The EMA and the European Commission have just updated the safety warnings for excipients in package leaflets. Excipients are the inactive ingredients in a medicine–diluents, binders, disintegrants, colouring agents–that give the medicine its final dosage form.
In practice, however, some excipients are not completely inactive and cause reactions in certain patients or under certain circumstances.
Excipients with a known action or effect must have safety information statements in package leaflets. These warnings are listed in an annex that was updated this week, following a public consultation. The result is five new excipients and updated safety information for ten excipients from the legacy 2003 annex.
The revised English annex has already been translated into all EU and EEA languages. All versions are published in the Human Regulatory section of the EMA website.
Changes in content
The five new excipients are boric acid, cyclodextrins, phosphate buffers, sodium laurilsulfate, and fragrances containing allergens.
Some existing excipients now have more detailed information.
For example, fructose:
Old version: If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product
New version: If your doctor has told you that you (or your child) have an intolerance to some sugars or if you have been diagnosed with hereditary fructose intolerance (HFI), a rare genetic disorder in which a person cannot break down fructose, talk to your doctor before you (or your child) take or receive this medicine.
Changes in information for specific population groups
In the old version, little information was given on population groups such as children and pregnant women. The new version provides more specific advice.
For example, benzyl alcohol:
Ask your doctor or pharmacist for advice if you have a liver or kidney disease. This is because large amounts of benzyl alcohol can build-up in your body and may cause side effects (called “metabolic acidosis”).
Another example, propylene glycol:
If your child is less than 5 years old, talk to your doctor or pharmacist before giving them this medicine
Changes in wording
Statements are now more patient friendly, with explanations of medical jargon and more direct language, addressed to the patient.
For example, aspartame:
Old version: Contains a source of phenylalanine. May be harmful for people with phenylketonuria
New version: Aspartame is a source of phenylalanine. It may be harmful if you have phenylketonuria (PKU), a rare genetic disorder in which phenylalanine builds up because the body cannot remove it properly.
Other changes include revised thresholds, additional routes of administration, and updated recommendations for the SmPC in the comments’ column of the annex.
Changes in the core guidelines
The updated annex forms part of the European Commission guideline on ‘Excipients in the labelling and package leaflet of medicinal products for human use’. The guideline itself is also being updated, but the revised version has yet to be published.
One interesting change in the new draft guideline is the more prescriptive nature of the warning statements. The old version says, It is not required that the information in the Annex should be applied verbatim to the package leaflet, so applicants may choose their own style to present this information to the patient, e.g. in a ‘direct’ or ‘indirect’ style. The content or meaning of the text must not be changed.
However, the new draft version says, The text of this information, written in clear and understandable terms for the patient, should be applied to the package leaflet by default. In some cases the applicant may adapt the style of the information if adequately justified (e.g. by means of user testing) as long as the information content and its meaning remain unchanged.
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The new annex applies to all new and existing medicines in the EU with centralised and national marketing authorisations. Medicines with existing authorisations must be updated with the new statements when they undergo any other updating procedure or otherwise within three years, in the form of a type-IB variation.
The updated annex will be a useful additional resource for translators who work in the field of marketing authorisations.