Hidden Dangers: Recognizing Excipients as Potential Causes of Drug and Vaccine Hypersensitivity Reactions

Abstract

Excipients are necessary as a support to the active ingredients in drugs, vaccines, and other products, and they contribute to their stability, preservation, pharmacokinetics, bioavailability, appearance, and acceptability. For both drugs and vaccines, these are rare reactions; however, for vaccines, they are the primary cause of immediate hypersensitivity. Suspicion for these "hidden dangers" should be high, in particular, when anaphylaxis has occurred in association with multiple chemically distinct drugs. Common excipients implicated include gelatin, carboxymethylcellulose, polyethylene glycols, and products related to polyethylene glycols in immediate hypersensitivity reactions and propylene glycol in delayed hypersensitivity reactions. Complete evaluation of a suspected excipient reaction requires detailed information from the product monograph and package insert to identify all ingredients that are present and to understand the function and structure for these chemicals. This knowledge helps develop a management plan that may include allergy testing to identify the implicated component and to give patients detailed information for future avoidance of relevant foods, drugs, and vaccines. Excipient reactions should be particularly considered for specific classes of drugs where they have been commonly found to be the culprit (eg, corticosteroids, injectable hormones, immunotherapies, monoclonal antibodies, and vaccines). We provide a review of the evidence-based literature outlining epidemiology and mechanisms of excipient reactions and provide strategies for heightened recognition and allergy testing.

Keywords: Allergy; Anaphylaxis; Biologic; Carboxymethylcellulose (CMC); Corticosteroid; Drug; Excipient; Gelatin; Inactive ingredient; Polyethylene glycol (PEG); Polysorbate; Vaccine; alpha-gal.

Figure 1:

In the left panel is skin prick testing read at 15 minutes demonstrating positive responses to methylprednisolone acetate (MP acetate), and polyethylene glycol 3350 (PEG 3350). S= saline negative control. H = histamine positive control. Other tested corticosteroids were negative. In the right panel is intradermal testing read at 15 minutes, which demonstrates a positive response to triamcinolone acetate at 1mg and 0.1mg. Other tested corticosteroids were interpreted as negative. Key: Drug used is indicated by the letter. A= polyethylene glycol 3350 (Miralax), B=Methylprednisolone sodium succinate 5mg/ml, C=Budesonide 0.6mg/ml, D=Dexamethasone 0.4mg/ml, E= Hydrocortisone 5mg/ml, F=Methylprednisolone acetate 4mg/ml G= Triamcinolone acetate 1mg/ml. A subscript 1= full strength, a subscript 2= 1:10 dilution and a subscript 3= 1:100 dilution. Image/case originally presented in Stone et al. JACI: In Practice, 2019

Figure 2:

Excipients whose chemical derivation utilizes ethylene oxides, some of which have demonstrated clinical cross reactivity in PEG allergic patients.

Figure 3:. Flow diagram for an approach to excipient testing.

Testing of excipients should generally be thought of as the second step after a patient tests positive to an implicated drug. In the setting of certain PEG containing products (e.g. PEG3350, 4000 in laxatives) PEG is the primary drug, however. Consider testing the excipient first if the active or primary drug is expensive or hard to obtain (e.g. biologics that cost thousands of dollars a dose) or infeasible depending on the drug and the setting (e.g. chemotherapy), in which case first step excipient testing may be useful for determining the need for avoiding alternative drugs. If a question is time dependent and crucial regarding future drug or vaccine therapy then testing the primary drug and excipients in a single visit makes the most sense. Testing strategies for certain drugs (e.g. corticosteroids) are available and have controls that are useful (e.g. methylprednisolone acetate has PEG3350 and methylprednisolone sodium succinate does not).

Figure 4:. Clinical and laboratory techniques that have been used in the literature to help confirm an excipient allergy diagnosis.

In some cases, a personalized diagnosis has been made using, as an example IgE-immunoblotting, to try detecting specific IgE to chemicals where commercial allergen testing is not available. Immunoblotting techniques, both SDS-PAGE/IgE-immunoblotting (western blot) and dot-blot appear to be useful for diagnosis of allergy to several pharmaceutical excipients: CMC^{, ,} , casein, macrogols of different MW and povidone or polyvinylpyrrolidone (PVP). The utility of specific IgE detection via ELISA based assays and dual bead cytometric assays have been reported in immediate hypersensitivity to PEGs in several skin test positive patients.^{, ,} Specific IgE to alpha-gal, gelatin, and many other food based excipients appear to have diagnostic utility in excipient reactions and are already commercially available.^{, ,}