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Quantitative Investigation on Exposure to Potentially Harmful Excipients by Injection Drug Administration in Children Under 2 Years of Age and Analysis of Association with Adverse Events: A Single-Center, Retrospective Observational Study

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Abstract

Introduction

Potentially harmful excipients (PHEs) for children have been reported and the need for information collection has been advocated. However, studies on the actual occurrence of adverse events are limited. This study investigated the quantitative exposure of PHEs via injection and their association with adverse events in children under 2 years of age.

Materials and Methods

As a single-center observational study, children aged 0–23 months received injectable drugs from April 1, 2018, to March 31, 2023 were included. Information on PHE exposure and adverse events after administration were extracted from medical records. Sodium benzoate, benzyl alcohol, ethanol, glycerol, lactose, polyethylene glycol paraben, polysorbate, propylene glycol, sorbitol, sucrose, sulfite, and thimerosal were selected as PHEs.

Results and Discussion

6265 cases, 333,694 prescriptions, and 368 drugs (264 ingredients) were analyzed. The median age was 0.63 years (interquartile range [IQR] 0.1–1.1). 72,133 prescriptions, 132 drugs and 99 ingredients contained PHE; 2,961 cases exposed to PHE and 1825 cases exceeding permitted daily exposure. The drug with the highest number of exposure cases was hydroxyzine, and the highest number of prescriptions was heparin (both drugs contain benzyl alcohol). In association between adverse events and PHE exposure, higher doses in cases of adverse event occurrence were found in benzyl alcohol, glycerol, polyethylene glycol, and polysorbate exposed cases. Among thimerosal-exposed cases, “developmental delay” was more frequent in exposed cases, but the causal relationship was unknown. Further investigation is needed to clarify the relationship between adverse events and PHE exposure. Additionally, more precise information on PDE for pediatrics including neonates is necessary.

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Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This work was conducted as part of “Regulatory science for better access to paediatric drugs in Japan (23mk0101243H0002)” awarded to HN. (Department of Research and Development Supervision, National Center for Child Health and Development) with support from the Research Program of the Japan Agency for Medical Research and Development.

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  1. Department of Pharmacy, National Center for Child Health and Development, 2-10-1, Okura, Setagayaku, Tokyo, 157-8535, Japan

    Jumpei Saito, Miki Akabane & Akimasa Yamatani

  2. Department of Research and Development Supervision, National Center for Child Health and Development, 2-10-1, Okura, Setagayaku, Tokyo, 157-8535, Japan

    Hidefumi Nakamura

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  1. Jumpei Saito
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JS: has contributed to drafting the work, the acquisition, analysis, and interpretation of data for the work. HN: has contributed to the conception. AY and MA: have contributed to the conception or design of the work, drafting, and revising the work critically for important intellectual content. All authors are responsible for the final approval of the version to be published.

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Saito, J., Nakamura, H., Akabane, M. et al. Quantitative Investigation on Exposure to Potentially Harmful Excipients by Injection Drug Administration in Children Under 2 Years of Age and Analysis of Association with Adverse Events: A Single-Center, Retrospective Observational Study. Ther Innov Regul Sci 58, 316–335 (2024). https://doi.org/10.1007/s43441-023-00596-0

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