Assessment of mandatory declaration excipients in pediatric off label prescriptions in Spain

Abstract

Pediatric patients are at increased risk of exposure to potentially harmful excipients when receiving off-label medicinal products primarily formulated for adults, raising concerns about adverse events. Based on data from a previously published study, this research focuses on the most frequently prescribed off-label medicinal products in order to assess the safety of their excipients. The aim was to identify Excipients of Mandatory Declaration (EMDs) that could pose additional safety risks in individuals under the age of 18. A descriptive, and retrospective observational population-based study in individuals under 18 was developed in the Spanish primary care setting between the years 2004–2005 and 2017–2020. The main data source was proprietary database, with nationwide coverage of prescriptions. The analysis included 4,922,984 off-label prescriptions, accounting for 16 active ingredients and 37 medicinal products (18 oral, 16 topical and three inhaled) that were scrutinized for EMD composition. Neonates and infants up to five years old accounted for nearly 50% of all off-label prescriptions among the under-18 population, exposing them to additional safety risks from potentially harmful EMDs in these formulations, which may lead to severe adverse events, causing permanent or long-term harm. The degree of harm of EMDs was assessed overall as “severe” for nine out of 22 EMDs, mostly used for oral formulations, and “moderate” for six EMDs. No EMDs were categorized as “no harm”. Results on EMDs in oral medicinal products, for instance, highlight the urgent unmet needs in this regard, especially for young children; EMDs like sodium, sorbitol, propylene glycol and sweeteners often exceeded EMA-recommended thresholds. This study underscores the need to address risks linked to off-label use of medicinal products in children, particularly those related to EMDs. Integrating excipient risk warnings into prescribing systems and monitoring related adverse events is strongly recommended.

Introduction

Excipients are inert substances that are mixed with the active ingredient(s) to make up the medicinal product, contributing to their consistency, shape, flavour, and other features that facilitate manufacturing and storage1,2. While generally regarded as inert” and lacking therapeutic effects, some excipients can have recognized actions that may lead to adverse events, particularly in individuals with specific allergies or intolerances. To address this, the European Medicines Agency (EMA) has established a list of “Excipients of Mandatory Declaration” (EMDs) that must be specified in the Summary of Product Characteristics (SmPC), Package Leaflet (PL), and on labelling, highlighting the risk of unintentional ingestion3,4. Similarly, the Spanish Agency of Medicines and Medical Devices (AEMPS), as a member state of the European Union (EU), adheres to this mandate5.

It has been almost 18 years since the publication of the Pediatric Regulation (1901/2006/EC) in Europe. The objective of this regulation was to ensure that adequate studies are carried out in neonates, children, and adolescents up to 17 years of age to obtain the necessary data for the assessment of risks and benefits for the authorization of medicinal products for the under-18 population6.

On a previous publication, Lizano-Díez and cols7. conducted an observational study within the primary health care context to analyse annual prescription rates among the under-18 population in Spain. The study compared four cross-sectional annual periods: one prior to the implementation of the Pediatric Regulation (October 2004 – September 2005) and three after (October 2017-September 2020) to allow sufficient time to observe potential changes. The authors scrutinized off-label prescriptions according to the age of use that was outlined in the SmPC and sought to identify changes in off-label prescription rates in Spain following the Regulation’s implementation; however, they did not observe any meaningful decrease. In addition to the challenges posed by off-label prescriptions, the under-18 population may be exposed to harmful excipients present in formulations primarily designed for adults, potentially leading to additional adverse events. Therefore, building on the findings from the research of Lizano-Díez and cols7., it was sought relevant to analyse the excipients from the most prescribed off-label medicinal products and identify which EMDs may represent a potential additional safety risk for individuals under 18.

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Table 1. Off-label medicinal products not including EMDs in their composition.

Table 2. Topical (non-cutaneous) off-label medicinal products including EMDs in their composition.

Table 3. Inhaled off-label medicinal products including EMDs in their composition.

Lizano-Díez, I., Aldalur-Uranga, I., Braza, A.J. et al. Assessment of mandatory declaration excipients in pediatric off label prescriptions in Spain. Sci Rep 15, 26293 (2025). https://doi.org/10.1038/s41598-025-11647-x