New Challenges in Drug Allergy: the Resurgence of Excipients

Purpose of Review

Allergy to excipients is a cause of multidrug allergy and if it is not taken into account, it can lead to unexpected severe reactions. If an excipient allergy is suspected, an accurate examination followed by algorithms is very important for a correct diagnosis and to give patients detailed information in order to avoid future reactions.

Recent Findings

In recent times, due to allergy COVID vaccine reactions, interest in excipients as polyethylene glycol derivatives (PEGs) has increased as a possible cause of drug and vaccine hypersensivity. In addition to PEGs many other excipients as gelatin, alpha-gal, protamine, benzalkonium chloride, and benzyl alcohol have been described as a cause of allergy to drugs and vaccines. For most excipients, the dilutions used for skin testing (ST) are not standardized and proper algorithms to reach a diagnosis are not available.

Summary

The purpose of this article is to review the excipients that may produce inmediate hypersensitivity drugs and vaccine reactions and update diagnostic procedures to reach an accurate diagnosis. We highlight the in vivo and in vitro diagnostic tests used in published reports and detail the dilution used for each excipient to perform ST in order to confirm this vital pathology and to prevent new reactions.

The European Medicines Agency (EMA) “Guideline on excipients in the dossier for application for marketing authorization of a medicinal product” [1] and the Current Good Manufacturing Practices [2] define an excipient or inactive ingredient as the constituents of the pharmaceutical form other than the active ingredient.

It should be noted that in recent times, due to the SARS-CoV2 pandemic and allergic reactions decribed to the COVID-19 vaccines, interest in excipients has increased as a possible cause of drugs and vaccine hypersensitity [3]. For both drugs and vaccines, these are rare reactions; however, for vaccines, they are the primary cause of immediate hypersensitivity reactions (IHRs) [4••].

We should suspect this problem when a patient reports unrelated multiple drug reactions. In this case, an accurate examination followed by algorithms is very important for correct diagnosis and to give patients detailed information in order to avoid future reactions.

However, the diagnostic procedure for allergy to excipients is not properly protocolized. The purpose of this article is to review the excipients that may produce inmediate hypersensitivity drug and vaccine reactions and update diagnostic procedures to asses the involvement of each excipient in this type of reactions. We focus on reactions suggestive of being due to a type I hypersensitivity mechanism and other reactions such as delayed ones are not included in this review.

Systematic review, using the electronic searching in engine Pubmed/Medline until March 2021, was performed. We draw up an alphabetical list of excipients detailing the publications found about each of them. We highlighted the in vitro and in vivo tests used to confirm the diagnosis.

Conclusion

Excipients in drug and vaccine formulations represent a true puzzle for allergists. At a first sight, the active pharmaceutical molecule is usually considered the responsible agent for a IHR, but all vaccine and drug components should be considered as potential triggers of an allergic reaction. For this reason, a careful investigation is required for the correct identification of the culprit agent.

We also would like to highlight the significance of clear labelling of all ingredients including excipients in pharmaceutical preparations and reiterate the importance and value of an allergological work-up in order to provide planning advice to avoid future reactions.

For some excipients such as gelatin, alpha-gal, and food-derived excipients, we have in vivo and in vitro diagnostic tests with high sensitivity and specificity, but for most excipients, we must continue working to improve diagnostic procedures.

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Venturini Díaz, M., Vidal Oribe, I., D’Elia Torrence, D. et al. New Challenges in Drug Allergy: the Resurgence of Excipients. Curr Treat Options Allergy (2022). https://doi.org/10.1007/s40521-022-00313-6