1. Introduction

On 22 November 2019, the European Medicines Agency (“EMA”) published an updated Annex to the European Commission’s Guidelines concerning excipients in the labelling and package leaflet of medicinal products for human use. This updated Annex provides a list of the excipients for which specific information should appear in the package leaflet. The list includes Ethanol. In this context, the EMA adopted a guidance document concerning the package leaflet of medicinal products in which ethanol is used as an excipient.

2. Ethanol as an excipient in medicinal products for human use

An excipient is a constituent of a medicinal product other than the active substance and the packaging material. It is added to the formulation of the product for a specific purpose. The guidance provides pharmaco-toxicoligical and clinical safety data concerning ethanol. Available data provides that ethanol can impair cognitive and psychomotor functions. The guidance also provides that the use of ethanol as an excipient in medicinal products is limited.

The guidance provides that although exposure to ethanol is usually low, there has been no evaluation of the effects of long-term exposure to even low levels of ethanol on the health and development of children. In the guidance document, the EMA raises a plausible risk to development arising from chronic exposure to ethanol during childhood. These potential effects in children are the main reason for updating the information in the package leaflet.

3. Safety information for the package leaflet

The guidance document provides that warnings in the package leaflet concerning the presence of ethanol should be based on each dose of a medicinal product, rather than related daily exposure. In all cases, the amount of ethanol contained in a dose or volume of a medicinal product must be given. The guidance provides three levels of warning:

• Below 15 mg/kg/dose, the patient should experience no noticeable effects.
• Between 15 mg to less than 75 mg/kg/dose, adults and older children should not experience any effect but effects on younger children are uncertain.
• At 75 mg/kg/dose and above, warnings must be given that all age groups may be affected. The guidance provides that this level is based on when effects first became apparent in studies in adults performing complex tasks.

Further warnings should be included in the package leaflet regarding risk to neonates as their skin is much more permeable to ethanol than is adult skin. The guidance document notes that significant local reactions and systemic toxicity have been noted in neonates exposed to cutaneous ethanol.

The guidance document includes a table concerning updated information in the package leaflet. The information to be provided depends on thresholds of mg/kg/dose and on the route of administration.

4. Implementation of new statements for excipients listed in the Annex

In the European Commission Guidelines it is provided that for new marketing authorisation applications, implementation of the new information obligations should be followed as of now. For marketing authorisations granted before publication of the revised Annex, the Commission provides that marketing authorisation holders should use the first upcoming regulatory procedure to implement the new wording. For products with no regulatory activities, marketing authorisation holders should submit a type-IB variation within 3 years.