmful Excipients in Neonates

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A Commentary to this article was published on 05 May 2016

Abstract

Objectives

Our objectives were to explore the possibility of avoiding neonatal exposure to potentially harmful excipients of interest (EOI)—parabens, polysorbate 80, propylene glycol, benzoates, saccharin sodium, sorbitol and ethanol—through product substitution in Europe.

Methods

We performed a 3-day service evaluation survey and a 1-day point prevalence study in 20 and 21 European countries, respectively. Analysis included active pharmaceutical ingredients (APIs) used in ≥10 % of units. We calculated the potential reduction in number of products with EOI through substitution in three stages: (1) similar API and route of administration, (2) plus similar dosage form and (3) plus similar strength. The reduction of individual exposure was analysed according to the second-stage criteria.

Results

We identified 137 products for 25 APIs that contained EOI. Substitution with EOI-free product(s) was available for 88 % (n = 120), 66 % (n = 91) and 31 % (n = 42) of products according to the first-, second- and third-stage criteria, respectively. Overall, 456 (63 % of 726) neonates received products containing EOI. Substitution of the products that had alternatives with similar API and dosage form would reduce the number of exposed neonates from 456 to 257 (44 % reduction).

Conclusions

EOI-free formulations are available for a substantial number of products currently used in European neonates. Replacement of only the most frequently used products may spare almost half of neonates from unnecessary exposure to EOI.

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Acknowledgments

Members of ESNEE are as follows: Susan Graham (UK), Utpal Shah (UK), Hussain Mulla (UK), Hitesh Pandya (UK), James McElnay (UK), Jeff Millership (UK), Shirish Yakkundi (UK), Andre Rieutord (France), Thomas Storme (France), Pascal Vaconsin (France). All members of ESNEE designed the study and monitored data collection. The authors thank all national contact people who provided lists of neonatal units and helped run the study in their own country: Bernhard Resch (Austria), Pieter De Cock (Belgium), Nelly Jekova (Bulgaria), Elisabeth Iyore (Denmark), Pascal Vaconsin (France), Kosmas Sarafidis (Greece), Aranka Vegso (Hungary), Noreen O’Callaghan (Ireland), Rocco Agostino (Italy), Daiga Kviluna (Latvia), Rasa Tameliene (Lithuania), Rene F. Kornelisse (Netherlands), Dag Bratlid (Norway), Almerinda Pereira (Portugal), Maria Livia Ognean (Romania), Milica Bajcetic (Serbia), Darja Paro (Slovenia), Elizabeth Valls (Spain), Per Nydert (Sweden), Hans Ulrich Bucher (Switzerland), Maria Cordina (Malta). We also thank local pharmacists for providing data on excipient content: Caroline Fonzo-Christe (Switzerland), Domenico Tarantino (Italy), Velina Grigorova (Bulgaria), Milica Bajcetic (Serbia), Elizabeth Valss (Spain), Claudine Milstein (France), Jennifer Duncan (England), Sabina Zalar (Slovenia), Per Gustaf Hartvig Honoré (Denmark).

Author information

Authors and Affiliations

  1. Institute of Microbiology, University of Tartu, Tartu, Estonia

    Georgi Nellis, Tuuli Metsvaht & Irja Lutsar

  2. Neonatal Unit, Children’s Clinic, Tartu University Hospital, N. Lunini 6, Tartu, 51014, Estonia

    Georgi Nellis & Heili Varendi

  3. Clinic of Anaesthesiology and Intensive Care, Paediatric Intensive Care Unit, Tartu University Hospital, Tartu, Estonia

    Tuuli Metsvaht

  4. Pharmacy Department, Tartu University Hospital, Tartu, Estonia

    Jana Lass

  5. Alder Hey Children’s NHS Foundation Trust, Liverpool, UK

    Jennifer Duncan & Anthony J. Nunn

  6. Neonatal Unit, Liverpool Women’s Hospital, Liverpool, UK

    Mark A. Turner

  7. Institute of Translational Medicine, University of Liverpool, Liverpool, UK

    Mark A. Turner

Authors
  1. Georgi Nellis
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  2. Tuuli Metsvaht
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  3. Heili Varendi
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  4. Jana Lass
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  5. Jennifer Duncan
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  6. Anthony J. Nunn
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  8. Irja Lutsar
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Corresponding author

Correspondence to Georgi Nellis.

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Conflict of Interest

GN, TM, HV, JL, JD, AJN, MAT and IL have completed the conflict of interest disclosure form(s) and declare they received no support from any organisation for the submitted work and have no financial relationships with any organisations that might have an interest in the submitted work in the previous 3 years. JL, AJN and IL are members of the Paediatric Committee (PDCO) of the European Medicines Agency; MAT is a Chair of the European Network for Paediatric Research at the European Medicines Agency (EnprEMA); AJN is an independent scientific expert to the European Medicines Agency and a member of the working group revising the EU guideline “Excipients in the Label and Package Leaflet of Medicinal Products for Human Use”.

Funding

ESNEE is funded through European Research Area-Network PRIOMEDCHILD by the following national agencies: Medical Research Council from the UK, Estonian Research Council (IUT 34-24) from Estonia, Agence Nationale de la Recherche from France. The funder of the study had no role in study design, data collection, data analysis, data interpretation, writing of the report, or in the decision to submit the paper for publication.

Transparency Declaration

The corresponding author affirms this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained. The corresponding author confirms he had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Ethical Considerations

The SES was performed as part of an audit with no personal data collected, and no Ethics Committee approval was required in participating countries. For the PPS, Ethics Committee approval was obtained in compliance with national guidelines. All data were anonymised before leaving the study sites.

Data sharing

No additional data available.

Additional information

On behalf of the ESNEE consortium.

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Nellis, G., Metsvaht, T., Varendi, H. et al. Product Substitution as a Way Forward in Avoiding Potentially Harmful Excipients in Neonates. Pediatr Drugs 18, 221–230 (2016). https://doi.org/10.1007/s40272-016-0173-5

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